Cyclophosphamide - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

CYCLOPHOSPHAMIDE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cyclophosphamide: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00323-6 1. Cyclophosphamide-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cyclophosphamide. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CYCLOPHOSPHAMIDE ............................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cyclophosphamide....................................................................... 15 E-Journals: PubMed Central ....................................................................................................... 77 The National Library of Medicine: PubMed ................................................................................ 80 CHAPTER 2. NUTRITION AND CYCLOPHOSPHAMIDE ................................................................... 127 Overview.................................................................................................................................... 127 Finding Nutrition Studies on Cyclophosphamide ..................................................................... 127 Federal Resources on Nutrition ................................................................................................. 128 Additional Web Resources ......................................................................................................... 129 CHAPTER 3. ALTERNATIVE MEDICINE AND CYCLOPHOSPHAMIDE............................................. 131 Overview.................................................................................................................................... 131 National Center for Complementary and Alternative Medicine................................................ 131 Additional Web Resources ......................................................................................................... 140 General References ..................................................................................................................... 143 CHAPTER 4. DISSERTATIONS ON CYCLOPHOSPHAMIDE............................................................... 145 Overview.................................................................................................................................... 145 Dissertations on Cyclophosphamide .......................................................................................... 145 Keeping Current ........................................................................................................................ 146 CHAPTER 5. PATENTS ON CYCLOPHOSPHAMIDE ......................................................................... 147 Overview.................................................................................................................................... 147 Patents on Cyclophosphamide.................................................................................................... 147 Patent Applications on Cyclophosphamide................................................................................ 160 Keeping Current ........................................................................................................................ 166 CHAPTER 6. BOOKS ON CYCLOPHOSPHAMIDE ............................................................................. 169 Overview.................................................................................................................................... 169 Chapters on Cyclophosphamide ................................................................................................. 169 CHAPTER 7. PERIODICALS AND NEWS ON CYCLOPHOSPHAMIDE ............................................... 173 Overview.................................................................................................................................... 173 News Services and Press Releases.............................................................................................. 173 Academic Periodicals covering Cyclophosphamide.................................................................... 175 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 177 Overview.................................................................................................................................... 177 U.S. Pharmacopeia..................................................................................................................... 177 Commercial Databases ............................................................................................................... 178 Researching Orphan Drugs ....................................................................................................... 178 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 183 Overview.................................................................................................................................... 183 NIH Guidelines.......................................................................................................................... 183 NIH Databases........................................................................................................................... 185 Other Commercial Databases..................................................................................................... 187 APPENDIX B. PATIENT RESOURCES ............................................................................................... 189 Overview.................................................................................................................................... 189 Patient Guideline Sources.......................................................................................................... 189 Finding Associations.................................................................................................................. 191 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 193 Overview.................................................................................................................................... 193 Preparation................................................................................................................................. 193 Finding a Local Medical Library................................................................................................ 193

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Medical Libraries in the U.S. and Canada ................................................................................. 193 ONLINE GLOSSARIES................................................................................................................ 199 Online Dictionary Directories ................................................................................................... 199 CYCLOPHOSPHAMIDE DICTIONARY.................................................................................. 201 INDEX .............................................................................................................................................. 275

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with cyclophosphamide is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about cyclophosphamide, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to cyclophosphamide, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on cyclophosphamide. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to cyclophosphamide, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on cyclophosphamide. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON CYCLOPHOSPHAMIDE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cyclophosphamide.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and cyclophosphamide, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “cyclophosphamide” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Collagen Vascular Diseases in Critical Care: An Overview Source: Care of the Critically Ill. 14(1): 29-33. January 1998. Contact: Available from Stockton Press. Houndmills, Basingstoke, Hampshire RG21 6XS, UK. 44(0) 1256 329242. Fax: 44(0) 1256 810526. Website: http://www.stocktonpress.co.uk/cci/. Summary: Although uncommon, when compared with other conditions seen in the intensive care unit (ICU), the collagen vascular diseases are life threatening, can pose diagnostic problems, and (because treatment often involves immunosuppression) can make management especially difficult in the septic patient. This article gives an overview of some of the more life threatening members of this group of disorders. The

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conditions most frequently encountered are Goodpasture's syndrome (GPS) and glomerular basement membrane disease (GBH); Wegener's granulomatosis (WG); polyarteritis nodosa (PAN); and systemic lupus erythematosis (SLE). Other, less common, diagnoses include microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and antiphospholipid antibody syndrome (APS). Most of these disorders are inflammatory and have evidence of autoimmunity, which can range from targeting of a single specific organ to many organs in the body. The author briefly reviews the symptoms of each type, then summarizes general principles of treatment. Treatment should treat underlying infection; support vital organs (lung and kidney failure are common to many of these conditions); ensure adequate nutrition; modify the immune response with steroids, azathioprine or cyclophosphamide; and remove immune complexes and antibodies, using plasma exchange. A brief posttest is appended to the article. 2 figures. 3 tables. 19 references. •

Long-Term Outcome of Anti-Glomerular Basement Membrane Antibody Disease Treated with Plasma Exchange and Immunosuppression Source: Annals of Internal Medicine. 134(11): 1033-1042. June 5, 2001. Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org. Summary: Antiglomerular basement membrane (GBM) antibody disease is an autoantibody-mediated disorder that usually presents as rapidly progressive glomerulonephritis (inflammation of the filtering units of the kidney), often with pulmonary (lung) hemorrhage (the Goodpasture syndrome). It is reported that patients with severe renal (kidney) failure do not generally recover renal function. This article reports on a study undertaken to examine the long term outcome of severe anti-GBM antibody disease. The authors conducted a retrospective review of patients treated for confirmed anti-GBM disease over 25 years. The study included 71 treated patients with anti-GBM antibody disease, all of whom received plasma exchange, prednisolone, and cyclophosphamide. Patients who presented with a creatinine concentration less than 5.7 milligrams per deciliter (n = 19) had 100 percent patient survival and 95 percent renal survival at 1 year, and 84 percent patient survival and 74 percent renal survival at last followup. In patients who presented with a creatinine concentration of 5.7 milligrams per deciliter or more (n = 13) but who did not require immediate dialysis, patient and renal survival were 83 percent and 82 percent at 1 year, and 62 percent and 69 percent at last followup. In patients who presented with dialysis dependent renal failure (n = 39), patient and renal survival were 65 percent and 8 percent at 1 year and 36 percent and 5 percent at last followup. All patients who required immediate dialysis and had 100 percent crescents on renal biopsy remained dialysis dependent. The authors conclude that patients with the Goodpasture syndrome and severe renal failure should be considered for urgent immunosuppression therapy, including plasma exchange, to maximize the chance of renal recovery. Patients needing immediate dialysis are less likely to recover. 4 figures. 3 tables. 26 references.

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Treatment of Hepatitis C-Associated Glomerular Disease Source: Seminars in Nephrology. 20(3): 286-292. May 2000. Contact: Available from W.B. Saunders Company. Periodicals Department. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452.

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Summary: Hepatitis C virus (HCV) infection can lead to chronic active hepatitis, cirrhosis (liver scarring), and liver failure; however, it is also associated with a wide range of extrahepatic features. This article reviews the treatment of glomerular disease (kidney disease) associated with HCV infection. Renal manifestations include cryoglobulinemic membranoproliferative glomerulonephritis and membranous nephropathy. The authors caution that treatment of HCV with alpha interferon is only moderately effective and suffers from a high relapse rate. More recently, combination therapy with ribavirin has led to improved suppression of HCV RNA levels. Rapidly progressive renal disease or severe cryoglobulinemic vasculitis may respond to immunosuppression with steroid, cyclophosphamide, and plasmapheresis in the acute phase. After 2 to 4 months of immunosuppression, antiviral therapy (with alpha interferon and ribavirin) should be tried. Promising new therapies on the horizon include agents directed at HCV replication. 2 figures. 1 table. 78 references. •

Treatment of IgA Nephropathy Source: Seminars in Nephrology. 20(3): 277-285. May 2000. Contact: Available from W.B. Saunders Company. Periodicals Department. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: IgA nephropathy (Berger's disease) is the most common primary glomerulonephritis (infection of the kidney glomeruli) worldwide and was once equated with benign recurrent hematuria (blood in the urine). This article reviews the patient care management of IgA nephropathy. Of the patient population with IgA nephropathy, 15 to 30 percent progress to end stage renal failure after 20 years of clinical manifestations. Because the pathogenesis remains enigmatic, therapy to slow disease progression cannot be disease specific. Control of blood pressure remains the cornerstone of treatment, as for patients with other types of kidney disease. Several approaches to treatment have generated increasing interest in the last few years, including angiotensin inhibition, glucocorticoids, fish oil, cyclophosphamide, tonsillectomy, and mycophenolate mofetil. For patients reaching end stage renal failure, recurrent disease after transplantation can be a clinically important problem (even in light of continued immunosuppression after the transplantation). 2 figures. 65 references.

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Progress in the Treatment of Proliferative Lupus Nephritis Source: Current Opinion in Nephrology and Hypertension. 9(2): 107-115. 2000. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 223-2300. Fax (301) 223-2400. Website: www.currentopinion.com. Summary: Lupus nephritis (kidney inflammation associated with systemic lupus erythematosus, or SLE) is often well developed at the time of diagnosis. This article reviews progress in the treatment of proliferative lupus nephritis. High dose corticosteroids are universally accepted as the initial approach to the control of severe inflammation in the kidney. Long term disease control and the minimization of iatrogenic (physician caused) risk usually require adjunctive therapies that target the more fundamental immunoregulatory disturbances of lymphoid cells. Of the available cytotoxic drugs, cyclophosphamide is currently among the most effective, although it cannot be considered ideal in terms of efficacy or toxicity. New prospects for the treatment of proliferative lupus nephritis include novel immunosuppressive agents (e.g., mycophenolate, cyclosporine, fludarabine), combination chemotherapy (e.g.,

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cyclophosphamide plus fludarabine), and sequential chemotherapy (e.g., cyclophosphamide followed by azathioprine), immunological reconstitution using intensive cytoreductive chemotherapy (with or without stem cell rescue), and co stimulatory molecule inhibition. Gene therapy remains an attractive prospect, but its feasibility clearly depends on the further definition of lupus promoting genes and the availability of methods to establish stable expression of disease corrective genes in the appropriate lymphoid cells. 3 figures. 83 references. •

Immunosuppressive Agents in Childhood Nephrotic Syndrome: A Meta-Analysis of Randomized Controlled Trials Source: Kidney International. 59(5): 1919-1927. May 2001. Contact: Available from Blackwell Science, Inc. Journals Fulfillment Department, 350 Main Street, Malden, MA 02148. (781) 388-8250. Summary: Many children with steroid sensitive nephrotic syndrome (SSNS, a kidney disorder treated with steroid treatment) relapse frequently and receive immunosuppressive agents (to help avoid some of the side effects of regular steroid use). This article offers a systematic review of randomized controlled trials (RCTs) in which the benefits and harms of these immunosuppressive agents are evaluated. Seventeen trials involving 631 children were identified. Cyclophosphamide and chlorambucil significantly reduced the relapse risk at 6 to 12 months compared with prednisone alone. In the single chlorambucil versus cyclophosphamide trial, there was no observed difference in relapse risk at 2 years. Cyclosporine was as effective as cyclophosphamide and chlorambucil, but the effect was not sustained when cyclosporine was ceased. During treatment, levamisole was more effective than steroids alone, but the effect was not sustained. The authors conclude that cyclophosphamide, chlorambucil, cyclosporine, and levamisole reduce the risk of relapse in children with relapsing SSNS compared with predisone alone. Clinically important differences in effectiveness among these agents are possible, and further comparative trials are still needed. Meanwhile, the choice between these agents depends on physician and patient preferences related to therapy duration and complication type and frequency. 1 figure. 4 tables. 42 references.

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Treatment of Minimal Change Nephropathy and Focal Segmental Glomerulosclerosis Source: Journal of the Royal College of Physicians of London. 31(2): 137-141. MarchApril 1997. Contact: Available from Royal College of Physicians. Publications Department, 11 Saint Andrews Place, Regent's Park, London NW1 4LE. 0171 935 1174. Fax 0171 487 5218. Summary: Minimal change nephropathy (MCN) and focal segmental glomerulosclerosis (FSGS) are together responsible for almost all cases of nephrotic syndrome in children and of 25 to 35 percent of cases in adults. This article focuses on the drug treatment of MCN and FSGS designed to cure the nephrotic syndrome. Nephrotic syndrome is a kidney condition characterized by massive edema (fluid accumulation), heavy proteinuria (protein in the urine), hypoalbuminemia (low protein levels in the blood), and susceptibility to intercurrent infections. The author begins with a review of the general management of these patients while they remain nephrotic, then discusses specific treatment of MCN and FSGS. Treatment for MCN is with corticosteroids, cyclosporin, alkylating agents, and levamisole (an antihelminthic drug). Traditionally, FSGS has been thought to have a poor prognosis, with 50 percent of patients progressing

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to end stage renal (kidney) failure in 10 years. Drugs used to treat FSGS include cyclophosphamide and cyclosporin. 2 figures. 2 tables. 20 references. •

Treatment of Lupus Nephritis Source: Seminars in Nephrology. 20(3): 265-276. May 2000. Contact: Available from W.B. Saunders Company. Periodicals Department. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: Patients with lupus nephritis pose a therapeutic challenge and stimulate investigation of innovative treatment strategies. This article reviews those current and potential strategies that may optimize management of lupus nephritis. The clinical presentations of lupus nephritis can vary from asymptomatic hematuria (blood in the urine) or proteinuria (protein in the urine) to acute nephritic or nephrotic syndromes and from rapidly progressive glomerulonephritis to insidious chronic renal insufficiency. Although patient survival and renal function outcomes have improved over the last 4 decades, contemporary immunosuppressive regimens are not consistently effective and often require extended courses (resulting in negative drug effects and toxicity). Several strategies are under investigation to induce remissions more rapidly and to reduce the risk of long courses of cytotoxic drug therapy. The combination of pulse methylprednisolone and pulse cyclophosphamide may be more effective than pulse cyclophosphamide alone for patients with relatively severe proliferative lupus nephritis. A particularly vigorous strategy employs immunoablative cyclophosphamide, with or without stem cell rescue. Several studies of sequential immunosuppressive therapy are in progress. It is anticipated that long term toxicities can be lessened by substituting various maintenance agents (e.g., azathioprine or mycophenolate mofetil) after initial cyclophosphamide therapy has induced a renal responses. Innovative approaches (e.g., costimulatory blockade) offer the hope of more effective treatments without the risks of contemporary regimens. 2 figures. 2 tables. 88 references.

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Natural History and Treatment of Lupus Nephritis Source: Seminars in Nephrology. 19(1): 2-11. January 1999. Contact: Available from W.B. Saunders Company. Periodicals Department. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: Renal involvement occurs in most patients with systemic lupus erythematosus (SLE). This article discusses the natural history and treatment of lupus nephritis. Contemporary therapeutic regimens for immunosuppression and for the treatment of hypertension, hyperlipidemia, infections, and seizures have likely contributed to improvements in the prognosis of these patients over the past four decades. Corticosteroids usually ameliorate the manifestations of lupus nephritis but achieve less complete and sustained remissions than cytotoxic drugs. Among the cytotoxic drugs, pulse cyclophosphamide has one of the best profiles of efficacy and toxicity. Because each episode of lupus nephritis exacerbation results in cumulative scarring, atrophy, and fibrosis, the authors recommend continued maintenance treatment for 1 year beyond the point of complete remission of proliferative lupus nephritis. Studies are in progress to determine whether innovative treatment strategies will enhance efficacy and minimize toxicity associated with cytotoxic drug therapies. Lupus membranous nephropathy poses a lower risk of renal failure, but persistent nephrotic syndrome confers risks of cardiovascular events; this form of lupus nephritis is usually treated with less intensive regimens of corticosteroids, cytotoxic drugs, or

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cyclosporine. The prognosis and overall success of treatment for lupus nephritis seem to vary widely among geographically and racially diverse populations. The causes for the apparently worse prognosis and poorer responses to treatment of lupus nephritis in African American patients are currently unexplained and require further study. Until such data are available, caution is clearly warranted in extrapolating evidence, particularly about the prognosis and effects of treatment among different populations of patients with lupus nephritis. 4 figures. 2 tables. 85 references. (AA). •

Advances in the Treatment of Lupus Nephritis Source: in Coggins, C.H.; Hancock, E.W., Eds. Annual Review of Medicine: Selected Topics in the Clinical Sciences, Volume 45. Palo Alto, CA: Annual Reviews Inc. 2001. p. 63-78. Contact: Available from Annual Reviews Inc. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (800) 523-8635. Fax: (415) 855-9815. PRICE: $47. ISBN: 0824305450. Summary: Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to the formation and deposition of immune complexes throughout the body, which are pathogenic (causing disease) for SLE. Different forms of glomerulonephritis (inflammation of the filtering units of the kidney) can occur in patients with SLE and can contribute significantly to the associated morbidity (illness and complications) and, ultimately, mortality (death) from the disease. Over the past two decades, there have been significant strides in the understanding of the disease and in treatments that attempt to control the formation and deposition of anti-DNA auto-antibodies and immune complexes, as well as the subsequent inflammatory cascade mediated through various cellular and humoral pathways leading to progressive renal (kidney) damage and end stage renal disease (ESRD). This article reviews the current understanding of the pathogenesis and treatment of lupus nephritis in its various stages and discusses the experimental and human data regarding some of the potential newer forms of therapy. The authors discuss data regarding the use of steroids, azathioprine, cyclophosphamide, cyclosporine A, mycophenolate mofetil, gammaglobulin, plasmapheresis, LJP 394, flaxseed oil, bindarit, anti-CD-40 ligand, and CRLA41g. The authors conclude that the long term morbidity and mortality for patients with lupus nephritis (LN) has improved markedly over the past two decades. This is due in part to the addition of newer adjunctive therapies to control blood pressure and intraglomerular pressure, reduce proteinuria (protein in the urine), and manage hyperlipidemia (high levels of fats in the blood). 89 references.

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Efficacy of Mycophenolate Mofetil in Patients with Diffuse Proliferative Lupus Nephritis Source: New England Journal of Medicine. 343(16): 1156-1162. October 19, 2000. Summary: The combination of cyclophosphamide and prednisolone is effective for the treatment of severe lupus nephritis (kidney inflammation associated with systemic lupus erythematosus or SLE) but has serious adverse effects. This article reports on a study that investigated the efficacy of mycophenolate mofetil in patients (n = 42) with proliferative lupus nephritis. The authors compared the efficacy and side effects of a regimen of prednisolone and mycophenolate mofetil given for 12 months (group 1) with those of a regimen of prednisolone and cyclophosphamide given for 6 months, followed by prednisolone and azathioprine for 6 months (group 2). Of the patients in Group 1 (n = 21), 81 percent had a complete remission, and 14 percent had a partial remission, as compared with 76 percent and 14 percent, respectively, of the 21 patients in Group 2.

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The improvements in the degree of proteinuria (protein in the urine) and the serum albumin (protein levels in the blood) and creatinine concentrations were similar in the two groups. One patient in each group discontinued treatment because of side effects. Infections were noted in 19 percent of the patients in Group 1 and in 33 percent of those in Group 2. Other adverse effects occurred only in group 2; they included amenorrhea (23 percent), hair loss (19 percent), leukopenia (10 percent), and death (10 percent). The rates of relapse were 15 percent in Group 1, and 11 percent in Group 2. The authors conclude that for the treatment of diffuse proliferative lupus nephritis, the combination of mycophenolate mofetil and prednisolone is as effective as a regimen of cyclophosphamide and prednisolone followed by azathioprine and prednisolone, with similar levels of toxicity. 2 figures. 4 tables. 15 references. •

Do Current Recommendations for Kidney Biopsy in Nephrotic Syndrome Need Modifications? Source: Pediatric Nephrology. 17(6): 404-408. June 2002. Contact: Available from Springer-Verlag. Service Center Secaucus, 44 Hartz Way, Secaucus, NJ 07094. (201) 348-4033. Summary: The current recommendations of kidney biopsy in childhood idiopathic nephrotic syndrome (CINS) were put forward to minimize unnecessary kidney biopsies in patients with underlying minimal change disease (MCD). However, there remains a diversity of opinion about the criteria for biopsying children with idiopathic nephrotic syndrome. This study was conducted to prospectively study the usefulness of these guidelines in avoiding biopsies in MCD and to evaluate further modifications for minimizing biopsies in CINS. Of 400 consecutive CINS patients, 222 patients were subjected to kidney biopsy according to the current recommendations. The histopathology spectrum of these selectively biopsied children revealed focal segmental glomerulosclerosis (FSGS) in 39 percent, MCD in 34.2 percent, membranoproliferative glomerulonephritis (MPGN) in 16.2 percent, mesangioproliferative glomerulonephritis (MesPGN) in 7.6 percent, membranous nephropathy (MN) in 1.8 percent, and diffuse mesangial sclerosis (DMS) in 0.9 percent. The authors observed that despite the current recommendations and efforts to minimize biopsy, 34 percent of children had MCD on histopathology. The authors recommend that biopsies in children (age 1 to 16 years) should be restricted to a subgroup with two or more clinical and biochemical parameters and in steroid non-responders. In addition, the decision to administer cyclophosphamide should be based on steroid response patterns without requiring a prior routine biopsy. 2 figures. 3 tables. 22 references.

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Gastrointestinal Complications of Immunosuppression Source: Gastroenterology Clinics of North America. 28(1): 233-245. March 1999. Contact: Available from W.B. Saunders. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: The gastrointestinal manifestations of drug induced immunosuppression may result from direct drug effects, from infectious complications, or both. Graft versus host disease (GVHD) is a third mechanism whereby immunosuppressive agents are linked with gastrointestinal injury. This article reviews individual immunosuppressive medications, first concentrating on their reported gastrointestinal side effects, then reviewing other gastrointestinal phenomena, which may represent side effects of immunosuppressive agents but have not been reported yet. Immunosuppressive medications covered include cyclosporin A and tacrolimus, azathioprine,

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mycophenolate mofetil, cyclophosphamide, corticosteroids, and monoclonal antibodies. The infectious complications of transplantation may arise from the graft, may result from reactivation of a clandestine infection in the recipient, or may represent acquisition of a new infection. The most common nosocomial gastrointestinal infection occurring after transplantation is Clostridium difficile enterocolitis. Clinical features of gastrointestinal disturbance can include dysphagia, nausea and vomiting, abdominal pain, diarrhea, and abnormal liver tests. 2 tables. 35 references. (AA-M). •

Mesangioproliferative Glomerulonephritis with IgM Deposition: Clinical Characteristics and Outcome Source: Renal Failure. 22(4): 445-457. 2000. Contact: Available from Marcel Dekker Journals. P.O. Box 5017, Monticello, NY 127015176. (212) 696-9000. Summary: The significance of IgM on immunofluorescence in renal biopsy specimens remains unclear. This article reports on a retrospective case study conducted to define the clinical features, response to therapy, and outcome of patients with mesangioproliferative glomerulonephritis (MGN) with diffuse IgM deposition. Of 1,919 native renal (kidney) biopsies performed over a 10 year period, 139 (7.2 percent) had light microscopic features of MGN and manifested IgM as the dominant immunoglobulin. When exclusion criteria were applied, 60 patients (3.1 percent) remained. Followup data were available for 54 of these cases, featuring patients with a mean age of 26.5 years (range 1.7 to 63 years). Mean followup period was 7.4 years (range 4.7 to 22.2 years). Patients presented with nephrotic syndrome (41 percent), asymptomatic proteinuria (26 percent), macroscopic hematuria (blood in the urine, 18 percent of the patients), and isolated microscopic hematuria (15 percent). Twenty-one percent of patients were hypertensive (had high blood pressure) at presentation. Creatinine was initially less than 120 (mol per L) in all but one patient. Only four patients (7.4 percent), all nephrotic, suffered a decline in renal function despite treatment; all four developed end stage renal disease (ESRD) after a mean of 5.6 years. Protein excretion rate fell into the normal range in 63 percent of those receiving steroids, with 82 percent becoming steroid dependent. Of those treated with cyclosporine (48 percent) or cyclophosphamide (52 percent), only 9.5 percent and 14.5 percent, respectively, remained in prolonged remission after discontinuing treatment. 4 figures. 3 tables. 24 references.

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Is It Interstitial Cystitis? Diagnostic Distinctions in Reduced Bladder Capacity Source: Contemporary Urology. 6(7): 13-16, 18-19, 22. July 1994. Contact: Available from Medical Economics Publishing Inc. Montvale, NJ 07645. (800) 432-4570. Summary: This article addresses the questions involved in the diagnostic distinctions between interstitial cystitis (IC) and other causes of reduced bladder capacity. Topics include difficulties in diagnosing IC; the physiology of bladder sensation; an historical review of IC; clinical terminology used, including sensory urgency, motor urgency, bladder pain, maximum cystometric capacity, and bladder compliance; the role of urodynamic testing; differential diagnosis, including bladder cancer and carcinoma in situ (CIS), radiation cystitis, cyclophosphamide cystitis, detrusor instability, malakoplakia, schistosomiasis, tuberculous cystitis, and eosinophilic cystitis; the diagnostic approach; and how the NIH defines IC. An algorithm summarizing the work-up of suspected IC is included. 3 figures. 1 table. 17 references.

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Wegener Granulomatosis: 3 Cases Source: Consultant. 40(8): 1451-1456. July 2000. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article challenges readers with a series of three cases of Wegener granulomatosis, a form of necrotizing systemic vasculitis that commonly involves the upper airways, lungs, and kidneys. The pathogenesis of the disease resembles an infectious process, but no pathogen has been isolated. Wegener granulomatosis most likely occurs secondary to a hypersensitivity response to an exogenous or endogenous antigen that enters or resides in the airways. The authors describe diagnostic criteria, occurrence, treatment, and outcome before exploring the three illustrative cases. The kidney involvement is typically focal necrotizing glomerulitis. The extent of disease involvement dictates treatment; the standard treatment is the cytotoxic drug cyclophosphamide and the glucocorticoid prednisone. High doses are initiated when the disease is diagnosed. After 4 weeks, the prednisone dose is slowly tapered and eventually discontinued after 3 to 4 months. The cytotoxic agent is continued for at least 1 year before tapering begins. As many as half of patients with Wegener granulomatosis experience relapse; this generally occurs within 2 years after cessation of medication but may occur during treatment. The cases include a 21 year old African American man, a 49 year old man with recalcitrant nasal congestion, and a middle aged woman with diffuse arthralgies (painful joints). 8 figures. 1 table. 4 references.

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Membranoproliferative Glomerulonephritis in Childhood: Factors Affecting Prognosis Source: International Urology and Nephrology. 29(6): 711-716. 1997. Contact: Available from VSP, P.O. Box 346, 3700 AH Zeist, The Netherlands. 31306925790. Fax 31306932081. E-mail: [email protected]. Summary: This article describes a study undertaken to identify the factors affecting prognosis in membranoproliferative glomerulonephritis (MPGN) in childhood. MPGN is a distinctive form of chronic glomerulonephritis with a 15 to 67 percent progression to end stage renal disease (ESRD). The study examined 64 male and 32 female pediatric patients diagnosed with MPGN from 1975 to 1995. Their age range was 2 to 17 years. All patients initially received oral corticosteroid therapy. Remission was achieved in 22.9 percent. The unresponsive 77.1 percent received either cyclophosphamide or pulse methylprednisolone, and 25.4 percent and 50.0 percent of these patients entered complete remission, respectively. The overall 1 year renal survivals of the MPGN patients were 90.1 percent, and 5 year and 10 year survival rates were 81.9 percent and 61 percent, respectively. At multivariate analysis, the factors affecting renal prognosis were hematuria (blood in the urine) at presentation and low hemoglobin values. The article suggests that more aggressive immunosuppressive therapy should in instituted in patients unresponsive to steroids and that the aforementioned risk factors are higher for the development of renal failure. 2 figures. 2 tables. 8 references.

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Low-Dose Oral Methotrexate Management of Patients with Bilateral Meniere's Disease Source: ENT. Ear, Nose and Throat Journal. 79(2): 82-83, 86, 88, 91-92. February 2000. Contact: Available from MEDQUEST Communications LLC. 629 Euclid Avenue, Suite 1200, Cleveland, OH 44114. (216) 522-9700. E-mail: [email protected].

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Summary: This article reports on a retrospective clinical trial that evaluated the effectiveness of low dose oral methotrexate in the management of bilateral Meniere's disease of immune mediated origin. The authors evaluated ten men and eight women who had longstanding bilateral Meniere's disease that had been unresponsive to traditional conservative medical management. Sixteen of these patients had steroid responsive bilateral (both ears) Meniere's disease. Two patients had contraindications to steroids, but their clinical and laboratory evaluations were consistent with an immune mediated process. Patients were treated with 7.5 to 20 milligrams per week of oral methotrexate. The mean duration of treatment was 16.7 months, with a mean follow up of 2 years. Vertigo resolved in 14 patients (78 percent), was substantially alleviated in three patients (17 percent), and remained unchanged in one patient (6 percent). Hearing improved in five patients (28 percent) and stabilized in seven patients (39 percent). Tinnitus (ringing or noises in the ears) and aural fullness resolved or was relieved in 11 of 17 (65 percent) and 13 of 14 (93 percent) patients, respectively. Side effects were minimal and reversible. The authors conclude that low dose methotrexate can be considered for patients with immune mediated bilateral Meniere's disease when long term treatment is required or when a steroid or cyclophosphamide is contraindicated. 5 tables. 41 references. •

Systemic Lupus Erythematosus: Emerging Concepts. Part 1: Renal, Neuropsychiatric, Cardiovascular, Pulmonary, and Hematologic Disease Source: Annals of Internal Medicine. 122(12): 940-950. June 15, 1995. Summary: This article reports on a review of advances and controversies in the diagnosis and management of systemic lupus erythematosus with visceral involvement (renal, neuropsychiatric, cardiopulmonary, and hematologic disease). The authors reviewed more than 400 English language articles in the medical literature. They note that recent debates pertaining to lupus nephritis have focused on the value of kidney biopsy data and the role of cytotoxic drug therapies. Many studies have shown that estimates of prognosis are enhanced by consideration of clinical, demographic, and histologic features. For patients with severe lupus nephritis, an extended course of pulse cyclophosphamide therapy is more effective than a 6-month course of pulse methylprednisone therapy in preserving renal function. They conclude that the optimal duration and intensity of cytotoxic therapy remain undefined. 3 figures. 3 tables. 124 references.

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Levamisole Therapy in Corticosteroid-Dependent Nephrotic Syndrome Source: Pediatric Nephrology. 11(4): 415-417. August 1997. Contact: Available from Springer-Verlag. Service Center Secaucus, 44 Hartz Way, Secaucus, NJ 07094. (201) 348-4033. Summary: This article reports on a study in which the effect of prolonged treatment with levamisole was examined in 43 patients (30 boys, 13 girls) with steroid dependent nephrotic syndrome (SDNS). Levamisole is a drug that modulates phagocytic (cells that surround and digest microorganisms and cellular debris) and lymphocytic (white blood cells that assist in immune function) activity. Nephrotic syndrome is a condition characterized by massive edema (fluid accumulation), heavy proteinuria (protein in the urine), hypoalbuminemia (low levels of protein in the blood), and susceptibility to infections. The mean age at the beginning of treatment was 4.0 years (plus or minus 2 years). Fourteen patients had previously received cyclophosphamide with an ensuring remission of 8.5 months (plus or minus 10 months). Following induction of remission

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with prednisolone, levamisole was administratered at a dose of 2.5 milligrams per kilogram of body weight on alternate days. Prednisolone was tapered to 0.5 milligrams per kilogram of body weight on alternate days. The duration of levamisole therapy ranged from 6 to 31 months; 15 patients received levamisole for more than 18 months and 10 for more than 24 months. Prednisolone was discontinued in 18 patients after a mean duration of 11.7 months, whereas in 21 patients, its dose was reduced to 0.2 to 0.4 milligrams per kilogram of body weight on alternate days. The mean relapse rate prior to levamisole therapy was 3.0 relapses per year, which reduced to 0.9 relapses per year during levamisole treatment. A comparison of the response in 14 patients who had previously received cyclophosphamide with the other 29 patients did not show any significant difference. There were no side effects of levamisole therapy The authors conclude that treatment with levamisole is beneficial and safe in SDNS, with a marked steroid sparing effect. A significant proportion of these patients can be kept in remission on levamisole alone. 3 tables. 16 references. •

Nephrotic Edema Source: Seminars in Nephrology. 21(3): 262-268. May 2001. Contact: Available from W.B. Saunders Company. Periodicals Department. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: This article starts with a concise synopsis of the history of edema (an accumulation of fluid in tissues, in organs, or in a body cavity). The authors then discuss the role of underfilling, overflow, antidiuretic hormone (ADH), and acquaporins. The authors emphasize the use of diuretics in patients with edema. Treatment of the nephrotic syndrome (one symptom of which is massive edema) includes steroids, cyclophosphamide, cyclosporine, and mycophenolate; the choice of drug depends on the cause of the syndrome. Sodium (salt) restriction should be applied to all patients, however. Loop diuretics alone or in combination with antialdosterone drugs are appropriate. The authors explain the role and risks of albumin infusion and discuss the new hypothesis of pulse reverse osmosis. The article concludes with a discussion of the measurement of colloid osmotic pressure in the clinical setting. 4 figures. 40 references.

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Treatment of Lupus Nephritis: A Work in Progress (editorial) Source: New England Journal of Medicine. 343(16): 1182-1183. October 19, 2000. Summary: Until the pathogenesis (development of disease state) of nephritis (kidney infection) due to systemic lupus erythematosus (SLE) is unraveled, optimal treatment for patients with this disease remains an elusive goal. This article outlines one option for treatment of lupus nephritis, serving as an introduction to a separate article in this issue of the Journal. The author first reviews the differing presentations of SLE, noting that in some patients the kidneys are not involved but in others, there is rapidly progressive destructive kidney disease. This difference may be due in part to genetic risk factors, to environmental factors (such as exposure to ultraviolet light, infectious pathogens, and silica dust), race, or socioeconomic factors. In general, the treatment of lupus glomerulonephritis depends on the severity of the disease. Intravenous cyclophosphamide is given, in addition to oral glucocorticoids, for the aggressive forms of the disorder. However, the adverse effects of these therapies have prompted the search for alternative treatments. The author then comments on the accompanying article which presents the results of a study in which patients with diffuse proliferative lupus nephritis were successfully treated with prednisolone and mycophenolate mofetil. The editorial author notes that there are several reasons for caution before generalizing

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these findings to other patients with proliferative lupus glomerulonephritis, notably underrepresentation of patients with poor prognosis and certain demographic characteristics. 10 references. •

Bactrim for Treatment of Wegener Granulomatosis Source: Journal of Rare Diseases. 4(1): 13-14. January-February 1998. Contact: Available from Dowden Publishing Company. 110 Summit Avenue, Montvale, NJ 07645. (800) 707-7040 or (202) 391-9100. Fax (201) 391-2778. Summary: Wegener granulomatosis (WG) is a multisystem disease characterized by necrotizing vasculitis of the lungs and upper respiratory tract and by glomerulonephritis (inflammation of the kidney glomeruli). Perhaps 90 percent of patients treated with cyclophosphamide and prednisone experience complete remission. However, respiratory tract infections can trigger relapse. This article reviews recent literature on the treatment of WG, focusing on the use of trimethoprimsulfamethoxazole (TS, or Bactrim). The author notes that recent research in this area has produced conflicting results. The author reports on various studies that utilized TS in treating WG patients. The results of one study demonstrate that the response to TS in inducing remission of WG may depend to some extent on the phase of the disease. While TS induced long term remission in more than 50 percent of those with initial phase WG, neither TS alone nor TS with prednisone contributed to sustained remission in those patients with generalized disease. Another study led researchers to conclude that low dose methotrexate, given along with prednisone, is a better choice than TS for preventing relapse in WG patients. 5 references.

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Use of Cytotoxic Agents and Cyclosporine in the Treatment of Autoimmune Disease. Part 2: Inflammatory Bowel Disease, Systemic Vasculitis, and Therapeutic Toxicity Source: Annals of Internal Medicine. 129(1): 49-58. July 1, 1998. Summary: When cytotoxic (cell-damaging) agents were introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease (cancer). It then became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward treating non-neoplastic diseases in which autoimmune mechanisms play a role. This article discusses the use of cytotoxic agents and cyclosporine in the treatment of inflammatory bowel disease (IBD) and systemic vasculitis, and reviews the toxic effects of these agents. The authors caution that because these medications can cause treatment-induced illness or even death, it is imperative to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. The authors review research studies that investigated the use of these drugs. Drugs used for IBD include azathioprine and 6-mercaptopurine, methotrexate, and cyclosporine. These drugs are frequently used in combination with other agents and require careful monitoring. The authors stress that the optimal use of various drug combinations requires not only a knowledge of appropriate indications and dosage but also a thorough assessment of patient expectations and quality of life, a careful weighing of the various risks of medical and surgical therapies, the judicious use of other supportive measures, and extensive patient education. The section on toxicity discusses cyclophosphamide, chlorambucil, methotrexate, azathioprine, 6-mercaptopurine, and cyclosporine. The authors caution that infection is still an important cause of illness and death that is largely related to the nonspecific actions of these agents on the immune response. 3 tables. 75 references.

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Federally Funded Research on Cyclophosphamide The U.S. Government supports a variety of research studies relating to cyclophosphamide. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to cyclophosphamide. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore cyclophosphamide. The following is typical of the type of information found when searching the CRISP database for cyclophosphamide: •

Project Title: ADJUVANT GINSENG USE DURING BREAST CANCER DRUG THERAPY Principal Investigator & Institution: Murphy, Laura L.; Associate Professor; Physiology; Southern Illinois University Carbondale 900 S. Normal Carbondale, Il 629014709 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Ginseng is an herb widely used by humans to treat lack of stamina, loss of appetite and cachexia, and impotence. In Asian medicine, ginseng is a common component in herbals used in treatment of cancer, including breast cancer. There is recent scientific evidence that ginseng and its ginsenoside components are effective in inhibiting breast cancer cell proliferation in vitro and tumor growth in vivo. Consequently, many patients may be taking ginseng supplements during treatment with standard chemotherapy and hormonal therapy regimens in an effort to enhance therapeutic results as well as ameliorate side effects of the cancer chemotherapeutic drugs. However, there is no information on how adjuvant ginseng use could influence the efficacy of the cancer therapeutic drugs. This R21 proposal will address the following questions. Will the adjuvant use of ginseng aid in or interfere with standard breast cancer chemo- or hormonal therapy? Will adjuvant ginseng use produce palliative effects in the breast cancer patient undergoing chemotherapy? To answer these questions, we will examine the effects of a wide dose-range of individual chemotherapy (doxorubicin, cyclophosphamide, paclitaxel) or hormonal (tamoxifen) therapy drugs, alone and in combinations with an extract of American ginseng, on the proliferation of human breast cancer cells (MCF-7, MDA-MB-231) in vitro. The results of this study will allow us to determine if adjuvant ginseng treatment alters the efficacy of standard cancer therapeutic drugs. From these results, we will determine the treatment regimens to be tested in vivo in female athymic nude mice inoculated with either MCF-7 or MDA-MB- 231 cells, monitoring tumor growth as well as general well-being and systemic toxicity. These preclinical studies will allow us to determine the potential palliative effects concomitant ginseng treatment may have in animals receiving the potent cancer therapeutic drugs. Thirdly, we will examine potential additive, synergistic

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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or sub-additive effects of combination ginseng/chemotherapy treatment on pathwayspecific genes/proteins involved in cell cycle regulation, apoptosis and cytotoxicity. Together, the results of these studies will provide us with a better understanding of American ginseng and will allow evidence-based decisions to be made by breast cancer patients and their physicians regarding complementary ginseng use during standard chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTICANCER DICTYOSTELIUM

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RESISTANCE

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Principal Investigator & Institution: Alexander, Stephen; Associate Professor; Biological Sciences; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: Human tumors frequently develop resistance to many of the widely used chemotherapeutic agents. Many different mechanisms have been proposed for the molecular basis of this resistance. Studies on drug resistance in tumor cells have often focused on the mechanism of action of the drug, and looked for resistance due to altered drug concentration in the cell, different models of drug inactivation or altered damage repair. As such, other pathways that may be involved with the cellular cytotoxic response to individual drugs have been overlooked. We propose to use the cellular slime mold Dictyostelium discoideum in an unbiased approach to identify novel molecular targets that can be modulated to increase sensitivity of tumor cells to chemotherapeutic drugs. The genes and pathways of Dictyostelium are highly conserved with those of humans, and molecular genetic methods are well developed for this organism. Our preliminary system on cisplatin resistance resulted in the identification of 6 genes. Significantly, none of these had been previously associated with cisplatin, and each represents a potential new target for therapy. The goal of the present study is to demonstrate the general utility of this system and to show that it can be applied to the understanding of resistance to other drugs. We have focused on four classes of DNA damaging drugs that damage DNA by different mechanisms. These include: both intra- and inter-strand crosslinkers, monoalkylators, and oxygen radicals. We will 1) create a comprehensive Dictyostelium insertional mutant library, 2) isolate mutants resistant to drugs of each of the four classes and identify the cognate genes, and 3) test the mutants for cross-resistance to the other drugs. These studies will identify new mechanisms for drug resistance and new targets for chemotherapeutic intervention which can subsequently be validated in human cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APLASTIC ANEMIA: PATHOPHYSIOLOGY AND TREATMENT Principal Investigator & Institution: Jones, Richard J.; Professor of Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2003 Summary: Our data, now confirmed by many groups, show that there are at least two classes of hematopoietic stem cells (HSC): primitive or high quality stem cells that are capable of producing life-ling engraftment of all hematologic lineages and committed or low quality stem cells that produce only short-term hematologic reconstitution. We found that high quality HSC do not produce assayable progenitors upon direct culture and are unable to produce rapid engraftment after transplantation; however, high quality HSC are capable of marked cellular expansion in vitro with the production of

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large numbers of progenitors. We hypothesize that the immune attack in severe aplastic anemia (SAA) is against low quality HSC, but spares high quality HSC. The persistence of high quality HSC in SAA would explain the success of high-dose cyclophosphamide without blood or marrow transplantation in this disease. Our preliminary data suggest that high quality HSC can be isolated, and expanded in vitro, from patients with SAA. The overall objective of this proposal is to study the biology of SAA with the plan to develop novel clinical treatments for the disease. Specifically, we plan to: 1) continue to study the biology of HSC in SAA, especially approaches that will allow their expansion in vitro; 2) investigate the immuno-pathophysiology of SAA; and 3) develop novel clinical trials, especially autologous HSC transplantation, for the patients with SAA and acute leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: B CLL SUBTYPES--CORRELATION WITH CLINICAL OUTCOME Principal Investigator & Institution: Kay, Neil E.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (provided by applicant): B-cell chronic lymphocytic leukemia (B-CLL) is a common leukemia with significant patient variability to therapy and without a definitive curative approach. However, B-CLL likely represents distinct disease subtypes defined by a variety of cellular and molecular features including apoptosis resistance, chromosomal abnormalities, and status of immunoglobulin (Ig) genes in the CLL B cell clones. Specifically, there are recent findings that a strong relationship exists between clinical outcome and the presence or absence of somatic mutations in the Ig heavy chain variable region genes in the B-CLL clone. The exact biologic features that determine why the two B-CLL patient subgroups fare so differently are unknown. More importantly, no correlation to date has been made between Ig mutation status and specific therapeutic strategies, response rates, and key biologic and molecular features such as apoptosis, drug sensitivities, and chromosomal abnormalities. In this proposal, therefore, we will characterize apoptosis, cytogenetic abnormalities, and gene expression profiles of germline versus somatic mutation type B-CLL clones and more importantly, we will directly correlate these molecular parameters with clinical outcome to therapy. Our specific hypothesis is that one or more of these key discriminating features of B-CLL clones will allow us to predict disease progression and therapeutic response in CLL subsets. To test this hypothesis, we will conduct laboratory studies in two North Central Cancer Treatment Group clinical trials for B-CLL: one trial designed to test the efficacy of Fludarabine given on an alternating basis with cyclophosphamide to previously untreated CLL patients; and the other which uses Gemcitabine for previously treated CLL patients. Specifically, we propose to 1) determine the relationship between B-CLL Ig VH gene region status and key biological, genetic, and molecular features exhibited by the leukemic clone; and 2) examine the association between clinical response parameters for patients treated with fludarabine and cyclophosphamide or Gemcitabine and clonal biologic and molecular features. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOMARKERS OF TREATMENT RELATED LEUKEMIA Principal Investigator & Institution: Felix, Carolyn A.; Associate Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005

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Summary: (Adapted from the investigator's abstract) The objective of this work is to develop new avenues to identify undergoing anticancer therapy who are at increased risk of leukemia as a treatment complication and to facilitate detection of the leukemic clone earlier in the course of the disease. For children with metastatic neuroblastoma receiving N6 therapy, the incidence of leukemia is 7%. About 40% of cases are related to alkylating agent therapy and have chromosome 5 and/or 7 loss; about 40% have translocation of the MLL gene at chromosome band 11q23, which occurs in leukemias related to DNA topoisomerase II inhibitors. Because of its efficacy against neuroblastoma, N6 therapy will be incorporated into the high-risk neuroblastoma trial for the Children's Cancer Group. Etoposide, doxorubicin and cyclophosphamide used in N6 therapy are metabolized by cytochrome P-450 (CYP) 3A; all are associated with leukemia as a treatment complication. The metabolites have genotoxic properties that may be relevant to leukemogenesis. The promoter of the CYP3A4 gene is polymorphic. Prior studies showed that the CYP3A4 wild-type genotype increased and CYP3A4 variant genotypes decrease the risk of treatment-related leukemia with MLL gene translocations. Prior studies also showed that the MLL gene translocation can be present early in the course therapy at how cumulative doses of DNA topoisomerase II inhibitors. MLL presents an extreme example of a translocation involving many partner genes; Southern blot analysis and cDNA panhandle PCR are two methods that can track the translocations in preleukemic samples regardless of the partner gene. They hypothesize that CYP3A4 genotype and MLL gene translocations are relevant biomarkers for treatment-related leukemia. The plans of the cooperative group to use N6 therapy not only mandate systematic investigation of who is most at risk, but also provide a unique clinical opportunity to examine CYP3A4 genotype and MLL gene translocations as a relevant biomarkders in the context of the therapeutic trial. The purpose of aim 1 is to validate the association of CYP3A4 genotype with treatmentrelated leukemia. The purpose of aims 2 and 3 is to determine and compare the utility of MLL gene translocations, detected by Southern blot analysis and cDNA panhandle PCR, as leukemia-specific markers that predict development of disease. The purpose of aim 4 is to explore the baseline frequency of MLL gene translocations in untreated pediatric patients diagnosed with neuroblastoma and to determine how chemotherapy affects this frequency during the course of treatment. Risk factors for treatment-related leukemia are poorly understood. Predictive biomarker assays will enable rational modifications of primary cancer therapies and provide new opportunities for early intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CALGB Principal Investigator & Institution: Bloomfield, Clara D.; Director; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 16-APR-1998; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): This is a multi-disciplinary collaborative research project for the development of more effective methods of prevention, detection, and treatment of human cancer in all its forms. This research focuses the efforts of medical oncologists, surgeons, radiotherapists, psychiatrists, pathologists, basic scientists, statisticians, epidemiologists, nurses, pharmacists, and clinical research associates on well designed and conducted studies asking interrelated clinical and basic science questions whose answers contribute significantly to patient care and to reduction of cancer within populations at increased risk for its development. Included in this project are the following: (1) the exploration of new therapeutic agents, and their associated toxicities, through a wide range of neoplastic diseases in Phase I, II,

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and III studies; (2) the evaluation of the efficacy and toxicity of new regimens including combinations of new and old agents in an effort to exploit synergistic combinations more effectively; (3) the development of multi-modal approaches to specific tumor problems using surgical, immunological, and radiotherapeutic measures in optimal combinations; (4) the involvement of pertinent basic science disciplines such as biochemistry, pharmacology, cellular biology, and mathematics in the formulation and execution of specific treatment protocols; (5) the improvement of cancer care in the community by using these programs in the educational effort directed at pre- and postdoctoral students, nurses, allied medical personnel and physicians; (6) the evaluation of biologic studies in correlation with clinical endpoints so as to build toward more rationally, based cancer management; (7) the evaluation of cancer control efforts such as early detection; and (8) the study of the psycho-social aspects of cancer. This application for permanent membership in the Cancer and Leukemia Group B represents a turning point in the cooperative group clinical research activities of The Ohio State University as it leaves its long-standing affiliation with the Southwest Oncology Group. Motivating this change is the recruitment of Drs. Clara D. Bloomfield, Michael A. Caligiuri, and Albert de la Chapelle. The research attributes of these outstanding investigators are synergistic with existing capabilities at Ohio State. Combining these separate strengths will enhance development of innovative clinical trials especially those with basic science correlates and strengthen Ohio State's cancer cooperative group participation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER AND ACUTE LEUKEMIA GROUP B (CALGB) INST GRANT Principal Investigator & Institution: Gelmann, Edward P.; Professor of Medicine & Cell Biology; None; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2002; Project Start 30-APR-1998; Project End 31-MAR-2003 Summary: (adapted from applicant's abstract): The overall objective of this project is to provide support for performance of clinical studies of the Cancer and Leukemia Group B at the Lombardi Cancer Center at Georgetown University Medical School. The LCC/GUMC is an NCI-designated Comprehensive Cancer Center. In 1988, Marc Lippman, M.D., assumed Directorship of the Lombardi Cancer Center. Under his direction, the Cancer Center was designated as a Federally Funded Cancer Center in 1989. The Cancer Center became a Federal designated "Comprehensive Cancer Center" in 1992, and the Cancer Center Support Grant was renewed in 1996 with an overall rating of "excellent to outstanding." During the previous funding period, LCC/GUMC has participated in CALGB studies as an unfunded affiliate institution of the University of Maryland Cancer Center. In March, 1997, the CALGB Board of Directors approved LCC/GUMC as a Main Member Institution. At that time, Dr. Daniel F. Hayes was named as Institutional Principal Investigator. LCC/GUMC will participate in the entire range of multimodatity clinical studies, including both therapeutic studies, correlative science studies. and companion studies of quality of life, survivorship, and cost effectiveness analyses. LCC faculty have been active in all three areas of CALGB activities: accrual, scientific leadership, and administrative tasks. As of May 1, 1997, 41 CALGB protocols were active at LCC/GUMC. A total of 129 patients have entered CALGB studies since LCC entered CALGB in 1990, with 78 of these during this funding period (1993-1996). Accrual has increased over the last three years: 1994, 10 patients; 1995, 26 patients, and 1996, 31 patients. 17 percent of these patients were from minority populations, and 69 percent of patients entered onto CALGB trials were women. A recent audit by CALGB rated LCC as "Acceptable." Several initiative are being used to

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increase accrual at LCC, including recruitment of onsite clinical faculty committed to clinical trials, organization of a highly coordinated Clinical Research Management Office, development of a clinical Research Consortium of off-site affiliates. and development of a Patient Accession Core Project. Lombardi has a major program to increase accrual of minorities and women to clinical trials, coordinated by the Associate Director of the Cancer Center, Dr. John Kemer. It is estimated that LCC will accrue 95 patients/year to CALCB therapeutic and companion studies. LCC faculty are already leaders in CALGB, with 12 cadre committee members, two of whom are Committee Chairs (Dr. Hayes, Solid Tumor Correlative Science; Dr. Raymond Weiss, Audit). Five faculty members are Study Chairs for 11 active CALGB trials or companion studies. Two faculty have two concepts under review that are likely to open in the next twelve months. Because of the depth of scientific accomplishments of the LCC faculty, it is anticipated that many more will assume leadership roles within CALGB now that LCC/GUMC has Main Member Status. Three faculty have had administrative roles, including Dr. Raymond Weiss who started and has been the only Chair of the Audit Committee. The LCC research infrastructure for clinical and translational science is substantial, and LCC faculty are expected to provide leadership in developing clinical and correlative science studies during the next funding cycle. In summary, with Main Membership status and maturation of the Cancer Center, the LCC is expected to become one of the leading institutions within the CALGB during the next five years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER AND LEUKEMIA GROUP B Principal Investigator & Institution: Niell, Harvey B.; Medicine; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): The aim of this project is to promote the integration of clinical cancer therapeutic research in the Mid-South area by joining a university-based cancer center with the major teaching and regional hospitals in a cooperative group effort. The University of Tennessee will continue to use its membership in Cancer and Leukemia Group B to support participation in therapeutic research and other clinical trials both in the University hospital complex and its affiliated institutions. The goals are the initiation and participation in phase I, II, and III cooperative clinical trials involving chemotherapy, surgery, and radiation therapy. A major emphasis is the development of new therapeutic strategies in collaborative investigations with interested members of CALGB. Data collection, monitoring, reporting, and publication of information is a primary emphasis. University of Tennessee members will continue to be actively involved in scientific and administrative committees of CALGB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANCER AND LEUKEMIA GROUP B Principal Investigator & Institution: Edelman, Martin J.; Director; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-APR-1982; Project End 31-MAR-2003 Summary: The GCC continues to grow and develop a scientific and clinical relationship with CALGB. A number of the faculty at GCC participate in CALGB scientific and administrative committees. GCC faculty design, conduct and chair many group studies and enter large numbers of patients onto CALGB studies. The GCC faculty are on five

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core committees and chair the Leukemia Committee and the Subcommittee on Thoracic Surgery. The funding to continue these activities will allow further growth in the scientific and administrative participation of GCC and its affiliates. GCC is one of the largest accruing institutions for leukemia and one of the largest accruing institutions overall. The basic science laboratories studying acute leukemia, cellular, animal and clinical pharmacology and cellular and molecular biology form an important correlative science resource for the group. The grant will allow GCC to continue its highly effective scientific and administrative participation in the group and will continue to allow them to develop a scientific base in the greater Baltimore area and across the state and region. The grant will also allow for continuation of meritorious pilot protocols and will allow GCC to monitor and collect data which will produce mutual benefit to the GCC and CALGB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER AND LEUKEMIA GROUP B Principal Investigator & Institution: Sugarbaker, David J.; Vice Chairman/Chief; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 26-APR-1993; Project End 31-MAR-2003 Summary: application intended to support surgical activities within CALGB including the recruitment of patients to adjuvant trials, development and performance of surgical trials, and surgical quality control. Historically, surgical participation within CALGB had been limited, in part due to the early focus of CALGB investigations of leukemia and late-stage solid malignancies. Increasing emphasis on adjuvant trials has required greater surgical participation, both for recruitment of perioperative patients, but as well for surgical quality control. The application describes five specific aims of the Surgery Modality Committee: (1) to develop a quality control program that will seek to standardize the surgical component of CALGB protocols; (2) to provide a platform to support the intellectual activity of CALGB surgeons; (3) to provide a mechanism for the practical support of surgical activity within the group; (4) to assure regular review and monitoring of individual surgical productivity; and (5) to permit CALGB surgeons to assume leadership roles in protocol development. The Surgery Modality Committee consists of a consortium of 29 surgeon members, each representing a CALGB institution. The group is organized and run by a central committee for which Dr. Sugarbaker is chair and Dr. Leslie Kohman is vice-chair, as well as three disease site subcommittees, including Thoracic, Breast, Gastrointestinal, and an Institutional Coordinators Committee. Protocol concepts are developed in the disease committees. Three stages of group development are described: (1) surgeon recruitment phase; (2) patient recruitment phase (educational activities about adjuvant therapy trials. etc.); and (3) protocol development phase (intellectual activities). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANCER AND LEUKEMIA GROUP B Principal Investigator & Institution: Schilsky, Richard L.; Associate Dean for Clinical Research; None; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 30-SEP-1983; Project End 31-MAR-2003 Summary: The CALGB is comprised of 31 academic medical centers and over 185 affiliated community hospitals joined in the pursuit of improved cancer treatment and better understanding of tumor biology via the conduct of controlled clinical trials. Over 3000 members of the Group including oncology physicians, statisticians, clinical

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research associates, oncology nurses, pharmacists, epidemiologists, and basic scientists participate in these studies. From 25-35 phase III protocols are active at any one time, along with Phase II, Phase I and pilot studies required for the appropriate design of large scale randomized trials. In 1996 the CALGB accrued nearly 4700 entries to its protocols. Multidisciplinary disease committees of the Group design and implement protocols for the treatment of patients with leukemia, lymphoma, breast, respiratory, GI, and prostate cancer. Modality Committees, including Clinical Economics, Correlative Sciences, Pharmacology and Experimental Therapeutics, Psycho-Oncology, Surgery, Pathology, Radiation Oncology, Transplantation, Oncology Nursing, and Clinical Research Associates serve as the sites for planning and implementing new approaches for these disciplines and most committees develop these concepts jointly with the appropriate Disease Committees. Major area of emphasis in CALGB include development of innovative treatments for patients with cancer; studies of molecular predictors of prognosis and response to therapy; studies of pharmacokinetics and pharmacodynamics of new and established anticancer drugs; evaluation of minimally invasive surgical techniques; determining the cost and cost-effectiveness of new cancer therapies; evaluating the impact of cancer and its treatment on the quality of life of cancer patients and their caregivers; developing new strategies for cancer prevention; and addressing the needs of special populations, particularly minorities and the elderly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER AND LEUKEMIA GROUP B (CALGB) Principal Investigator & Institution: Ernstoff, Marc S.; Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-APR-1979; Project End 31-MAR-2004 Summary: (adapted from the applicant's abstract): Patients with breast cancer, lung cancer, gastrointestinal malignancies, prostate carcinoma, leukemia and lymphoma and other malignancies will be entered into therapeutic, cancer control and correlative science trials developed by the Cancer and Leukemia Group B (CALGB). A broader base for recruitment of patients to CALGB has been established in much of New Hampshire, eastern Vermont and northern Massachusetts through the eight member Cooperative Group Oncology Program, and with this network it is planned to increase the numbers of patients accrued to CALGB studies. Dartmouth will continue to make significant contributions to the scientific and administrative activities of CALGB. Within the Norris Cotton Cancer Center (NCCC) strategies to refocus the scientific directions will allow more translational programs to be piloted for future testing in the CALGB setting. The six areas of development are immunotherapy, retinoid development, clinical pharmacology, genetics and gene modulation, drug development and interactions with radiation, tumor markers, pain and psychosocial initiatives. It is anticipated that phase I, II and pilot clinical trials currently underway at the Norris Cotton Cancer Center will soon be ready for expanded trials in CALGB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANCER AND LEUKEMIA GROUP B--MINNESOTA ONCOLOGY GROUP Principal Investigator & Institution: Peterson, Bruce A.; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-1979; Project End 31-MAR-2003

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Summary: (adapted from the applicant's abstract): The University of Minnesota has been a participating member of the Cancer and Leukemia Cooperative Group B (CALGB) for the clinical studies of hematologic malignancies and solid tumors since August 1973. The Minnesota Oncology Group consists of established investigators from the Department of Medicine, the Department of Therapeutic Radiology, the Department of Laboratory Medicine and Pathology, the Department of Surgery, and the Department of Pediatrics/School of Public Health with extensive expertise in clinical cancer research, including clinical trials, bone marrow transplantation, immunology, cytogenetics, pathology and epidemiology. The Minnesota Oncology Group participates in the CALGB in order to pool its intellectual, technical and clinical resources with other academic institutions to expedite progress in clinical cancer research. The specific aims of this proposal include: (1) to contribute to and participate in the scientific endeavors of CALGB; (2) to reach our accrual potential and then to maintain patient accrual at that increased level; (3) to assist in the administrative and organizational matters of CALGB. The methods of study are through the clinical research protocols established by the CALGB. The clinical material provided by the Minnesota Oncology Group is composed primarily of patients with leukemia, lymphoma, breast cancer, gastrointestinal cancer and lung cancer, and participation is in the entire range of trials, including bone marrow transplantation and phase I drug testing. Major scientific positions held by Minnesota participants are the Chair of the Lymphoma Committee and Vice-Chair of the Pathology Committee for Hematologic Malignancies. In addition, 10 participants are members of various scientific core committees and a major group service in leukemic research is centered at Minnesota. The Minnesota Oncology Group is active in administrative activities with the Chair of the Constitution Committee and membership on the Institutional Performance Evaluation Committee (Standards, Ethics and Peer Review Committee), Membership Committee, Data Audit Committee and the Board of Directors. The objective of this research program is to participate in inter-institutional clinical research to resolve unanswered and important questions in the therapy and biology of malignant diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER AND LEUKEMIA GROUP B--MOUNT SINAI Principal Investigator & Institution: Silverman, Lewis R.; Chairman; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-APR-1979; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): Mount Sinai intends to continue its vigorous participation in activities of the Cancer and Leukemia Group B. We will commit intellectual and patient resources to research in leukemia, lymphomas, breast cancer, respiratory cancers, gastrointestinal cancer, prostate cancer, transplantation and companion studies. These clinical undertakings involve psycho-oncology, pathology, cytogenetics, immunology and epidemiology. Various members of the Mount Sinai faculty serve as Study Chairs, and bring some of their pilot observations to Group consideration. Our efforts are particularly focused on breast cancer, myelodysplastic syndrome and innovations in chemotherapy. The objectives of the Group are to discover and validate effective treatments for the cure and long term palliation of cancer. Mount Sinai is wholeheartedly committed to these objectives and will devote energy to make the most effective studies available to the Group for research purposes. We will participate in single and multi-disciplinary trials, Phase I, II, III and will contribute specimens to the Group's correlative science studies. We will conduct scientific inquiries on Group specimens. Mount Sinai will coordinate the studies of Cooperative Group

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Outreach Program (CGOP) participants, and serve as a research base for Community Clinical Oncology Program (CCOP) institutions. With these associated investigators in 12 affiliated institutions, Mount Sinai plans to participate in all Group activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER AND LEUKEMIA GROUP B--PET COMMITTEE Principal Investigator & Institution: Ratain, Mark J.; Professor of Medicine and Chairman; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-APR-1986; Project End 31-MAR-2003 Summary: (Adapted from the applicant's abstract): The overall objectives for the Pharmacology and Experimental Therapeutics (PET) Committee of the CALGB are to study population pharmacokinetics and pharmacodynamics of new and established anticancer agents in a multi-institutional setting; to introduce new drugs and combinations, including immunomodulatory and cytostatic agents into the CALGB for eventual phase II and III testing; to initiate and conduct a program of mucositis prevention in the CALGB; and to organize educational symposia for the Group on topics in cancer pharmacology and experimental therapeutics. The committee meets twice annually in addition to sponsoring an educational session at each of the full Group meetings. Population pharmacology are ongoing of suramin, carboplatin, paclitaxel, 9aminocamptothecin, 5-fluorouracil and etoposide. Studies are planned of irinotecan and docetaxel, in addition to two additional studies of paclitaxel with regard to the effects of age and body surface on toxicity and pharmacokinetics, Other special populations to be studied include race (docetaxel and irinotecan) and end-organ dysfunction (gemcitabine, irinotecan). Two novel therapeutic studies involving biologics are planned, including IL-2 in combination with an anti-HER-2 monoclonal antibody and interferon alpha in combination with tamoxifen. Another new initiative is a program to prevent mucositis. The initial study will evaluate the effect of IL-11 on mucositis secondary to cisplatin, 5-FU and leucovorin. Since many of the studies include analysis of pharmacological specimens, the Committee utilizes three core laboratories--at the University of Chicago, the University of Maryland and the University of Tennessee. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANCER AND LEUKEMIA GROUP B--RPCI/SUNYAB Principal Investigator & Institution: Levine, Ellis G.; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 15-APR-1993; Project End 31-MAR-2003 Summary: (Adapted from applicant's abstract): Roswell Park Cancer Institute (RPCI) is requesting support to continue its participation in the Cancer and Leukemia Group B (CALGB). The goals of our participation in CALGB include the following: (1) to continue our strong contribution to the scientific agenda of the group, (2) to continue our performance of pilot activity at the local level that can be considered for group adaption, (3) to continue our administrative support for the efficient functioning of the group, (4) to sustain accrual in order to allow the rapid accumulation of clinical data and experience through the cooperative group process, and (5) to continue to provide data of high quality in a timely manner. Over the last 3-plus years during which we have had funding, we have contributed substantially to the scientific, administrative, core, and publication activities of the CALGB. More specifically, five RPCI members serve or have served as chairs or vice chairs of scientific committee; 22 serve or have served as members on 33 scientific committees; 14 serve or have served as study chairs on 21

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protocols; 7 provide or have provided core services to the Group; and 5 have performed pilot studies that have led to the development of CALGB protocols, 3 have protocols pending activation, and 3 have submitted concepts for development. Moreover, RPCI members have contributed to 111 publications and given over 70 educational sessions. Furthermore, several members have administrative roles in the Group. Accrual is customarily between 150-200 credits/year. Data quality and timeliness of submission is regularly cited by the Group's quality assurance committee as among the best in the Group. Continued funding should allow us to sustain the vigor of our activities and therefore meet our specific aims. Founded in 1898, RPCI was one of the first institutions dedicated exclusively to the research and treatment of cancer and allied diseases. The campus spans 25 acres in downtown Buffalo and consists of 15 research and clinical buildings with approximately one million square feet of space. Projected statistics for fiscal year 1996-1997 include 2381 new cancer cases, 5300 hospital admissions, and 104,000 outpatient visits from patients in 42 states and 22 foreign countries. The Institute is currently undergoing a $241 million modernization of its facilities. When completed in 1998, Roswell Park will have a new 133 bed hospital, a diagnostic and treatment center, outpatient clinics, and medical research laboratories, as well as renovated education, research, and support space. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER CENTER CALGB PARTICIPATION Principal Investigator & Institution: Muss, Hyman B.; Professor of Medicine; Vermont Cancer Center; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 20-APR-1998; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): The Vermont Cancer Center (VCC), an NCI designated Comprehensive Cancer Center, joined the CALGB in 1995. In that short time the VCC has made significant headway in becoming a major participant in CALGB activities. Eight VCC members have made major commitments to supporting CALGB efforts. Dr. Hyman Muss continues to be extremely active in CALGB and serves as the Co-Chair of the Working Group for the Elderly and the Vice Chair of the Breast Cancer Committee, in addition to chairing two CALGB protocols (8869 and 9670). Dr. Steven Grunberg, a member of the Clinical Economics Committee, is currently developing a clinical protocol that will compare cost with symptom control for antiemetics. Dr. David Krag is an active member of the Breast Core Committee and is helping CALBG develop a protocol for sentinel node staging for women with early stage breast cancer. Dr. Seth Harlow will assume Dr. Krag's role as member of the Surgery Committee. Dr. Donald Weaver participates extensively in pathology group activities and has a major interest in breast cancer. Drs. Michael Cooper, Barbara Grant, and Richard Branda have major interest in urologic cancer, leukemia and lymphoma, and nutrition and cancer, respectively, and have developed concepts for CALGB clinical investigations. The development of multidisciplinary, disease-site oriented, affinity groups within our Center has established major liaisons between laboratory and clinical scientists. This will strengthen our institutional commitment to the group and allow VCC members to develop innovative companion trials for the CALGB. Recently, Drs. Grant and Branda presented two concepts-one related to assessing the importance of folate status on chemotherapy toxicity in women with early breast cancer, and a second that utilizes a novel reporter gene (hprt) to monitor and possibly define women with early stage breast cancer who might be at high risk for developing secondary acute nonlymphocytic leukemia. Drs. Weaver and other VCC scientists are drafting a concept

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that will explore the role of erbB-2 associated signaling proteins as mediators of apoptosis for women with early stage breast cancer treated with anthracyclines (CALGB 8541). We anticipate a major increase in accrual in the next year. The Green Mountain Oncology Group (CCOP) selected the VCC as its research base beginning in April, 1997. In one month they have entered 10 patients on CALGB protocols. Two new faculty will join the VCC this summer who have major interests in genetics and high-dose therapy; it is anticipated they will be active in CALGB activities. Also, we are developing a major outreach program and expect to add several affiliates with interest in clinical trials. In addition, we have developed a high-dose chemotherapy autologous stem cell support program and expect to become a CALGB Transplant Center by the start of the next funding period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOIMMUNOTHERAPY FOR BREAST CANCER TREATMENT Principal Investigator & Institution: Emens, Leisha A.; Oncology Center; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Dr. Emens is an Assistant Professor in the Department of Oncology at Johns Hopkins. She has completed formal training in basic scientific research and clinical oncology. During her fellowship she participated in the preclinical Work that forms the barns for the trials proposed in this application. She also developed a human whole cell GM-CSF-secreting breast cancer vaccine, and designed a clinical trial that tests it in patients with metastatic breast cancer, directly translating the vaccination regimen and immune monitoring assays from the preclinical to the clinical setting. Her career development plan is to obtain the formal and practical training in clinical research to complement her previous training and position her for a successful career as an independent clinically oriented translational investigator. "Her mentors will be Elizabeth Jaffee, MD and Steven Piantadosi, MD PhD, who will provide mentorship in immunotherapy and clinical trial design and analysis respectively. One promising immunotherapeutic strategy for overcoming drug resistance in advanced breast cancer utilizes whole tumor cells secreting GM-CSF to activate the patient's own immune system to recognize and eliminate cancer cells. Because it is unlikely that this approach will induce durable clinical responses in patients with advanced disease, we have utilized the clinically relevant neu transgenic mouse for developing more potent vaccination strategies. We found that sequencing a neu-targeted, GM-CSF-secreting vaccine with 10w doses of Cyclophosphamide (CY) and Doxorubicin (DOX) augmented the vaccine-activated HER-2/neu-specifie immune response, delaying rates of tumor outgrowth compared to vaccine or drugs alone. This was reflected in enhanced HER2/neu-specific T helper cell, CTL, and antibody responses. The specific research goals are to: (1) identify the doses of CY and DOX that optimize vaccine-activated immunity in a Phase I trial targeting breast cancer patients with metastatic disease, (2) develop in vitro assays of vaccine-activated immunity using HER-2/neu as a target antigen, and (3) develop a Phase 1FItrial testing the optimal vaccination regimen in patients with high risk primary breast cancer. The overall objective of this proposal is to establish the foundation for a clinical program in breast cancer immunotherapy that integrates GMCSF-secreting vaccines with other treatment modalities for advanced breast cancer in an additive or synergistic fashion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CITY OF HOPE SOUTHWEST GROUP CLINICAL TRIALS Principal Investigator & Institution: Doroshow, James H.; Associate Director for Clinical Research; City of Hope National Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2002; Project Start 01-JAN-1988; Project End 31-DEC-2002 Summary: The overall objective of this proposal is to support the participation of the City of Hope National Medical Center (COH) in the investigational clinical trials of the Southwest Oncology Group (SWOG). The COH, an NCI-designated Cancer Research Center, has provided strong support for the clinical research activities of SWOG over the past four years. SWOG members at COH have provided substantial scientific input into the development of new therapeutic programs for hematologic malignancies as well as all aspects of high-dose chemotherapy with bone marrow or stem cell support for the group; in addition, expertise in oncologic pharmacology, cytogenetics, immunotherapy, and gynecologic pathology and virology will continue to support pilot protocol development for SWOG as well as groupwide phase II and phase III studies and biological response modifier protocols. In addition, SWOG members from COH will participate heavily in research activities in oncologic surgery and cancer prevention. The most notable change in SWOG activities at COH over the past four years has been a marked increase in both the scientific and administrative leadership contributed by COH investigators to the SWOG clinical research endeavor. COH physicians and scientists now chair the Cytogenetics Discipline Committee, the Bone Marrow and Stem Cell Transplantation Committee, the Gynecology Committee s Tumor Biology and Pathology Subcommittees, and the Bone Marrow and Stem Cell Transplantation Breast Cancer Subcommittee. COH also now had three designated members on the SWOG Board of Governors, representing not only the parent institution but the Cytogenetics Discipline Committee and the stomatology activities of the Head and Neck Committee. In addition to these new leadership positions, the scientific productivity of COH investigators in SWOG has dramatically increased. At the time of the last competitive review of this proposal in 1992, 8 COH investigators had contributed one paper and four abstracts reporting SWOG clinical investigations; over the past four years, 13 COH investigators have published 18 papers and 14 abstracts describing SWOG research in high quality, peer-reviewed publications. Based upon the presence of a strong, multidisciplinary team of physicians in Pathology, Surgical Oncology, Radiation Oncology, and Cancer Control as well as Medical Oncology and Hematology who are committed to the investigations pursued by SWOG, as well as an expanding network of CGOP affiliates serving an underserved minority population in Southern California, strong scientific leadership of and patient accrual to SWOG clinical trials can be predicted to continue over the coming funding cycle, and the innovative treatment concepts devised by SWOG and COH will become more widely available in this region. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL DEVELOPMENT OF 4-HYDROPEROXYIFOSFAMIDE Principal Investigator & Institution: Morgan, Lee Roy R.; Chief Executive Officer; DekkTec, Inc. 4200 Canal St, Ste a New Orleans, La 70119 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (provided by applicant): The objective of the proposed research is to synthesize 4-hydroperoxyifosfamide (HOO-IFOS) in sufficient quantity for evaluation in vivo against a human osteosarcoma xenograft and additional tumor xenografts of breast, lung (small cell and non-small cell) and ovary cancers. A cyclophosphamideresistant human melanoma xenograft will also be used in order to determine the efficacy

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of this pre-activated form of the clinical antitumor drug ifosfamide (IFOS) in comparison with IFOS, cyclophosphamide (CPA) and 4-hydroperoxycyclophosphamide (4-HC) as a guide to possible further development of HOO-IFOS as a clinical anticancer agent. Plasma levels of chloroacetaldehyde, a metabolite of IFOS implicated as the causative agent in its neurotoxicity, and acrolein, the metabolite of IFOS and CPA that causes dose-limiting hemorrhagic cystitis, generated by HOO-IFOS vs. IFOS will be measured as an indication of comparative neurotoxic or hemorrhagic cystitic potential, resp. Possible clinical advantages of HOO-IFOS in comparison to IFOS or CPA are (1) elimination of variation in active drug administered to patients, (2) reduction or elimination of toxicities associated with IFOS or CPA and (3) possible reduction in CPArelated resistance. PROPOSED COMMERCIAL APPLICATIONS: It is possible that HOO-IFOS could become a superior clinical drug to CPA or IFOS for treating certain tumor types now treated with these two drus because of comparable/superior activity but with reduced toxicities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL TRAILS IN PEDIATRIC RHEUMATOLOGY Principal Investigator & Institution: Lovell, Daniel J.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: (Taken from the applicant's abstract): This application is focused on the performance of two prospective, multicentered trials in children with juvenile rheumatoid arthritis (JRA). In addition, this career development grant is intended to enhance the ability of many pediatric rheumatology centers in North America to perform trials to determine the efficacy and safety of currently used but untested and also newly developed drugs in children with JRA by increasing the ability of the principal investigator (PI) to focus on the direction and coordination of the efforts of the Pediatric Rheumatology Collaborative Study Group (PRCSG) of which the PI is the chairman. The PRCSG is a consortium of over 45 academic pediatric rheumatology centers that have performed over 30 trials in children with JRA. Trial 1: Osteopenia is a significant and frequent complication of JRA. This research proposal includes a prospective, randomized, multicenter, placebo-controlled trial (RCT) to determine the efficacy of daily oral calcium supplementation (1000 mg/day of calcium carbonate) for two years to increase total body bone mineral density (TB BMD) by 10% (1.5 SD) compared to placebo treatment. In addition, the persistence of the treatment effect will be determined for 1.5 years after the RCT. This will be the first longitudinal study of bone mineralization in JRA and the control group will demonstrate the natural history of bone mineralization. Trial 2: This research proposal also includes a prospective, randomized, actively controlled, open clinical trial to determine the efficacy of combination drug therapy to induce prolonged drug-free remission in children with severe systemic JRA (sJRA). Patients will be enrolled early in the disease course but eligibility criteria will select those with a 115% risk of developing severe, erosive polyarthritis. One therapy regimen is composed of intravenous methylprednisolone for 3 consecutive days, intravenous cyclophosphamide on the third day, and up to 20 mg/M2/wk of methotrexate. The second pulse therapy regimen is identical to the first, except no cyclophosphamide is given. Up to 5 cycles of these regimens may be given over a 9-month period. Patients in both groups may also receive background medications including 1 non-steroidal anti-inflammatory drug and up to 0.5 mg/kg/d of oral prednisone. The short and intermediate (0-18 months) safety of these treatment regimens will be compared. Long-term goals: 1. Assess the efficacy and safety of current

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and emerging pharmacologic and biologic treatments as adjunctive therapy to calcium in JRA patients with osteopenia. 2. Determine the long-term efficacy and safety of these treatment regimens in sJRA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COLUMBIA UNIVERSITY SOUTHWEST ONCOLOGY GROUP PROGRAM Principal Investigator & Institution: Antman, Karen H.; Director of Cancer Center, Professor Of; Medicine; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-MAY-1995; Project End 31-DEC-2003 Summary: The Columbia University was accepted for probationary membership at the May 1994 SWOG meeting. The specific aims of our first modest (25,000 dollars) grant was to build the infrastructure for SWOG participation-- hire and train CRAs and research nurses, provide travel for physician investigators to become involved in SWOG, and recruit affiliated community cancer centers. This has largely been accomplished. Objectives for the new Southwest Oncology Group Institutional Grant are the following: 1. To develop and pilot promising strategies for cancer at Columbia for eventual evaluation in larger clinical trials in the Southwest Oncology Croup. 2. To participate in SWOG phase II and III studies to identify more effective prevention, diagnostic and treatment strategies for cancer. 3. To support the infrastructure for an coordinated multimodality SWOG clinical research program. 4. To enhance participation by minority groups in SWOG trials. We intend to further develop leadership roles of Columbia University faculty in SWOG, to accrue patients to SWOG studies, and to increase accrual of our affiliates. This will be facilitated by increasing the CRA and research nurse FTEs and support for travel of Columbia faculty, affiliate investigators and CRAs to SWOG meetings. Based on substantial laboratory strength, we intend to integrate Columbia laboratory resources as core support for SWOG clinical studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--PHARMACOLOGY FACILITY Principal Investigator & Institution: Colvin, Michael E.; Division Leader; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: (Applicant's Description) Objectives: 1) The measurement of prodrugs and activated drugs from in-vitro assays and in samples of brain tumor, plasma and other tissues. This CORE has been strongly affiliated with Projects 1 and 4 over the prior three years. During the five years of funding requested, this CORE will provide measurements of metabolites of CPA, CPT-11 from tissue culture systems and rodent models whether the prodrugs are activated by herpes vectors or herpes-based amplicons. 2) Evaluation of the interaction of the effects of CPA and CPT-11. This CORE will provide the pharmacologic basis for the scheduling and mode of administration of drug combinations for the MGH-2 vector system. 3) To provide biodegradable polymers containing prodrugs for implantation in animals for local prodrug delivery. As in prior years, Dr. Ludeman will construct CPA and CPT-11 polymer systems for implantation into rodent brains. Contractual arrangements will be made for GMP polymers in human studies. 4) Studies of drug resistance in transfected tumor cells. Tumor cells from rodents will be examined for scavenger enzyme, mismatched repair enzymes.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE GENE THERAPY OF RESIDUAL LEUKEMIA Principal Investigator & Institution: Gautam, Subhash C.; Senior Staff Investigator; Internal Medicine; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Applicant's Abstract) Our long-term goal is to develop novel biotherapies that will specifically target and destroy residual leukemia. The proposed studies will test the general hypothesis that site-directed gene therapy with hematopoietic progenitor cells, genetically modified to secrete human tumor necrosis factor-alpha (hTNF-a), will significantly increase the destruction of leukemia cells remaining after high-dose chemotherapy/bone marrow (BM) transplantation. Our preliminary data show that administration of hTNF-a secreting progenitor cells following chemotherapy with cyclophosphamide (CY) and BM transplantation dramatically enhances survival (80 percent) of mice inoculated with a lethal dose of 32Dp210 murine myeloid leukemia cells without toxic side effects. We will test the hypothesis that combined therapy with CY, BM-transplant, and TNF-a secreting progenitor cells generates a greater antileukemic effect than is produced by any modality alone. We will accomplish this by the following specific aims: 1) determine the extent to which immunomodulatory effects of CY on T-helper (Th) cells and cytotoxic effector cells (CTLs and NK cells) contribute toward the antileukemic activity of CY/TNF-a gene therapy, 2) identify the cell population(s) within BM-transplant (e.g., T cells, mesenchymal cells or progenitor cells) that enhances the efficacy of combined therapy, and 3) determine whether the mechanism(s) of the antileukemic effect of CY/TNF-a treatment involves: a) augmentation of leukemia antigen presentation by dendritic cells, b) generation of leukemia specific (CTLs) and non-specific (NK cells/macrophages) cytotoxic effector cells, c) production of secondary cytokines with antileukemic activity, and d) the induction of programmed cell death (apoptosis) in leukemia cells. The results of these studies will demonstrate the value of combining this novel approach of site-directed TNFa gene therapy with other commonly used anticancer treatment strategies to achieve maximum destruction of residual leukemia. This would make possible the rapid implementation of this novel treatment strategy to eradicate residual leukemia in humans, without the toxic side effects of systemic TNF-a therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYDRAZINES

DEVELOPMENT

OF

ANTICANCER

1,

2-BIS(SULFONYL)

Principal Investigator & Institution: Sartorelli, Alan C.; Professor; Pharmacology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Alkylating agents are among the most useful and extensively used anticancer agents. Thus, they occupy a central position in cancer chemotherapy. Our laboratory has been involved in the design and synthesis of a new class of tumor inhibitory compounds, the 1, 2 bis(sulfonyl)hydrazines, which generate through activation reactive electrophilic structures with the capacity to cross-link DNA. Preliminary studies have demonstrated that 1, 2-bis (methylsulfonyl)- 1 -(2-chloroethyl)2- about (methylamino) ca (designated 10 1M throughout this application) is therapeutically superior to other 1, 2-bis (sulfonyl) hydrazines and to 1, 3-bis(2-

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chloroethyl)- 1-nitrosourea (BCNU), which, like 1O1M, are biological chloroethylating agents, against transplanted murine and human tumors. Compound 1O1M also is capable of readily crossing the blood brain barrier, is active when administered both orally and parenterally, is not cross-resistant with cyclophosphamide, BCNU and melphalan, and a by-product of its activation, methyl isocyanate, is capable of inhibiting 06-alkylguanine-DNA alkyltransferase activity (AGT), a major mechanism of resistance to compounds which alkylate the 06 position of guanine in DNA. Thus, 1O1M has properties that are sufficiently promising to warrant clinical evaluation and 1O1M is currently in a phase I trial. The limited aqueous solubility of 1O1M, however, has created difficulties in formulating this agent for clinical usage and the formulation being used in the phase I trial increase the toxicity of this agent. Therefore, the specific aims of this application include not only studies on the mechanism of action of 1O1M but also (a) the design and synthesis of prodrugs of 1O1M with aqueous solubility, and the synthesis of analogs thereof with various electron donating and withdrawing abilities, thereby varying the rates (t1/2) of prodrug activation in an effort to further increase therapeutic efficacy; (b) the synthesis of a prodrug of 1O1M to target BCNU resistant tumor cells rich in GST mu prodrugs of this agent targeting hypoxic tumor cells and 1O1M analogs with decreased toxicity to bone marrow and intestinal mucosa; and (c) a comparison of the mechanism of action of newly synthesized prodrugs with that of 1O1M to ensure the superiority of newly generated second generation agents. These studies will include measurements of antitumor efficacy, toxicity, capacity for activation and cross-linking of DNA and capacity to inhibit AGT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA REPAIR MEDIATED RESISTANCE IN CNS TUMORS Principal Investigator & Institution: Friedman, Henry S.; Professor; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 22-JUN-1992; Project End 31-MAY-2004 Summary: Malignant central nervous system (CNS) tumors are perhaps the most difficult and frustrating neoplasms to treat, in large part due to the eloquent site in which these lesions arise and grow. Medulloblastoma, the most common malignant brain tumor in childhood, continues to represent a therapeutic challenge. The prognosis for most patients with primary malignant gliomas remains even worse. Demonstration of the activity of bifunctional alkylators such as cyclophosphamide in the treatment of medulloblastoma and glioma has provided the opportunity for significant advances in the treatment of these tumors. Resistance to cyclophosphamide is multifactorial, with a diverse spectrum of mechanisms observe in murine and human neoplasia, including increased aldehyde dehydrogenase activity, increased GST activity and elevated levels of GSH. More recent studies indicate preferential repair of DNA interstrand crosslinks (ICL) in a 4-HC resistant medulloblastoma line compared to a parental line, supporting further studies designed to define the scope and relevance of a DNA ICL repair as a mechanism underlying resistance of medulloblastoma and glioma to cyclophosphamide. However, several considerations need to be addressed in analyzing the role of crosslink repair in alkylator resistance (Chaney and Sancar 1996). Not only will it be necessary to demonstrate an increased removal of adducts of crosslinks but also to demonstrate which repair pathway(s) is (are) involved. Demonstration of repair enzymes at increased levels in resistant cell lines must be followed by studies demonstrating that these enzymes are rate limiting for the repair pathway. The ultimate proof of principle will be the demonstration that the repair pathway is more active in the resistant cells. These studies will require technological approaches/reagents not

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Cyclophosphamide

currently available until now. The hypothesis of this proposal is that: repair of DNA ICL is a major mechanism of resistance to cyclophosphamide in medulloblastoma and glioma. The specific aims of this proposal are 1) to define the molecular events mediating repair of phosphoramide mustard-induced DNA ICL by human cell extracts; 2) to define the role of repair of phosphoramide mustard-induced DNA ICL in mediating cyclophosphamide resistance in medulloblastoma and malignant glioma; and 3) to define the pathways operational in the repair of phosphoramide mustardinduced DNA ICL in cyclophosphamide resistant medulloblastoma and glioma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF YOGA ON QUALITY OF LIFE DURING BREAST CANCER Principal Investigator & Institution: Moadel, Alyson B.; Assistant Professor; Epidemiology & Population Health; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (provided by applicant) Breast cancer and its treatment are often associated with great psychological, physical and functional impairment. Recent research indicates that newly diagnosed cancer patients of all cultural backgrounds are seeking out increased behavioral/complementary medicine modalities to help them cope with cancer and its treatment. Yoga is one such practice that is becoming increasingly popular among cancer support organizations and cancer patients. While Yoga has been empirically shown to provide numerous physical and psychological benefits in both healthy and chronically ill individuals, there has been only one published study to date of Yoga's effects on quality of life (QOL) in cancer patients. The overall aim of this pilot study is to examine the effect of a Yoga intervention to improve QOL among breast cancer patients receiving chemotherapy within an urban, multi-ethnic cancer center. This clinical trial will utilize a stratified (by type of chemotherapy)-randomized, prospective, single-blinded design. Breast cancer patients (n=130) will be randomly assigned (before the initiation of chemotherapy) to either a Yoga program (n=65), or a Wait List Control group (n=65; Standard Care), and followed for a 3-month period. Measures will be obtained at three time points: baseline (T1) (prior to chemotherapy and group assignment), at one month (T2); and at three months (T3), by blinded interviewers using standardized QOL measurements (e.g., Functional Assessment of Cancer Therapy) and clinician ratings. Objective health measures will include adverse medical events and treatment compliance. Multivariate analyses will be used to examine the hypothesis that a Yoga program will improve upon overall QOL by at least 15 percent (based on a.25 effect size) in comparison to Standard Care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENZYMOLOGY/MOLECULAR DEHYDROGENASE

BIOLOGY

OF

ALDEHYDE

Principal Investigator & Institution: Weiner, Henry; Professor of Biochemistry; Biochemistry; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2004; Project Start 15-JUN-1983; Project End 31-MAY-2008 Summary: (provided by applicant): There are 17 genes coding for various forms of human aldehyde dehydrogenase (ALDH). The physiological role of most members of the ALDH family is not known though much is known about the structure and mechanisms of a few of the isozymes. An error prone PCR mutational approach has

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allowed us to produce mutants of some of the isozymes that have properties that differ from those of the parent enzyme. We will build upon this finding to use the mutational approach to select for isozymes that have increased activity as well as enhanced stability as compared to the parent enzyme. The rate-limiting step is the class 1, 2 and 3 isozymes, enzymes whose structure and mechanism have been studied, are different in each enzyme form. We will introduce the mutations found with any one isozyme into the others to determine if we can increase the same step in the catalytic process. The purpose is both to learn more about what controls the rate limiting step in each isozyme and then try to improve the catalytic efficiencies in the other isozymes using information gain from a different isozyme. Isozymes with increased stability will be identified from the screening procedure and then studied both in vitro and in vivo with the goal of producing a more stable enzyme. In addition we will try to select for an enzyme with an enhanced ability to oxidize aldophophamide, a toxic aldehyde produced during the transformation of the pro-drug cyclophosphamide, a compound that will destroy some tumors. Unfortunately, the drug will kill any cell that does not have an ALDH to protect it by oxidizing the toxic aldehyde. Bone marrow is one such cell. If we can produce a mutant with enhanced activity against aldophophamide we will use cell culture work to determine if cells transformed with the more active mutant ALDH can protect the cell from the toxic effects of the compound. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: G-CSF RECEPTOR AND PROGENITOR MOBILIZATION Principal Investigator & Institution: Link, Daniel C.; Associate Professor; Barnes-Jewish Hospital Ms 90-94-212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2003 Summary: The long range objective of this research is to characterize the molecular mechanisms involved in hematopoietic progenitor cell (HPC) mobilization. The use of HPC to reconstitute hematopoiesis following myeloablative therapy has significantly improved the clinical outcome in patients with a variety of malignancies. Recently, mobilized peripheral blood HPC instead of bone marrow-derived HPC have been used because of their reduce engraftment times, relative ease of collection, and possibly reduced risk of graft-versus-host disease. Currently to mobilize HPC from the bone marrow to blood are well tolerate but not universally effective and are often associated with co-mobilization of neoplastic cells. A better understanding of the mechanisms that regulate HPC mobilization may lead to the design of novel mobilization strategies that overcome these problems. We recently showed that mobilization of HPC in response to cyclophosphamide (CY) or interleukin-8 but not fit-3 ligand is markedly impaired in granulocyte colony-stimulating factor receptor (G-CSFR) deficient mice. These surprising results suggested that G-CSFR signals in hematopoietic- or bone marrow stromal-cells play an important and previously unexpected role in HPC migration. This proposal is designed to characterize these these G- CSFR-dependent mechanisms of HPC mobilization. The following specific aims are proposed. 1. We will characterize in detail the mobilization response in G-CSFR deficient mice to CY, interleukin-12 (IL-12), or stem cell factor (SCF). HPC mobilization in G-CSFR deficient mice in response to SCF or IL-12 will be analyzed. To explore mechanisms for the mobilization defect in G- CSFR deficient mice, the phenotype of hematopoietic cells, in particular HPC , in the bone marrow of wild-type versus G-CSFR deficient mice after CY treatment will be compared. 2. We will identify the cell type responsible for G-CSFR dependent mobilization. Preliminary studies of HPC mobilization in G-CSFR deficient radiation chimeras suggest that a functional G-CSFR on mature hematopoietic cells but not on

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Cyclophosphamide

HPC or stromal cells is required for CY- induced mobilization. The first objective of this specific aim is to confirm these surprising results and to determine whether primitive HPC are mobilized in a similar fashion. The second objective of this specific aim is to characterize G-CSF induced mobilization in these radiation chimeras. 3. We will define the role of neutrophils in G-CSFR dependent mobilization. A neutropenic mouse line will be generated by driving expression of the attenuated diphtheria toxin A subunit in myeloid cells using murine cathepsin G regulatory sequences. CY- and G-CSF induced HPC mobilization will be characterized in these mice. 4. We will define the regions of the G-CSFR that are required for HPC mobilization. CY- and G-CSF-induced mobilization will be characterized in two recently generated targeted "knock-in" mutations of the G-CSFR. The role of STAT-3 in the generation of the HPC mobilization signal by the G- CSFR will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR BRAIN TUMORS Principal Investigator & Institution: Hochberg, Fred H.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 15-AUG-1996; Project End 31-JUL-2005 Summary: Malignant gliomas represent the single most costly and morbid neoplasm per capita. The prognosis for patients with these tumors has been largely unchanged by advances in surgery, radiation therapy and drug design. Our proposal provides an integrated effort to translate to clinical human trials laboratory advances in the design of herpes virus (HSV) vectors for the delivery of drug-enhancing genes to tumor cells. These effects build on achievements including over 35 publications over the past 2.5 years, the conduct of a human retroviral "gene-marking trial" and the design of three human therapeutic trials Four Projects and four Cores are united , in collaboration with GMP vector facilities, as a resource for the brain-tumor Consortium (NABTT) to provide gene therapies of glioblastomas. Our studies explore vascular and migratory cell delivery systems (Project 4- Breakfield) of herpes virus and herpes-based amplicon vector systems. Studies are designed to provide high titers of HSV vector containing enzymes and herpes-based amplicon vector systems. Studies are designed to provide high titers of HSV vector containing enzymes which separately and in synergy activate pro-drugs including cyclophosphamide and irinotecan. Initial toxicity studies in Aoutus and Scientific Advisory meetings have resulted in the addition of two new scientific aims: We will track the delivery of vector, transgene and delivery cells using novel radiolabels in rodents and we will evaluate the Cytotoxic T Lymphocyte response to novel tumor antigens B-gal and OVA as distinguished from herpes vectors. In Aoutus and Human Trials we will distinguish from herpes vectors. In Aoutus and Human trials we will examine the local CTL responses that follow herpes vector transduction into brain. Human and in-vitro drug studies will be supported by for manufacture of polymeric pro-drug systems, and analysis and modeling for single and multiple activated drugs. All studies will be supported by histologic and immunohistochemical evaluations of gene expression and changes in tumor and surrounding brain, as well as the molecular characterization of tumors. Our program defines a rational and scientific means to evaluate and expand the potential of gen therapy for brain tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOREGULATORY ERYTHEMATOSUS

NK

T

CELL

/SYSTEMIC

35

LUPUS

Principal Investigator & Institution: Porcelli, Steven A.; Associate Professor; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: A population of T lymphocytes known as NK T cells recognizes specific lipid ligands in the context of MHC class I-like CD1d molecules and has recently been found to contribute to the regulation of immune responses and the maintenance of immunological tolerance to self antigens. Numerous published reports have linked the loss of NK T cells and changes in their function to the progression of autoimmune diseases, including systemic lupus erythematosus (SLE) and mouse models of this disease. The central hypothesis of the current proposal is that NK T cells constitute an important regulatory arm of the immune system that normally assists in preventing the development of aggressive autoimmunity such as that which occurs in full-blown SLE. The proposed studies will evaluate changes in NK T cells during the progression of spontaneous lupus-like disease in NZB/W F1 mice, and will determine the influence of NK T cells on SLE-associated autoantibody production in murine models of spontaneous and induced SLE-like disease. These studies will build on preliminary findings that strongly implicate NK T cells as a major factor in the regulation of marginal zone B cells, a distinct B cell subset with inherent autoreactivity that has recently become a significant focus for research into the origins of autoantibody production in SLE. Methods that should allow the direct stimulation of NK cells in vivo will be investigated as potential approaches to therapy of SLE that could take advantage of the natural functions of these regulatory T cells. The program project format provides an optimal environment for these studies by providing numerous collaborative interactions with the other members of the program who bring it a wealth of expertise and resources for the analysis of murine models of SLE that are highly relevant to this proposal. These studies will also benefit from extensive usage of all of the Program's proposed core facilities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFLUENCE IMMUNOTHERAPY

OF

TUMOR

IMMUNOGENICITY

TO

Principal Investigator & Institution: Norton, Jeffrey A.; Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAY-2007 Summary: (provided by applicant): Our proposed study is based on two recent observations made in our laboratory. The first observation is that IL-12 or cyclophosphamide (Cy) +IL-12 treatment is highly effective/curative against established large tumor burdens in mice bearing immunogenic, but not nonimmunogenic, tumors. One critical factor that is required for optimal response to IL-12based therapy is the presence of tumor-sensitized T cells in tumor-bearing hosts before start of IL-12 treatment. Since only immunogenic tumors are able to induce T cell sensitization spontaneously from their hosts upon establishment in vivo, this requirement of pre-existing immunity would explain the failure of established nonimmunogenic tumors to IL-12-based therapy. The second observation is that a spontaneously derived murine metastatic breast tumor 4T1 is non-immunogenic in normal BALB/c mice and is resistant to IL-12-based therapy as expected based on the pre-existing immunity requirement. However, in STAT6 gene knockout mice 4T1

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Cyclophosphamide

becomes immunogenic and responsive to IL-12-based immunotherapy. Based on these two observations, we hypothesize that there is a close correlation between tumor immunogenicity and response to immunotherapy and eradication of established nonimmunogenic tumors by IL-12-based therapy may be improved if tumor-sensitized T cells can be raised in the host bearing non-immunogenic tumors prior to therapy. Furthermore, we hypothesize that certain host factors such as STAT6 critically influence the immunogenicity of a tumor. By manipulating these factors and their corresponding pathways, we may be able to increase T cell sensitization against non-immunogenic tumors, which would directly contribute to a better response of these tumors to immunotherapy. Our proposed study focuses on 1) confirmation of the effect of STAT6 deletion on tumor immunogenicity in multiple tumor models and different mouse strains, 2) identification of the mechanism by which STAT6 is involved in regulating tumor immunogenicity, and 3) testing the correlation between increased T cell sensitization against nonimmunogenic tumors and their response to immunotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INNOVATIVE TOXICOLOGY MODELS FOR DRUG EVALUATION Principal Investigator & Institution: Yee, Jiing-Kuan; Associate Professor; City of Hope/Beckman Research Institute Helford Building Duarte, Ca 910103000 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): A. Specific Aims: The overall goal of this proposal is to use reversible immortalization approach to establish cell lines derived from primary human renal proximal tubule epithelial cells (RPTECs) and hepatocytes. Liver and kidney are two critical organs for drug metabolism and excretion, and are frequently affected by drug-induced toxicity. Currently, no suitable human kidney cell line is available for drug screening in the early stages of drug discovery and development. While primary human hepatocytes are available, the high cost to culture such cells precludes their use in the drug screening process. If immortalized cell lines that are phenotypically stable and retain all or most of the primary cell functions can be established, they can be used for high-throughput screening of potential drugs. There are three specific aims in this proposal. I. Characterization of TH1 and TH7 cells for kidney functions: In our preliminary study, we used human immunodeficiency virus (HIV)-based vectors containing the cDNAs encoding the SV40 T antigen (Tag) and the catalytic subunit of human telomerase (hTERT) to establish several immortalized cell lines derived from primary human RPTECs. We propose to characterize the biochemical and functional activities in two of these cell lines, TH1 and TH7. We will determine the basal expression and the activity of xenobiotic metabolizing enzymes in these two cell lines. We will evaluate the activity of drug transport proteins, drug uptake and efflux. We also propose to use Cre-LoxP mediated recombination system to remove the introduced Tag and the hTERT cDNAs from these two cell lines and examine its effect on cell proliferation, differentiation and biochemical functions. II. Establishment and characterization of immortalized human hepatocytes: We propose to use the same strategy as described in specific aim I to establish and characterize immortalized human hepatocytes. Ill. Evaluation of drug toxicity in the immortalized cell lines: We will determine the drug sensitivity of the established cell lines, including methotrexate (MTX), cisplatin, cyclophosphamide and paclitaxel. The toxicity induced by these drugs in primary human cells and in cell lines derived from hepatocytes and RPTECs will also be examined and the results will be compared with those from the immortalized cell lines established in this current study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM OF NICOTINE INHIBITION OF APOPTOSIS Principal Investigator & Institution: Wright, Susan C.; Senior Scientist; Palo Alto Institute/Molecular Medicine Molecular Medicine Mountain View, Ca 94043 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Apoptosis is a form of physiological cell death that is thought to be an important mechanism for the elimination of abnormal or transformed cells. It is also the form of death induced in cancer cells by chemotherapeutic drugs and gammairradiation. An agent which interferes with the process of apoptosis could potentially promote tumor formation as well as interfere with cancer therapies. Our previous studies demonstrated that nicotine inhibits cytokine and chemotherapeutic druginduced apoptosis of a ability of nicotine to inhibit apoptosis may promote tobaccorelated carcinogenesis as well as decrease the efficacy of cancer therapies. Our previous studies demonstrated that nicotine inhibits cytokine and chemotherapeutic druginduced apoptosis of a variety of tumor cell lines, including those types related to tobacco use. We hypothesize that the ability of nicotine to inhibit to inhibit apoptosis may promote tobacco-related carcinogenesis as well as decrease the efficacy of cancer therapies. The aims of this proposal are: 1) to further define the conditions under which nicotine inhibits apoptosis in tumor cell lines and in normal epithelial cells; 2) investigate the molecular mechanism in which nicotine obstructs the apoptotic pathway; 3) determine if nicotine will decrease the efficacy of chemotherapy in a mouse model. We will examine the effects of acuter high dose, chronic low dose exposure, and the reversibility of nicotine's ability to inhibit apoptosis in tumor cell lines and normal lung epithelial cells. We will test the effects of nicotine on different inducers of apoptosis in tumor cell lines and normal lung epithelial cells. We will test the effects of nicotine on different inducers of apoptosis including ionizing radiation, chemotherapeutic drugs, and anoikis (enforced cell detachment). We will analyze the mechanism of inhibition with special focus on signal transduction pathways that have been implicated as negative modulators of apoptosis. Studies will analyze the effects of nicotine on expression of Bcl-2, protein kinase C activity, the mitogen activated protein kinase pathway, and the PI3-kinase/Akt kinase pathway. Mice bearing transplantable tumors will be treated with different chemotherapeutic drugs with and without coadministration of nicotine to determine if there is a reduction in the therapeutic effect. The results of these studies should increase our understanding of the mechanisms underlying development of cancer in cigarette smokers and in smokeless tobacco users. This investigation will also provide insight into the potential hazards of continued tobacco use in patients undergoing cancer therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF ACROLEIN ON PROLIFERATION AND APOPTOSIS Principal Investigator & Institution: Kehrer, James P.; Professor and Head; Div/Pharmoacology & Toxicology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Acrolein is a highly electrophilic alpha, beta-unsaturated aldehyde to which humans are exposed in a variety of environmental situations. At low doses, acrolein inhibits cell proliferation without causing cell death and can enhance apoptosis from secondary toxins. The overall goals of this project are to determine the molecular mechanism(s) by which acrolein enhances apoptosis and inhibits proliferation. The

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Cyclophosphamide

hypothesis to be studied is that acrolein enhances apoptosis from secondary stressors including cell-cycle-non-specific anti-cancer drugs and that this is due to changes in genes or transcription factors regulating this process. Since acrolein is a metabolite of cyclophosphamide, this hypothesis leads to the conclusion that the unique effectiveness of this anti-cancer drug is a feature of both acrolein and the phosphoramide mustard metabolite. A related hypothesis is that the acrolein-mediated decrease in cell proliferation is caused by effecting changes in the expression of one or more growth- or stress-related genes or transcription factors secondary to a reduction in GSH which is rapidly depleted following acrolein treatment. The specific aims of this project to address these hypotheses are: 1) to assess in detail the ability of acrolein to enhance the susceptibility of cells to apoptosis form a secondary pro-apoptotic treatment; and 2) to determine the mechanism of the enhanced apoptosis and decreased proliferation following acrolein treatment. Since acrolein transiently depletes GSH, experiments will be run to differentiate effects directly related to a loss of antioxidant capacity to those related to changes in transcription factors or gene expression (even in those are secondary to the loss of GSH which may allow secondary agents better access to molecular targets). Preliminary data have implicated NF-kappaB as a target for acrolein. This will be further studied by determining the ability of diethyl maleate (DEM) (which blocks NF-kappaB activation at doses that do not deplete GSH) to affect apoptosis and by examining the effects of acrolein on NF-kappaB activation at doses that do not deplete GSH) to affect apoptosis and by examining the effects of acrolein on NF-kappaB and apoptosis in a second cell line. A role for other selected genes in the effects of acrolein will be determined. Specifically, the activation of AP-1 will be measured as well as any changes in mRNA levels and protein products of p53, c-jun, c-fos, c-myc, bcl-2, bcl-x, and bax at various times following acrolein insult. The results of these studies will provide important new information on pathways regulating cell proliferation and apoptosis, as well as provide data on the risk associated with low-level exposure to reactive species such as acrolein. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEMORIAL HOSPITAL AND CANCER AND ACUTE LEUKEMIA GROUP B Principal Investigator & Institution: Hudis, Clifford A.; Chief; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 30-JUL-1998; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): This is the first application for support of Cancer and Leukemia Group B (CALGB) research activities by Memorial Sloan-Kettering Cancer Center (MSKCC) as a Main Member institution. MSKCC's mission is devoted to clinical and laboratory research related to cancer treatment and biology. Previously an affiliate of the New York Hospital, MSKCC became a Main Member in February 1996. This change from affiliate to Main Member represents our commitment to participate in a broad-based cooperative group in order to participate in national group and intergroup randomized trials and to interdigitate the national agenda into our extensive clinical trials program. Strong research interactions already exist between CALGB and MSKCC. Larry Norton, M.D., Chair, Breast Committee, and Jimmie Holland, M.D. first and only Chair, Psycho-Oncology Committee, both play dominant roles in shaping group and national clinical trials. In addition, Nancy Kemeny, M.D., is a member of the GI Committee and Medical Oncology Chair of CALGB 9481, studying intrahepatic chemotherapy in colorectal cancer patients with hepatic metastases. We plan to augment participation in these areas, and Clifford Hudis,

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M.D., and Andrew Seidman, M.D., are already actively presenting to the Breast Committee. Alice Kornblith, Ph.D., leads several psycho-oncology efforts, and Russell Porenoy, M.D., and Raymond Wesson, Ph.D., will join palliative care and minority issue efforts. Committee participation has expanded, with 19 MSKCC faculty appointed to 12 committees. Protocol accrual has increased, with 69 credits between 3/1/96 and 5/1/97, and 47 credits since 12/96 alone. Increased clinical trial accrual will result from newly activated CALGB therapeutic and nontherapeutic studies from additional disease and modality committees and, by introducing new drugs and biologics under development at MSKCC, into Group studies. This integration is under way. R.S.K. Chaganti, Ph.D., will participate in Leukemia/Lymphoma Correlative Sciences studies by providing the introduction of comparative genomic hybridization into the study of malignant lymphomas. Accrual from affiliation with McGill University will augment MSKCC activities in CALGB. MSKCC looks forward to participation in CALGB's excellent group science. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MNSOD AND DRUG RESISTANCE AND CARDIAC TOXICITY Principal Investigator & Institution: St. Clair, Daret K.; Professor; Toxicology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-MAY-2004 Summary: Cardiotoxicity is a major complication of cancer treatment in protocols involving adriamycin (ADR), radiation, and high doses of cyclophosphamide (cytoxan). Because ADR and radiation are the most frequently used agents in the treatment of cancer, and cytoxan is also used in preparation of patients for bone marrow transplantation, efforts to overcome the dose limiting toxicities of these agents is likely to be beneficial for many cancer patients. The ultimate goal of this research is to develop an antioxidant-based pharmacological intervention for cancer therapy associated cardiac injury. Many studies have been conducted which suggest that both reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced in vivo by cancer therapeutic agents. However, the contribution of these ROS/RNS to the development of cardiac injury and the mechanism by which ROS/RNS mediates cardiac toxicity is unclear. We hypothesize that removal of superoxide radicals in the mitochondria is the critical step in protection against ROS/RNS-induced cardiac toxicity and tumor necrosis factor (TNF)-modulated cardiac injury during cancer therapy. To test this hypothesis, expression of MnSOD and GPX in the mitochondria of heart tissue will be elevated by transgenic manipulations, and the level of inducible nitric oxide synthase (iNOS) will be manipulated by targeted gene disruptions. The effects of the anticancer agents, ADR, cytoxan, and ionizing radiation on heart tissue will be examined in transgenic mice expressing increased individual or combined MnSOD (MnSOD-Tg) and mitochondrial GPX (mGPX-Tg) activity as well as in mice deficient in the inducible form of nitric oxide synthase (iNOS-KO). Cardiac injury will be assessed by determining the production of oxidatively damaged products, the respiratory function of isolated mitochondria, the formation of ultrastructural and histopathological lesions, as well as the extent of cardiomyocyte injury or cell death. The role of TNF in therapy-induced cardiac toxicity will be examined in TNF receptors knockout mice (TNFRs-KO) that express the human MnSOD transgenes (MnSOD-Tg/TNFRs-KO) using the same molecular, biochemical, and pathological end points. The results obtained from this study should demonstrate clearly how ROS/RNS contribute to cardiac toxicity and suggest potential points for pharmacological intervention of cardiac injury during cancer treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOUNT SINAI COMMUNITY CLINICAL ONCOLOGY PROGRAM Principal Investigator & Institution: Lilenbaum, Rogerio C.; Mount Sinai Medical Center (Miami Beach) 4300 Alton Rd Miami Beach, Fl 331402800 Timing: Fiscal Year 2002; Project Start 13-JUL-1987; Project End 31-MAY-2007 Summary: (provided by applicant): Over the next five years, the overall aim of the CCOP is to reduce cancer incidence, morbidity, and mortality by accelerating the transfer of newly developed cancer prevention, early detection, treatment, patient management, rehabilitation, and continuing care technology to widespread community application. The immediate goals of the MSCCOP are to continue to increase our accrual rate to treatment and cancer control trials approved by NCI; to increase our ascending minority accrual in treatment and cancer control research; to maintain standards of excellence in data management; to cultivate contacts with primary care physicians and other specialists who may contribute to cancer control initiatives; to continue to refine cancer control data management capabilities, including the use of a range of resources to identify potential candidates for cancer control research projects; and to continue to develop our affiliate network of 7 clinical research sites in 5 cities. The track record of the MSCCOP demonstrates the ability to manage complex clinical research and cancer control activities while producing the highest quality data. The CCOP staffing pattern, protocol management procedures, patient/participant management approaches, quality control mechanisms, pharmacy control mechanisms, IRB structure and liaison are all in place and functioning to support current and future therapeutic and cancer control activities. The Mount Sinai Community Clinical Oncology Program provides access to national cooperative clinical trials to South Florida. The 6 hospitals in the MSCCOP see nearly 7000 newly diagnosed cancer patients per year, including rapidly rising minority and elderly populations. The MSCCOP brings together the strength and resources of a strong group of investigators who collaborate in the conduct of studies from CALGB, NSABP, RTOG, and the H. Lee Moffitt Cancer Center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NATIONAL SURGICAL ADJUVANT BREAST AND BOWEL PROJECT Principal Investigator & Institution: Wolmark, Norman; Associate Professor of Surgery; Nsabp Foundation, Inc. East Commons Professional Bldg Pittsburgh, Pa 15212 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 31-JAN-2006 Summary: The NSABP is comprised of 177 active member institutions that are participating in treatment trials in the United States, Canada, Puerto Rico, and Australia. The Group has a more than 40-year history of conducting large-scale controlled clinical trials that have improved treatment for patients with breast or colorectal cancer and have provided a better understanding of tumor biology. This application requests continued funding for the NSABP Operations Center for the period February 1, 2000, through January 31, 2006. Major areas of emphasis in the NSABP include: evaluation of therapies in the adjuvant treatment of breast and bowel cancer; testing of new drugs, combinations of drugs, and biological agents in patients with advanced disease, with the primary goal of determining therapies that should be further evaluated in the adjuvant setting; identification of and validation of molecular markers of prognosis and response to therapy; reduction of the morbidity associated with breast cancer surgery through the evaluation of minimally invasive cancer surgery procedures; assessment of quality-oflife issues in selected studies, particularly equivalence trials of newer or less toxic therapies; analysis of data and publication of the results of NSABP studies in peer-

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reviewed medical journals; and enhancement of the participation of women and underrepresented minorities in NSABP trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW ENGLAND PEDIATRIC ONCOLOGY CONSORTIUM Principal Investigator & Institution: Ferguson, William S.; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 01-JAN-1981; Project End 31-DEC-2002 Summary: The specific aims of the New England Pediatric Oncology Consortium (NEPOC) are: Development and enhanced productivity of a consortium of regional pediatric cancer centers (Brown University/Rhode Island Hospital; Dartmouth University/Dartmouth-Hitchcock Medical Center; Harvard University/Massachusetts General Hospital; SUNY at Stony Brook/Children's Medical Center at Stony Brook; University of Vermont/Medical Center Hospital-Vermont Regional Cancer Center) for the purposes of: A. Contributing to the understanding and treatment of children and adolescents with malignancies through: 1. Input into national cooperative studies through membership in the Pediatric Oncology Group (POG): a. Patient accrual: Achieve significant number and quality of patient entries on protocols; b. Study development and evaluation: Assist in the development of new protocols through committee memberships, institutional reviews of proposed protocol designs, analysis of study results, and proposal of new protocols for POG implementation based on NEPOC studies; c. Administration: Accept responsibilities for POG administrative functions. 2. Cooperative efforts within NEPOC (New England Pediatric Oncology Consortium) in studies of joint interest in the areas of childhood malignancies, particularly toward developing potential pilot studies for POG. B. Enhancement of the care of children and adolescents with cancer in the geographical areas served by the member institutions through: 1. Assuring comprehensive and modern management of children and adolescents with malignancies as a benefit of membership in POG; 2. Sharing staff expertise and investigative facilities at each of the member institutions; 3. Joint efforts in promotion of education of the local community in the area of cancer in children and adolescents. Through a centralized administration, this Consortium integrates the activities and resources (staff, facilities, patients) at each institution into a single program aimed at achieving these goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW VECTORS SYSTEMS FOR EXTENDED GENE DELIVERY Principal Investigator & Institution: Breakefield, Xandra O.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: This project will carry out basic research on the development of new vectors and delivery systems to target invasive tumor cells in the brain, as well as provide testing of pro-drug activation systems for Project 1 (Chiocca) and expertise on Herpes Simplex Virus (HSV) amplicon vectors for Project 3 (Weissleder). New targeting strategies will involve use of vehicle cells to carry therapeutic genes that have a bystander effect and to produce therapeutic vectors on site. Vehicle cells involve neuroprogenitor cells, which have been shown to migrate within the adult brain towards tumor cells, and primary human cell types, CD34+ cells, fibroblasts and endothelial cells, which can enter into tumors through the vasculature. These cells will be marked to follow their distribution in vivo using imaging technologies developed by

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Dr. Weissleder and the neuropathologic expertise of Dr. Louis. Cells will also be engineered to carry pro-drug activation genes and tested for therapeutic efficacy and brain tumor and subcutaneous tumor models. Two modes of vector delivery will be explored. The first involves conversion of tumor or vehicle cells to retrovirus packaging cells by infection with an HSV "tribrid" amplicon vector which contains elements of Epstein Barry Virus, to allow episomal maintenance in host cells and retrovirus to produce retrovirus vectors The second involves delivery of replication-conditional HSV in a quiescent state from which it can be activated. by drug administration. This will be done using the piggy-back system in which an HSV mutant defective in an immediate early gene is coupled with an amplicon vector bearing this gene under a tetracycline (silencer/tet-on) regulatory element. Pro-drug activation genes to be tested in these vectors for synergistic interactions include: folypolylglutamate synthatase, which enhances the activation of anti-folates P450 reductase, which potentiates conversion of cyclophosphamide to active metabolites; and carboxylesterase which activates CPT-11, tested in collaboration with Drs. Chiocca and Colvin. These HSV-based cellular targeting strategies and therapeutic gene combinations are designed to be compatible with strategies being developed in this P01 for clinical applications by Drs. Hochberg and Chiocca, as well as with current clinical treatment of brain tumor patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NORADRENERGIC INTERACTIONS AND IMMUNITY Principal Investigator & Institution: Karp, Jonathan D.; Biology; Rider University 2083 Lawrenceville Rd Lawrenceville, Nj 08648 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): The integration of nervous and immune system function is an important component for understanding human disease. Through innervation of immune organs and shared chemical messengers, our nervous system influences our susceptibility to and progression of infections, autoimmune diseases and cancer. The goal of this application is to better understand the involvement of sympathetic nervous system (SNS)-derived norepinephrine (NE) in coordinating and modulating host immune defenses. In particular, we are interested in studying the role of the SNS in modulating immune responses in subjects who are taking chemotherapeutic agents. Studying these interactions will help us determine if pharmacologically immunomodulated subjects are more susceptible to opportunistic infections in part because of underlying perturbations in neural-immune communication. Consistent with this idea, preliminary data show that splenic NE concentrations are elevated by low doses of the widely used chemotherapeutic drug cyclophosphamide (CY). We also show that the combination of CY and psychological stress increases antibody production to a greater extent than either CY or stress alone. Based on these observations, we propose that low doses of CY can modulate the neurochemical environment and that CY-induced elevations in neurochemical milieu, especially NE, act to exaggerate the neuroimmunomodulatory consequences of SNS activation. We will use this AREA application to develop and evaluate a murine model for studying the effects of CY on noradrenergic activity as well as on humoral and cellular immune effector responses. To achieve these goals, the first part of this proposal further characterizes CY-induced changes in NE concentration in immune and nonimmune organs. The second part of this project investigates CY-induced changes in cytokine and antibody responses. The third part of this project examines the interaction of pharmacological (CY-induced) and behavioral (stressor-induced) changes in NE concentrations on measures of humoral and cell-mediated immunity. Our data will be

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evaluated in the context of a model in which NE promotes humoral immune effector responses and attenuates cell mediated immune effector responses via stimulation of beta-adrenergic receptors on T-helper-1 and B cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OPTIMIZING RADIOIMMUNOTHERAPY FOR NON HODGKIN'S LYMPHOMA Principal Investigator & Institution: Gopal, Ajay K.; Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 21-AUG-2000; Project End 31-JUL-2005 Summary: I am a physician-scientist committed to patient-oriented research involving radioimmunotherapy (RIT) for the treatment of non- Hodgkin's lymphoma (NHL). My immediate career development plans include specialized clinical research training in biostatistics, epidemiology, and clinical trial design at the School of Public Health at the University of Washington (UW), as well as didactic and mentored instruction in ethical aspects of clinical research, Quality of Life assessment, and research group involvement at the UW and Fred Hutchinson Cancer Research Center. The overall scientific objectives of this project are to expand and optimize RIT for the treatment of relapsed non-Hodgkin's lymphoma by (1) determining the toxicities and efficacy of myeloablative I-131- anti-CD20 antibody (Ab) combined with cyclophosphamide and etoposide and autologous stem cell transplantation (ASCT) in a Phase II trial for patients (pt) with relapsed NHL, (2) investigating the feasibility, tolerability, and potential efficacy of single agent myeloablative I-131-anti-CD20 Ab followed by ASCT in pt greater than or equal to 60 years old with relapsed NHL in a Phase I/II study, (3) assessing the quality of life (QOL) and neurocognitive function (NCF) of high dose RIT on pt treated in aims 1 and 2, and (4) performing pre-clinical and clinical studies of biological agents with minimal toxicity (cytokines and retinoids) to further augment the efficacy of anti-CD20 antibody therapy. We hypothesize that targeting radiation specifically to B cell lymphomas with I-131-anti-CD20 antibodies will augment the efficacy and decrease the toxicity of therapy compared with transplant regimens containing nonspecific external beam total body irradiation (TBI). We further postulate that I-131-anti-CD20 targeted RIT will improve the post- transplant QOL and NCF compared to those of pt transplanted with traditional conditioning regimens containing TBI (which deliver greater than or equal to 12 Gy to the brain). We anticipate that the tolerable toxicity of single agent I-131-anti-CD20 + ASCT (established in previous trials) will allow us to safely extend this potentially curative therapy to elderly pt who may not otherwise be eligible for stem cell transplantation. Finally, we hypothesize that augmenting CD20 antigen expression on malignant B cells with cytokines such as GMCSF and enhancing anti-CD20 Ab mediated apoptosis with retinoic acid derivatives will amplify the cytotoxicity of both unmodified and radiolabeled anti-CD20 Ab. We anticipate that these interventions will ultimately enhance the prognosis for patients with relapsed lymphoma by increasing the response and survival rates, while simultaneously minimizing toxicities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PARTICIPATE AS MEMBER OF SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Garrison, Mitchell A.; U.S. Brooke Army Med Ctr(Ft Sam Houston) Fort Sam Houston San Antonio, Tx 78234 Timing: Fiscal Year 2002; Project Start 25-AUG-1998; Project End 31-DEC-2003

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Summary: The Brook Army Medical Center Membership includes the Brooke Army Medical Center and Wilford Hall Medical Center, Army and Air Force tertiary referral medical centers in San Antonio, Texas, respectively. In addition, it serves as the headquarters for five affiliated CGOP affiliates including Eisenhower Army Medical Center, South Georgia Medical Center, Lee Memorial Hospital, Cape Coral Hospital, and Southwest Florida Regional Medical Center. BAMC and WHMC tumor registries include a combined 1500 new cases per year. They have an integrated fellowship training program as well as combined educational activities with the University of Texas Health Science Center in San Antonio. The patients seen at the primary centers are active and retired military personnel. In the past two years, 19 percent of patients enrolled to SWOG protocols have been non-Caucasian and 44 percent have been female. The membership is led by Dr. Ian Thompson, a urologist, with support of all relevant multidisciplinary specialists. Dr. Thompson is also Chair of the BMAC/WHMC UCOP. Dr. Thompson is an acknowledged expert in genitourinary malignancies. He leads the prostate cancer prevention trial, a major effort of the SWOG program. From 1992 until the present, this membership has furnished principal investigators for four phase II trials and one cancer control trial. They have been co-coordinators for four phase II, one phase III, and one cancer control trial in the past but have protocol coordinators now. Members have been first author on six manuscripts and co-authors on nine published manuscripts. They have provided first authors for two and co-authors for three abstracts. As a member institution, they have had three individuals serve on the Board of Governors. Dr. Thompson has served as the Chair of the Localized Prostate Subcommittee. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOPHYSIOLOGY OF PNH Principal Investigator & Institution: Brodsky, Robert A.; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2007 Summary: Paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) are closely related, life-threatening bone marrow stem cell disorders. AA results from an immune-mediated attack against hematopoietic stem cells. PNH is a clonal hematopoietic stem cell disorder caused by a somatic mutation of the PIGA gone and may arise de novo or evolve from AA. The biochemical consequence of PIGA mutations is a global loss of glycosylphosphatidyl-inositol (GPI) anchors. We have shown that the GPI-anchor is the receptor for the channel forming toxin aerolysin and that PNH cells are uniquely resistant to aerolysin. A novel diagnostic assay using aerolysin to detect PNH cells has demonstrated that the majority of AA patients harbor small populations of PNH cells. We have also shown that high-dose cyclophosphamide (CY) can lead to durable treatment-free remissions in the majority of patients with AA. The objective of these studies is to explore the relationship between AA and PNH and to elucidate the mechanism of clonal dominance in PNH. We will directly test whether PNH gains clonal dominance through immunologic escape or whether PIGA mutations themselves give HSCs an intrinsic survival advantage. The use of PNH as a model to study clonal expansion and clonal progression should give insight into other clonal hematopoietic diseases such as myelodysplastic syndromes and leukemogenesis. Specfici Aim 1: Detect PIGA mutations in normal human HSC. Specific Aim 2: Study the relationship between AA and PNH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Kavan, Petr; Montreal Children's Hospital 2300 Tupper St Montreal, Pq Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The Pediatric Oncology Group (POG) is a multi-disciplinary, multiinstitutional research community which collaborates to increase knowledge of and improve treatment for cancer and leukemia in children and adolescents. The Montreal Children's Hospital/McGill University (MCH), a founding member, requests funding for itself and its two affiliates, the Children's Hospital of Eastern Ontario (CHEO) and the University of Sherbrooke Medical Center (USMC) to continue to participate fully in administrative and scientific activities of the POG during the next 5 years. We expect to enroll a total of 70 patients a year on therapeutic protocols for childhood leukemias, lymphomas, solid tumors and brain tumors, with continued emphasis on Phase I and II studies of new agents and coordination or co-coordination of a minimum of 13 protocols. We expect to enroll 110 patients per year on non-therapeutic studies of cancer etiology, epidemiology, biology, psychologic impact and late effects of therapy with particular emphasis on the pharmacology and molecular pharmacology of methotrexate in acute lymphoblastic leukemia (ALL). We will comply with all requirements of the POG constitution, with MR regulations governing ethical conduct of clinical research and with OPRR and IRB requirements for informed consent and protection of subjects from research risks. In addition to an anticipated doubling of patient accruals since 5 years ago, our major contributions to POG research will include: confirmation that the extent of accumulation of methotrexate polyglutamates by lymphoblasts in B-progenitor cell ALL correlates with event-free survival (EFS) and characterization of the mechanisms regulating this metabolism (Whitehead); promotion of new agent drug development through New Agents and Pharmacology Committee leadership (Whitehead and Bernstein) and protocol coordination (Bernstein, Baruchel); introduction of stereotactic and fractionated stereotactic radiation therapy in brain tumors (Freeman); coordination of treatment protocols of newly-diagnosed and relapsed B-progenitor cell ALL (Abish, Bernstein); introduction of new agents and combinations in recurrent lymphoid disease as Sub-committee Chair, Lymphoid Relapse (Bernstein); chemotherapy and surgery of brain tumors (Baruchel, Ventureyra); and study of the biology, including p53 gene mutations, and treatment of HIV-related lymphomas (Baruchel, Whitehead). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Kung, Faith H.; Associate Professor; Pediatrics; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: This proposal represents a request to support continued participation in the pediatric Oncology Group (POG). This cooperative research is devoted to the investigation of chemotherapeutic, immunological and molecular biological approaches to the treatment of acute leukemia and other neoplastic diseases of childhood. Significant disease free survival has been achieved and contributions have been made in clinical pharmacology, tumor immunology and biology of cancer. However the real objective of these studies is the eradication of neoplastic diseases by treatment. Studies are being designed to reflect an increasing intensity of attack on the neoplastic cell. The cooperative group technique permits prompt evaluation in series of reasonable size of

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promising leads in chemotherapy. These leads or new approaches are often suggested by the results of the group's own work in clinical oncology. Thus, a completed protocol often suggests new avenues to be explored in new protocols. POG led in the investigation in the immunophenotyping of acute lymphoblastic leukemia, NTX polyglutamates accumulation in leukemic cells, and N-myc gene amplication in neuroblastoma, correlated the findings with patient outcome, and then incorporated them in new treatment protocols designed to improve the survival of children with cancer. The Division of pediatric Hematology/Oncology at the University of California, San Diego has 24 years experience (10 years in CALGB and 14 in POG) in cooperative clinical trials. In the past 5 years the 4 consortium member institutions had entered 332 patients on both therapeutic and non- therapeutic studies and the satellites, 211 patients. Our investigators served on 12 committees, designed/coordinated 16 group protocol studies. We also contributed to 15 group publications/presentations. Our investigators will continue to design and chair therapeutic protocols,and serve on committees. Dr. Yu's laboratory will continue to explore new immunotherapeutic agents for Group use, and serve as the Group Reference Laboratory. We plan to continue our active participation in all phases of POG activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Castleberry, Robert P.; Professor of Pediatrics; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-MAR-1979; Project End 31-DEC-2002 Summary: The University of Alabama at Birmingham (UAB) is a leading contributor to the ongoing clinical and basic research activities of the Pediatric Oncology Group (POG) which are focused upon improving the care and cure for children with cancer. Current results of these trials are in some cases already published and are available in the Progress Report. The leadership from UAB in POG is evident in several areas: l) through enrollment of substantial numbers of assessable patients on Phase I, II and III therapeutic trials, including multidiscipline (surgery, chemotherapy, and radiotherapy) management studies; through participation in and development of Group-wide biological studies of selected hematopoietic and solid malignancies; through evolving, coordinating and reporting data from POG therapeutic trials; and by providing discipline and disease committee, and administrative leadership within the group. UAB will continue to enroll all eligible patients on active POG therapeutic and biological studies, including phase I investigations, and maintain high evaluability. UAB investigators will continue to coordinate clinical trials for children with neuroblastoma, bone tumors, and juvenile chronic myelogenous leukemia (JCML) and to assess the therapeutic utility of IL6. Further, UAB investigators will be principal to the development of new studies in neuroblastoma, brain tumors, JCML and acute myelogenous leukemia. UAB will continue to supervise laboratories for POG in the following areas: 1) Banded chromosomal analysis in newly diagnosed patients with lymphoid leukemia; 2) A required reference laboratory for children with JCML (POG #9265) studying the pathogenesis of myeloproliferation; 3) A required serum/plasma repository (POG #9047) with clinical and demographic data referenced on a computer data base; and 4) A non- mandatory reference laboratory to evaluate the biological and clinical significance of rnicrotubular associated protein (MAP) and tubulin isotype expression in neuroblastoma. UAB investigators will continue their scientific and administrative leadership roles on the Neuroblastoma and Other Embryonal Tumors, Myeloid Disease Core, Biologic Response Modifier Core, Executive, Principal

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Investigator Core, Clinical Research Associate Core, and Diagnostic Imaging Core Committees. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Ravindranath, Yaddanapudi; Pediatrics; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUN-1981; Project End 31-DEC-2002 Summary: This proposal is a request for funding for our continued involvement in the Pediatric Oncology Group (POG). The aims and objectives are to find better means of management for malignant diseases in children and adolescents, and thus increase disease-free survival rates. The Children's Hospital of Michigan (CHM) provides diagnostic evaluation and multimodal therapy for children throughout the State of Michigan. While there is one other Pediatric Oncology facility in the State, the Hematology/Oncology service sees almost all children and adolescents with malignant disease who live in the greater metropolitan Detroit area, and also sees large numbers of such children referred from other parts of the State (and from Canada) regardless of their ability to pay. Until 1979, the oncology service at CHM remained "independent". In September 1979, the CHM oncology team joined the pediatric division of the Southwest Oncology Group and in January 1981 joined the Pediatric Oncology Group, which appears to have even a greater potential for development of better treatment regimens for childhood malignant disease. At the time of referral and/or admission to CHM for possible malignancy, each child is seen and evaluated by the appropriate oncology team members. Following appropriate diagnostic evaluation, each child is presented and discussed at the Tumor Board, which meets weekly and is attended by pediatric oncologists, pathologists, radiologists, surgeons, surgical subspecialities, and radiotherapists. A plan of action is outlined for each child's management. All such children are registered with POG, and whenever judged appropriate, children are entered on POG treatment protocols. By our participation in such a cooperative children's cancer group, our investigators are able to share new information and ideas and gain access to new multimodal therapy regimens and investigational drugs which hopefully provide the best available care to these children. Our objectives in the coming years are: 1) increased participation in POG cancer biology and epidemiology studies; 2) to continue our leukemia biology studies particularly pharmacology studies in AML/T ALL, and 3) to develop new strategies for treatment of brain tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Grier, Holcombe E.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1986; Project End 31-DEC-2002 Summary: The principal activity of this grant is to improve the care and treatment of children with cancer by participating in the Pediatric Oncology Group (POG). The three specific goals of the participation of the Dana-Farber Cancer Institute/Children's Hospital (DFCI/CH) and Maine Children's Cancer Program (MCCP) are to 1) enter and follow children with malignancies on appropriate Pediatric Oncology Group (POG) protocols 2) provide leadership in planning and executing POG protocols and 3) provide pilot clinical studies and scientific leadership to POG. 1) Patient entry: the referral patterns at the two institutions has not changed and the commitment to POG

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protocols remains high. Therefore, patients accrual will continue at the high level previously noted over the last grant period. 2) Leadership within POG: Drs. Weinstein and Grier respectively are the disease chairs for the Myeloid and Sarcoma Committees. The disease committee chairs have primary responsibility for all scientific and clinical activities within POG. Investigators from these institutions are currently or were in the last cycle chairs for 7 separate POG protocols and co chairs of 35 more. They also have 18 positions on disease or discipline committees within POG. Enthusiasm remains strong, and involvement at the current level will continue. 3) Pilot POG protocols and scientific leadership: Scientific leadership is detailed in part above. Dr. Arceci provided scientific leadership for and analyzed the samples of the MEC protocol (#9222) that piloted the use of multidrug resistance reversal agents (cyclosporine) in relapsed AML. This protocol provided the background for the about to open group wide AML up-front protocol (#9394) that will randomize whether or not patients will receive cyclosporine during maintenance therapy. DFCI ALL protocols have provided the background for one of the arms of the proposed new T- cell protocol (#9404). In addition, the background for the current stereotactic protocol (#9373) was in part developed at the Joint Center for Radiation Therapy and the DFCI. Finally, POG has embarked on a major effort to study the autologous transplant protocols for ALL (#9421) developed at the DFCl. Finally Dr. Lipshultz ran at DFCI/CH the pilot studies of late cardiac toxicity from anthracyclines that provides the background data for the randomized trial of enalapril for patients with elevated after load. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Cohn, Susan L.; Associate Professor of Pediatrics; Children's Memorial Hospital (Chicago) Chicago, Il 606143394 Timing: Fiscal Year 2002; Project Start 01-DEC-1978; Project End 31-DEC-2002 Summary: The objectives of this project are to enroll children with cancer in clinical trials, to develop clinical trials and study the biologic behaviors of childhood cancer, and to improve and evaluate the disease- free survival of patients enrolled in these clinical trials. In order to achieve these goals, the member institutions of the Pediatric Oncology Group (POG) meet biannually to discuss, develop, and implement clinical trials for the most common childhood malignancies and to supply the reference research laboratories of the proper material or tissue necessary for the research. Since 1989, CMH has been one of the member institutions of POG who is actually involved in the accrual of children with cancer to clinical trials. CMH's faculty is also involved in the coordination of studies either as the Principal Investigator or co-Investigator. These protocols are POG 9443, POG 9240/41/42, POG 9135/6, POG 9410, NTWS #5. Participation in administrative activities within POG include the POG Chairperson, the POG Executive Officer, the Head of the Neuroblastoma Biology Committee, the Head of the Neuroblastoma Bone Marrow Transplant Working Group, along with members of the following committees: Non- Hodgkin's Lymphoma, Neuroblastoma, Bone Marrow Transplantation, Hodgkin's Disease, New ALL, Wilms' Tumor, Nursing, and Surgery, Radiotherapy, and Pathology Disciplines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Link, Michael P.; Professor; Pediatrics; Stanford University Stanford, Ca 94305

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Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The overall goal of this research proposal is for Stanford University, the University of Arizona, and the Kaiser Permanente Medical Centers of the South San Francisco Bay Area to continue their active involvement in Pediatric Oncology Group research activities. Stanford faculty and the University of Arizona faculty have already assumed key leadership positions in POG and have or have had major roles in the scientific and administrative aspects of the Group. Further, Stanford, the University of Arizona, and Kaiser have maintained excellent performance ratings in their participation in POG studies and have received commendations for the large numbers of evaluable patients placed on therapeutic protocols. Specifically: l) We plan to continue to enter patients on appropriate POG studies where they exist. The number of patient entries from Stanford has increased each year as appropriate POG studies become available. We anticipate that between 65 and 80 patients will be entered on front-line therapeutic studies each year from Stanford in addition to patients who will be entered from the affiliates; in addition, 40-50 patients or more will be entered on POG non-therapeutic studies. 2) We anticipate that the activities of individual investigators from Stanford and the University of Arizona will continue and increase during the period of this research proposal. Currently, our faculty serve as study coordinators for front- line therapeutic studies in lymphoma and leukemia, and they have coordinated and analyzed data from recently closed protocols in osteosarcoma, lymphoma, leukemia, and Ewing's sarcoma. Our faculty also serve key scientific and administrative roles as Group Vice Chair, Disease and Discipline Committee Chairmen and CoChairmen, as members of Disease and Discipline Core Committees, and as members of the Executive Committee. Thus, our faculty are in position to influence the future direction of the scientific activities of POG. 3) We anticipate that involvement of Stanford faculty in the laboratory scientific activities of POG will continue. The laboratories of Drs. Link and Cleary have served as immunology reference laboratories and molecular biologic reference laboratories for leukemia studies of POG. 4) We anticipate that non-POG related laboratory and clinical research conducted at Stanford University and its affiliates will become increasingly relevant to POG activities. Some of these activities have already been incorporated into POG laboratory and therapeutic studies and others are targeted for incorporation into future POG studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Breitfeld, Philip P.; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The goal of the proposed research is to determine optimum care for children with all types of cancer. The research mechanism involves participation by pediatric investigators in a consortium of medical institutions in North Carolina and West Virginia in collaborative multidisciplinary clinical cancer research protocols generated through the Pediatric Oncology Group. The proposed research grant will allow for the continued participation of Duke University Medical Center, Charlotte Memorial Hospital, East Carolina University School of Medicine and West Virginia University School of Medicine in Pediatric Oncology Group activities. These activities involve studies of the epidemiology and tumor biology of selected neoplasms and the natural history and optimum multimodal therapy of all childhood malignancies. Cooperative studies among physicians from a group of medical centers allow for rapid accrual of a statistically significant number of children with cancer in order to define quickly both

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those avenues of biologic research which have immediate clinical relevance and those therapeutic approaches which provide prolonged disease-free survival. Through participation in cooperative studies, the entire medical community engaged in the care of children with cancer has a focal point to provide not only improved patient care but also improved multidisciplinary teaching and research. Our objectives for the coming years are: 1) to develop new protocols for the immunologic stratification and chemotherapeutic management of patients with malignant lymphoproliferative and myeloproliferative disorders; 2) to develop protocols for specific brain tumor therapy which take advantage of our expanding knowledge of the biology and pharmacologic sensitivity of human brain tumors in vitro and in vivo; 3) to expand our studies of the pharmacologic agents which influence intermediary metabolism, using our in vitro data as the basis for drug scheduling in clinical trials; 4) to expand our innovative groupwide epidemiology studies to include studies of neuroblastoma and T-cell malignancies which include laboratory investigation (immunologic, biochemical and cytogenetic) where relevant; 5) to expand our multidisciplinary therapeutic research efforts in other pediatric malignancies; and 6) to expand our outreach programs for patient care and education through our regional consortium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Steuber, C P.; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: The concept of the pediatric cooperative cancer group was introduced over 30 years ago because of the rarity of pediatric malignant diseases and the vital importance of controlled trials to improve the outcome for such patients. For such a group to succeed, the collaborative contributions of individuals from a large variety of specialties and fields of research are absolutely essential. This multimodal organized approach to the treatment of childhood cancer through the cooperative group has welldemonstrated its value. The Section of Pediatric Hematology-Oncology at Baylor College of Medicine has been involved in the genesis of this kind of clinical research and has participated in the activities at even level. The current goals of the Section regarding cancer prevention, treatment, and research have lead to the recent development of the Texas Children's Cancer Center. The Center is a joint effort of Texas Children's Hospital and Baylor College of Medicine and is committed to providing the finest possible patient care, education and research in the areas of pediatric and adolescent cancer and hematological disorders. Major expansion of the clinic and research lab facility is underway. New faculty are being recruited to expand the current research program in the areas of gene therapy, bone marrow transplantation, molecular biology, clinical pharmacology, and experimental therapeutics. Additional personnel including data managers, pediatric nurse practitioners, and research personnel have been recruited to support the new faculty members and the expanded programs. In addition, outreach efforts are making the Center known to communities in Texas that would benefit from a service dedicated to the treatment of children with cancer. The development of the Texas Children's Cancer Center will enhance Baylor's contributions to the Pediatric Oncology Group (POG) by expanding the research and treatment programs that have so successfully contributed to POG throughout the years, by developing new and innovative treatment and research programs, and by increasing study populations for those programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Meyer, William H.; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: Children's Hospital of Oklahoma (CHO) at the University of Oklahoma is a member institution of the Pediatric Oncology Group. One of our primary goals is the enrollment of the majority of pediatric patients with cancer in the state of Oklahoma in a cooperative cancer program (POG). Participation in group studies guarantees optimal care for these patients and the opportunity to study in depth the natural history of childhood cancer, develop effective therapeutic regimens, and evaluate the toxicity. and effectiveness of new anti-cancer agents in the treatment of childhood cancer. In addition to the POG studies, institutional non- therapeutic protocols have been developed, i.e., evaluation of leukemic therapy on the central nervous system of newly diagnosed leukemic patients and longitudinal evaluation of coping mechanisms with stress among patients and parents of children with cancer. For all these programs, patient resources and scientific expertise are available in Children's Hospital of Oklahoma. The team at the University of Oklahoma is multidisciplinary. It consists of pediatric hematologistsoncologists, radiation therapists, radiologists, pediatric surgeons, immunologists, pathologists and psychologists. All protocols are reviewed by the Institutional Review Board and informed consent is obtained on all patients entered into these protocols. Protocol compliance remains a high priority. The evaluability rate for the last four years averaged 92.5%. St. Francis Hospital of Tulsa was previously considered a branch of CHO. At the request of the POG Operations Office, Tulsa has applied to become an affiliate institution. The University of New Mexico is also affiliated with the University of Oklahoma. It serves an economically disadvantaged population (native American Indians) which needs to be included in the population studied by cooperative cancer groups. The Pathology Department at the University of New Mexico has special expertise in molecular diagnostic hematopathology and in solid tumors which can benefit the research efforts of the Pediatric Oncology Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Lauer, Stephen J.; Professor of Pediatrics; Pediatrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-MAR-2003 Summary: The Pediatric Oncology Program at Emory University is the only comprehensive children's cancer center in Georgia and one of the largest of its kind in the Southeast. It serves a racially, ethnically, and socioeconomically diverse population from metropolitan Atlanta, the State of Georgia, and other states including Alabama, Arkansas, the Carolinas, Florida, and Mississippi. Since the inception of the Pediatric Oncology Group (POG), Emory is consistently one of the largest single-institution contributors to POG clinical and laboratory studies. Emory is a center for Phase I and pilot POG trials and has initiated numerous protocols that have subsequently been implemented by POG. The specific aims of the Emory POG Program are: l) to continue as a major source of patients for POG-sponsored Phase I, pilot, groupwide, and intergroup studies; 2) to provide leadership by its investigators as POG Study Coordinators, Co- coordinators, and Core Committee members; 3) to develop innovative institutional clinical trials on which to base future POG investigations; and 4) to maintain strong basic and translational research programs in pediatric oncology. To

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address these aims, Emory investigators are Coordinators for several major POG studies, including standard-risk new ALL (#9405), high-risk new ALL (#9006), salvage chemotherapy in relapsed neuroblastoma (#9140), and chemotherapy vs. autologous bone marrow transplantation (ABMT) in AML (#8821). Emory POG members actively participate in POG Core Committees, Subcommittees, and new protocol development. Institutional pilot studies include therapy of relapsed AML with idarubicin and chlordeoxyadenosine, treatment of relapsed solid tumors with high-dose busulfan/melphalan and ABMT, transplantation of haploidentical CD34+ cells for relapsed ALL or AML, and vincristine plus dose-escalated cyclophosphamide and infusions of peripheral blood-derived progenitor cells in refractory solid tumors. Complementary laboratory research activities include molecular biology of ALL (mechanisms of IL-6- mediated autocrine growth and aberrations in tumor-suppressor genes); in vitro sensitivity of leukemia cells to antineoplastic agents mid biological response modifiers; mechanisms of resistance of AML cells to alkylating agents; molecular neuro-oncology; and xenogeneic models to evaluate normal and neoplastic human hematopoiesis. Investigators at Emory are participating in the POG laboratory study of methotrexate metabolism by ALL cells (ALinC #16) and coordinate the study of alterations in p53 tumor-suppressor gene pathways in relapsed ALL (SIMAL #l0). Taken together, these activities of the Emory POG Program will continue to contribute to our knowledge of the biology, therapy, and prevention of neoplastic diseases in infancy, childhood and adolescence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Luchtman-Jones, Lori; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: The Washington University Medical Center in St. Louis is one of the 39 full member institutions, 48 affiliate, 12 consortia and 9 CCOP institutions of the Pediatric Oncology Group who has pooled their patient resources and scientific expertise to study the natural history of childhood cancer, develop and compare effective therapeutic regimens and investigate the toxicity and effectiveness of new anticancer agents in the treatment of children with cancer. Additionally tumor specimens and occasionally normal tissue and blood samples are collected to determine more about the basic cancer biology and pathology of the disease. Group studies are ongoing in epidemiology, cancer control, pharmacology and pharmacokinetics. The investigators at the Washington University Medical Center include pediatric oncologists, radiologists, radiation oncologists, cytogenetists, neurologists, surgeons, and pathologists. All children with malignant disease are placed on cooperative group protocols if they are eligible and if informed consent is obtained. Data accessioned at the time the patient is placed on study protocol, during the study, and when off therapy is submitted to the Group Statistical Office for data analysis, interpretation and eventual publication. The investigators at Washington University Medical Center serve in multiple administrative and research capacities for the Group. The diagnostic studies, pathological findings, surgical procedure and therapeutic plan for all new patients and patients who relapse are discussed at the weekly Tumor Board Conference. The Principal Investigator has a phase I contract and works with 16 other POG institutions to establish the maximum tolerated dose of a new agent along with the pharmacology and, if indicated, the biologic response of the agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP ACTIVITIES Principal Investigator & Institution: Winick, Naomi J.; Professor of Pediatrics; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: This grant application seeks continued support for the Pediatric Oncology Group (POG) activities of The University of Texas Southwestern Medical Center (UT Southwestern) Consortium, which consists of UT Southwestern (Dallas), Cook-Ft. Worth Children's Medical Center (Ft. Worth), and Scott & White Clinic (Temple). Since joining POG in 1981, this partnership of children's cancer treatment and research centers in North Texas has grown to become POG's largest contributing member with regard to patients enrolled on therapeutic studies (over 100 annually). During the current grant cycle, consortium investigators have held administrative and scientific leadership positions on major Group committees, including Executive Committee, Principal Investigator's Committee, New ALL Committee, T-cell Committee, and Lymphoid Relapse Committee. UT Southwestern Consortium investigators have also served or are serving as study coordinators on multiple POG treatment protocols studying ALL (newly diagnosed patients with B-lineage and T-cell disease as well as following relapse), non-Hodgkin's lymphoma, bone marrow transplantation and new agents being explored in Phase I-II trials. UT Southwestern Consortium investigators have also had prominent roles in the arenas of data management, protocol development, molecular and pharmacologic monitoring in authorized POG reference laboratories, and supportive care. Results of pilot projects conducted at UT Southwestern have been instrumental in the construct of group-wide treatment strategies, especially involving use of methotrexate for B-lineage ALL. To support the UT Southwestern Consortium's continued commitment to POG research during the next 5 years, this new grant proposal describes personnel and facilities in the 3 consortium centers. Specifically, during 1996-2000 the Consortium aims to advance POG research by: (l) enrolling as many patients as possible on POG treatment, biological classification, and epidemiology protocols; (2) collecting, recording, and submitting research data in an accurate and timely fashion; (3) providing administrative and scientific expertise to the Group through continued active participation on major committees, including service as disease committee chairs and protocol coordinators; and (4) continuing to conduct innovative in-house pilot studies for subsequent use by the Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP MEMBERSHIP Principal Investigator & Institution: Schwartz, Cindy L.; Associate Professor; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: The aim of this research is to improve the treatment of childhood cancer through participation in organized clinical trials with fellow members of the Pediatric Oncology Group. In addition, we intend to expand our understanding of these diseases by collaborative laboratory investigations. Multiple projects are described which reflect the intense commitment of our faculty to work within the Pediatric Oncology Group. Our faculty are leaders of the POG commitments in ALL phenotyping, Neuropathology, Bone Tumors, Hodgkins disease, Rhabdomyosarcoma, Radiation Oncology, Bone Marrow Transplantation, Myeloid disease, Germ Cell Tumors, Late Effects of Childhood Cancer Therapy, and Multiple Drug Resistance. Pediatrics is the program that describes patient accrual and protocol activity within the division of Pediatric Oncology at Johns

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Hopkins under the supervision of Dr. Cindy Schwartz as POG PI. The disciplines of Radiation Oncology, Pathology, Pediatric Surgery, Orthopedic Surgery, Neurosurgery and Nursing also play a major role in patient accrual and protocol activity. In addition, Fairfax Hospital under the direction of Dr. Jay Greenberg is an active affiliate of our institution. With the limited numbers of children admitted with any single oncologic diagnosis to an individual institution, it is clear that cooperative clinical research is required if significant advances are to be made. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP PARTICIPATION Principal Investigator & Institution: Pui, Ching-Hon; Acting Chairman; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 01-JAN-1982; Project End 31-DEC-2002 Summary: We propose continued participation in the Pediatric Oncology Group (POG). Our goals are as follows: (1) to improve cure rates for children with cancer through participation in Phase I, II, and III clinical trials designed to test new agents or concepts; and (2) to participate in laboratory-based research aimed at clarifying the basis of drug resistance and pathogenetic mechanisms of childhood cancers. We are committed to Group participation because we believe: (1) that collaborative efforts are both desirable and necessary for study of childhood cancers, since all are relatively rare; and (2) that well-designed randomized clinical trials provide the most definitive test of efficacy and general applicability of new therapies and that pooled intellectual resources are advantageous as well. Our contribution to the Group can be categorized as follows: (1) contribution of selected patients (those with rare tumors or less common stages of other cancers, n approximately 80-100/year) to Group studies; (2) administrative and scientific leadership (e.g., disease or discipline committee chairs, and protocol coordinators); (3) provision of multiple reference laboratories (flow cytometry analyses of leukemia and solid tumors, cell bank, AML cytogenetics, pharmacokinetics/pharmacodynamics, molecular genetics of leukemia and solid tumor); (4) regular presentation of results of in-house research to the group. Since our center has an unusually large number of patients and staff (both clinical and basic), the latter contribution assumes unusual importance. We have an extensive in-house developmental therapeutics program which is independent of, but complementary to, the Group's clinical research programs. We also have extensive programs in basic research. The aim of these programs, to determine the pathogenesis of pediatric neoplasia, is expected to positively influence the Group's central goal -- curing children with cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP STUDIES Principal Investigator & Institution: Mclean, Thomas W.; Pediatrics; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-DEC-2002 Summary: The overall objective of the proposed research effort is to continue work towards determining the optimum care for children with all types of cancer. The research mechanism involves participation by pediatric investigators at the Bowman Gray School of Medicine in the development and execution of collaborative multidisciplinary clinical protocols of the pediatric Oncology Group. The proposed research grant will support the continued participation of the Bowman Gray School of

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Medicine as a full member of the pediatric Oncology Group. Our accomplishments in the past grant period are described in detail in the proposal. Our institutional goals for the five year period of this grant include: (1) continuing our high level of patient accrual and excellent clinical contributions to the POG including our outstanding patient evaluability and protocol compliance which has merited a letter of commendation from the operations office at every 6-month analysis in the past (2) maintaining our institutional involvement in POG leukemia studies and our representation on the new ALL core committee (3) continuation and further development of our multi-disciplinary institutional commitment to POG Hodgkin's disease activities (4) a major role on the POG cytogenetics committee including optimal use of our new reference laboratory status (5) increased institutional development of late effects studies in collaboration with the POG late effects efforts (6) expansion of our efforts in neuro-oncology including increased enrollment on brain tumor studies and investigator roles on the POG brain tumor committee (7) use of in situ studies of tumor cell ploidy in collaboration with POG and other investigators (8) continued contributions to the administrative aspects of the POG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER CTR

PEDIATRIC

ONCOLOGY

GROUP--MIDWEST

CHILDREN'S

Principal Investigator & Institution: Camitta, Bruce M.; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The primary objective of the Midwest Children's Cancer Center is to reduce the incidence of and mortality from childhood cancers. This is approached by: 1) providing the best possible patient care (diagnostic and therapeutic; 2) education of medical and nonmedical groups as to the types of, treatments for, and availability of care for different childhood cancers; and 3) clinical and laboratory research. Investigators at the Cancer Center include specialists in pediatric oncology, surgery, orthopedic surgery, neurosurgery, radiology, radiation therapy, pathology, neurology, psychology and nursing. All new patients are discussed at a multidisciplinary Tumor Board. The children are then treated on Pediatric Oncology Group (POG) or institutional protocols. Results are analyzed and reported regularly. The purpose for the Midwest Children's Cancer Center's participation in POG are: l) to enhance the probability of achieving the above objectives by collaboration with other institutions in the design and execution of clinical protocols; and 2) to evaluate, through laboratory investigations, aspects of tumor biology which result in successful and unsuccessful therapy. Pediatric tumors are relatively rare. The POG is composed of more than 50 member institutions. By pooling resources, biologic and therapeutic studies on these uncommon tumors are facilitated. Similar collaboration permits more rapid development of new drugs. In addition, participation in a common milieu promotes dissemination of information between institutions and investigators. If all children with cancer receive the best possible care, morbidity and mortality will be minimized. The Midwest Children's Cancer Center has been a major contributor to POG by: 1) patient accrual; 2) coordination of POG protocols; 3) institutional pilot studies that were advanced to POG studies; and 4) participation in POG disease and administrative committees. In the next grant period we will continue each of these activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP--THE CAROLINAS CONSORTIUM Principal Investigator & Institution: Barredo, Julio C.; Professor; Pediatrics; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-JUN-1996; Project End 31-DEC-2002 Summary: (Adapted from the applicant's description): The institutions included in this proposal have been part of the Pediatric Oncology Group (POG) and received good performance scores during the past five years. There are two primary goals of this proposed research; the first is to accrue patients to the Group clinical trials in order to determine the optimal care of children with all types of cancers. The second is to contribute scientific expertise to the Group in areas of both patient care and tumor biology. This proposed research will allow participation in POG activities through a consortium effort of East Carolina University (ECU) School of Medicine, Carolinas Medical Center, Medical University of South Carolina (MUSC), Greenville Hospital, Presbyterian Hospital, and Memorial Mission Hospital (The Carolinas' Consortium). In addition to these clinical activities, their scientific efforts in next five years will include: (1) development of new protocols for the treatment of children with cancer focusing mainly on pediatric lymphomas; (2) expansion of studies of minimal marrow residual disease (using RT-PCR analysis) and assessment of new purging techniques in neuroblastoma; (3) participation in the laboratory evaluation of folylpolyglutamate synthetase (FPGS) in lymphoblasts of newly diagnosed patients; and (4) evaluation of the role hematopoietic growth factors in the treatment of pediatric malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHARMACOLOGY OF CYCLOPHOSPHAMIDE AND OTHER ALKYLATORS Principal Investigator & Institution: Colvin, Oliver Michael.; Professor; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 30-SEP-1977; Project End 31-JAN-2005 Summary: In this application we propose to continue our studies of the chemistry and pharmacology of cyclophosphamide and ifosfamide. The studies proposed focus on two critical aspects of the pharmacology of these agents, the definitive characterization of the DNA interstrand crosslinks produced by phosphoramide mustard and isophosphoramide mustard and the elucidation of the chemical and enzymatic determinants of the two P450 oxidations which determine the activation and inactivation of cyclophosphamide and ifosfamide. Our studies have demonstrated significant differences in the chemistry of phosphoramide mustard and isophophoramide mustard and in the interstrand crosslinks which will be produced by these molecules and their decomposition products. We have also recently discovered that acrolein produced from 4-hydroxycyclophosphamide gives O[6]-guanylate alkylation, probable crosslinking of DNA, and selects for resistance to BCNU by increased O[6]-alkyltransferase. We will explore the mechanisms of these reactions and determine if chloroacetaldehyde will produce similar effects. The repair of the demonstrated DNA crosslinks will be studied in our separately funded collaboration with Dr. Henry Friedman. We will also continue our studies of the P450 activation and dechlorethylation of cyclophosphamide and ifosfamide - determining the relative ratio of these reactions for different P450 enzymes, measuring deuterium isotope effects, defining the mechanism of the reactions, and examining the pharmacokinetic and antitumor properties of ifosfamide after altering the metabolism of ifosfamide by isotope and alkyl substitution induced kinetic switching of dechlorethylation to

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activation. We believe the results of these studies will have important implications for improving the clinical effectiveness of these important and unique antitumor agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PODOCYTES & STRESS RESPONSE IN NEPHROTIC SYNDROME Principal Investigator & Institution: Smoyer, William E.; Pediatrics & Communicable Dis; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: Nephrotic syndrome is one of the most common forms of kidney disease in children. It is characterized by massive leakage of protein across the kidney's filtration barrier and dramatic structural changes in podocytes, which in part comprise the barrier. These changes include retraction (effacement) of the actin-rich podocyte foot processes with disruption of their actin filaments, and can be attenuated by treatment with reactive oxygen molecule scavengers, suggesting a link between NS and oxidant injury to podocytes. We recently detected a reported regulator of actin polymerization, heat shock protein 27 (hsp27), in normal podocytes, and reported induction of hsp27 in glomeruli during NS. We hypothesize that hsp27 has an important role in mediating the podocyte structural changes which occur in NS, via regulation of actin filament dynamics. We also hypothesize that hsp27 has an important role in the podocyte response to oxidant stress, and that the therapies commonly used to treat NS act by protecting podocytes from oxidant-induced injury via alterations in hsp27 expression and/or phosphorylation. To test these hypotheses we will: 1) Determine if induced changes in podocyte hsp27 expression and/or phosphorylation protect against NS, 2) Identify glomerular hsp27-binding proteins and measure changes in the interaction between hsp27 and the identified proteins during NS, and 3) Measure the protective effects of induced alterations in podocyte hsp27 on the podocyte stress response, and compare these effects to those resulting from podocyte treatment with corticosteroids, cyclosporine A, and cyclophosphamid (common treatments for NS). We will use both in vivo (PAN nephrosis in rats) and in vitro (PAN and protamine treatment of cultured "differentiated" podocytes) models of NS to determine if induction of hsp27 in vivo (whole animal hyperthermia, hsp27 transgenic animals) or in vitro (hsp27 sense/antisense/phosphorylation mutant stable transfections) protects podocytes against foot process effacement and NS. A yeast two hybrid library from rat kidney glomeruli will be used to identify, and define hsp27-binding proteins, and alterations in their interactions with hsp27 during NS will be determined by biochemical analyses. Cultured "differentiated" podocytes transfected with hsp27 sense/antisense/phosphorylation mutants will be treated with stressors with specific biological relevance to NS (oxidant stress, actin filament disruption, heat shock) and the cellular stress response (survival, actin filament structure, induction of hsps and antioxidants) compared to that after treatment with drugs used for NS. Identification of a biologically important role for hsp27 in regulating podocyte structure in NS would permit the development of more highly targeted and less toxic therapies for this very common form of kidney disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREDICTION OF LUPUS OUTCOME BY GENE EXPRESSION PATTERNS Principal Investigator & Institution: Winchester, Robert J.; Professor; Pediatrics; Columbia University Health Sciences Po Box 49 New York, Ny 10032

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Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Support is sought for performing mechanistic studies to define the gene expression profiles of glomeruli isolated from biopsy sections of lupus glomerulonephritis with the overall goals of determining whether the glomerular gene expression phenotype will predict outcome and efficacy in an ongoing parent trial. The parent trial compares administration of CellCept versus IV Cytoxan for initiating control of biopsy-proven lupus nephritis. We have demonstrated the feasibility of studying gene expression profiles by microarray analysis in glomeruli isolated from frozen biopsy sections by laser microdissection t6 characterize the molecular pathologic mechanisms leading to lupus nephritis. This work revealed considerable heterogeneity in gene expression patterns in samples classified as proliferative glomerulonephritis, suggesting the feasibility of lupus renal biopsy subclassification by gene expression criteria. The expressed genes formed 8 main clusters and the presence or absence of genes comprising these clusters in a given sample divided the biopsies into 3 distinct types. The hypothesis underlying the proposed studies is that differences in molecular pathologic mechanisms revealed by the various transcriptional phenotypes will predict the heterogeneous natural history and therapeutic outcome of lupus. The first aim of the proposed mechanistic studies is to cluster glomerular gene expression patterns in diagnostic renal biopsies performed in the current trial and use them to extend understanding of pathways involved in the molecular pathogenesis of lupus glomerulitis. Parallel quantitative PCR for selected genes found through the microarray assessment will be performed to validate the patterns found and determine if their differential expression can be used as a surrogate. The second aim will correlate the clusters and pathways with conventional pathologic features to identify the molecular basis of the pathologic findings. The third aim will determine whether particular outcomes of the trial could be predicted by the gene expression phenotype of the initial renal biopsy. In particular we will address, first, whether one gene expression type, characterized by apoptosis, TNF signaling and fibrosis, is highly correlated with poor outcome and thus predict the subset of nonresponders to Cytoxan or CellCept. Second, whether CellCept will prove to be efficacious in a different gene expression subset, suggesting it could be used in these cases as a less toxic alternative to Cytoxan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF IFOSFAMIDE INDUCED NEPHROTOXICITY Principal Investigator & Institution: Nissim, Itzhak; Research Professor Pediatrics; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: Ifosfamide (IFO), an alkylating oxazaphosphorine, has been found to be very effective for the treatment of relapsed solid tumors and in patients who respond poorly following treatment with other chemotherapeutic agents. However, the efficacy of IFO is severely limited by a high incidence of nephrotoxicity. This proposal entails a comprehensive investigation of the as yet unknown mechanism(s) involved in IFOinduced renal injury and prevention of such injury by administration of glycine (Gly), which we found to be an effective cytoprotective agent both in vitro and in vivo. Our ultimate goal is to develop a clinically applicable protocol involving administration of glycine with IFO to prevent nephrotoxcity in cancer patients treated with this antineoplastic drug. The main hypothesis to be explored is that the induction of renal injury during IFO treatment is mediated via accumulation in the kidney cortex of one or

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more of the active metabolites of IFO, i.e., 4-hydroxy-IFO (4- OH-IFO) and/or isophosphoramide mustard (IPM), secondary to depletion of [GSH] by chloroacetaldehyde (CAA) and/or acrolein (ACR). These metabolites may react with SH-groups of the plasma membrane or mitochondrial membrane proteins, thereby damaging cellular integrity. An alternative, but not mutually exclusive hypothesis is that the primary mechanism in evoking renal injury during IFO treatment is mediated via inhibition of mitochondrial oxidative metabolism by CAA and/or ACR, resulting in defective energy production, multiple metabolic abnormalities, and thereby, cellular damage. However, concomitant oral supplementation of Gly with IFO will attenuate IFO-induced nephrotoxicity by maintaining the renal proximal tubule integrity without diminishing the antitumor action of IFO. Unique features of the current proposal are: (a) the successful development of a rat model system for investigation of IFO-induced renal toxicity; (b) the use of Nuclear Magnetic Resonance (NMR), Gas Chromatography-Mass Spectrometry (GC-MS), LC-MS-MS, Laser- Scanning Confocal Microscopy and techniques of molecular biology to explore the biochemical/molecular lesions responsible for IFO-induced renal injury; and (c) a prevention of such injury by oral supplementation of Gly. The proposed studies are of clinical as well as scientific significance. The data to be generated will potentially have considerable importance for prevention of renal dysfunction associated with cancer chemotherapy, and thus allow for a greater therapeutic efficacy and enhanced survival of cancer patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REDUCING THE TOXICITY OF BMT IN SICKLE CELL ANEMIA Principal Investigator & Institution: Iannone, Robert; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The main objective of the research proposal is to reduce the toxicity of bone marrow transplantation (BMT) for sickle cell disease (SCD) in order to extend this potentially curative therapy to more patients. Despite current therapies, SCD is associated with substantial morbidity and mortality. Myeloablative BMT can cure SCD but its application is limited by a 5-10% mortality risk, a 10% failure rate, graft-versus-host disease (GVHD) and the risk of gonadal and endocrine dysfunction. Nonmyeloablative BMT (NST) can result in mixed hematopoietic chimerism, stable co-existence of host and donor marrow, and may be less toxic than myeloablative BMT. Because normal red blood cells (RBCs) survive much longer than sickle RBCs, a low-level of normal donor chimerism may substantially reduce the fraction of sickle cells in the circulation and prevent their pathologic effects. There is limited experience, however, with NST in patients with SCD. We have studied animal models of mixed chimerism to treat SCD, tested novel NST regimens for inducing donor-specific tolerance and reducing GVHD, and piloted a clinical trial of NST in patients with SCD. Six of seven patients treated had initial donor engraftment and toxicities were mild and reversible, however, all patients experienced late graft failure. We now hypothesize that HLA-identical sibling bone marrow will engraft in >80% of patients with SCD who receive pre-transplantation fludarabine and low-dose total body irradiation, with or without cyclophosphamide (Cy), followed by post-transplantation Cy, tacrolimus and mycophenolate mofetil. We will study in-vitro anti-donor reactivity as a predictor of rejection, track other factors associated with engraftment and GVHD, assess immune reconstitution after NST, and evaluate the effect of this treatment on multiple clinical parameters. I was recently recruited to the Children's Hospital of Philadelphia to establish a clinical research program in BMT for non-malignant diseases,

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emphasizing SCD. My objective is to become an independent clinical scientist by obtaining formal instruction and conducting mentored patient-oriented research on reducing the toxicity of BMT for SCD. I have a strong mentoring committee composed of scientists with expertise in clinical trial development, SCD, BMT, biostatistics, bioethics and transplant biology. As part of my training, I will obtain a Master's Degree in Clinical Research through the Center for Clinical Epidemiology and Biostatistics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF DNA IN PROTECTING AGAINST SECONDARY LEUKEMIAS Principal Investigator & Institution: Dolan, M Eileen.; Associate Professor; Medicine; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2004; Project Start 01-JUL-1999; Project End 31-MAR-2009 Summary: (provided by applicant): Despite the growing number of available agents designed to retard cancer growth, alkylating agents remain an important mainstay of cancer therapeutics. However, effective modulation of existing agents is necessary both to improve efficacy and to attenuate toxicity. Of the clinically useful alkylating agents, cyclophosphamide and ifosfamide are widely used for a variety of solid and hematologic malignancies and are thus important targets for manipulation. Major clinical toxicities include urotoxicity, nephrotoxicity, neurotoxicity, and, to a lesser extent, a risk of secondary leukemias. An important issue that has been raised, but not addressed directly, is the possibility that the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (MGMT), protects against toxicities associated with ifosfamide and cyclophosphamide. Specific aims 1 and 2 will establish if MGMT plays a role in protecting against secondary leukemia by evaluating the repair of DNA adducts introduced by cyclophosphamide and ifosfamide by MGMT. Initially, we will determine if acrolein creates toxic/mutagenic lesions on DNA that are repaired by MGMT. These studies will be extended to the Nfl+/- mouse model of cyclophosphamide-induced leukemia. Shannon and colleagues have shown that mice heterozygous for the Nf1 gene, which encodes for a GTPase activating protein of Ras, have a higher incidence of leukemia at 15 months of age after treatment with cyclophosphamide than wild type mice. The NF1+/- mouse model of alkylating agentinduced leukemia will be crossed with MGMT-/- mice to determine if the absence of MGMT (Nfl+/-, MGMT-/-) results in an increase in the incidence of leukemia after treatment with cyclophosphamide as compared to littermates wild type for MGMT (Nf1+/-, MGMT+/+). Specific aim 3 will focus on modulating the antitumor effect of cyclophosphamide and ifosfamide without increasing toxicities associated with acrolein or chloracetaldehyde (CAA). We have identified substituted guanine analogs that increase the sensitivity of human cancer cells to phosphoramide mustard (PM), isophosphoramide mustard (IPM) but not CAA or acrolein. We will determine if the mechanism of enhancement is due to inhibition of repair of crosslinks. In this renewal, we will continue to work towards our long-term goal of developing means to protect against the toxic and mutagenic effects of alkylating agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Rivkin, Saul E.; Swedish Medical Center, First Hill 747 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2003

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Summary: The Puget Sound Oncology Consortium (PSOC) has been a funded member of the Southwest Oncology Group (SWOG) since 1976. A multi-modality approach is utilized which includes: Pathology, Surgery, Chemotherapy, Radiation Therapy, Biological Response Modifier Therapy and Quality of Life evaluations for the aim of improving cancer care. Overall objectives are prolongation of life, increased quality of life, decreased toxicities, prolonged disease free survival, improvement in techniques of screening, early detection and prevention of cancer and the rapid transfer of innovative therapies from the laboratory to the clinic. PSOC is one of the largest SWOG member groups and altogether comprises a network of 27 hospitals and medical centers throughout the Pacific Northwest (Alaska, California, Montana, Oregon, and Washington). The scientific agenda of PSOC is determined by disease-specific committees who have contributed eight pilot studies to SWOG in the past grant period. PSOC has 22 investigators who coordinate or co-coordinate 26 studies and has 12 members who hold primary or contributing authorship in 42 published reports of SWOG studies. PSOC supports a urological cancer outreach program (UCOP) as well as five prostate cancer prevention trial (PCPT) sites. PSOC ranks number one in follow- up with a total caseload of 1,245 patients and averages an annual accrual of approximately 170 patients. The Prostate Cancer Prevention Trial has accrued 800 patients and the UCOP program has accrued 53 patients in this past grant period. PSOC maintains autologous and allogeneic bone marrow transplant programs as well as an active stem cell transplant program. Cytogenetics laboratories of SHMC and the UWMC are certified as submitting and reference laboratories. The Clinical Practices Committee formed by Saul E. Rivkin, MD, is evaluating resource utilization and cost effectiveness issues for patients receiving treatment on research protocols. Membership has steadily increased in the past grant period with the addition of three new CGOP affiliates and a total of 54 new members over the last five years. PSOC members are active in scientific and administrative activities and are dedicated to support the goals of the Southwest Oncology Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Nichols, Craig R.; Division Chief; Surgery; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-JAN-1988; Project End 31-DEC-2003 Summary: The purpose of this application is to obtain continued funding to support a multi-disciplinary program to conduct clinical research with cancer patients through participation in the Southwest Oncology Group (SWOG). This approach to cancer management is unique in this portion of the Pacific Northwest and provides contemporary treatment alternatives to an otherwise relatively isolated population. Specifically, the program proposes to: 1. Combine the disciplines of Surgical, Medical, and Radiation Oncology, Pathology, Immunology, and Nursing oncology in a synergistic attack on clinical cancer management by participation in SWOG protocols. 2. Participate in SWOG phase II, III, and adjuvant studies. 3. Develop and conduct preclinical and clinical pilot studies for possible use by SWOG. Such studies will include, but are not limited to, the neuroendocrine control of breast and prostate cancer, regional chemotherapy by perfusion, infusion, and chemoembolization, suppression of functioning tumors of the gastrointestinal tract and other cancers by the synthetic somatostatin (Octreotide), multiple modality therapy in the treatment of tumors such as alveolar soft part sarcoma metastatic to lung, retroperitoneal sarcomas and mesothelioma of the pleura, the genetics of hematopoietic growth factors, bone marrow

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transplantation, and gene therapy. 4. To return SWOG information and expertise to the local area by consultation, lecture and symposia for the benefit of regional physicians and patients and by expanding our community outreach program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Mills, Glenn M.; Medicine; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, La 71103 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-DEC-2003 Summary: LSUMC-S has been a member of SWOG since 1982 and has had funding since 1993. After a period of time with relatively low accrual to protocols, accrual has recently markedly increased and currently is about 180/year and ranks within the top six institutions. LSUMC-S accounts for nearly 12 percent of all minority patients accrued to SWOG studies. Forty-seven percent of all patients placed on SWOG protocols from LSUMC-S are minority. LSUMC-S has four primary sites for patient accrual to studies. These include the University Hospital, the Overton Brooks VAMC, the Willis Knighton Medical Center and the E. A. Conway Hospital. Three CGOP sites are present--St. Francis Hospital, Monroe, Louisiana; Highland Hospital, Shreveport and Baptist Medical Center in New Orleans, Louisiana. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Thigpen, James T.; Professor and Director; Medicine; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2003 Summary: Many of the therapeutic advances in the treatment of cancer and related diseases are a result of collaborative efforts, and specifically, cooperative group studies. Because of this, the University of Mississippi Medical Center has been an active participant in the Southwest Oncology Group since 1971. The University of Mississippi Medical Center can best utilize its resources and offer our patients access to new cancer treatment, prevention and cancer control studies through full participation in the Southwest Oncology Group. Our collaborative efforts include participation in the Southwest Oncology Group's Cooperative Group Outreach Program. A multidisciplinary approach to the management of patients is employed by a team of medical oncologists, hematologists, radiation oncologists, surgeons and surgical subspecialties, pathologists, and cancer prevention and dental researchers. A centralized system for management of data on cancer clinical trials is in place at the institution. Trained clinical trials coordinators and nurses are actively involved in identifying patients for study participation and monitoring patients placed on studies. Institutional investigators actively participate in disease, discipline, standing and administrative committees of the Southwest Oncology Group. Group-wide leadership is demonstrated by this institution's chairing of the Clinical Research Associates Committee, participation in disease committee working groups, and the Board of Governors. The institution continues to serve as the depot pharmacy for an intergroup prostate cancer study. Minorities, primarily African-Americans, comprised approximately 45% of registrations during the period 1992 to 1996. The high percentage of minorities registered on clinical trials should continue during the next grant period. Over the next five years, the University of Mississippi Medical Center plans to increase its accrual to

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studies, maintain our standards of excellence in the management of data, and increase the level of participation by investigations in committee activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Budd, George T.; Staff Physician; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2003 Summary: The Cleveland Clinic is the largest cancer treatment center in the Mideast: 42 percent of the cancer patients are local, 28 percent have come from other areas of northeast Ohio, 13 percent from the remainder of Ohio, and 16 percent out of state. In 1995, there were 4057 new cancer patients seen at the Cleveland Clinic, 2768 new cases in which the diagnosis was first made or received initial treatment at the Cleveland Clinic. In 1995, there were 9,548 hospital admissions attributed to cancer related diagnoses. The in-patient facilities include 58 dedicated medical oncology beds, 16 laminar flow treatment rooms for bone marrow transplant patients and of importance, 23 beds dedicated to a palliative care service. Overall, cancer patients represent 27 percent of all of the Cleveland Clinic in-patients as compared to 16 percent in 1985. In 1995, the Cleveland Clinic provided 74,058 out-patient visits for cancer patients or an average of 284 cancer out-patient visits per day. The out-patient visits have increased since 1985 from 8 percent to 11 percent of all patients seen at the Cleveland Clinic. The major divisions of oncology at the Cleveland Clinic include Medical Oncology, Radiation Oncology and Surgical Oncology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Raghavan, Derek; Director and Professor; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-FEB-1993; Project End 31-DEC-2003 Summary: The USC/Norris Comprehensive Cancer Center began participating in the research activities of the Southwest Oncology Group (SWOG) in 1987 and became a newly funded member institution in 1992. Our participation over the past five years has been characterized by steadily increasing administrative and scientific contributions (consistently ranking in the 2nd-to-3rd quartile among SWOG institutions) and patient accrual (current ranking, 3rd quartile). This has been achieved through the strong support of our Cancer Center which organized and developed several disease-based clinical research programs, provided essential core support for protocol administration, data management, quality assurance monitoring and investigational pharmacy, and implemented an NCI-approved (and grant supplemented) plan to augment the accrual of women and minorities to both intramural and SWOG clinical trials. The diseasebased orientation of our Center has allowed SWOG protocols to have a high priority in our Gastrointestinal (GI), Genitourinary (GU), Breast, Hematology/Retroviral and Experimental Therapeutics programs leading to the steady growth in our SWOG patient accrual. In turn, SWOG has been the vehicle through which a growing number of our faculty have been able to bring Center-supported pilot studies and translational research efforts to a national cooperative group. Examples of these latter interactions include our GI Program (members serve as Vice- Chairman SWOG GI Committee, coordinate several SWOG GI protocols and serve as PI of two SWOG U01 grants), GU Program (Program leader serves as principal coordinator of national high-priority neoadjuvant

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MVAC bladder trial, members participate in funded UCOP and support our designation as a major PCPT study site) and Experimental Therapeutics Program (two highly promising regimens have been adopted into group-wide protocols, SWOG 9509 and 8835). The mutual benefit of this interaction is further reflected by the fact that 15 newly recruited USC faculty in eight different departments or divisions (GI Surgery, Surgical Oncology, Urology, Radiation Oncology, Pathology, Pulmonary Medicine, Hematology, and Oncology) have become SWOG members over the past three years. Despite major challenges from managed care in Southern California and diminished support for public health care facilities such as the USC/Los Angeles County Hospital over the past several years, our SWOG activities have grown. We therefore renew our commitment to SWOG research activities with confidence and the expectation of continued growth in patient and minority accrual, CGOP affiliates and administrative/ scientific leadership in several disease-focused areas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Baker, Laurence H.; Professor of Internal Medicine; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JAN-1980; Project End 31-DEC-2003 Summary: Description (Adapted from the applicant s abstract): This grant allows the University of Michigan to continue to participate in the activities and study protocols of the Southwest Oncology Group which involve development and testing of investigational therapies in patients with solid tumor or hematologic malignancies that have less than 100 percent cure rates with standard therapies. They believe that the pooling of patient data from multiple institutions is a scientifically valid and efficient method for quickly evaluating new therapeutic strategies. They participate in three specific areas of this cooperative group process: (1) significant patient accrual onto group studies, (2) scientific and administrative contributions to the development and coordination of group studies, and (3) act as the administrative scientific and quality control link between several community oncologist (cancer control affiliates) and the Southwest Oncology Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Hutchins, Laura F.; Internal Medicine; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2002; Project Start 15-JUL-1984; Project End 31-DEC-2003 Summary: This application is for the participation of the Arkansas Cancer Research Center (ACRC) at the University of Arkansas in the cooperative clinical trials of SWOG. They have participated since 1959. The University of AK Medical Center, ACRC, John McClellan VA Hospital and nine CGOPs affiliates make up the group. Bart Barlogie, M.D., Ph.D., Professor of Medicine and Pathology, Director of the Division of Hematology-Oncology and Deputy Director of the ACRC is Principal Investigator. ACRC investigators are listed on 13 SWOG committees and Dr. Barlogie serves on the SWOG Board of Governors, and Co-Chairs the Myeloma Committee. Arkansas submitted seven protocol concept papers during the last year. During the last funding period 437 patient have been enrolled on SWOG trials and they rank eighth in patient enrollment. New clinical and basic investigators have been recruited to the institution.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP (UTAH) Principal Investigator & Institution: Samlowski, Wolfram E.; Associate Professor of Medicine; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 25-FEB-1993; Project End 31-DEC-2003 Summary: This application requests continued support for the Utah member institution of SWOG for clinical trials collaboration. The Utah membership consists of three major institutions including the University of Utah, Salt Lake City VA Medical Center and LDS Hospital (totaling approximately 2020 beds, serving a catchment area of approximately 2.5 million). The group is led by Dr. Wolfram E. Samlowski who replaced Dr. Herman J. Eyre as the Principal Investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP CA-13612 Principal Investigator & Institution: Miller, Thomas P.; Research Scientist; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2003 Summary: Funding is requested to support the Arizona Cancer Center (University of Arizona) participation in Southwest Oncology Group cooperative cancer clinical research to improve the treatment of cancer in humans. Specific aims and objectives are: 1. To continue to meet current scientific leadership and core service commitments including: (A) protocol coordination (multiple studies); (B) disease/discipline committee administration; (C) reference and repository laboratory administration; and (D) group quality assurance and quality control. 2. To continue to promote the rapid integration of promising new research leads, including those developed at the Arizona Cancer Center, into cooperative group testing to improve patient treatment options and patient care. 3. To continue to meet institutional clinical research commitments in the recruitment of appropriate patients for SWOG studies and all attendant commitments to long-term follow up, quality control, etc. 4. To continue to promote community physician and patient awareness and participation in SWOG clinical trials by continued support of the Cooperative Group Outreach Program (CGOP) and other outreach and continuing education programs and activities. 5. To continue efforts to understand factors affecting accrual, particularly those in special populations (e.g., minority, elderly, financially disadvantaged), and to implement appropriate interventions where possible. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP STUDIES Principal Investigator & Institution: Taylor, Sarah A.; Medicine; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2003 Summary: The University of Kansas has participated in SWOG studies since 1973. The Principal Investigator since 1993 has been Dr. Sarah Taylor, an enthusiastic and productive clinical investigator. Twenty clinical investigators participate in SWOG studies at the University of Kansas, utilizing both the University Medical Center and the nearby VA Hospital. The goals of this research group are to participate in the design and conduct of multidisciplinary clinical trials in malignant diseases, to investigate biological aspects of these diseases within the group, to investigate issues of quality of

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life, cost of care and long-term complications of treatment, to develop new methods such as telemedicine to increase patient accrual and improve follow-up, to participate in cancer prevention trials, and to contribute to the overall leadership of the SWOG. Participants in SWOG studies at the University of Kansas include specialists from medical oncology, hematology, surgery, urology, radiation oncology, gynecological oncology, and pathology. Dr. Giri is the chair of the Head and Neck Radiation Therapy Subcommittee, and Dr. Kimler is the chair of the Pre-Clinical Therapeutics Workshop and co-chair of the Developmental Therapeutics Committee. Kansas investigators have coordinated six multidisciplinary protocols (four phase II and two phase III intergroup protocols). In addition, Kansas investigators have coordinated 18 other phase II or III protocols and eight intergroup studies. SWOG participants from Kansas were the primary authors of 14 manuscripts and 5 abstracts and co-authors of 30 manuscripts and 12 abstracts. The University of Kansas and its 10 affiliates registered 115 patients to SWOG studies in 1995 and 91 patients in 1996. In 1996, Kansas was the seventeenth leading accruer in SWOG. Currently, 587 patients are alive and being followed on SWOG studies, ranking tenth among SWOG institutions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP STUDY Principal Investigator & Institution: Chapman, Robert A.; Staff Physician, Medical Oncology; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-MAY-1993; Project End 31-DEC-2003 Summary: This is an application for the conduct of cancer clinical research activities as a member institution of the Southwest Oncology Group (SWOG). The specific aims are: 1) to conduct single and multidisciplinary clinical trials as sponsored by SWOG; 2) to recruit large numbers of patients to cooperative group clinical trials with an emphasis on the inclusion of women and minorities populations; 3) to conduct institutional pilot trials as potential group trials; 4) to expand the Cooperative Group Outreach Program (CGOP) as supported by this member institution; 5) to educate health care professionals as to the methods and procedures involved in the conduct of cancer clinical trials; 6) to participate in the administrative and scientific activities of SWOG; 7) to support a data management system which provides for high quality and timely data submission. These activities are supported through the interdisciplinary efforts of individuals within the Division of Hematology/Oncology and the Departments of Surgery, Radiation Oncology, Urology, Cytogenetics, Pathology, Diagnostic Radiology, Pulmonary Medicine, Otolaryngology, Gastroenterology and Neurosurgery. Our team of high trained research nurses and clinical research associates work directly with our physician investigators to assure a high level of patient eligibility and the generation of accurate and timely data for each human subject enrolled. Likewise, this staff brings the identical attention to each of our CGOP affiliate institutions to assist each in developing and achieving good clinical practices in the conduct of cooperative group clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP/UNIVERSITY OF CALIFORNIA, DAVIS Principal Investigator & Institution: Gandara, David R.; Professor of Medicine; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200

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Timing: Fiscal Year 2002; Project Start 01-JAN-1993; Project End 31-DEC-2003 Summary: This is a dynamic, multicenter and multidisciplinary site with high accrual (average 200/year, highest 2-4 percent of all SWOG institutions) with an extensive CGOP, including the Kaiser system, and a large VA/Air Force site. During the last cycle there have been increasing scientific contributions, Group leadership, provision of special resources, and pilot studies which have been translated into SWOG protocols. Despite excellent performance, it has been functioning with less than adequate support. This has led to several periods of a self-imposed cap on registration until all data becomes current. The cancer program has been designated by the University as a Center of Excellence, and the physical facilities seem excellent. This level of activity has been maintained in an environment of 90 percent managed care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP--CLINICAL TRIALS Principal Investigator & Institution: Ozer, Howard; Professor; Medicine; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 24-MAY-1993; Project End 31-DEC-2003 Summary: Participation in the Southwest Oncology Group (SWOG) has been a major part of the clinical investigative effort of the section of Hematology- Oncology in the Department of Medicine at the University of Oklahoma Health Sciences Center (OUHSC). This effort results in the enrollment of a consistent number of eligible and evaluable patients into SWOG trials. SWOG protocols at the University of Oklahoma provide the major opportunity for Oklahoma residents to participate in large scale, well designed clinical trials. Patients are accrued via both the parent institution and affiliated CGOPs. Most patients in the state, including a large number of Native Americans and rural Oklahomans, are treated by physicians who are part of this network. Annual accrual for the entire network has been ninety-seven patients. We have been working to increase our involvement in the scholarly aspects of clinical trials. At the member institution, we have focused our efforts in five areas including breast cancer, head and neck cancer, genitourinary cancer, lung cancer, and hematological malignancies. This effort has resulted in the establishment of multidisciplinary programs in these areas which has helped to facilitate identification and enrollment of patients on SWOG protocols. In addition, it has allowed for the development of in-house protocols which might serve as pilot studies for future SWOG trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOUTHWEST ONCOLOGY GROUP--OPERATIONS OFFICER Principal Investigator & Institution: Coltman, Charles A.; Chairman; Ctrc Research Foundation San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 16-JUL-1981; Project End 31-DEC-2003 Summary: The Southwest Oncology Group is an adult multi-disease, multi-modality clinical research organization with 33 Member Institutions, 23 Community Clinical Oncology Program (CCOP) institutions, including 5 Minority- Based CCOPs, 27 Urologic Cancer Outreach Program (UCOP) members, 22 High Priority program members and a network of 1,441 Cooperative Group Outreach Program (CGOP) investigators at 272 affiliate hospitals, and 15 institutions participating in the CTEP Minority program. Special emphasis areas for the Group with respect to the inclusion of women and minorities have come under the responsibility of the new Committee on Women and Special Populations. This group will focus on detailed analyses of women

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in the various disease categories. There have been gender differences identified in melanoma and lung cancer trials. The special populations include a commitment to optimize the enrollment of minorities in Group trials. Analyses of race and ethnicity impacts on the outcome of patients in our clinical trials are in progress. Additional special populations include the elderly patient advocates, and survivors of cancer. The Committee on Women and Special Populations portion of this application details the heavy current and future involvement of patient advocates in the committee activities of the Group. The Group will involve cancer survivors in our clinical trial committee structure. The Chairman of the Group has created an ethics training program which is delivered between 2-3 times to separate audiences, at every Group Meeting in order to help members understand the moral and ethical principles of the conduct of clinical trials. Tied to this, is the fully implemented Conflict of Interest Policy which identifies potential conflicts from all investigators, who then agree to recuse themselves from decision making related to their identified potential conflict(s) of interest. We have an Affirmation of Integrity statement on file for all members of the Group that come in contact with clinical trial data. The Group application includes correlative biologic studies from banked tumor specimens of homogeneously treated patients in breast, gastrointestinal, head and neck, leukemia, lymphoma, and multiple myeloma cancers. There are two new initiatives involved in this application. A proposal in lung cancer biology proposes a 2-year study of the molecular composition of lung cancer specimens obtained from patients on completed Group clinical trials. The second new initiative deals with a 5-year plan for upgrading Informatics at the Statistical Center and at Group institutions to become ready for all electronic data and information transfer into the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTHWEST ONCOLOGY GROUP--SUMMARY Principal Investigator & Institution: Gaynor, Ellen R.; Medical Oncologist; Medicine; Loyola University Chicago Lewis Towers, 13Th Fl Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-JAN-1988; Project End 31-DEC-2003 Summary: Description (Adapted from the applicant's abstract): Loyola University of Chicago has made significant contributions to the Southwest Oncology Group(SWOG) during the current grant cycle by accruing large numbers of patients, with submission of high quality data, and by making significant scientific contributions to SWOG. Loyola has continued to maintain excellent accrual in spite of the threats to clinical research from managed care. During the last year they had 143 registrations with 106 (74 percent) coming from the member institution; 55 percent of those patients were female and 15 percent were minorities. Ninety-eight percent of those cases were considered evaluable. Five faculty members have served as Chairs or Co-Chairs of committees or subcommittees. Thirty-eight faculty members actively participated in one or more committees. Seventeen faculty members have served as principal or co-coordinators of over 73 protocols. Twenty-three of these protocols were based on pilot studies conducted by Loyola investigators. Twelve faculty members have made significant contributions to SWOG core services. Eleven faculty members have published over 63 SWOG papers and 53 abstracts. The multi-disciplinary nature of Loyola's participation is evidenced by the fact that hematologists/oncologists, surgeons, radiotherapists, and pathologists have each made scientific contributions to SWOG. Multi-disciplinary interactions are also fostered by the movement of faculty clinics and offices to the newly opened Cardinal Bernardin Cancer Center. In addition. the Cancer Center will replace Hematology/Oncology as the organization responsible for this grant and data

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management will become a Cancer Center core service. In the latest SWOG evaluation of Loyola, this institution ranked in the top quartile of all members in the following categories: patient registration, committee membership, study coordination, and authorship. In addition, the Loyola SWOG grant has always been viewed as having a low cost per case and the grant has never had a Type V funding reduction. As outlined in the CCIRC guidelines, support is requested to permit continuation of Loyola's scientific leadership and patient accrual during the next grant cycle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ST.LOUIS-CAPE GIRARDEAU CCOP Principal Investigator & Institution: Henry, Patrick H.; Chairman; St.Louis-Cape Girardeau Ccop 12800 Corporate Hill Dr St. Louis, Mo 63131 Timing: Fiscal Year 2002; Project Start 01-JUN-1987; Project End 31-MAY-2007 Summary: (provided by applicant): The St. Louis-Cape Girardeau CCOP is a consortium of four hospitals in two separate bi-state health service areas serving parts of eastern Missouri and western Illinois. The Investigators from the St. Louis Metropolitan area are affiliated with one or both of the two hospitals in the consortium and have worked together for the past eighteen years in cancer treatment research protocols and more recently, in cancer control research studies. The Cape Girardeau Investigators have worked with CCOP for the past nine years and are affiliated with two hospitals in that city. During the next five years we expect to accrue at least sixty credits per year for cancer treatment research protocols of the NSABP and SWOG and at least seventy five credits (new participants and follow-up) per year for cancer control and prevention studies. These cancer control credits will be derived primarily from our participation in the Breast Cancer Prevention Trial-1, Prostate Cancer Prevention Trial-1 and the Breast Cancer Prevention Trial-2. We will continue to provide high quality data to the Southwest Oncology Group and the National Surgical Adjuvant Breast and Bowel Project which are our research bases, utilizing the data management system developed during the past eighteen years. In summary, we will continue our excellent performance of the past eighteen years in cancer treatment research studies and extend our more recent participation in cancer control and prevention trials. The past experience and capabilities of the Investigators and Clinical Research Associates provides a strong base for continuing development of this Community Clinical Oncology Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRATEGIES FOR CURE IN NEWLY DIAGNOSED MULTIPLE MYELOMA Principal Investigator & Institution: Barlogie, Bart; Director; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2003 Summary: (Applicant's Description) Project 1 will explore novel therapeutic strategies for newly diagnosed MM patients in an effort to improve upon clinical results obtained with the "Total Therapy Program," developed and instituted during the past funding period. Total Therapy, which comprises multi-regimen induction and myeloablative therapy in the tandem transplant setting, has allowed advances in myeloma therapy to be made at last, achieving CRs in 40-50 percent of patients, which lasted a median of 50 months. The goal of future therapies must be to further enhance the incidence and duration of CR, which is the focus of Project 1. We will develop and test new treatment strategies based on our long-standing hypothesis that therapies that increase the

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incidence of CR are key to eliciting longer event-free survival and overall survival in newly diagnosed myeloma patients. Four specific aims will address two problem areas: being able to achieve a high incidence of sustained CR and identifying obstacles to sustaining CR (genetically defined resistance, tumor burden). SA1: Evaluate, in a randomized phase III clinical trial, whether the addition of the anti-angiogenesis compound, thalidomide, to the total therapy regimen can improve CR rate and extend CR duration as well as event-free and overall survival in newly diagnosed patients. SA2: Determine, in a randomized trial, whether further intensification of consolidation therapy after tandem autotransplants can increase CR rate and prevent disease recurrence. SA3: Prospectively dissect the genetic heterogeneity of myeloma by performing metaphase and interphase FISH karyotyping at defined intervals during therapeutic intervention in the context of clinical outcome related to the 2 therapeutic trial questions posed in Aims 1 & 2. SA4: Evaluate, systematically and in a prospective fashion, the usefulness of serial magnetic resonance (MR) imaging analysis of axial marrow to document the pattern and extent of marrow involvement (tumor burden) and changes during therapy ("MR-CR") as they relate to outcome. These studies are a logical extension of the findings obtained during the previous funding period and, in concert with research conducted in 5 other projects and with access to 3 cores, will provide currently unavailable insights into myeloma biology and staging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHWAYS

TARGETED

INTERVENTION

OF

BREAST

ONCOGENIC

Principal Investigator & Institution: Sebti, Said M.; Professor of Oncology, Biochemistry, And; H. Lee Moffitt Cancer Ctr & Research Ins and Research Institute, Inc. Tampa, Fl 336129497 Timing: Fiscal Year 2003; Project Start 13-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The overall goal of this project is to understand the role of the oncogenic and tumor survival pathways, Mek/Erk, JAK/STAT3 and PI3K/Akt in breast oncogenesis and to develop new strategies for more effective breast cancer treatment. The receptor tyrosine kinase ErbB2 is overexpressed in human breast cancer and this is associated with poor prognosis. ErbB2 heterodimerizes with ErbB1(EGFR), ErbB3 or ErbB4 and stimulates many signal transduction pathways leading to the constitutively activated Akt, STAT3 and Erkl/2 in breast cancer. It remains; however, unclear which of these pathways are most important for maintaining malignant transformation. Furthermore, the contribution of Mek/Erk, JAK/STAT3 and PI3K/Akt pathways to breast oncogenesis and treatment outcome is not known. We and others have developed disrupters of these signaling pathways including antibodies to ErbB2 and inhibitors of ErbB1 tyrosine kinase, Mek and PI3K kinases, JAK/STAT3 signaling and farnesyltransferase, an enzyme required for the activation of farnesylated proteins such as Ras which activates Mek/Erk and PI3K/Akt pathways. In this project we propose to test the hypothesis that constitutively activated Mek/Erk, JAK/STAT3 and/or PI3K/Akt pathways contribute to breast oncogenesis and tumor resistance, and that targeted intervention of these pathways blocks malignant transformation, induces apoptosis and sensitizes breast tumors to chemotherapy. This hypothesis will be tested through the following specific aims: 1) To investigate the role of constitutively activated PI3K/Akt, JAK/STAT3 and Mek/Erk, in breast cancer oncogenesis. Here we will determine if genetic and pharmacological disruptions of these pathways reverse malignant transformation and induce apoptosis. Dominant negative forms of PI3K, Akt, Mek, STAT3 and Ras will be used. Pharmacological inhibitors of JAK/STAT3 pathway,

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PI3K, Mek and farnesyltransferase will also be used individually or in combination. 2) To determine if resistance to Herceptin or Iressa of ErbB2 and/or EGFR overexpressing breast cancer cells is due to constitutively activated Akt/PI3K, JAK/STAT3 and/or MEK/Erk pathways. To this end, we will determine if inhibitors of these pathways sensitize breast cancer cells to Herceptin and/or Iressa. 3) To determine if resistance of breast cancer cells to Adriamycin, cyclophosphamide and/or taxotere could be overcome by targeted pharmacological intervention of PI3K/Akt, Mek/Erk and/or JAK/STAT3 pathways. 4) To conduct a hypothesis-driven phase I/lI clinical trial of preoperative Adriamycin (A), cyclophosphamide (C) and FTI R115777 (Zarnestra) in patients with locally advanced breast cancer and metastatic breast cancer. Here we will determine if pre-treatment levels of ErbB1, ErbB2, ErbB3 and/or ErbB4, and phosphorylated levels of Akt, STAT3 and/or Erkl/2 predict clinical response to AC/FTI. We will also correlate clinical response to ability to suppress protein farnesylation and the levels of phospho Akt, phospho Erkl/2 and/or phospho STAT3. Results from these studies will enhance our understanding of the role of Mek/Erk, JAK/STAT3 and PI3K/Akt pathways in breast cancer oncogenesis and treatment outcome and will result in improved therapies of human breast cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPEUTIC RESPONSE IN LGL LEUKEMIA Principal Investigator & Institution: Loughran, Thomas P.; Internal Medicine; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2002; Project Start 03-APR-2001; Project End 31-MAR-2006 Summary: (Applicant's Abstract) The broad long term of this proposal is to design better treatment for large granular lymphocyte (LGL) leukemia. LGL leukemia is a clonal lymphoproliferative disorder associated with autoimmune disease. Our central hypothesis is that LGL leukemia results from dysregulated apoptosis. The goal of this proposal is to understand the mechanisms of treatment response in this model by pursuing correlative laboratory studies associated with an ECOG trial. Patients with neutropenia or anemia will initially receive oral methotrexate. Patients failing to respond to methotrexate will then receive oral cyclophosphamide. Samples from patients receiving cyclosporine on a CALGB study will also be evaluated. Each specific aim will test a postulated mechanism of treatment efficacy: Specific Aim 1: To determine if treatment induces apoptosis in leukemic LGL; Specific Aim 2: To determine if treatment results in decreased secretion of Fas ligand; Specific Aim 3: To determine if treatment response is related to constitutive STAT signaling and regulation of STATresponsive genes. Correlative studies in Specific Aim 1 include development of a predictive in vitro apoptotic assay and measurement of decoy Fas receptors on treatment. Mechanistic studies will investigate the mitochondrial-dependent apoptotic pathway induced by MTX. Correlative studies in Specific Aim 2 will measure levels of Fas ligand on treatment. Mechanistic studies will examine regulation of Fas ligand gene transcription. Correlative studies in Specific Aim 3 will measure levels of STAT activation and Mcl-1 protein expression on treatment. Treatment effects on expression of STAT-regulated genes will be examined using microarray analyses. Results of these studies should identify important molecular targets for drug development in hematologic malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Cyclophosphamide

Project Title: LEUKEMIA

TRANSLATIONAL

STUDIES

OF

ALKYLATOR

INDUCED

Principal Investigator & Institution: Weiss, Brian D.; Pediatrics; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Applicant's Description): Our laboratory recently discovered a high incidence of myeloid malignancies in heterozygous Nf1 mutant (Nf1 +/-) mice treated with the commonly used chemotherapeutic agent cyclophosphamide (CP). The subject of this application is to utilize this novel murine model for translational and mechanistic studies of CP-induced myeloid leukemia. These goals will be pursued through three specific aims. In aim 1, we will test the hypotheses (a) that increasing CP dose intensity will increase the incidence of t-ML in Nf1 +/- mice, and (b) that the chemopreventive agent amifostine will partially protect CP-treated Nf1 +/- mice from t-ML. Aim 2 will test the hypothesis that inactivation of the normal Nf1 allele correlates with clinical evidence of t-ML in Nf in mutant mice, and will perform molecular analyses to characterize the mechanism of Np inactivation in CP- treated mice. We will also determine the frequency of Hprt gene inactivation in lymphocytes from control mice and from mice that have been treated with CP, amifostine, or with both agents. These experiments will allow us to ascertain if Hprt mutation rates provide a useful surrogate marker. CP is metabolized to acrolein and to phosphoramide mustard (PM). While PM is responsible for the anti-tumor effects of CP, recent data implicate acrolein as contributing to its leukemogenic properties. Resolving this question has important implications for designing cytotoxic agents with reduced mutagenic potential. Therefore, our final aim will involve determining the incidence of leukemia in cohorts of Nf1+/- mice treated with CP, with an analog that produces only acrolein, or with an analog that generates only PM. In addition, we will perform correlative studies as described under aim 2. These experiments will allow us to compare the leukemogenic effects of these two major metabolites of CP, as well as the type(s) of genetic lesions which occur at Nf1 in hematopoietic cells from mice that received these agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATING ACUPRESSURE

CHEMOTHERAPY

INDUCED

NAUSEA

WITH

Principal Investigator & Institution: Dibble, Suzanne L.; Professor; Institute for Health and Aging; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 02-AUG-2001; Project End 31-MAR-2004 Summary: Although the newer antiemetic agents have controlled a notable portion of the vomiting associated with chemotherapy administration, nausea continues to be a significant problem. Therefore, the specific aims of this [randomized clinical trial] are to compare differences in the nausea experience and intensity among three groups (Total N=237) undergoing doxorubicin hydrochloride (Addamycin ) and cyclophosphamide with or without fluorouracil chemotherapy for breast cancer. The groups are those receiving a) usual nausea care plus "Active Acupressure" via finger pressure on the nei guan point (P6), b) usual nausea care plus placebo acupressure and c) usual nausea care. Secondarily, the differences in quality of life, anxiety, and functional status among these group participants will be explored. Using eight oncology settings, participants will be recruited who had experienced nausea with their previous chemotherapy treatment. They will be randomly assigned to treatment groups. Stratification criteria will include

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regimen and site. The interventions will be conducted by carefully trained research assistants. All participants will be followed on a daily basis for two cycles of chemotherapy (a cycle is usually 21- 28 days). Analyses will be done using repeated measures analysis of variance and analysis of covariance, when baseline data is an appropriate covariate. A strength of this study is that it does not pit modem Western and Chinese medicine against each other to determine which is more effective. All participants will continue to receive their Western medical care, but the added value of acupressure will be explored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT OF CHILDHOOD CANCER Principal Investigator & Institution: Brecher, Martin L.; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: Cooperative trials in pediatric cancer patients have played a major role in the remarkable improvement in cure of childhood cancers. Because most childhood cancers are rare, it is only through this mechanism that adequate numbers of patients can be accrued in reasonable lengths of time for randomized controlled studies. The Department of Pediatrics at Roswell Park Cancer Institute (RPCI) has actively participated in cooperative group trials via the Pediatric Oncology Group (POG) to answer treatment questions which would be impossible to answer were we to conduct only single institution studies. Some pediatric solid tumors are so rare that national intergroup studies are required. We also participate in these intergroup studies. RPCI investigators are coordinators for a number of POG protocols including front-line studies for the treatment of advanced Hodgkin's disease, advanced small non- cleaved cell lymphoma, non-rhabdomyosarcoma soft tissue sarcomas, acute lymphoblastic leukemia in relapse, the National Wilms Tumor Study, brain tumors in infants, and the Intergroup Ewing's Sarcoma Study. Roswell Park investigators have also developed POG phase II studies of continuous infusion 5-fluouracil and the combination of cisplatin, ifosfamide and etoposide. Roswell Park investigators chair the Wilms Tumor Committee, the Neuroscience Subcommittee of the Brain Tumor Committee, and cochair the Pathology Discipline Core Committee, as well as being active on a number of other POG Core Committees. They have made major contributions over the last few years in the areas of solid tumor oncology, neuro- oncology and the treatment of lymphoid malignancies. We are strongly committed to the interdisciplinary approach to pediatric cancer and have established collaboration with the necessary clinical specialties including Radiation Medicine, Pediatric Surgery, Pediatric Neurology, Neurosurgery, and Orthopedic Surgery, as well as with researchers in immunology, pharmacology and molecular biology. As more children are cured of their cancers, the identification and prevention, when feasible, of complications of therapy have become imperative. We have been a major contributor to the identification and understanding of the long-term medical and psychosocial effects of the treatment of leukemia, Hodgkin's disease, and a number of solid tumors, both through the cooperative group mechanism and through institutional studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: UCLA/JCCC--SOUTHWEST ONCOLOGY GROUP Principal Investigator & Institution: Barstis, John; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024

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Timing: Fiscal Year 2002; Project Start 05-FEB-1993; Project End 31-DEC-2003 Summary: Support is requested to permit the University of California, Los Angeles, Center for the Health Sciences (UCLA/CHS) and its affiliated hospitals and physicians to continue participation as a full member in the scientific efforts of the Southwest Oncology Group (SWOG). UCLA/CHS affiliated hospitals include Olive View Medical Center (OVMC), Wadsworth Veterans Administration Medical Center (WVA), and Harbor General Hospital (HGH), and will be referred to as the University. The University entered SWOG as a probationary member in May 1990 with full membership status established in October 1991. Using the SWOG group mechanism as a multidisciplinary focus for clinical cancer research, the University's objectives include: (1) continue to further strengthen clinical cancer investigations at the University and within the NCI designated Jonsson Comprehensive Cancer Center (JCCC); (2) bridge the expertise in translational research within the University to strengthen SWOG's scientific efforts; (3) become major patient contributors to the group's phase III and multimodality studies with special emphasis on recruiting minority patients to clinical trials; and (4) enhance accrual by expanding the current University CGOP relationships to include the recently established UCLA/JCCC Network sites. Specifically, the University's aim is to continue its clinical research leadership by developing appropriate proposals in its areas of expertise, utilizing the University's translational and clinical strengths as they apply to: (1) the use of biological agents, products of molecular genetics, combination cytokine therapy, gene therapy, and cellular adoptive immunotherapy, in the treatment of solid tumors; (2) integrate the JCCC Clinical Program Areas of (A) leukemia (lymphoma, myeloma), BMT, and (B) solid tumor oncology, into the three specific aims noted above; and (3) enhance the SWOG program by using UCLA/JCCC expertise in cancer control, quality of life issues including minority initiatives in breast cancer and lung cancer, survivorship issues for lymphoma patients, and behavioral modification programs. Lastly, the diverse sociocultural atmosphere of Southern California, particularly at OVMC and HGH, provides the University with a large minority patient population. This, along with the designation of UCLA/CHS as a NCI designated Comprehensive Cancer Center, attracts patients seeking new therapeutic modalities and clinical trials and provides a large pool of patients for these studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UCSF AUTOIMMUNITY CENTER OF EXCELLENCE Principal Investigator & Institution: Wofsy, David; Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The broad aim of this application is to translate advances in immunology and molecular biology into practical, safe, and effective therapies for people with autoimmune diseases. Toward this end, we will participate in collaborative clinical trials of novel immunotherapies, and we will conduct basic research into the mechanisms that lead to autoimmunity as well as the mechanisms that can be harnessed to prevent autoimmunity. This proposal to become an Autoimmunity Center of Excellence consists of a Clinical Center, two basic research projects, and an Immune Function Monitoring Core as described below: Clinical Center (David Wofsy, PI). Investigators involved in this application have extensive experience in the conduct of clinical trials in diverse autoimmune diseases. This application focuses primarily on systemic lupus erythematosus (SLE), multiple sclerosis (MS), and type I diabetes mellitus (IDDM). Two clinical protocols are proposed, both based on basic research conducted at UCSF by participants in this proposal. Protocol 1 is based on the

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observation that blockade of T cell co-stimulation by CTLA4Ig, in combination with conventional therapy with cyclophosphamide, produces long-lasting benefit in murine lupus. It tests the hypothesis that this approach to therapy will be effective in people with lupus nephritis. Protocol 2 is based on the observation that HMG-CoA inhibitors ('statins') retard murine models for MS. It tests the hypothesis that atorvastatin will prevent progression to MS in patients at high risk. Project 1 - Activation and functions of regulatory T lymphocytes (Abul Abbas and Jeffrey Bluestone, co-PIs): The principal goals of this project are: (1) to clarify the signals involved in the induction and maintenance of regulatory T cells (Treg); and (2) to understand the mechanisms by which Treg control potentially pathogenic effector cells. Project 2 - Targeting antigenspecific T cells in SLE (David Daikh, PI): The principal goals of this project are: (1) to use murine models for SLE to clarify the mechanisms of disease, and to understand the basis for the efficacy of specific therapeutic interventions; and (2} to develop novel antigenspecific approaches to the treatment of autoimmune disease in murine models as a prelude to clinical trials in humans. Immune Function Monitoring Core (Lawrence Fong, PI): This core facility will provide the capability for developing and performing cellular and antibody-based immune assays on samples (e.g., blood, lymph node, etc.) derived from patients participating in ACE trials. Assays that will be available include: flow cytometry; MHC/peptide tetramer production and staining; cytokine analysis by ELISA, ELISPOT, and flow; T cell proliferation; and cytotoxicity assays. This core will support the Clinical Center and Project 2. Together, the Clinical Center, individual projects, and Immune Monitoring Core comprise a tightly linked program to bring novel therapies from bench to bedside and to investigate the mechanisms by which these therapies retard autoimmune disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UNIV OF IOWA CALGB INSTITUTIONAL GRANT Principal Investigator & Institution: Clamon, Gerald H.; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): This application is to continue the University of Iowa participation in studies of Cancer and Leukemia Group B. Our goals over the next 5 year period will include: (1) maintenance of accrual to clinical trials of over 100 patients per year (2) add new studies to the CALGB program in the area of: (a) use of Perillyl alcohol as an inhibitor of RAS function both as an antineoplastic in combination with other agents and possibly as a chemopreventive agent, (b) assessment of RAS mutations in the peripheral blood of women who have had chemotherapy as an adjuvant for breast cancer and would be at risk for myelodysplastic syndrome and leukemia, (c) further trials of omega three fatty acids as therapy for cancer cachexia and as an adjuvant to therapy in cancer, (d) continue to develop combined modality therapy for stage 3 and 4 non-small cell lung cancer. In particularly, a pilot at the University of Iowa of Gemcitabine/Carboplatin for non-small cell lung cancer may be able to help CALGB in the future (3) expand CALGB trials to rural hospitals in Iowa where University of Iowa physicians are now providing oncology care (Washington, Iowa; Keosauqua, Iowa; Dubuque, Iowa; Muscatine, Iowa; Fairfield, Iowa; Fort Madison, Iowa) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: WESTERN REGIONAL COMMUNITY CLINICAL ONCOLOGY PROGRAM Principal Investigator & Institution: King, David K.; Banner Good Samaritan Medical Center Phoenix, Az 85006 Timing: Fiscal Year 2002; Project Start 01-SEP-1983; Project End 31-MAY-2003 Summary: The Greater Phoenix Community Clinical Oncology Program (GPCCOP)is a consortium of five hospitals with 67 investigations led by principal investigator David K. King, M.D. Dr. King and many of the investigators have been associated with the CCOP since its initial planning stage in 1982. The continuing long-term goals and specific aims of the GPCCOP include: 1) increased clinical research activities; 2) access to additional clinical trials; 3) further development of cancer control research initiatives and patient accrual; 4) maintenance of quality data management; 5) pharmacy resources to coordinate and manage drug distribution; 6) involvement of primary care physicians in state-of-the- art cancer management and education; and 7) continued development of data management systems to support NCI evaluations. GPCCOP's organizational structure requires the involvement of the Co- Principal Investigators and hospital administrators from each of the participating institutions in the planning and policymaking decisions of the CCOP. The physicians, nurses and administrative staff have active roles in guiding the GPCCOP toward attainment of its goals. This experienced team has demonstrated their commitment and ability to accrue patients to both therapeutic and cancer control protocols while maintaining high levels of quality control and timely submissions. GPCCOP's data management systems were recognized by SWOG in 1991 with the Outstanding Achievement Award. Additional investigators, specializing in medical and radiation oncology, have been recruited to the GPCCOP to ensure the availability of total patient care for the 3000 average new patients seen each year. By adding investigators from the Tucson area and adding the GOG as a research base, a higher level of participation is expected. The above resources, the placement of 347 patients on treatment protocols and 1097 patients on cancer control trials during the period 1989 to present demonstrate GPCCOP's preparedness to continue its active participation in NCI's Community Oncology Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: WUSM CANCER AND LEUKEMIA GROUP B Principal Investigator & Institution: Bartlett, Nancy L.; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 08-MAY-1998; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): Washington University has been a CALGB main member institution since 1986. Due to loss of key personnel and limited groupwide CALGB funding, we were not funded during the previous grant cycle. Therefore, this proposal serves as a new institutional application to re-establish Washington University in the funded scientific activities of the CALGB. In 1994, Washington University recruited Dr. Daniel Ihde, a national expert in the treatment of lung cancer and Dr. John DiPersio, an expert in hematopoietic stem cell biology, as Chief of the Division of Bone Marrow Transplantation and Stem Cell Biology. Since joining the faculty, Dr. Ihde has served as Washington University's CALGB Principal Investigator. Both Drs. lhde and DiPersio have a strong commitment to clinical research and have recruited and fostered many new clinical Investigators. The University was awarded a National Cancer Institute Cancer Center Planning Grant in July, 1995. Dr. Ihde and Dr. Stanley Korsmeyer lead the Cancer Center planning efforts and have stimulated

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vigorous collaboration between clinical and basic science investigators over the last 18 months. Many of these collaborations have resulted in new institutional pilot studies, including studies of new multidrug resistance modulators and regulators of programmed cell death. Promising pilot studies will be presented to CALGB committees for possible incorporation into group protocols during the next grant cycle, Since Dr. lhde's recruitment, Washington University's commitment to CALGB has been demonstrated in several ways. Accrual has increased from 52 in 1994 to 118 in 1996. Our data management has improved substantially with our most recent IPEC report placing us in the top one third of CALGB institutions in completeness and consistency. The number of investigators on scientific committees has increased from five in 1993 to eighteen at present. Eleven current, recently closed, or proposed studies are chaired by Washington University investigators. Three members have participated in audit site visits, the membership committee, and the conflict of interest committee. Our large patient base will help us maintain excellent CALGB accrual during the coming years. Barnes-Jewish Hospital, the largest hospital in St. Louis, diagnoses more than 4,000 patients a year with cancer and is the major referral center for southeast Missouri and southern Illinois. We expect referrals to increase significantly over the next five years with the construction of our new approved and funded state-of-the-art clinical cancer center building which is projected to be completed in 2000. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “cyclophosphamide” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for cyclophosphamide in the PubMed Central database: •

Correlation between in vivo and in vitro studies of modulation of resistance to experimental Candida albicans infection by cyclophosphamide in mice. by Bistoni F, Baccarini M, Blasi E, Marconi P, Puccetti P, Garaci E.; 1983 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264816

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Cytochrome P-450 2C9 Sensitizes Human Prostate Tumor Cells to Cyclophosphamide via a Bystander Effect. by Zhou D, Lu Y, Steiner MS, Dalton JT.; 2000 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90131

3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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D-Tryptophan-6 analog of luteinizing hormone-releasing hormone as a protective agent against testicular damage caused by cyclophosphamide in baboons. by Lewis RW, Dowling KJ, Schally AV.; 1985 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397689

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Effect of cyclophosphamide in vitro and on vaccinia virus replication in tissue culture. by Ginsberg AH, Monte WT, Johnson KP.; 1977 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=353813

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Effect of cyclophosphamide on experimental Nocardia asteroides infection in mice. by Beaman BL, Maslan S.; 1977 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=421062

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Effect of Cyclophosphamide on Histoplasma capsulatum Infections in Mice. by Cozad GC, Lindsey TJ.; 1974 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=414796

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Effect of cyclophosphamide on infections in mice caused by virulent and avirulent strains of influenza virus. by Hurd J, Heath RB.; 1975 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=415152

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Effect of cyclophosphamide on the growth of Rickettsia sennetsu in experimentally infected mice. by Tachibana N, Kobayashi V.; 1975 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=415333

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Effect of cyclophosphamide on the immune response to Pseudomonas aeruginosa in mice. by Pierson CL, Johnson AG, Feller I.; 1976 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=420860

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Effect of cyclophosphamide on the immune responsiveness of jirds infected with Brugia pahangi. by Katz SP, Lammie PJ.; 1984 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264365

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Effect of cyclophosphamide on the response of chickens to a virulent strain of Marek's disease virus. by Kermani-Arab V, Moll T, Cho BR, Davis WC, Lu YS.; 1975 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=415397

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Effects of corticosteroids and cyclophosphamide on a mouse model of Chlamydia trachomatis pneumonitis. by Stephens RS, Chen WJ, Kuo CC.; 1982 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351095

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Effects of cyclophosphamide and a metabolite, acrolein, on Naegleria fowleri in vitro and in vivo. by Zhang L, Marciano-Cabral F, Bradley SG.; 1988 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=172325

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Effects of cyclophosphamide and ceftriaxone on gastrointestinal colonization of mice by Candida albicans. by Samonis G, Karyotakis NC, Anaissie EJ, Barbounakis E, Maraki S, Tselentis Y, Bodey GP.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163505

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Effects of immunosuppression with cyclophosphamide on acute murine cytomegalovirus infection and virus-augmented natural killer cell activity. by Selgrade MK, Daniels MJ, Hu PC, Miller FJ, Graham JA.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=347855

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Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates. by Gillio AP, Gasparetto C, Laver J, Abboud M, Bonilla MA, Garnick MB, O'Reilly RJ.; 1990 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296606

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Failure of cyclophosphamide to significantly enhance isolation of Rickettsia tsutsugamushi from wild Philippine rats. by van Peenen PF, Ho CM, See R.; 1977 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=274528

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Increased Bone Marrow Production of Granulocytes and Mononuclear Phagocytes Induced by Mycobacterial Adjuvants: Improved Recovery of Leukopoiesis in Mice After Cyclophosphamide Treatment. by Buhles WC Jr, Shifrine M.; 1978 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=421550

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Influence of etoposide and cyclophosphamide on the efficacy of cloxacillin and erythromycin in an experimental staphylococcal infection. by Calame W, van der Waals R, Mattie H, van Furth R.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284270

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Modulation of delayed-type hypersensitivity and cellular immunity to microbial vaccines: effects of cyclophosphamide on the immune response to tularemia vaccine. by Ascher MS, Parker D, Turk JL.; 1977 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=421233

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Suppressive effect of cyclophosphamide on the T-cell system in chickens. by Sharma JM, Lee LF.; 1977 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=421104

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Susceptibility of mice treated with cyclophosphamide to lethal infection with Leptospira interrogans Serovar pomona. by Adler B, Faine S.; 1976 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=420943

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Cyclophosphamide

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with cyclophosphamide, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “cyclophosphamide” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for cyclophosphamide (hyperlinks lead to article summaries): •

A dose-intensive, cyclophosphamide-based regimen for the treatment of recurrent/progressive or advanced solid tumors of childhood: a report from the Australia and New Zealand Children's Cancer Study Group. Author(s): Carpenter PA, White L, McCowage GB, Nayanar V, Toogood I, Shaw PJ, Lockwood L, Tiedemann K. Source: Cancer. 1997 August 1; 80(3): 489-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9241083

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A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma. Author(s): Einsele H, Bamberg M, Budach W, Schmidberger H, Hess CF, Wormann B, Meisner C, Straka C, Hebart H, Trumper L, Kroger N, Zander AR, Hegewisch-Becker S, Hossfeld DK, Schmidt H, Muller P, Schlimok G, Hertenstein B, Peest D, Metzner B, Frickhofen N, Kanz L, Bensinger WI. Source: Bone Marrow Transplantation. 2003 September; 32(6): 593-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12953132

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A pilot study of chemoimmunotherapy (cyclophosphamide, prednisone, and rituximab) in patients with post-transplant lymphoproliferative disorder following solid organ transplantation. Author(s): Orjuela M, Gross TG, Cheung YK, Alobeid B, Morris E, Cairo MS. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 September 1; 9(10 Pt 2): 3945S-52S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506193

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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A prospective study of concurrent cyclophosphamide/methotrexate/5-fluorouracil and reduced-dose radiotherapy in patients with early-stage breast carcinoma. Author(s): Bellon JR, Shulman LN, Come SE, Li X, Gelman RS, Silver BJ, Harris JR, Recht A. Source: Cancer. 2004 April 1; 100(7): 1358-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15042668

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Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. Author(s): Papaldo P, Lopez M, Cortesi E, Cammilluzzi E, Antimi M, Terzoli E, Lepidini G, Vici P, Barone C, Ferretti G, Di Cosimo S, Nistico C, Carlini P, Conti F, Di Lauro L, Botti C, Vitucci C, Fabi A, Giannarelli D, Marolla P. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 September 15; 21(18): 3462-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972521

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Adjuvant cyclophosphamide, methotrexate and fluorouracil for node-positive breast cancer: a lifetime cost-utility analysis based on a modified Q-TWIST method. Author(s): Trippoli S, Becagli P, Messori A. Source: European Journal of Clinical Pharmacology. 1997; 53(3-4): 281-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9476047

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Adverse effects of tumour necrosis factor in cyclophosphamide-treated mice subjected to gut-derived Pseudomonas aeruginosa sepsis. Author(s): Matsumoto T, Tateda K, Miyazaki S, Furuya N, Ohno A, Ishii Y, Hirakata Y, Yamaguchi K. Source: Cytokine. 1997 October; 9(10): 763-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9344509

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Allogeneic bone marrow transplantation with matched unrelated donors for patients with hematologic malignancies using a preparative regimen of high-dose cyclophosphamide and fractionated total body irradiation. Author(s): Geller RB, Devine SM, O'Toole K, Persons L, Keller J, Mauer D, Holland HK, Dix SP, Piotti M, Redei I, Connaghan G, Heffner LT, Hillyer CD, Waller EK, Winton EF, Wingard JR. Source: Bone Marrow Transplantation. 1997 August; 20(3): 219-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9257890

82

Cyclophosphamide

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Allogeneic transplantation for recurrent or refractory non-Hodgkin's lymphoma with poor prognostic features after conditioning with thiotepa, busulfan, and cyclophosphamide: experience in 44 consecutive patients. Author(s): van Besien K, Thall P, Korbling M, Pugh WC, Khouri I, Mehra R, Giralt S, Anderlini P, Amin K, Mirza N, Seong D, Gajewski J, Hester J, Andersson B, Cabanillas F, Champlin R, Przepiorka D. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 1997 August; 3(3): 150-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9310192

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An overview of cyclophosphamide and ifosfamide pharmacology. Author(s): Fleming RA. Source: Pharmacotherapy. 1997 September-October; 17(5 Pt 2): 146S-154S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9322882

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Anemia in stage II and III breast cancer patients treated with adjuvant doxorubicin and cyclophosphamide chemotherapy. Author(s): Kirshner J, Hatch M, Hennessy DD, Fridman M, Tannous RE. Source: The Oncologist. 2004; 9(1): 25-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14755012

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Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? Author(s): Enns GM, Roeder E, Chan RT, Ali-Khan Catts Z, Cox VA, Golabi M. Source: American Journal of Medical Genetics. 1999 September 17; 86(3): 237-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10482872

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Application of a continual reassessment method to a phase I clinical trial of capecitabine in combination with cyclophosphamide and epirubicin (CEX) for inoperable or recurrent breast cancer. Author(s): Morita S, Toi M, Kobayashi T, Ito Y, Hozumi Y, Ohno S, Iwata H, Sakamoto J. Source: Japanese Journal of Clinical Oncology. 2004 February; 34(2): 104-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15067105

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Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer. Author(s): Petros WP, Broadwater G, Berry D, Jones RB, Vredenburgh JJ, Gilbert CJ, Gibbs JP, Colvin OM, Peters WP. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2002 March; 8(3): 698-705. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11895898

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Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia. Author(s): Bosanquet AG, Sturm I, Wieder T, Essmann F, Bosanquet MI, Head DJ, Dorken B, Daniel PT. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 June; 16(6): 1035-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12040435

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Bcl-2/bcl-xL bispecific antisense treatment sensitizes breast carcinoma cells to doxorubicin, paclitaxel and cyclophosphamide. Author(s): Simoes-Wust AP, Schurpf T, Hall J, Stahel RA, Zangemeister-Wittke U. Source: Breast Cancer Research and Treatment. 2002 November; 76(2): 157-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12452453

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Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes. Author(s): Griskevicius L, Yasar U, Sandberg M, Hidestrand M, Eliasson E, Tybring G, Hassan M, Dahl ML. Source: European Journal of Clinical Pharmacology. 2003 June; 59(2): 103-9. Epub 2003 April 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684728

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Biologically based risk assessment model for cyclophosphamide hematotoxicity in animal species: concluding comments. Author(s): Andersen ME, Krewski D. Source: Journal of Toxicology and Environmental Health. Part A. 2000 November; 61(56): 543-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11086966

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Bladder carcinoma associated with cyclophosphamide therapy for ovarian cancer occurring with a latency of 20 years. Author(s): Volm T, Pfaff P, Gnann R, Kreienberg R. Source: Gynecologic Oncology. 2001 July; 82(1): 197-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11426986

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Bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone (BLEO-CCVPP) in patients with Hodgkin's disease who relapsed after radiotherapy alone: a long-term follow-up study of the Eastern Cooperative Oncology Group (E3481). Author(s): Wiernik PH, Leong T, Oken MM, Neiman RS, Habermann TM, Bennett JM, Schuster S, Glick JH. Source: Leukemia & Lymphoma. 2001 January; 40(3-4): 357-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11426558

84

Cyclophosphamide

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Bone marrow transplantation for patients with acquired severe aplastic anemia using cyclophosphamide and antithymocyte globulin: the experience from a single center. Author(s): Abdelkefi A, Ben Othman T, Ladeb S, Torjman L, Hsairi M, Ben Abdeladhim A. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2003; 4(3): 208-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764353

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Bone marrow transplantation for patients with Fanconi anemia: reduced doses of cyclophosphamide without irradiation as conditioning. Author(s): Medeiros C, Zanis-Neto J, Pasquini R. Source: Bone Marrow Transplantation. 1999 October; 24(8): 849-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10516695

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Bone marrow transplantation for transfused patients with severe aplastic anemia using cyclophosphamide and total lymphoid irradiation as conditioning therapy: long-term follow-up from a single center. Author(s): Gaziev D, Giardini C, Galimberti M, Lucarelli G, Angelucci E, Polchi P, Baronciani D, Erer B, Sotti G. Source: Bone Marrow Transplantation. 1999 August; 24(3): 253-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10455362

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Bone marrow transplantation from matched siblings in patients with fanconi anemia utilizing low-dose cyclophosphamide, thoracoabdominal radiation and antithymocyte globulin. Author(s): Ayas M, Solh H, Mustafa MM, Al-Mahr M, Al-Fawaz I, Al-Jefri A, Shalaby L, Al-Nasser A, Al-Sedairy R. Source: Bone Marrow Transplantation. 2001 January; 27(2): 139-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11281382

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Bronchial epithelial atypia mimicking squamous cell carcinoma secondary to cyclophosphamide therapy. Author(s): Walker T, Mukerjee D, Levine TS. Source: Cytopathology : Official Journal of the British Society for Clinical Cytology. 2002 October; 13(5): 330-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421451

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Bulky disease is an adverse prognostic factor in patients treated with chemotherapy comprised of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy for aggressive lymphoma. Author(s): Wilder RB, Rodriguez MA, Ha CS, Pro B, Hess MA, Cabanillas F, Cox JD. Source: Cancer. 2001 June 15; 91(12): 2440-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11413536

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Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. Author(s): Crivellari D, Bonetti M, Castiglione-Gertsch M, Gelber RD, Rudenstam CM, Thurlimann B, Price KN, Coates AS, Hurny C, Bernhard J, Lindtner J, Collins J, Senn HJ, Cavalli F, Forbes J, Gudgeon A, Simoncini E, Cortes-Funes H, Veronesi A, Fey M, Goldhirsch A. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2000 April; 18(7): 1412-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10735888

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Busulfan and cyclophosphamide as a conditioning regimen for pediatric acute lymphoblastic leukemia patients undergoing bone marrow transplantation. Author(s): Shah AJ, Lenarsky C, Kapoor N, Crooks GM, Kohn DB, Parkman R, Epport K, Wilson K, Weinberg K. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2004 February; 26(2): 91-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767194

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Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and marrow transplantation in patients with non-Hodgkin's lymphoma. Author(s): Kiss TL, Panzarella T, Messner HA, Meharchand J, Reddy V, Schimmer AD, Lipton JH. Source: Bone Marrow Transplantation. 2003 January; 31(2): 73-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621486

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Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Author(s): Socie G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ, Remberger M, Deeg HJ, Ruutu T, Michallet M, Sullivan KM, Chevret S. Source: Blood. 2001 December 15; 98(13): 3569-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11739158

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Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with malignant lymphoma. Author(s): Hanel M, Kroger N, Sonnenberg S, Bornhauser M, Kruger W, Kroschinsky F, Hanel A, Metzner B, Birkmann J, Schmid B, Hoffknecht MM, Fiedler F, Ehninger G, Zander AR. Source: Annals of Hematology. 2002 February; 81(2): 96-102. Epub 2002 January 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11907790

86

Cyclophosphamide

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Busulfan-cyclophosphamide versus total body irradiation-cyclophosphamide as preparative regimen before allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia: what have we learned? Author(s): Ferry C, Socie G. Source: Experimental Hematology. 2003 December; 31(12): 1182-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14662323

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Carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss. Author(s): Mukhopadhyay S, Shrimpton AE, Jones LA, Nsouli IS, Abraham NZ Jr. Source: Archives of Pathology & Laboratory Medicine. 2004 January; 128(1): E8-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14692829

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Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial. Author(s): Untch M, Eidtmann H, du Bois A, Meerpohl HG, Thomssen Ch, Ebert A, Harbeck N, Jackisch C, Heilman V, Emons G, Wallwiener D, Wiese W, Blohmer JU, Hoffken K, Kuhn W, Reichardt P, Muscholl M, Pauschinger M, Langer B, Luck HJ. Source: European Journal of Cancer (Oxford, England : 1990). 2004 May; 40(7): 988-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15093573

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Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma. Author(s): Akpek G, Koh HK, Bogen S, O'Hara C, Foss FM. Source: Cancer. 1999 October 1; 86(7): 1368-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10506727

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Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. Author(s): Loehrer PJ Sr, Chen M, Kim K, Aisner SC, Einhorn LH, Livingston R, Johnson D. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1997 September; 15(9): 3093-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9294472

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Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and Fluorouracil in operable breast cancer. Author(s): Bonadonna G, Zambetti M, Moliterni A, Gianni L, Valagussa P. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 May 1; 22(9): 1614-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15117983

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Collection of peripheral blood progenitor cells after the administration of cyclophosphamide, etoposide, and granulocyte-colony-stimulating factor: an analysis of 497 patients. Author(s): Weaver CH, Schwartzberg LS, Birch R, Greco FA, Rhinehart S, Hainsworth J, Beeker T, Price H, Geier L, Foster J, West J, Hazelton B, Buckner CD. Source: Transfusion. 1997 September; 37(9): 896-903. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9308634

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Combined initial cyclophosphamide with repeated methylprednisolone pulse therapy for severe paraquat poisoning from dermal exposure. Author(s): Lin NC, Lin JL, Lin-Tan DT, Yu CC. Source: Journal of Toxicology. Clinical Toxicology. 2003; 41(6): 877-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677801

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Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis. Author(s): Lehman TJ, Edelheit BS, Onel KB. Source: Annals of the Rheumatic Diseases. 2004 March; 63(3): 321-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14962970

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Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Author(s): Anagnostopoulos A, Aleman A, Ayers G, Donato M, Champlin R, Weber D, Alexanian R, Giralt S. Source: Cancer. 2004 June 15; 100(12): 2607-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15197803

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Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma: high-dose cyclophosphamide plus GM-CSF vs G-CSF alone. Author(s): Alegre A, Tomas JF, Martinez-Chamorro C, Gil-Fernandez JJ, FernandezVillalta MJ, Arranz R, Diaz MA, Granda A, Bernardo MR, Escudero A, Lopez-Lorenzo JL, Fernandez-Ranada JM. Source: Bone Marrow Transplantation. 1997 August; 20(3): 211-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9257889

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Comparison of two different schedules of granulocyte-colony-stimulating factor during treatment for acute lymphocytic leukemia with a hyper-CVAD (cyclophosphamide, doxorubicin, vincristine, and dexamethasone) regimen. Author(s): Weiser MA, O'Brien S, Thomas DA, Pierce SA, Lam TP, Kantarjian HM. Source: Cancer. 2002 January 15; 94(2): 285-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11900213

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Cyclophosphamide

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Consolidation therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of cytosine arabinoside, epipodophyllotoxins and cyclophosphamide. Author(s): Estlin EJ, Yule SM, Lowis SP. Source: Cancer Treatment Reviews. 2001 December; 27(6): 339-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11908927

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Cyclophosphamide as alternative immunosuppressive therapy for autoimmune hepatitis--report of three cases. Author(s): Kanzler S, Gerken G, Dienes HP, Meyer zum Buschenfelde KH, Lohse AW. Source: Zeitschrift Fur Gastroenterologie. 1997 July; 35(7): 571-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9273991

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Cyclophosphamide metabolism is affected by azole antifungals. Author(s): Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M, McDonald GB. Source: Blood. 2004 February 15; 103(4): 1557-9. Epub 2003 September 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504090

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Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis. Author(s): Karni A, Balashov K, Hancock WW, Bharanidharan P, Abraham M, Khoury SJ, Weiner HL. Source: Journal of Neuroimmunology. 2004 January; 146(1-2): 189-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698862

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Cyclophosphamide or ifosfamide in patients with advanced and/or recurrent endometrial carcinoma: a randomized phase II study of the EORTC Gynecological Cancer Cooperative Group. Author(s): Pawinski A, Tumolo S, Hoesel G, Cervantes A, van Oosterom AT, Boes GH, Pecorelli S. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 1999 October; 86(2): 179-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10509788

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Cyclophosphamide, methotrexate, and cytarabine embropathy: is apoptosis the common pathway? Author(s): Vaux KK, Kahole NC, Jones KL. Source: Birth Defects Research. Part A, Clinical and Molecular Teratology. 2003 June; 67(6): 403-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962283

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Cyclophosphamide-associated uroepithelial toxicity. Author(s): Aviles RJ, Vlahakis SA, Elkin PL. Source: Annals of Internal Medicine. 1999 October 5; 131(7): 549. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10507982

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Cyclophosphamide-induced transitional cell carcinoma of bladder in lupus nephritis. Author(s): Chow SK, Looi LM, Loh CS, Yeap SS. Source: Internal Medicine Journal. 2002 March; 32(3): 114-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11885838

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DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an effective regimen for peripheral blood stem cell collection in multiple myeloma. Author(s): Lazzarino M, Corso A, Barbarano L, Alessandrino EP, Cairoli R, Pinotti G, Ucci G, Uziel L, Rodeghiero F, Fava S, Ferrari D, Fiumano M, Frigerio G, Isa L, Luraschi A, Montanara S, Morandi S, Perego D, Santagostino A, Savare M, Vismara A, Morra E. Source: Bone Marrow Transplantation. 2001 November; 28(9): 835-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781643

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Detection of radiation and cyclophosphamide-induced mutations in individual mouse sperm at a human expanded trinucleotide repeat locus transgene. Author(s): Zhang Y, Monckton DG, Siciliano MJ, Connor TH, Meistrich ML. Source: Mutation Research. 2002 April 26; 516(1-2): 121-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11943618

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Dexamethasone, paclitaxel, etoposide, cyclophosphamide (d-TEC) and G-CSF for stem cell mobilisation in multiple myeloma. Author(s): Bilgrami S, Bona RD, Edwards RL, Li Z, Naqvi B, Shaikh A, Furlong F, Fox J, Clive J, Tutschka PJ. Source: Bone Marrow Transplantation. 2001 July; 28(2): 137-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11509931

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Dexamethasone-cyclophosphamide pulse therapy for autoimmune-vesiculobullous disorders at Victoria hospital, Bangalore. Author(s): Sacchidanand S, Hiremath NC, Natraj HV, Revathi TN, Rani S, Pradeep G, Tenneti V. Source: Dermatology Online Journal [electronic Resource]. 2003 December; 9(5): 2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996375

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Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. Author(s): Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Source: The Journal of Clinical Investigation. 2003 January; 111(2): 187-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12531874

90

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DNA vaccination with heat shock protein 60 inhibits cyclophosphamide-accelerated diabetes. Author(s): Quintana FJ, Carmi P, Cohen IR. Source: Journal of Immunology (Baltimore, Md. : 1950). 2002 November 15; 169(10): 6030-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421990

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Docetaxel alternating with epirubicin and cyclophosphamide: a feasibility study in breast cancer patients. Author(s): ten Bokkel Huinink WW, Lustig V, Dubbelman R, Hiemstra A, Rodenhuis S. Source: European Journal of Cancer (Oxford, England : 1990). 1997 August; 33 Suppl 7: S23-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9486100

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Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. Author(s): Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 March 15; 21(6): 968-75. Erratum In: J Clin Oncol. 2003 May 15; 21(10): 2048. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12637459

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Does cyclophosphamide benefit relapsing thrombotic thrombocytopenic purpura? Author(s): Agarwal V, Sharma BL, Aggarwal A, Misra R. Source: J Assoc Physicians India. 2002 November; 50: 1440-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583481

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Does hepatocellular carcinoma develop after treatment of Wegener's granulomatosis with cyclophosphamide? Author(s): Ueno T, Sata M. Source: Intern Med. 2003 May; 42(5): 379-80. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12793704

Studies

91

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Dose-dense biweekly doxorubicin/docetaxel versus sequential neoadjuvant chemotherapy with doxorubicin/cyclophosphamide/docetaxel in operable breast cancer: second interim analysis. Author(s): Jackisch C, von Minckwitz G, Eidtmann H, Costa SD, Raab G, Blohmer JU, Schutte M, Gerber B, Merkle E, Gademann G, Lampe D, Hilfrich J, Tulusan AH, Caputo A, Kaufmann M. Source: Clinical Breast Cancer. 2002 October; 3(4): 276-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12425756

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Dose-escalated cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) chemotherapy for patients with diffuse lymphoma: Cancer and Leukemia Group B studies 8852 and 8854. Author(s): Bartlett NL, Petroni GR, Parker BA, Wagner ND, Gockerman JP, Omura GA, Canellos GP, Robert M, Johnson JL, Peterson BA. Source: Cancer. 2001 July 15; 92(2): 207-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11466671

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Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer. Author(s): Pagani O, Sessa C, Martinelli G, Cerny T, de Jong J, Goldhirsch A, Zimatore M, Cavalli F. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 1997 July; 8(7): 655-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9296218

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Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. Author(s): Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 February 15; 19(4): 943-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11181656

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Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. Author(s): Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 March 15; 19(6): 1707-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11251000

92

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Doxorubicin followed by sequential paclitaxel and cyclophosphamide versus concurrent paclitaxel and cyclophosphamide: 5-year results of a phase II randomized trial of adjuvant dose-dense chemotherapy for women with node-positive breast carcinoma. Author(s): Fornier MN, Seidman AD, Theodoulou M, Moynahan ME, Currie V, Moasser M, Sklarin N, Gilewski T, D'Andrea G, Salvaggio R, Panageas KS, Norton L, Hudis C. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2001 December; 7(12): 3934-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11751485

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Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Author(s): Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, DiazRubio E; GEICAM Group (Spanish Breast Cancer Research Group), Spain. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 June; 14(6): 833-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796019

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Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Author(s): Brodsky RA, Sensenbrenner LL, Smith BD, Dorr D, Seaman PJ, Lee SM, Karp JE, Brodsky I, Jones RJ. Source: Annals of Internal Medicine. 2001 October 2; 135(7): 477-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11578150

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E2F1 expression is related with the poor survival of lymph node-positive breast cancer patients treated with fluorouracil, doxorubicin and cyclophosphamide. Author(s): Han S, Park K, Bae BN, Kim KH, Kim HJ, Kim YD, Kim HY. Source: Breast Cancer Research and Treatment. 2003 November; 82(1): 11-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14672398

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Effect of corticosteroid and cyclophosphamide in IgA nephropathy patients with heavy proteinuria and/or moderate-severe pathological changes. Author(s): Chen KJ, Cheng CH, Wu MJ, Chen CH, Shu KH. Source: J Chin Med Assoc. 2003 May; 66(5): 263-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12908567

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Effect of open label pulse cyclophosphamide therapy on MRI measures of disease activity in five patients with refractory relapsing-remitting multiple sclerosis. Author(s): Gobbini MI, Smith ME, Richert ND, Frank JA, McFarland HF. Source: Journal of Neuroimmunology. 1999 September 1; 99(1): 142-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10496187

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93

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Effects of oral cyclophosphamide and prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis. Author(s): Apras S, Ertenli I, Ozbalkan Z, Kiraz S, Ozturk MA, Haznedaroglu IC, Cobankara V, Pay S, Calguneri M. Source: Arthritis and Rheumatism. 2003 August; 48(8): 2256-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12905480

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Effects of paclitaxel, cyclophosphamide, ifosfamide, tamoxifen and cyclosporine on the metabolism of methoxymorpholinodoxorubicin in human liver microsomes. Author(s): Beulz-Riche D, Robert J, Riche C, Ratanasavanh D. Source: Cancer Chemotherapy and Pharmacology. 2002 April; 49(4): 274-80. Epub 2002 January 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11914905

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Efficacy of cisplatin and cyclophosphamide combination for recurrent and metastatic carcinoma of the uterine cervix. Author(s): Eralp Y, Saip P, Sakar B, Tas F, Aydiner A, Topuz E. Source: Eur J Gynaecol Oncol. 2003; 24(3-4): 323-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807249

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Efficacy of cyclophosphamide combined with prednisolone in patients with AA amyloidosis secondary to rheumatoid arthritis. Author(s): Nakamura T, Yamamura Y, Tomoda K, Tsukano M, Shono M, Baba S. Source: Clinical Rheumatology. 2003 December; 22(6): 371-5. Epub 2003 November 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677008

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Efficacy of low-dose versus high-dose cyclophosphamide in lupus nephritis: comment on the article by Houssiau et al. Author(s): Block JA. Source: Arthritis and Rheumatism. 2003 May; 48(5): 1466; Author Reply 1466-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746929

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Elevated monocytic IL-12 and TNF-alpha production in Wegener's granulomatosis is normalized by cyclophosphamide and corticosteroid therapy. Author(s): Lamprecht P, Kumanovics G, Mueller A, Csernok E, Komocsi A, Trabandt A, Gross WL, Schnabel A. Source: Clinical and Experimental Immunology. 2002 April; 128(1): 181-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11982607

94

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Enhancement of the antitumor effect of cyclophosphamide with the hypoxia-selective cytotoxin NLCQ-1 against murine tumors and human xenografts. Author(s): Papadopoulou MV, Ji M, Bloomer WD, Hollingshead MG. Source: Journal of Experimental Therapeutics & Oncology. 2002 September-October; 2(5): 298-305. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416033

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Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal nodepositive breast cancer patients. A GEICAM 9401 study. Author(s): Pico C, Martin M, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J; GEICAM Group. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2004 January; 15(1): 79-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679124

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Epstein-Barr virus-associated B-cell lymphoproliferative disorder in CLL patients after treatment with fludarabine and cyclophosphamide followed by high-dose chemotherapy with autologous stem cell transplantation. Author(s): Jindra P, Koza V, Boudova L, Vozobulova V, Cerna K, Karas M, Lysak D, Svojgrova M. Source: Bone Marrow Transplantation. 2003 May; 31(10): 951-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748677

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Erdheim-Chester disease: pulmonary infiltration responding to cyclophosphamide and prednisolone. Author(s): Bourke SC, Nicholson AG, Gibson GJ. Source: Thorax. 2003 November; 58(11): 1004-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586060

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EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Author(s): Yee CS, Gordon C, Dostal C, Petera P, Dadoniene J, Griffiths B, Rozman B, Isenberg DA, Sturfelt G, Nived O, Turney JH, Venalis A, Adu D, Smolen JS, Emery P. Source: Annals of the Rheumatic Diseases. 2004 May; 63(5): 525-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15082482

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Evaluating the role of immunoablative high-dose cyclophosphamide therapy in pemphigus vulgaris. Author(s): Nousari CH, Brodsky R, Anhalt GJ. Source: Journal of the American Academy of Dermatology. 2003 July; 49(1): 148-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12833031

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95

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Evaluation of myocardial functional parameters during intravenous cyclophosphamide pulse therapy: a case report. Author(s): Merico A, Levedianos G, Gallo P, Zanco P, Piccione F, Tonin P. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2002 April; 8(2): 179. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11990877

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Extraovarian peritoneal serous papillary carcinoma: a phase II trial of cisplatin and cyclophosphamide with comparison to a cohort with papillary serous ovarian carcinoma-a Gynecologic Oncology Group Study. Author(s): Bloss JD, Brady MF, Liao SY, Rocereto T, Partridge EE, Clarke-Pearson DL; Gynecologic Oncology Group Study. Source: Gynecologic Oncology. 2003 April; 89(1): 148-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12694669

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Extremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin. Author(s): De Jonge ME, Mathot RA, Van Dam SM, Beijnen JH, Rodenhuis S. Source: Cancer Chemotherapy and Pharmacology. 2002 September; 50(3): 251-5. Epub 2002 July 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12203108

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Factor VIII inhibitor in a patient with mild haemophilia A and an Asn618-->Ser mutation responsive to immune tolerance induction and cyclophosphamide. Author(s): Vlot AJ, Wittebol S, Strengers PF, Turenhout EA, Voorberg J, van den Berg HM, Mauser-Bunschoten EP. Source: British Journal of Haematology. 2002 April; 117(1): 136-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11918545

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Factors influencing collection of peripheral blood progenitor cells following highdose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma. Author(s): Goldschmidt H, Hegenbart U, Wallmeier M, Hohaus S, Haas R. Source: British Journal of Haematology. 1997 September; 98(3): 736-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9332333

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Fatal cardiac toxicity in two patients receiving same-day administration of cyclophosphamide and cytarabine as conditioning for hematopoietic stem cell transplantation. Author(s): Kanda Y, Matsumura T, Maki K, Matsuyama T, Chiba S, Hirai H. Source: Haematologica. 2001 September; 86(9): 1002-3. Erratum In: Haematologica 2001 October; 86(10): Following 1120. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11532636

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Fatal haemorrhagic myocarditis secondary to cyclophosphamide therapy. Author(s): Birchall IW, Lalani Z, Venner P, Hugh J. Source: The British Journal of Radiology. 2000 October; 73(874): 1112-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11271907

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Favourable results with a single autologous stem cell transplant following conditioning with busulphan and cyclophosphamide in patients with multiple myeloma. Author(s): Toor AA, Ayers J, Strupeck J, Parthasarathy M, Creech S, Rodriguez T, Stiff PJ. Source: British Journal of Haematology. 2004 March; 124(6): 769-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009065

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Filgrastim support during combination chemotherapy using cisplatin, doxorubicin, and cyclophosphamide to treat advanced or recurrent endometrial cancer: a clinical study and literature review. Author(s): Hall DJ, Martin DA, Kincaid K. Source: Eur J Gynaecol Oncol. 2003; 24(6): 481-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14658586

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Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. Author(s): Therasse P, Mauriac L, Welnicka-Jaskiewicz M, Bruning P, Cufer T, Bonnefoi H, Tomiak E, Pritchard KI, Hamilton A, Piccart MJ; EORTC. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 March 1; 21(5): 843-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12610183

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Fludarabine and cyclophosphamide using an attenuated dose schedule is a highly effective regimen for patients with indolent lymphoid malignancies. Author(s): Tam CS, Wolf MM, Januszewicz EH, Prince HM, Westerman D, Seymour JF. Source: Cancer. 2004 May 15; 100(10): 2181-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15139062

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Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Author(s): Flinn IW, Byrd JC, Morrison C, Jamison J, Diehl LF, Murphy T, Piantadosi S, Seifter E, Ambinder RF, Vogelsang G, Grever MR. Source: Blood. 2000 July 1; 96(1): 71-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10891432

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Fludarabine in combination with cyclophosphamide or with cyclophosphamide plus mitoxantrone for relapsed or refractory low-grade non-Hodgkin's lymphoma. Author(s): Santini G, Nati S, Spriano M, Gallamini A, Pierluigi D, Congiu AM, Truini M, Rubagotti A, Chisesi T, Vimercati R, Rossi E, Sertoli MR, Mattei D, Marino G, Gobbi M. Source: Haematologica. 2001 March; 86(3): 282-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11255275

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Fludarabine plus cyclophosphamide for the treatment of advanced chronic lymphocytic leukemia. Author(s): Schiavone EM, De Simone M, Palmieri S, Annunziata M, Pocali B, Copia C, D'Amico MR, Vecchio LD, Ferrara F. Source: European Journal of Haematology. 2003 July; 71(1): 23-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801295

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Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group. Author(s): Hallek M, Schmitt B, Wilhelm M, Busch R, Krober A, Fostitsch HP, Sezer O, Herold M, Knauf W, Wendtner CM, Kuse R, Freund M, Franke A, Schriever F, Nerl C, Dohner H, Thiel E, Hiddemann W, Brittinger G, Emmerich B; German Chronic Lymphocytic Leukaemia Study Group. Source: British Journal of Haematology. 2001 August; 114(2): 342-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11529853

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Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Author(s): Bosch F, Ferrer A, Lopez-Guillermo A, Gine E, Bellosillo B, Villamor N, Colomer D, Cobo F, Perales M, Esteve J, Altes A, Besalduch J, Ribera JM, Montserrat E; For the GELCAB (Grup per l'Estudi dels Limfomes a Catalunya i Balears). Source: British Journal of Haematology. 2002 December; 119(4): 976-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12472576

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Fluorouracil, doxorubicin, and cyclophosphamide followed by tamoxifen as adjuvant treatment for patients with stage IV breast cancer with no evidence of disease. Author(s): Rivera E, Holmes FA, Buzdar AU, Asmar L, Kau SW, Fraschini G, Walters R, Theriault RL, Hortobagyi GN. Source: The Breast Journal. 2002 January-February; 8(1): 2-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11856154

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Fractionated cyclophosphamide and etoposide for children with advanced or refractory solid tumors: a phase II window study. Author(s): Mantadakis E, Herrera L, Leavey PJ, Bash RO, Winick NJ, Kamen BA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2000 July; 18(13): 2576-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10893289

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Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter's syndrome. Author(s): Dabaja BS, O'Brien SM, Kantarjian HM, Cortes JE, Thomas DA, Albitar M, Schlette ES, Faderl S, Sarris A, Keating MJ, Giles FJ. Source: Leukemia & Lymphoma. 2001 July; 42(3): 329-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11699397

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Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Author(s): Tsimberidou AM, Kantarjian HM, Cortes J, Thomas DA, Faderl S, GarciaManero G, Verstovsek S, Ferrajoli A, Wierda W, Alvarado Y, O'Brien SM, Albitar M, Keating MJ, Giles FJ. Source: Cancer. 2003 April 1; 97(7): 1711-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12655528

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Frequent, moderate-dose cyclophosphamide administration improves the efficacy of cytochrome P-450/cytochrome P-450 reductase-based cancer gene therapy. Author(s): Jounaidi Y, Waxman DJ. Source: Cancer Research. 2001 June 1; 61(11): 4437-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11389073

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From cyclophosphamide hematotoxicity to modeling cancer. Author(s): Luebeck EG. Source: Journal of Toxicology and Environmental Health. Part A. 2000 November; 61(56): 515-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11086961

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Gastric antral vascular ectasia in systemic sclerosis: complete resolution with methylprednisolone and cyclophosphamide. Author(s): Lorenzi AR, Johnson AH, Davies G, Gough A. Source: Annals of the Rheumatic Diseases. 2001 August; 60(8): 796-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11454645

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G-CSF alone vs cyclophosphamide plus G-CSF in PBPC mobilization of patients with lymphoma: results depend on degree of previous pretreatment. Author(s): Milone G, Leotta S, Indelicato F, Mercurio S, Moschetti G, Di Raimondo F, Tornello A, Consoli U, Guido G, Giustolisi R. Source: Bone Marrow Transplantation. 2003 May; 31(9): 747-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12732880

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99

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Gemcitabine/cyclophosphamide/5-fluorouracil/folinic acid triplet combination in anthracycline- and taxane-refractory breast cancer patients: a Southern Italy Cooperative Oncology Group phase I/II study. Author(s): Frasci G, D'Aiuto G, Comella P, Thomas R, Capasso I, Botti G, Cortino GR, De Rosa V, Comella G; Southern Italy Cooperative Oncology Group; National Tumor Institute of Naples. Source: Seminars in Oncology. 2001 June; 28(3 Suppl 10): 50-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11510034

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Gene therapy for malignant gliomas using replication incompetent retroviral and adenoviral vectors encoding the cytochrome P450 2B1 gene together with cyclophosphamide. Author(s): Manome Y, Wen PY, Chen L, Tanaka T, Dong Y, Yamazoe M, Hirshowitz A, Kufe DW, Fine HA. Source: Gene Therapy. 1996 June; 3(6): 513-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8789801

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Generalized eruptive keratoacanthoma of Grzybowski: response to cyclophosphamide. Author(s): Grine RC, Hendrix JD, Greer KE. Source: Journal of the American Academy of Dermatology. 1997 May; 36(5 Pt 1): 786-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9146546

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Glomerular chemokine expression and the effect of steroid and cyclophosphamide pulse therapy in human crescentic glomerulonephritis. Author(s): Chen S, Liu Z, Chen H, Zhou H, Wang J, Li L. Source: Chinese Medical Journal. 2002 September; 115(9): 1301-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12411099

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Glutathione antagonized cyclophosphamide- and acrolein-induced cytotoxicity of PC3 cells and immunosuppressive actions in mice. Author(s): Liu XL, Chen K, Ye YP, Peng XY, Qian BC. Source: Zhongguo Yao Li Xue Bao. 1999 July; 20(7): 643-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10678131

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Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. Author(s): Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B; Zoladex Early Breast Cancer Research Association Study. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002 December 15; 20(24): 4628-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12488406

100

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Graft failure after donor leucocyte infusion in relapsed chronic myeloid leukaemia: successful treatment with cyclophosphamide and antithymocyte globulin followed by peripheral blood stem cell infusion. Author(s): Keil F, Kalhs P, Haas OA, Fritsch G, Mitterbauer G, Brugger S, Lechner K, Schwarzinger I, Mannhalter C, Linkesch W, Kurz M, Greinix HT. Source: British Journal of Haematology. 1996 July; 94(1): 120-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8757519

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Granulocyte colony-stimulating factor treatment for cyclophosphamide-induced severe neutropenia in Wegener's granulomatosis. Author(s): Hellmich B, Schnabel A, Gross WL. Source: Arthritis and Rheumatism. 1999 August; 42(8): 1752-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10446877

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) priming of high-dose etoposide and cyclophosphamide: a pilot trial. Author(s): Bernstein SH, Christiansen NP, Fay JP, Brown R, Herzig R, Frankel S, Blumenson L, Herzig GP. Source: Experimental Hematology. 1996 October; 24(12): 1363-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8913281

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Granulocyte-macrophage colony-stimulating factor treatment before doxorubicin and cyclophosphamide chemotherapy priming in women with early-stage breast cancer. Author(s): Kobrinsky NL, Sjolander DE, Cheang MS, Levitt R, Steen PD. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1999 November; 17(11): 3426-30. Erratum In: J Clin Oncol 2000 January; 18(1): 237. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10550137

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Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. Author(s): Afify Z, Shaw PJ, Clavano-Harding A, Cowell CT. Source: Bone Marrow Transplantation. 2000 May; 25(10): 1087-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10828870

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Growth in children undergoing bone marrow transplantation after busulfan and cyclophosphamide conditioning. Author(s): Shankar SM, Bunin NJ, Moshang T Jr. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 1996 November; 18(4): 362-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8888742

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101

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Growth of human hematopoietic cells in immunodeficient mice conditioned with cyclophosphamide and busulfan. Author(s): Basch RS, Quito FL, Beh J, Hirst JA. Source: Stem Cells (Dayton, Ohio). 1997; 15(4): 314-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9253116

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GST-pi gene-transduced hematopoietic progenitor cell transplantation overcomes the bone marrow toxicity of cyclophosphamide in mice. Author(s): Matsunaga T, Sakamaki S, Kuga T, Kuroda H, Kusakabe T, Akiyama T, Konuma Y, Hirayama Y, Kobune M, Kato J, Sasaki K, Kogawa K, Koyama R, Niitsu Y. Source: Human Gene Therapy. 2000 August 10; 11(12): 1671-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10954901

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Guillain-Barre syndrome as presenting feature in a patient with lupus nephritis, with complete resolution after cyclophosphamide treatment. Author(s): van Laarhoven HW, Rooyer FA, van Engelen BG, van Dalen R, Berden JH. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001 April; 16(4): 840-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274284

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Hepatocellular carcinoma associated with long-term cyclophosphamide therapy for Wegener granulomatosis. Author(s): Okano A, Matsusue R, Takakuwa H, Nishio A. Source: Intern Med. 2003 May; 42(5): 406-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12793710

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High dose cyclophosphamide for severe refractory myasthenia gravis. Author(s): Gladstone DE, Brannagan TH 3rd, Schwartzman RJ, Prestrud AA, Brodsky I. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2004 May; 75(5): 789-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15090586

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High dose cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) in the treatment of follicular, low grade non-Hodgkin's lymphoma: CALGB 9150. Author(s): Lichtman SM, Petroni G, Schilsky RL, Johnson JL, Perri RT, Niedzwiecki D, Sklar J, Barcos M, Peterson BA. Source: Leukemia & Lymphoma. 2001 November-December; 42(6): 1255-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11911406

102

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High dose cyclophosphamide treatment for autoimmune disorders. Author(s): Brodsky RA. Source: Scientificworldjournal. 2002 June 28; 2: 1808-15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12806171

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High dose cyclophosphamide with carboplatin: a tolerable regimen suitable for dose intensification in children with solid tumors. Author(s): Kreissman SG, Rackoff W, Lee M, Breitfeld PP. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 1997 July-August; 19(4): 309-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9256829

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High-dose chemotherapy with carboplatin, cyclophosphamide and etoposide and autologous transplantation for multiple myeloma relapsing after a previous transplant. Author(s): Mehta J, Tricot G, Jagannath S, Desikan KR, Siegel D, Singhal S, Munshi N, Vesole D, Mattox S, Bracy D, Barlogie B. Source: Bone Marrow Transplantation. 1997 July; 20(2): 113-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9244413

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High-dose cyclophosphamide as salvage therapy for severe aplastic anemia. Author(s): Brodsky RA, Chen AR, Brodsky I, Jones RJ. Source: Experimental Hematology. 2004 May; 32(5): 435-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15145211

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High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study. Author(s): Yule SM, Foreman NK, Mitchell C, Gouldon N, May P, McDowell HP. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1997 October; 15(10): 3258-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9336363

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High-dose cyclophosphamide in multiple sclerosis patients undergoing autologous stem cell transplantation. Author(s): McGuire TR, Gwilt P, Manouvilov K, Healey K, Ursick MM, Nash RA, Pavletic SZ. Source: International Immunopharmacology. 2003 February; 3(2): 279-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12586609

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High-dose cyclophosphamide in severe aplastic anaemia. Author(s): Jones RJ, Brodsky RA. Source: British Journal of Haematology. 2004 May; 125(3): 408-9; Author Reply 409-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15086426

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High-dose cyclophosphamide therapy without stem cell rescue for severe refractory autoimmune illnesses: comment on the article by Moore et al. Author(s): Prestrud AA, Hoch S, Brodsky I, Gladstone DE. Source: Arthritis and Rheumatism. 2003 May; 48(5): 1463; Author Reply 1464-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746926

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High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus. Author(s): Ann Intern Med. 2003 Jan 21;138(2):I38 Source: Arthritis and Rheumatism. 2003 January; 48(1): 166-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12529111

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High-dose cyclophosphamide, BCNU, and VP-16 (CBV) conditioning before allogeneic stem cell transplantation for patients with non-Hodgkin's lymphoma. Author(s): Rossi HA, Becker PS, Emmons RV, Westervelt P, Levy W, Liu Q, Clark Y, Ballen K. Source: Bone Marrow Transplantation. 2003 March; 31(6): 441-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12665838

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High-dose thiotepa, busulfan, cyclophosphamide and ASCT without whole-brain radiotherapy for poor prognosis primary CNS lymphoma. Author(s): Cheng T, Forsyth P, Chaudhry A, Morris D, Gluck S, Russell JA, Stewart DA. Source: Bone Marrow Transplantation. 2003 April; 31(8): 679-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692608

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HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Author(s): Radich JP, Gooley T, Bensinger W, Chauncey T, Clift R, Flowers M, Martin P, Slattery J, Sultan D, Appelbaum FR. Source: Blood. 2003 July 1; 102(1): 31-5. Epub 2003 February 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595317

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Hodgkin's type of Richter's syndrome in familial chronic lymphocytic leukemia treated with cladribine and cyclophosphamide. Author(s): Robak T, Szmigielska-Kaplon A, Smolewski P, Wawrzyniak E, Korycka A, Bartkowiak J, Kordek R. Source: Leukemia & Lymphoma. 2003 May; 44(5): 859-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12802926

104

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Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma. Author(s): Kropff MH, Lang N, Bisping G, Domine N, Innig G, Hentrich M, Mitterer M, Sudhoff T, Fenk R, Straka C, Heinecke A, Koch OM, Ostermann H, Berdel WE, Kienast J. Source: British Journal of Haematology. 2003 August; 122(4): 607-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899716

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Ifosfamide and cyclophosphamide: effects on immunosurveillance. Author(s): Binotto G, Trentin L, Semenzato G. Source: Oncology. 2003; 65(Suppl 2): 17-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586142

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IL-15 mediates anti-tumor effects after cyclophosphamide injection of tumor-bearing mice and enhances adoptive immunotherapy: the potential role of NK cell subpopulations. Author(s): Evans R, Fuller JA, Christianson G, Krupke DM, Troutt AB. Source: Cellular Immunology. 1997 July 10; 179(1): 66-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9259773

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Immediate and delayed complications of dexamethasone cyclophosphamide pulse (DCP) therapy. Author(s): Jain R, Kumar B. Source: The Journal of Dermatology. 2003 October; 30(10): 713-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684952

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Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: increased interleukin-4 production and associated eosinophilia. Author(s): Smith DR, Balashov KE, Hafler DA, Khoury SJ, Weiner HL. Source: Annals of Neurology. 1997 September; 42(3): 313-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9307252

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Immunosuppressive treatment in severe connective tissue diseases: effects of low dose intravenous cyclophosphamide. Author(s): Martin-Suarez I, D'Cruz D, Mansoor M, Fernandes AP, Khamashta MA, Hughes GR. Source: Annals of the Rheumatic Diseases. 1997 August; 56(8): 481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9306871

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105

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Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia. Author(s): Tournilhac O, Cazin B, Lepretre S, Divine M, Maloum K, Delmer A, Grosbois B, Feugier P, Maloisel F, Villard F, Villemagne B, Bastit D, Belhadj K, Azar N, Michallet M, Manhes G, Travade P. Source: Blood. 2004 January 1; 103(1): 363-5. Epub 2003 September 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12969985

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In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Author(s): Bellosillo B, Villamor N, Colomer D, Pons G, Montserrat E, Gil J. Source: Blood. 1999 October 15; 94(8): 2836-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10515887

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Induction of cytochrome P450 2B6 and 3A4 expression by phenobarbital and cyclophosphamide in cultured human liver slices. Author(s): Martin H, Sarsat JP, de Waziers I, Housset C, Balladur P, Beaune P, Albaladejo V, Lerche-Langrand C. Source: Pharmaceutical Research. 2003 April; 20(4): 557-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12739762

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Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity. Author(s): Yu WD, Chang MJ, Trump DL, Johnson CS. Source: Cancer Immunology, Immunotherapy : Cii. 1997 August; 44(6): 316-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9298933

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Intermediate-dose cyclophosphamide and granulocyte colony-stimulating factor is a valid alternative to high-dose cyclophosphamide for mobilizing peripheral blood CD34+ cells in patients with multiple myeloma. Author(s): Petrucci MT, Avvisati G, La Verde G, De Fabritiis P, Ribersani M, Palumbo G, De Felice L, Rusignuolo A, Simone F, Meloni G, Mandelli F. Source: Acta Haematologica. 2003; 109(4): 184-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853690

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Intravenous cyclophosphamide and high dose corticosteroids improve MRI lesions in demyelinating syndrome in systemic lupus erythematosus. Author(s): Leung FK, Fortin PR. Source: The Journal of Rheumatology. 2003 August; 30(8): 1871-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12913950

106

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Intravenous cyclophosphamide improves cardiac dysfunction in lupus myocarditis. Author(s): Chan YK, Li EK, Tam LS, Chow LT, Ng HK. Source: Scandinavian Journal of Rheumatology. 2003; 32(5): 306-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14690145

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Intravenous cyclophosphamide in steroid-resistant nephrotic syndrome. Author(s): Bajpai A, Bagga A, Hari P, Dinda A, Srivastava RN. Source: Pediatric Nephrology (Berlin, Germany). 2003 April; 18(4): 351-6. Epub 2003 March 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700961

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Intravenous cyclophosphamide is the drug of choice for steroid dependent nephrotic syndrome. Author(s): Bircan Z, Kara B. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2003 February; 45(1): 65-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654072

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Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Author(s): Riley P, Maillard SM, Wedderburn LR, Woo P, Murray KJ, Pilkington CA. Source: Rheumatology (Oxford, England). 2004 April; 43(4): 491-6. Epub 2004 January 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722349

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Intravenous pulse administration of cyclophosphamide is an effective and safe treatment for sensitized cardiac allograft recipients. Author(s): Itescu S, Burke E, Lietz K, John R, Mancini D, Michler R, Rose E, Oz M, Edwards N. Source: Circulation. 2002 March 12; 105(10): 1214-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11889016

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Intravenous pulse cyclophosphamide--is it effective in children with steroid-resistant nephrotic syndrome? Author(s): Alshaya HO, Al-Maghrabi JA, Kari JA. Source: Pediatric Nephrology (Berlin, Germany). 2003 November; 18(11): 1143-6. Epub 2003 September 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680329

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Intravenous pulse versus oral administration of cyclophosphamide: comment on the article by Haubitz et al. Author(s): Savage CO, Jayne DR. Source: Arthritis and Rheumatism. 1999 September; 42(9): 2019-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10513825

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Is biopsy required prior to cyclophosphamide in steroid-sensitive nephrotic syndrome? Author(s): Stadermann MB, Lilien MR, van de Kar NC, Monnens LA, Schroder CH. Source: Clinical Nephrology. 2003 November; 60(5): 315-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14640236

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Kasabach-Merritt syndrome-associated kaposiform hemangioendothelioma successfully treated with cyclophosphamide, vincristine, and actinomycin D. Author(s): Hu B, Lachman R, Phillips J, Peng SK, Sieger L. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 1998 November-December; 20(6): 567-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9856681

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Kinetic modeling and efficacy of intraperitoneal paclitaxel combined with intravenous cyclophosphamide and carboplatin as first-line treatment in ovarian cancer. Author(s): Hofstra LS, Bos AM, de Vries EG, van der Zee AG, Willemsen AT, Rosing H, Beijnen JH, Mulder NH, Aalders JG, Willemse PH. Source: Gynecologic Oncology. 2002 June; 85(3): 517-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12051884

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Kinetics of hepatitis C (HCV) viraemia and quasispecies during treatment of HCV associated cryoglobulinaemia with pulse cyclophosphamide. Author(s): Thiel J, Peters T, Mas Marques A, Rosler B, Peter HH, Weiner SM. Source: Annals of the Rheumatic Diseases. 2002 September; 61(9): 838-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176813

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Kinetics of PBPC mobilization by cyclophosphamide, as compared with that by epirubicin/paclitaxel followed by G-CSF support: implications for optimal timing of PBPC harvest. Author(s): Dettke M, Greinix HT, Kalhs P, Kuhrer I, Worel N, Hocker P. Source: Transfusion. 2001 May; 41(5): 681-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11346706

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Kinetics of serum granulocyte-colony stimulating factor (G-CSF) concentration and G-CSF receptor expression during G-CSF treatment of cyclophosphamide-treated mice. Author(s): Matsuzaki G, Li XY, Ohyama Y, Nomoto K. Source: International Journal of Immunopharmacology. 1996 June-July; 18(6-7): 363-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9024937

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Lack of impact of platinum dose intensity on the outcome of ovarian cancer patients. 10-year results of a prospective randomised phase III study comparing carboplatincisplatin with cyclophosphamide-cisplatin. Author(s): Dittrich Ch, Sevelda P, Salzer H, Obermair A, Speiser P, Breitenecker G, Schemper M, Kaider A; Austrian Ovarian Cancer Study Group. Source: European Journal of Cancer (Oxford, England : 1990). 2003 May; 39(8): 1129-40. Erratum In: Eur J Cancer. 2004 March; 40(4): 627. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736113

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Langerhans cell histiocytosis in a patient with systemic lupus erythematosus: a clonal disease responding to treatment with cladribine, and cyclophosphamide. Author(s): Robak T, Kordek R, Robak E, Bartkowiak J, Biernat W, Liberski P, Blonski J. Source: Leukemia & Lymphoma. 2002 October; 43(10): 2041-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481906

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Late complications following treatment for severe aplastic anemia (SAA) with highdose cyclophosphamide (Cy): follow-up of a randomized trial. Author(s): Tisdale JF, Maciejewski JP, Nunez O, Rosenfeld SJ, Young NS. Source: Blood. 2002 December 15; 100(13): 4668-70. Epub 2002 June 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12393567

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Left ventricular diastolic dysfunction induced by cyclophosphamide in blood stem cell transplantation. Author(s): Mori T, Yanagi N, Maruyama T, Gondo H, Okamura T, Kaji Y, Harada M. Source: Japanese Heart Journal. 2002 May; 43(3): 249-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12227700

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Leiomyosarcoma of urinary bladder following cyclophosphamide therapy: report of two cases. Author(s): Tanguay C, Harvey I, Houde M, Srigley JR, Tetu B. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 2003 May; 16(5): 512-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748258

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Leukemic cell insensitivity to cyclophosphamide and other oxazaphosphorines mediated by aldehyde dehydrogenase(s). Author(s): Sladek NE. Source: Cancer Treat Res. 2002; 112: 161-75. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481716

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Localized non-Hodgkin's lymphoma with B-cell histology: cure without cyclophosphamide? A report of the United Kingdom Children's Cancer Study Group on studies NHL 8501 and NHL 9001 (1985-1996). Author(s): Amos Burke GA, Imeson J, Hobson R, Gerrard M. Source: British Journal of Haematology. 2003 May; 121(4): 586-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12752099

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Long term survival of children with Burkitt lymphoma in Malawi after cyclophosphamide monotherapy. Author(s): Kazembe P, Hesseling PB, Griffin BE, Lampert I, Wessels G. Source: Medical and Pediatric Oncology. 2003 January; 40(1): 23-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12426682

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Long-term follow-up of a phase I study of high-dose decitabine, busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias. Author(s): de Lima M, Ravandi F, Shahjahan M, Andersson B, Couriel D, Donato M, Khouri I, Gajewski J, van Besien K, Champlin R, Giralt S, Kantarjian H. Source: Cancer. 2003 March 1; 97(5): 1242-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12599231

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Long-term follow-up of allogeneic stem cell transplantation in patients with severe aplastic anemia after conditioning with cyclophosphamide plus antithymocyte globulin. Author(s): Kroger N, Zabelina T, Renges H, Kruger W, Kordes U, Rischewski J, Schrum J, Horstmann M, Ayuk F, Erttmann R, Kabisch H, Zander AR. Source: Annals of Hematology. 2002 November; 81(11): 627-31. Epub 2002 November 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454700

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Low-dose (550 cGy), single-exposure total body irradiation and cyclophosphamide: consistent, durable engraftment of related-donor peripheral blood stem cells with low treatment-related mortality and fatal organ toxicity. Author(s): Blum W, Brown R, Lin HS, Zehnbauer B, Khoury H, Goodnough LT, Westervelt P, Vij R, DiPersio J, Adkins D. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002; 8(11): 608-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12463480

110

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Low-dose epirubicin in combination with cyclophosphamide, vinblastine and prednisone (mini-CEOP) for the treatment of aggressive non-Hodgkin's lymphoma in elderly patients. Author(s): Veneri D, Zanetti F, Franchini M, Krampera M, Pizzolo G. Source: Haematologica. 2002 November; 87(11): Elt43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414364

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Low-dose intravenous cyclophosphamide in systemic sclerosis: a preliminary safety study. Author(s): D'Angelo S, Cuomo G, Paone C, Colutta E, La Montagna G, Valentini G. Source: Clinical Rheumatology. 2003 December; 22(6): 393-6. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677013

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Low-dose or intermediate-dose cyclophosphamide plus granulocyte colonystimulating factor for progenitor cell mobilisation in patients with multiple myeloma. Author(s): Jantunen E, Putkonen M, Nousiainen T, Pelliniemi TT, Mahlamaki E, Remes K. Source: Bone Marrow Transplantation. 2003 March; 31(5): 347-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634725

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Low-dose pulse cyclophosphamide in the treatment of neuropsychiatric lupus. Author(s): Sanna G, Khamashta MA, Sanni G. Source: Lupus. 2003; 12(1): 1-2. Review. Erratum In: Lupus. 2003; 12(4): 340. Sanni G [corrected to Sanna G]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12587818

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Lymphocytic interstitial pneumonitis associated with Epstein-Barr virus in Systemic Lupus Erythematosus and Sjogren's Syndrome. Complete remission with corticosteriod and cyclophosphamide. Author(s): Yum HK, Kim ES, Ok KS, Lee HK, Choi SJ. Source: Korean J Intern Med. 2002 September; 17(3): 198-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12298431

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Maximum tolerable dose of cyclophosphamide and azathioprine in Pakistani patients with primary renal disease. Author(s): Ali SS, Rabbani MA, Moinuddin SS, Virani S, Farooque F, Salam A, Ahmad A. Source: J Pak Med Assoc. 2004 January; 54(1): 39-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15058645

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Medium-sized arterial vasculitis associated with vascular deposits of immunoglobin E. Favorable response to intravenous methylprednisolone and cyclophosphamide. Author(s): Lavalle C, Santos-Argumedo L, Hernandez-Cueto A, Luria-Perez R, Gonzalez-Bonilla C. Source: Archives of Medical Research. 2002 March-April; 33(2): 195-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11886722

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Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy in postmenopausal women with estrogen receptor-positive, nodepositive breast cancer. Author(s): Hartman AR, Fleming GF, Dillon JJ. Source: Clinical Breast Cancer. 2001 July; 2(2): 138-43; Discussion 144. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11899785

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Meta-analysis of chemotherapy regimens for ovarian carcinoma: a reassessment of cisplatin, cyclophosphamide and doxorubicin versus cisplatin and cyclophosphamide. Author(s): West RJ, Zweig SF. Source: Eur J Gynaecol Oncol. 1997; 18(5): 343-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9378150

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Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Author(s): Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R. Source: Cancer. 2003 October 15; 98(8): 1643-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534880

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Mitoxantrone-cyclophosphamide-rituximab: an effective and safe combination for indolent NHL. Author(s): Emmanouilides C, Territo M, Menco H, Patel R, Rosen P. Source: Hematological Oncology. 2003 September; 21(3): 99-108. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579238

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Mobilization of peripheral blood stem cells with high-dose cyclophosphamide or the DHAP regimen plus G-CSF in non-Hodgkin's lymphoma. Author(s): Pavone V, Gaudio F, Guarini A, Perrone T, Zonno A, Curci P, Liso V. Source: Bone Marrow Transplantation. 2002 February; 29(4): 285-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11896424

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Modified guanines representing O(6)-alkylation by the cyclophosphamide metabolites acrolein and chloroacetaldehyde: synthesis, stability, and ab initio studies. Author(s): Balu N, Gamcsik MP, Colvin ME, Colvin OM, Dolan ME, Ludeman SM. Source: Chemical Research in Toxicology. 2002 March; 15(3): 380-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11896686

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Mononeuritis in Churg-Strauss syndrome in Asians responding to intravenous cyclophosphamide. Author(s): Loo KL, Ramachandran R, Chow SK, Goh EM, Yeap SS. Source: Rheumatology (Oxford, England). 2004 February; 43(2): 251-2; Author Reply 251. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14739474

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Mycophenolate therapy in frequently relapsing minimal change disease that has failed cyclophosphamide therapy. Author(s): Pesavento TE, Bay WH, Agarwal G, Hernandez RA Jr, Hebert LA. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2004 March; 43(3): E3-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981634

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Nadir neutrophil counts in patients treated for breast cancer with doxorubicin and cyclophosphamide. Author(s): Othieno-Abinya NA, Nyabola LO, Nyong'o AO, Baraza R. Source: East Afr Med J. 2001 July; 78(7): 370-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11957262

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Neoadjuvant chemotherapy for Ewing's sarcoma of bone: no benefit observed after adding ifosfamide and etoposide to vincristine, actinomycin, cyclophosphamide, and doxorubicin in the maintenance phase--results of two sequential studies. Author(s): Bacci G, Picci P, Ferrari S, Mercuri M, Brach del Prever A, Rosito P, Barbieri E, Tienghi A, Forni C. Source: Cancer. 1998 March 15; 82(6): 1174-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9506366

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Nephrotic syndrome caused by membranous nephropathy: response to a short course of cyclophosphamide alternating with prednisolone. Author(s): Fujimoto S, Hara S, Sato Y, Yamada K, Hisanaga S, Eto T. Source: Intern Med. 2004 January; 43(1): 30-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14964576

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113

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Neuropsychiatric lupus favourable response to low dose i.v. cyclophosphamide and prednisolone (pilot study). Author(s): Stojanovich L, Stojanovich R, Kostich V, Dzjolich E. Source: Lupus. 2003; 12(1): 3-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12587819

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Neutrophilic eccrine hidradenitis mimicking cutaneous vasculitis in a lupus patient: a complication of cyclophosphamide. Author(s): Lienesch DW, Mutasim DF, Singh RR. Source: Lupus. 2003; 12(9): 707-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14514135

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Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Author(s): O'Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M, Rhubart P, Cowan K, Piantados S, Fuchs EJ. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002; 8(7): 377-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12171484

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Nonpredictable pharmacokinetic behavior of high-dose cyclophosphamide in combination with cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea. Author(s): Nieto Y, Xu X, Cagnoni PJ, Matthes S, Shpall EJ, Bearman SI, Murphy J, Jones RB. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1999 April; 5(4): 747-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10213208

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Nonspecific interstitial pneumonia/fibrosis completely recovered by adding cyclophosphamide to corticosteroids. Author(s): Nanki N, Fujita J, Yamaji Y, Maeda H, Kurose T, Kaji M, Satoh K, Miyatani K, Yamadori I, Ohtsuki Y, Ishida T. Source: Intern Med. 2002 October; 41(10): 867-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12413012

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NSABP Protocol B-27. Preoperative doxorubicin plus cyclophosphamide followed by preoperative or postoperative docetaxel. Author(s): Mamounas EP. Source: Oncology (Huntingt). 1997 June; 11(6 Suppl 6): 37-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9213327

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Ocular involvement in Takayasu's arteritis: response to cyclophosphamide therapy. Author(s): Rodriguez-Hurtado FJ, Sabio JM, Lucena J, Jimenez-Alonso J. Source: European Journal of Medical Research. 2002 March 28; 7(3): 128-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11953284

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Ocular involvement in Wegener's granulomatosis responding to intravenous cyclophosphamide. Author(s): Cuende E, Mena AR, Andonegui J, Minguela I, Vesga JC. Source: Rheumatology (Oxford, England). 2001 September; 40(9): 1066-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11561123

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Ondansetron suppository: a randomised, double-blind, double-dummy, parallelgroup comparison with oral ondansetron for the prevention of cyclophosphamideinduced emesis and nausea. The Ondansetron Suppository emesis study group. Author(s): Davidson NG, Paska W, Van Belle S, Goedhals L, McQuade B, McRae J. Source: Oncology. 1997 September-October; 54(5): 380-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9260599

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Oral cyclophosphamide for treatment of pemphigus vulgaris and foliaceus. Author(s): Cummins DL, Mimouni D, Anhalt GJ, Nousari CH. Source: Journal of the American Academy of Dermatology. 2003 August; 49(2): 276-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894077

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Oral cyclophosphamide therapy for patients with residual or relapsed indolent-type lymphoma after initial treatment for aggressive lymphomas. A sub-group of patients with apparent transformed indolent lymphoma. Author(s): Riccioni R, Galimberti S, Cervetti G, Fazzi R, Caracciolo F, Petrini M. Source: Leukemia & Lymphoma. 2002 September; 43(9): 1803-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685835

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Oral UFT and cyclophosphamide combination chemotherapy for metastatic breast cancer. Author(s): Ogawa Y, Ishikawa T, Chung SH, Ikeda K, Takashima T, Onoda N, Nakata B, Nishiguchi Y, Hirakawa K. Source: Anticancer Res. 2003 July-August; 23(4): 3453-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12926089

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Outcome and prognostic indicators of diffuse proliferative lupus glomerulonephritis treated with sequential oral cyclophosphamide and azathioprine. Author(s): Mok CC, Ho CT, Chan KW, Lau CS, Wong RW. Source: Arthritis and Rheumatism. 2002 April; 46(4): 1003-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11953978

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Outcome of single fraction total body irradiation-conditioned stem cell transplantation in younger children with malignant disease--comparison with a busulphan-cyclophosphamide regimen. Author(s): Lahteenmaki PM, Chakrabarti S, Cornish JM, Oakhill AH. Source: Acta Oncologica (Stockholm, Sweden). 2004; 43(2): 196-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15163170

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Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver microsomes. Author(s): Ren S, Yang JS, Kalhorn TF, Slattery JT. Source: Cancer Research. 1997 October 1; 57(19): 4229-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9331082

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Peculiar pattern of nail pigmentation following cyclophosphamide therapy. Author(s): Dave S, Thappa DM. Source: Dermatology Online Journal [electronic Resource]. 2003 August; 9(3): 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952761

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Phase I study of oral cyclophosphamide and oral topotecan for children with recurrent or refractory solid tumors. Author(s): Bowers DC, Aquino VM, Leavey PJ, Bash RO, Journeycake JM, Tomlinson G, Mulne AF, Haynes HJ, Winick NJ. Source: Pediatric Blood & Cancer. 2004 January; 42(1): 93-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752800

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Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: a pediatric oncology group study. Author(s): Aquino VM, Weitman SD, Winick NJ, Blaney S, Furman WL, Kepner JL, Bonate P, Krailo M, Qu W, Bernstein M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 April 15; 22(8): 1413-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084615

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Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Author(s): Hellerstedt B, Pienta KJ, Redman BG, Esper P, Dunn R, Fardig J, Olson K, Smith DC. Source: Cancer. 2003 October 15; 98(8): 1603-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534875

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Polyarteritis nodosa complicated by intrahepatic-perihepatic hemorrhage and acute appendicitis: successful treatment with cyclophosphamide and corticosteroids. Author(s): Kart-Koseoglu H, Yucel AE, Aytekin C, Sahin B. Source: Clinical Rheumatology. 2003 September; 22(3): 251-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14505223

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Pulse cyclophosphamide inadequately suppresses reoccurrence of minimal change nephrotic syndrome in corticoid-dependent children. Author(s): Donia AF, Gazareen SH, Ahmed HA, Moustafa FE, Shoeib AA, Ismail AM, Khamis S, Sobh MA. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 October; 18(10): 2054-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679480

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Pulse IV cyclophosphamide in ocular inflammatory disease: efficacy and short-term safety. Author(s): Durrani K, Papaliodis GN, Foster CS. Source: Ophthalmology. 2004 May; 111(5): 960-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15121375

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QT dispersion as a predictor of acute heart failure after high-dose cyclophosphamide. Author(s): Nakamae H, Tsumura K, Hino M, Hayashi T, Tatsumi N. Source: Lancet. 2000 March 4; 355(9206): 805-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10711930

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Quality of life in goserelin-treated versus cyclophosphamide + methotrexate + fluorouracil-treated premenopausal and perimenopausal patients with node-positive, early breast cancer: the Zoladex Early Breast Cancer Research Association Trialists Group. Author(s): de Haes H, Olschewski M, Kaufmann M, Schumacher M, Jonat W, Sauerbrei W; Zoladex Early Breast Cancer Research Association Trialists Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 December 15; 21(24): 4510-6. Epub 2003 November 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14610048

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Quality of life in women with breast cancer during the first year after random assignment to adjuvant treatment with marrow-supported high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin or tailored therapy with Fluorouracil, epirubicin, and cyclophosphamide: Scandinavian Breast Group Study 9401. Author(s): Brandberg Y, Michelson H, Nilsson B, Bolund C, Erikstein B, Hietanen P, Kaasa S, Nilsson J, Wiklund T, Wilking N, Bergh J; Scandinavian Breast Group Study 9401. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 October 1; 21(19): 3659-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512398

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Questions regarding the design of the study of pulse versus oral cyclophosphamide in the treatment of Wegener's granulomatosis: comment on the article by Guillevin et al. Author(s): Stone JH, Hellmann DB. Source: Arthritis and Rheumatism. 1998 September; 41(9): 1705-6; Author Reply 1707-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9751110

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Randomized study comparing carboplatin/cyclophosphamide and cisplatin/cyclophosphamide as first-line treatment in patients with stage III/IV epithelial ovarian cancer and small volume disease. German Ovarian Cancer Study Group (GOCA). Author(s): Meerpohl HG, Sauerbrei W, Kuhnle H, Schumacher M, Pfleiderer A. Source: Gynecologic Oncology. 1997 July; 66(1): 75-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9234925

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Randomized trial to compare the efficacy and toxicity of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with methotrexate mitoxantrone (MM) in advanced carcinoma of the breast. Author(s): Harper-Wynne C, English J, Meyer L, Bower M, Archer C, Sinnett HD, Lowdell C, Coombes RC. Source: British Journal of Cancer. 1999 September; 81(2): 316-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10496359

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Randomized, double-blind, dose-finding study of dexamethasone in preventing acute emesis induced by anthracyclines, carboplatin, or cyclophosphamide:. Author(s): Italian Group For Antiemetic Research. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 February 15; 22(4): 725-9. Erratum In: J Clin Oncol. 2004 May 15; 22(10): 2038. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966097

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Randomized, double-blind, placebo-controlled trial to evaluate the hematopoietic growth factor PIXY321 after moderate-dose fluorouracil, doxorubicin, and cyclophosphamide in stage II and III breast cancer. Author(s): Jones SE, Khandelwal P, McIntyre K, Mennel R, Orr D, Kirby R, Agura E, Duncan L, Hyman W, Roque T, Regan D, Schuster M, Dimitrov N, Garrison L, Lange M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1999 October; 17(10): 3025-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10506596

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Rapidly progressive interstitial lung disease associated with dermatomyositis responding to intravenous cyclophosphamide pulse therapy. Author(s): Shinohara T, Hidaka T, Matsuki Y, Ishizuka T, Takamizawa M, Kawakami M, Kikuma H, Suzuki K, Nakamura H. Source: Intern Med. 1997 July; 36(7): 519-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9240505

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Rationale for high-dose cyclophosphamide and medium-dose total body irradiation in the conditioning of children with progressive systemic and polyarticular juvenile chronic arthritis before autologous stem cell transplantation. Author(s): Vossen JM, Brinkman DM, Bakker B, Hoogerbrugge PM, ten Cate R. Source: Rheumatology (Oxford, England). 1999 August; 38(8): 762-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10501429

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Responsiveness of thrombotic thrombocytopenic purpura to rituximab and cyclophosphamide. Author(s): Fakhouri F, Teixeira L, Delarue R, Grunfeld JP, Veyradier A. Source: Annals of Internal Medicine. 2004 February 17; 140(4): 314-5. Erratum In: Ann Intern Med. 2004 May 4; 140(9): 767. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14970167

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Results of the cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) +/bleomycin treatment and evaluation of prognostic factors in aggressive lymphomas in Turkey. Author(s): Dincol D, Akbulut H, Icli F, Samur M, Karaoguz H, Demirkazik A, Cay F. Source: Oncology. 1997 September-October; 54(5): 376-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9260598

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Retropharyngeal and splenic aseptic abscesses treated with prednisone and cyclophosphamide in a patient with ulcerative colitis. Author(s): Andre M, Piette JC, Frances C, Wechsler B, Delevaux I, Aumaitre O. Source: Digestive Diseases and Sciences. 2003 June; 48(6): 1193-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12822884

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Safety and tolerability of cyclophosphamide 'pulses' in multiple sclerosis: a prospective study in a clinical cohort. Author(s): Portaccio E, Zipoli V, Siracusa G, Piacentini S, Sorbi S, Amato MP. Source: Multiple Sclerosis (Houndmills, Basingstoke, England). 2003 October; 9(5): 44650. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582767

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Salvage chemotherapy with cyclophosphamide for recurrent, temozolomiderefractory glioblastoma multiforme. Author(s): Chamberlain MC, Tsao-Wei DD. Source: Cancer. 2004 March 15; 100(6): 1213-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15022289

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Secondary malignant neoplasms of the bladder after cyclophosphamide treatment for childhood acute lymphocytic leukemia. Author(s): Kersun LS, Wimmer RS, Hoot AC, Meadows AT. Source: Pediatric Blood & Cancer. 2004 March; 42(3): 289-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752871

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Serum bone markers in breast cancer patients during 5-fluorouracil, epirubicin and cyclophosphamide (FEC) therapy. Author(s): Kailajarvi ME, Salminen EK, Paija OM, Virtanent AM, Leino AE, Irjala KA. Source: Anticancer Res. 2004 March-April; 24(2C): 1271-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15154659

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Serum levels of HER2 ECD can determine the response rate to low dose oral cyclophosphamide and methotrexate in patients with advanced stage breast carcinoma. Author(s): Sandri MT, Johansson H, Colleoni M, Zorzino L, Passerini R, Orlando L, Viale G. Source: Anticancer Res. 2004 March-April; 24(2C): 1261-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15154657

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Simultaneous quantification of cyclophosphamide, 4-hydroxycyclophosphamide, N,N',N"-triethylenethiophosphoramide (thiotepa) and N,N',N"triethylenephosphoramide (tepa) in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Author(s): de Jonge ME, van Dam SM, Hillebrand MJ, Rosing H, Huitema AD, Rodenhuis S, Beijnen JH. Source: Journal of Mass Spectrometry : Jms. 2004 March; 39(3): 262-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039933

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Stem cell mobilization in resistant or relapsed lymphoma: superior yield of progenitor cells following a salvage regimen comprising ifosphamide, etoposide and epirubicin compared to intermediate-dose cyclophosphamide. Author(s): McQuaker IG, Haynes AP, Stainer C, Anderson S, Russell NH. Source: British Journal of Haematology. 1997 July; 98(1): 228-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9233591

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Successful treatment of steroid and cyclophosphamide-resistant hemolysis in chronic lymphocytic leukemia with rituximab. Author(s): Chemnitz J, Draube A, Diehl V, Wolf J. Source: American Journal of Hematology. 2002 March; 69(3): 232-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11891815

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Synchronization of plasma-pheresis and pulse cyclophosphamide in the treatment of thrombotic thrombocytopenic purpura and SLE associated with pregnancy. Author(s): Song HJ, Suh YJ, Suh CH. Source: Clin Exp Rheumatol. 2003 July-August; 21(4): 523. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942710

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The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis. Author(s): Calguneri M, Apras S, Ozbalkan Z, Ertenli I, Kiraz S, Ozturk MA, Celik I. Source: Clinical Rheumatology. 2003 October; 22(4-5): 289-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579158

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The NIH pulse cyclophosphamide regime: the end of an era? Author(s): Karim Y, D'Cruz DP. Source: Lupus. 2004; 13(1): 1-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14870910

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The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Author(s): Garcia-Sanz R, Gonzalez-Porras JR, Hernandez JM, Polo-Zarzuela M, Sureda A, Barrenetxea C, Palomera L, Lopez R, Grande-Garcia C, Alegre A, Vargas-Pabon M, Gutierrez ON, Rodriguez JA, San Miguel JF. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 April; 18(4): 856-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14973508

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The potential for oral combination chemotherapy of 5'-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer. Author(s): Yoshimoto M, Tada K, Tokudome N, Kutomi G, Tanabe M, Goto T, Nishimura S, Makita M, Kasumi F. Source: British Journal of Cancer. 2003 November 3; 89(9): 1627-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583760

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Treatment of corticosteroid-resistant neurosarcoidosis with a short-course cyclophosphamide regimen. Author(s): Doty JD, Mazur JE, Judson MA. Source: Chest. 2003 November; 124(5): 2023-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605084

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Treatment of pediatric idiopathic pulmonary hemosiderosis with low-dose cyclophosphamide. Author(s): Huang SH, Lee PY, Niu CK. Source: The Annals of Pharmacotherapy. 2003 November; 37(11): 1618-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14565801

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Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients. Author(s): Zephir H, de Seze J, Duhamel A, Debouverie M, Hautecoeur P, Lebrun C, Malikova I, Pelletier J, Senechal O, Vermersch P. Source: Journal of the Neurological Sciences. 2004 March 15; 218(1-2): 73-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759636

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Treatment of xanthoma disseminatum with cyclophosphamide. Author(s): Seaton ED, Pillai GJ, Chu AC. Source: The British Journal of Dermatology. 2004 February; 150(2): 346-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996108

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UFT/leucovorin plus bolus epirubicin and cyclophosphamide in advanced/metastatic breast cancer. Author(s): Gregory RK, Johnston SR, Smith IE, Miles D. Source: Oncology (Huntingt). 2000 October; 14(10 Suppl 9): 47-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11098493

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Unfavorable response to cyclophosphamide in steroid-dependent nephrotic syndrome. Author(s): Kemper MJ, Altrogge H, Ludwig K, Timmermann K, Muller-Wiefel DE. Source: Pediatric Nephrology (Berlin, Germany). 2000 August; 14(8-9): 772-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10955925

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University of Washington high-dose cyclophosphamide, mitoxantrone, and etoposide experience in metastatic breast cancer: unexpected cardiac toxicity. Author(s): Gralow JR, Livingston RB. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 September 15; 19(18): 3903-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11559728

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Unrelated donor marrow transplantation in children with severe aplastic anaemia using cyclophosphamide, anti-thymocyte globulin and total body irradiation. Author(s): Kojima S, Inaba J, Yoshimi A, Takahashi Y, Watanabe N, Kudo K, Horibe K, Maeda N, Kato K, Matsuyama T. Source: British Journal of Haematology. 2001 September; 114(3): 706-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11553002

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Unusual cervical spinal cord toxicity associated with intra-arterial carboplatin, intraarterial or intravenous etoposide phosphate, and intravenous cyclophosphamide in conjunction with osmotic blood brain-barrier disruption in the vertebral artery. Author(s): Fortin D, McAllister LD, Nesbit G, Doolittle ND, Miner M, Hanson EJ, Neuwelt EA. Source: Ajnr. American Journal of Neuroradiology. 1999 November-December; 20(10): 1794-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10588099

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Update on cyclophosphamide for systemic lupus erythematosus. Author(s): Ortmann RA, Klippel JH. Source: Rheumatic Diseases Clinics of North America. 2000 May; 26(2): 363-75, Vii. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10768217

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Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin. Author(s): van Maanen MJ, Huitema AD, Rodenhuis S, Beijnen JH. Source: Anti-Cancer Drugs. 2001 July; 12(6): 519-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11459998

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Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse. Author(s): Langford CA, Talar-Williams C, Barron KS, Sneller MC. Source: The American Journal of Medicine. 2003 April 15; 114(6): 463-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727579

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Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Author(s): De Feo LG, Schottlender J, Martelli NA, Molfino NA. Source: Muscle & Nerve. 2002 July; 26(1): 31-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12115946

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Use of tacrolimus in steroid- and cyclophosphamide-resistant minimal change nephrotic syndrome. Author(s): Tang S, Tang AW, Tam MK, Ho YW. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2003 November; 42(5): E13-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582073

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VACOP-B, high-dose cyclophosphamide and high-dose therapy with peripheral blood progenitor cell rescue for aggressive non-Hodgkin's lymphoma with bone marrow involvement: a study by the non-Hodgkin's Lymphoma Co-operative Study Group. Author(s): Santini G, Coser P, Congiu AM, Salvagno L, De Souza C, Sertoli MR, Olivieri A, Chisesi T, Rubagotti A, Truini M, Contu A, Porcellini A, Zambaldi G, Nati S, Marino G, Rizzoli V. Source: Haematologica. 2000 February; 85(2): 160-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10681723

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VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85). Author(s): Mineur P, Menard JF, Le Loet X, Bernard JF, Grosbois B, Pollet JP, Azais I, Laporte JP, Doyen C, De Gramont A, Wetterwald M, Euller-Ziegler L, Peny AM, Monconduit M, Michaux JL. Source: British Journal of Haematology. 1998 November; 103(2): 512-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9827927

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Variability in determination of body weight used for dosing busulphan and cyclophosphamide in adult patients: results of an international survey. Author(s): Grigg A, Harun MH, Szer J. Source: Leukemia & Lymphoma. 1997 May; 25(5-6): 487-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9250819

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Variability of cyclophosphamide uptake into human bronchial carcinoma: consequences for local bioactivation. Author(s): Bohnenstengel F, Friedel G, Ritter CA, McClellan M, Fritz P, Eichelbaum M, Linder A, Toomes H, Dierkesmann R, Kroemer HK. Source: Cancer Chemotherapy and Pharmacology. 2000; 45(1): 63-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10647504

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Variation in administration of cyclophosphamide and mesna in the treatment of childhood malignancies. Author(s): Sievers TD, Lagan MA, Bartel SB, Rasco C, Blanding PJ. Source: Journal of Pediatric Oncology Nursing : Official Journal of the Association of Pediatric Oncology Nurses. 2001 January-February; 18(1): 37-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11172408

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Venoocclusive disease of the liver after chemotherapy with vincristine, actinomycin D, and cyclophosphamide for the treatment of rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study Group. Childrens Cancer Group, the Pediatric Oncology Group, and the Pediatric Intergroup Statistical Center. Author(s): Ortega JA, Donaldson SS, Ivy SP, Pappo A, Maurer HM. Source: Cancer. 1997 June 15; 79(12): 2435-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9191535

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Viability and quantification of progenitor cells in venesected blood from patients receiving escalated-dose epirubicin and cyclophosphamide with G-CSF for lymphoma: potential role in further increasing dose-intensity. Author(s): O'Flaherty E, Cebon J, Grigg AP. Source: Leukemia & Lymphoma. 1997 October; 27(3-4): 343-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9402332

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Vincristine, doxorubicin, cyclophosphamide, prednisone and etoposide (VACPE) in high-grade non-Hodgkin's lymphoma--a multicenter phase II study. Author(s): Bergmann L, Karakas T, Lautenschlager G, Jager E, Knuth A, Mitrou PS, Hoelzer D. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 1995 December; 6(10): 1019-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8750155

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Visual symptoms in patients on cyclophosphamide may herald sight threatening disease. Author(s): Agrawal A, Dick AD, Olson JA. Source: The British Journal of Ophthalmology. 2003 January; 87(1): 122-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12488280

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Water intoxication after low dose cyclophosphamide. Author(s): McCarron M, Wright GD, Roberts SD. Source: Bmj (Clinical Research Ed.). 1995 July 29; 311(7000): 292. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7633237

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Weekly administration of vincristine, cyclophosphamide, mitoxantrone and bleomycin (VEMB) in the treatment of elderly aggressive non Hodgkin's lymphoma. Gruppo Italiano per lo Studio dei Linfomi. Author(s): Merli F, Federico M, Avanzini P, Ilariucci F, Stelitano C, Iannitto E, Colombi M, Vallisa D, Santagati G, Picinini L. Source: Haematologica. 1998 March; 83(3): 217-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9573675

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Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. Author(s): Bolis G, Favalli G, Danese S, Zanaboni F, Mangili G, Scarabelli C, Tateo S, Valsecchi MG, Scarfone G, Richiardi G, Frigerio L, Melpignano M, Villa A, Parazzini F. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1997 May; 15(5): 1938-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9164205

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Wegener's granulomatosis: long-term follow-up of patients treated with pulse cyclophosphamide. Author(s): Koldingsnes W, Gran JT, Omdal R, Husby G. Source: British Journal of Rheumatology. 1998 June; 37(6): 659-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9667621

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What is the ideal duration of adjuvant therapy for primary breast cancer: are four cycles of cyclophosphamide and doxorubicin enough? Author(s): Shulman LN. Source: Current Oncology Reports. 2001 November; 3(6): 523-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11595121

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WR-2721 (amifostine) infusion in patients with Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna: drug and thiol levels in plasma and blood cells, a Pediatric Oncology Group study. Author(s): Souid AK, Fahey RC, Dubowy RL, Newton GL, Bernstein ML. Source: Cancer Chemotherapy and Pharmacology. 1999; 44(6): 498-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10550571

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Yuehchukene, a bis-indole alkaloid, and cyclophosphamide are active in breast cancer in vitro. Author(s): Leung TW, Cheng G, Chui CH, Ho SK, Lau FY, Tjong JK, Poon TC, Tang JC, Tse WC, Cheng KF, Kong YC. Source: Chemotherapy. 2000 January-February; 46(1): 62-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10601799

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CHAPTER 2. NUTRITION AND CYCLOPHOSPHAMIDE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and cyclophosphamide.

Finding Nutrition Studies on Cyclophosphamide The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “cyclophosphamide” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following information is typical of that found when using the “Full IBIDS Database” to search for “cyclophosphamide” (or a synonym): •

Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. Author(s): Investigational Drug Branch for Breast Cancer, European Organization for the Research and Treatment of Cancer Data Center, and Jules Bordet Institute, Brussels, Belgium. Source: Biganzoli, L Cufer, T Bruning, P Coleman, R Duchateau, L Calvert, A H Gamucci, T Twelves, C Fargeot, P Epelbaum, R Lohrisch, C Piccart, M J J-Clin-Oncol. 2002 July 15; 20(14): 3114-21 0732-183X

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Effect of SCG, 1,3-beta-D-glucan from Sparassis crispa on the hematopoietic response in cyclophosphamide induced leukopenic mice. Author(s): Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy & Life Science, Hachioji, Japan. Source: Harada, T Miura, N Adachi, Y Nakajima, M Yadomae, T Ohn, N Biol-PharmBull. 2002 July; 25(7): 931-9 0918-6158

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Maternal protein-and-energy restriction reduces the developmental toxicity of cyclophosphamide and hydroxyurea in rats. Author(s): Institut fur Klinische Pharmakologie und Toxikologie, Freie Universitat Berlin, 14195 Berlin, Germany. [email protected] Source: Chahoud, I Kuriyama, S N Paumgartten, F J Toxicology. 2002 September 30; 179(1-2): 137-49 0300-483X

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Phase I study of docetaxel in combination with cyclophosphamide as first-line chemotherapy for metastatic breast cancer. Author(s): Department of Medical Oncology, Cancer Research UK, West of Scotland Clinical Trials Unit, Beatson Oncology Centre, E Block, Western Infirmary, Glasgow, G11 6NT, Scotland, UK. [email protected] Source: Vasey, P A Roche, H Bisset, D Terret, C Vernillet, L Riva, A Ramazeilles, C Azli, N Kaye, S B Twelves, C J Br-J-Cancer. 2002 November 4; 87(10): 1072-8 0007-0920

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMD®Health: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

The following is a specific Web list relating to cyclophosphamide; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Vitamin A Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com

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Minerals Cisplatin Source: Healthnotes, Inc.; www.healthnotes.com

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Zinc Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER

3.

ALTERNATIVE MEDICINE CYCLOPHOSPHAMIDE

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Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cyclophosphamide. At the conclusion of this chapter, we will provide additional sources.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cyclophosphamide and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “cyclophosphamide” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to cyclophosphamide: •

14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group. Author(s): Sieber M, Bredenfeld H, Josting A, Reineke T, Rueffer U, Koch T, Naumann R, Boissevain F, Koch P, Worst P, Soekler M, Eich H, Muller-Hermelink HK, Franklin J, Paulus U, Wolf J, Engert A, Diehl V; German Hodgkin's Lymphoma Study Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 May 1; 21(9): 1734-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12721249

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A comparison of the incidence, duration, and degree of the neurologic toxicities of cisplatin-paclitaxel (PT) and cisplatin-cyclophosphamide (PC). Author(s): Bacon M, James K, Zee B.

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Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 July-August; 13(4): 428-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911718 •

A Phase I study of docetaxel plus cyclophosphamide in solid tumors followed by a Phase II study as first-line therapy in metastatic breast cancer. Author(s): Trent JC, Valero V, Booser DJ, Esparza-Guerra LT, Ibrahim N, Rahman Z, Vernillet L, Patel S, David CL, Murray JL, Cristofanilli M, Hortobagyi GN. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 July; 9(7): 2426-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855614

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A phase I study of pegylated liposomal doxorubicin hydrochloride (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small-cell lung cancer. Author(s): Leighl NB, Burkes RL, Dancey JE, Lopez PG, Higgins BP, David Walde PL, Rudinskas LC, Rahim YH, Rodgers A, Pond GR, Shepherd FA. Source: Clinical Lung Cancer. 2003 September; 5(2): 107-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596693

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A phase II study of sequential docetaxel followed by doxorubicin/cyclophosphamide as first-line chemotherapy for metastatic breast cancer. Author(s): Anton A, Hornedo J, Lluch A, Massuti B, Corral M, Colomer R. Source: Clinical Breast Cancer. 2003 October; 4(4): 286-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14651774

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A pilot study of dose intense doxorubicin and cyclophosphamide followed by infusional paclitaxel in high-risk primary breast cancer. Author(s): Zujewski JA, Eng-Wong J, O'Shaughnessy J, Venzon D, Chow C, Danforth D, Kohler DR, Cusack G, Riseberg D, Cowan KH. Source: Breast Cancer Research and Treatment. 2003 September; 81(1): 41-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14531496

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Adjuvant treatment for early ovarian cancer: a randomized phase III trial of intraperitoneal 32P or intravenous cyclophosphamide and cisplatin--a gynecologic oncology group study. Author(s): Young RC, Brady MF, Nieberg RK, Long HJ, Mayer AR, Lentz SS, Hurteau J, Alberts DS. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 December 1; 21(23): 4350-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645424

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Adjuvant treatment of breast cancer patients with 1-3 positive lymph nodes: vinorelbine plus epirubicin; vinorelbine plus epirubicin sequential followed up by

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paclitaxel; epirubicin plus cyclophosphamide; epirubicin plus cyclophosphamide sequential followed up by paclitaxel. A phase II study. Author(s): Elling D, Eggemann H, Kummel S, Breitbach P, Kohls A, Morack G, Schlosser H, Krocker J. Source: Breast (Edinburgh, Scotland). 2003 June; 12(3): 208-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14659328 •

Age is a risk factor for chemotherapy-induced hepatopathy with vincristine, dactinomycin, and cyclophosphamide. Author(s): Arndt C, Hawkins D, Anderson JR, Breitfeld P, Womer R, Meyer W. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 May 15; 22(10): 1894-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15143082

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An expanded phase I/II trial of cyclophosphamide, etoposide, and carboplatin plus total body irradiation with autologous marrow or stem cell support for patients with hematologic malignancies. Author(s): Shea TC, Bruner R, Wiley JM, Serody JS, Sailer S, Gabriel DA, Capel E, Moore DT, Dent G, Bentley S, Brecher ME. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2003 July; 9(7): 443-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869958

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Aqueous extract of walnut (Juglans regia L.) protects mice against cyclophosphamideinduced biochemical toxicity. Author(s): Haque R, Bin-Hafeez B, Parvez S, Pandey S, Sayeed I, Ali M, Raisuddin S. Source: Human & Experimental Toxicology. 2003 September; 22(9): 473-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14580007

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Bleomycin, epidoxorubicin, cyclophosphamide, vincristine and prednisone (BACOP) in patients with follicular non-Hodgkin's lymphoma: results of a prospective, multicenter study of the Gruppo Italiano Per Lo Studio Dei Linfomi (GISL). Author(s): Lombardo M, Morabito F, Merli F, Molica S, Cavanna L, Sacchi S, Broglia C, Angrilli F, Ilariucci F, Stelitano C, Luisi D, Berte R, Luminari S, Federico M, Brugiatelli M; GISL. Source: Leukemia & Lymphoma. 2002 September; 43(9): 1795-801. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685834

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Busulfan, cyclophosphamide, and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma. Author(s): Cogle CR, Moreb JS, Leather HL, Finiewicz KJ, Khan SA, Reddy VS, Wingard JR. Source: American Journal of Hematology. 2003 July; 73(3): 169-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12827653

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CHOP with high dose cyclophosphamide consolidation versus CHOP alone as initial therapy for advanced stage, indolent non-Hodgkin's lymphomas. Author(s): Pan D, Qin J, Farber C, O'Brien J, Filippa D, Portlock CS. Source: Leukemia & Lymphoma. 2003 June; 44(6): 967-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854895

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Combination of rituximab, cyclophosphamide, and vincristine induces complete hematologic remission of splenic marginal zone lymphoma. Author(s): Arcaini L, Orlandi E, Scotti M, Brusamolino E, Passamonti F, Burcheri S, Colombo N, Vanelli L, Sbalzarini G, Lazzarino M. Source: Clinical Lymphoma. 2004 March; 4(4): 250-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15072617

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Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). Author(s): Blayney DW, LeBlanc ML, Grogan T, Gaynor ER, Chapman RA, Spiridonidis CH, Taylor SA, Bearman SI, Miller TP, Fisher RI; Southwest Oncology Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 July 1; 21(13): 2466-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829664

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Double high-dose chemotherapy with adriamycin, paclitaxel, cyclophosphamide, and thiotepa followed by autologous peripheral blood stem cell transplantation in women with metastatic breast cancer. Author(s): Sayer HG, Schilling K, Vogt T, Blumenstengel K, Issa MC, Mugge LO, Kasper C, Kath R, Hoffken K. Source: Journal of Cancer Research and Clinical Oncology. 2003 June; 129(6): 361-6. Epub 2003 June 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12884031

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Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice. Author(s): Bhattacharya A, Lawrence RA, Krishnan A, Zaman K, Sun D, Fernandes G. Source: Journal of the American College of Nutrition. 2003 October; 22(5): 388-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14559931

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Effect of millimeter waves on cyclophosphamide induced suppression of T cell functions. Author(s): Makar V, Logani M, Szabo I, Ziskin M. Source: Bioelectromagnetics. 2003 July; 24(5): 356-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820293

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Effect of Potentiated Antibodies to Cyclophosphamide on the Development of Tumors and Effectiveness of Cytostatic Therapy under Experimental Conditions. Author(s): Amosova EN, Zueva EP, Razina TG, Krylova SG, Shilova NV, Epstein OI. Source: Bulletin of Experimental Biology and Medicine. 2003; 135 Suppl 1: 54-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12949650

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Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children's Oncology Group study. Author(s): Walterhouse DO, Lyden ER, Breitfeld PP, Qualman SJ, Wharam MD, Meyer WH. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 April 15; 22(8): 1398-403. Epub 2004 March 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15007087

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Evaluation for the development of 11q23 rearrangements in lymphoma patients treated with a high dose VP-16 and cyclophosphamide salvage regimen. Author(s): Mangel J, Duncan A, Lachance S. Source: Leukemia & Lymphoma. 2003 June; 44(6): 1001-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854902

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Fludarabine versus cyclophosphamide, vincristine, and prednisone in recurrent lowgrade lymphomas. Author(s): Alliot C. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 July 1; 21(13): 2626; Author Reply 2626-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829689

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Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. Author(s): Ayers M, Symmans WF, Stec J, Damokosh AI, Clark E, Hess K, Lecocke M, Metivier J, Booser D, Ibrahim N, Valero V, Royce M, Arun B, Whitman G, Ross J, Sneige N, Hortobagyi GN, Pusztai L. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 June 15; 22(12): 2284-93. Epub 2004 May 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15136595

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Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Author(s): Mohammad RM, Al-Katib A, Aboukameel A, Doerge DR, Sarkar F, Kucuk O. Source: Molecular Cancer Therapeutics. 2003 December; 2(12): 1361-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707277

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High molecular response rate and clinical correlation in patients with follicular lymphoma treated with cyclophosphamide-vincristine-prednisone plus interferon alpha 2b. Author(s): Fernandez-Ruiz E, Cabrerizo M, Ortega M, Blas C, Llamas P, Santos-Roncero M, Nieto S, Acevedo A, Perez G, Nicolas C, Fernandez-Ranada JM, Arranz R. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 July; 9(7): 2497-503. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12855623

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High-dose carboplatin, cyclophosphamide, etoposide with hematological growth factors, without stem cell support in patients with advanced cancer. Author(s): Recchia F, De Fillipis S, Piccinini M, Rea S. Source: Anticancer Res. 2003 September-October; 23(5B): 4141-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666615

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High-dose cyclophosphamide and etoposide for patients with refractory acute myeloid leukemia: a case series. Author(s): Talbot J, Rizzieri DA, DeCastro CM, Moore JO, Buckley P, Laney R, Stevenson D, Brumbaugh H, Gockerman JP. Source: American Journal of Hematology. 2003 August; 73(4): 295-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879438

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Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Author(s): Wang ES, Straus DJ, Teruya-Feldstein J, Qin J, Portlock C, Moskowitz C, Goy A, Hedrick E, Zelenetz AD, Noy A. Source: Cancer. 2003 September 15; 98(6): 1196-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12973843

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Involvement of nitric oxide and hyperbaric oxygen in the pathogenesis of cyclophosphamide induced hemorrhagic cystitis in rats. Author(s): Korkmaz A, Oter S, Deveci S, Ozgurtas T, Topal T, Sadir S, Bilgic H. Source: The Journal of Urology. 2003 December; 170(6 Pt 1): 2498-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14634459

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Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer. Author(s): Piccart MJ, Bertelsen K, Stuart G, Cassidy J, Mangioni C, Simonsen E, James K, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson R, Swenerton K, Trope C, Nardi M, Kaern J, Tumolo S, Timmers P, Roy JA, Lhoas F, Lidvall B, Bacon M, Birt A, Andersen J, Zee B, Paul J, Pecorelli S, Baron B, McGuire W.

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Source: International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society. 2003 November-December; 13 Suppl 2: 1448. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14656271 •

Long-term follow-up of patients with intermediate or high-grade non-Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone. Author(s): Rossini F, Terruzzi E, Perego D, Miccolis I, Rivolta F, Manca E, Pogliani EM. Source: Cancer. 2004 January 15; 100(2): 350-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716771

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Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B. Author(s): Weiss RB, Woolf SH, Demakos E, Holland JF, Berry DA, Falkson G, Cirrincione CT, Robbins A, Bothun S, Henderson IC, Norton L; Cancer and Leukemia Group B. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 May 1; 21(9): 1825-35. Erratum In: J Clin Oncol. 2003 December 1; 21(23): 4469. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12721260

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Nonmyeloablative stem cell transplantation with fludarabine and cyclophosphamide for patients with hematologic malignancies. Author(s): Nakajima H, Oki M, Kishi K, Ueyama J, Miyakoshi S, Hatsumi N, Sakura T, Miyawaki S, Yokota A, Fujisawa S, Mori S, Tanaka Y, Sakamaki H; Kanto Study Group for Cell Therapy. Source: Clinical and Laboratory Haematology. 2003 December; 25(6): 383-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14641143

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Nutritional benefits of enteral alanyl-glutamine supplementation on rat small intestinal damage induced by cyclophosphamide. Author(s): Satoh J, Tsujikawa T, Fujiyama Y, Bamba T. Source: Journal of Gastroenterology and Hepatology. 2003 June; 18(6): 719-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12753156

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Outcome after hyperbaric oxygen treatment for cyclophosphamide-induced refractory hemorrhagic cystitis. Author(s): Kalayoglu-Besisik S, Abdul-Rahman IS, Erer B, Yenerel MN, Oguz FS, Tunc M, Sargin D. Source: The Journal of Urology. 2003 September; 170(3): 922. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12913734

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Paclitaxel and epidoxorubicin or doxorubicin versus cyclophosphamide and epidoxorubicin as first-line chemotherapy for metastatic breast carcinoma: a randomised phase II study. Author(s): Gebbia V, Blasi L, Borsellino N, Caruso M, Leonardi V, Agostara B, Valenza R. Source: Anticancer Res. 2003 January-February; 23(1B): 765-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12680181

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Paclitaxel/carboplatin versus cyclophosphamide/carboplatin in peritoneal carcinomatosis of the ovary. Author(s): Balat O. Source: Eur J Gynaecol Oncol. 2004; 25(2): 195-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15032280

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Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer. Author(s): Shimizu T, Enomoto K, Haga S, Fukuda M, Iino Y, Ikeda T, Taguchi T. Source: Breast Cancer. 2003; 10(2): 140-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736567

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Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). Author(s): Sparano JA, Lee S, Chen MG, Nazeer T, Einzig A, Ambinder RF, Henry DH, Manalo J, Li T, Von Roenn JH. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 April 15; 22(8): 1491-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084622

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Phase II trial of infusional cyclophosphamide, idarubicin, and etoposide in poor prognosis non-Hodgkin's lymphoma. Author(s): Salman H, Perez A, Sparano JA, Ratech H, Negassa A, Hopkins U, Villani G, Fuks J, Wiernik PH. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2003 August; 26(4): 338-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902881

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Phase III study of ranimustine, cyclophosphamide, vincristine, melphalan, and prednisolone (MCNU-COP/MP) versus modified COP/MP in multiple myeloma: a Japan clinical oncology group study, JCOG 9301. Author(s): Takenaka T, Itoh K, Suzuki T, Utsunomiya A, Matsuda S, Chou T, Sai T, Sano M, Konda S, Ohno T, Mikuni C, Deura K, Yamada T, Mizorogi F, Nagoshi H, Tomonaga M, Hotta T, Kawano K, Tsushita K, Hirano M, Shimoyama M; Lymphoma Study Group of the Japan Clinical Oncology Group.

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Source: International Journal of Hematology. 2004 February; 79(2): 165-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15005346 •

Protective effect of a polyherbal formulation (Immu-21) against cyclophosphamideinduced mutagenicity in mice. Author(s): Jena GB, Nemmani KV, Kaul CL, Ramarao P. Source: Phytotherapy Research : Ptr. 2003 April; 17(4): 306-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12722129

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Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexatecytarabine regimen. Author(s): Weiser MA, Cabanillas ME, Konopleva M, Thomas DA, Pierce SA, Escalante CP, Kantarjian HM, O'Brien SM. Source: Cancer. 2004 March 15; 100(6): 1179-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15022284

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Severe pulmonary toxicity in patients with advanced-stage Hodgkin's disease treated with a modified bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine (BEACOPP) regimen is probably related to the combination of gemcitabine and bleomycin: a report of the German Hodgkin's Lymphoma Study Group. Author(s): Bredenfeld H, Franklin J, Nogova L, Josting A, Fries S, Mailander V, Oertel J, Diehl V, Engert A; German Hodgkin's Lymphoma Study Group. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 June 15; 22(12): 2424-9. Epub 2004 May 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15136597

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Synergistic interaction between cyclophosphamide or paclitaxel and the bioreductive compound NLCPQ-1, in vivo. Author(s): Papadopoulou MV, Ji M, Bloomer WD. Source: Oncology Research. 2003; 13(12): 561-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899246

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Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats. Author(s): Vieira MM, Macedo FY, Filho JN, Costa AC, Cunha AN, Silveira ER, Brito GA, Ribeiro RA. Source: Phytotherapy Research : Ptr. 2004 February; 18(2): 135-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15022166

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The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National

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Surgical Adjuvant Breast and Bowel Project Protocol B-27. Author(s): Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project Protocol B-27. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 November 15; 21(22): 4165-74. Epub 2003 October 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14559892 •

The prognostic significance of the immunohistochemical expression of p53, bcl-2, cerb B-2 and cathepsin-D in ovarian cancer patients receiving platinum with cyclophosphamide or paclitaxel chemotherapy. Author(s): Protopapas A, Diakomanolis E, Bamias A, Milingos S, Markaki S, Papadimitriou C, Dimopoulos AM, Michalas S. Source: Eur J Gynaecol Oncol. 2004; 25(2): 225-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15032288

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Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy. Author(s): Escobar PF, Lurain JR, Singh DK, Bozorgi K, Fishman DA. Source: Gynecologic Oncology. 2003 December; 91(3): 552-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675675

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMD®Health: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

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The following is a specific Web list relating to cyclophosphamide; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Multiple Sclerosis Source: Healthnotes, Inc.; www.healthnotes.com Rheumatoid Arthritis Source: Healthnotes, Inc.; www.healthnotes.com Scleroderma Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc.; www.healthnotes.com

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Herbs and Supplements Alpha-Lipoic Acid Source: Integrative Medicine Communications; www.drkoop.com Astragalus Alternative names: Astragalus membranaceus Source: Integrative Medicine Communications; www.drkoop.com Astragalus Mem Alternative names: Huang-Qi; Astragalus membranaceus Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Astragalus Membranaceus Alternative names: Astragalus Source: Integrative Medicine Communications; www.drkoop.com Astragalus Mongholicus Alternative names: Astragalus Source: Integrative Medicine Communications; www.drkoop.com Beta-Carotene Source: Healthnotes, Inc.; www.healthnotes.com Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com

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Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cyclophosphamide Source: Healthnotes, Inc.; www.healthnotes.com Cysteine Source: Integrative Medicine Communications; www.drkoop.com Docetaxel Source: Healthnotes, Inc.; www.healthnotes.com Echinacea Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Echinacea Alternative names: Echinacea angustifolia Source: Integrative Medicine Communications; www.drkoop.com Echinacea angustifolia Alternative names: Echinacea Source: Integrative Medicine Communications; www.drkoop.com Echinacea pallida Alternative names: Echinacea Source: Integrative Medicine Communications; www.drkoop.com Echinacea purpurea Alternative names: Echinacea Source: Integrative Medicine Communications; www.drkoop.com Fluorouracil Source: Healthnotes, Inc.; www.healthnotes.com Glutamine Source: Healthnotes, Inc.; www.healthnotes.com Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Huang-Qi Alternative names: Astragalus Source: Integrative Medicine Communications; www.drkoop.com Melatonin Source: Healthnotes, Inc.; www.healthnotes.com Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com

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Milk-Vetch Root Alternative names: Astragalus Source: Integrative Medicine Communications; www.drkoop.com N-Acetyl Cysteine Source: Healthnotes, Inc.; www.healthnotes.com Paclitaxel Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Purple Coneflower Alternative names: Echinacea Source: Integrative Medicine Communications; www.drkoop.com Spleen Extracts Source: Healthnotes, Inc.; www.healthnotes.com Taurine Source: Healthnotes, Inc.; www.healthnotes.com Thymus Extracts Source: Healthnotes, Inc.; www.healthnotes.com Withania Ashwagandha Alternative names: Ashwagandha; Withania somnifera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON CYCLOPHOSPHAMIDE Overview In this chapter, we will give you a bibliography on recent dissertations relating to cyclophosphamide. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “cyclophosphamide” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cyclophosphamide, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Cyclophosphamide ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to cyclophosphamide. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

ABCC2(cMOAT): Role in 4-hydroxycyclophosphamide elimination from the liver and survival of high dose cyclophosphamide regimens by Qiu, Ruolun, PhD from UNIVERSITY OF WASHINGTON, 2003, 114 pages http://wwwlib.umi.com/dissertations/fullcit/3111124

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Analysis of cyclophosphamide and phosphoramide mustard, their pharmacokinetics and the relationship of serum drug concentrations to toxicity in patients undergoing cancer chemotherapy by Hardy, Robert; PhD from UNIVERSITY OF TORONTO (CANADA), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL43431

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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. PATENTS ON CYCLOPHOSPHAMIDE Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “cyclophosphamide” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cyclophosphamide, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Cyclophosphamide By performing a patent search focusing on cyclophosphamide, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 8Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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The following is an example of the type of information that you can expect to obtain from a patent search on cyclophosphamide: •

(N-Phosphonacetyl-L-aspartato)(1,2-diaminocyclchexane)platinum(II) or alkali metal salt Inventor(s): Gale; Glen R. (Charleston, SC), Meischen; Sandra J. (Charleston, SC), Naff; Marion B. (Bethesda, MD) Assignee(s): The United States of America as represented by the of the Department of (Washington, DC) Patent Number: 4,284,579 Date filed: June 9, 1980 Abstract: In binary treatment with cis-dichlorodiamine-platinum(II) (or cisplatin) the preferred ratio of the present compound to cisplatin is about 10:1 with a range of about 10:1 to 1:10 in mg/kg of body weight.As to the variations in the formula on the left hand side of the formula, it may be varied as monodentate, such as cisplatin containing a single amine group proceeding from the ring, or bidentate, such as the present compound. The saturated cyclo ring may be C.sub.4 or C.sub.5 -C.sub.7 in addition to the present cyclohexane.The present platinum compound may be prepared by reacting the known L-aspartic acid, N-(phosphonacetyl-) disodium salt (PALA; NSC-224131), with dinitrato(1,2-diaminocyclohexane)platinum(II) (NSC-239851). This compound Nphosphonacetyl-L-aspartato(1,2-diaminocyclohexane)platinum(II) may be combined in multiple drug regimen with substantially improved yield cures over the parent compounds. For example, the compound denoted Pt-268 may be combined in a dual regimen with cyclophosphamide (CY), hydroxyurea (HU), and cisplatin. Excerpt(s): In binary treatment with cis-dichlorodiamineplatinum(II) (or cisplatin) the preferred ratio of the present compound to cisplatin is about 10:1 with a range of about 10:1 to 1:10 in mg/kg of body weight. As to the variations in the formula on the left hand side, it may be varied as monodentate, such as cisplatin containing a single amine group proceeding from the ring, or bidentate, such as the present compound. The saturated cyclo ring may be C.sub.4 or C.sub.5 -C.sub.7 in addition to the present cyclohexane. where A and B are monodentate (A-, B-) or bidentate (AB-) amine (or other donor atoms/groups) compounds binding to platinum. Web site: http://www.delphion.com/details?pn=US04284579__

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Cyclophosphamide Inventor(s): Alam; Abu S. (Libertyville, IL), Kapoor; John N. (Lake Forest, IL), Koziol; Kenneth J. (Bensenville, IL) Assignee(s): Lyphomed, Inc. (Rosemont, IL) Patent Number: 4,879,286 Date filed: April 4, 1988 Abstract: A storage-stable liquid oncolytic formulation of cyclophosphamide for parenteral administration is presented. Currently utilized lyophilized formulations have inherent diseconomies and increased hazard is associated with reconstitution. The liquid formulations of the present invention comprise a solution of cyclophosphamide with an organic polyol as cosolvent, which provide enhanced shelf-life and greater ease

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of administration. The polyol is either propylene glycol, polyethylene glycol or glyerol. The solution of cyclophosphamide is either aqueous, or in the case of propylene glycol may constitute 10-30% by weight of an alcohol. Excerpt(s): Cyclophosphamide is the generic name for 2-[bis(2chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide monohydrate, a widely used antineoplastic drug chemically related to the nitrogen mustards. The nitrogen mustards are known as alkylating agents. These alkylating agents undergo strongly electrophilic reactions with such biologically important molecules as DNA. By alkylating DNA, these agents interfere with replication which ultimately interferes with cell viability. When exposed to these alkylating agents at low doses, the cell is capable of remaining viable by relying on its DNA repair enzymes which remove these alkylators prior to replication, thus allowing replication to proceed normally. The efficiency of these repair enzymes will be related to the degree and type of alkylation which must be repaired. For example, alkylation of a single strand of DNA may often be repaired with relative ease allowing normal cell division. However, damage to DNA caused by interstrand cross linkers (bifunctional agents such as cyclophosphamide) are more difficult to repair and involve more complex mechanisms. Thus, with increasing doses there is more extensive cross linking resulting in DNA breakdown with concomitant cell death. These agents are cell cycle nonspecific being capable of combining with cells at any phase of their cycle. The therapeutic efficacy of these compounds arises from their interference with replication in cells which are dividing faster than their DNA repair enzymes can de-alkylate. It is through this destructive interference with replication in these rapidly dividing cells which these alkylating agents exert their cytotoxicity. Cancer cells are notorious for being just such rapidly proliferating cells. This affords the pharmacologist a target at which chemotherapeutic agents may be aimed. Cancerous tissue growth outpaces the corrective effect of the DNA repair enzymes. These tissues then undergo extensive cell death due to breakdowns in replication and tissue growth falls off. Web site: http://www.delphion.com/details?pn=US04879286__ •

Cyclophosphamide Inventor(s): Alam; Abu S. (Libertyville, IL), Kapoor; John N. (Lake Forest, IL), Koziol; Kenneth J. (Bensenville, IL), Sayeed; Fakrul A. A. (Mundelein, IL) Assignee(s): Fujisawa USA, Inc. (Deerfield, IL) Patent Number: 5,036,060 Date filed: November 24, 1989 Abstract: A mannitol-free lyophilized formulation of cyclophosphamide is disclosed. Sodium chloride is present as an excipient. Excerpt(s): This invention relates generally to the field of antineoplastic agents and more specifically to cyclophosphamide and formulations thereof suitable for use in parenteral administration. Cyclophosphamide is one of the most significant antineoplastic drugs of today. Cyclophosphamide is disclosed and claimed in U.S. Pat. No. 3,018,302 granted Jan. 23, 1962 to H. Arnold et al., and is denoted chemically as 2-[bis(2chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine -2-oxide monohydrate. Cyclophosphamide was initially commercially available as the monohydrate, in a parenteral dosage pre-mix consisting of a sterile, packaged, dry-powder admixture of

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the drug and sodium chloride. The premix was dissolved in water prior to administration which could be oral as well as parenteral. Web site: http://www.delphion.com/details?pn=US05036060__ •

Cyclophosphamide - alanine lyophilizates Inventor(s): Hutt; Julie A. (Dublin, OH), Palepu; Nageswara R. (Dublin, OH) Assignee(s): Erbamont, Inc. (Dublin, OH) Patent Number: 5,066,647 Date filed: September 17, 1990 Abstract: A stable rapidly dissolving lyophilized composition of cyclophosphamide and alanine is provided. Excerpt(s): The present invention relates to a novel lyophilized composition containing cyclophosphamide and alanine as an excipient. U.S. Pat. No. 4,537,883 to Alexander et al. (Mead Johnson & Co.) discloses various lyophilizats of cyclophosphamide. These lyophilizates are prepared by lyophilizing a solution of cyclophosphamide and one or more excipients and re-hydrating the product such that it contains about 4% moisture. The patent is based upon a comparative study of lyophilizate cakes and the dissolution time for lyophilizates of cyclophosphamide prepared using a number of excipients. The study concludes that the lyophilizate prepared with mannitol gives a better cake and faster dissolution time than the lyophilizates prepared with other excipients. The patent also teaches that the lyophilized cyclophosphamide-mannitol composition exhibits better thermal stability if it contains an equimolar amount of water based on cyclophosphamide. The preferred lyophilizate contains 20 parts cyclophosphamide, 1.25 to 2 parts water and 10 to 85 parts mannitol. Among the excipients evaluated in the patent are mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid and combinations of mannitol and various organic acids including the amino acids glycine and arginine as secondary excipients. The lyophilizates illustrated in the patent prepared with the amino acids provided poor cakes which exhibited poor dissolution times. It has now been found that lyophilizates of cyclophosphamide having improved dissolution times and good shelf stability can be obtained using alanine as the excipient. Lyophilizates in accordance with the present invention, generally contain about 50 to 150 parts by weight of alanine per 100 parts by weight cyclophosphamide and water in the amounts discussed below. The alaninecyclophosphamide combination is believed to be unique in that upon lyophilization it yields an anhydrous product which is crystalline whereas cyclophosphamide with other excipient combinations produced an amorphous lyophilizate. Web site: http://www.delphion.com/details?pn=US05066647__

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Cyclophosphamide - sodium bicarbonate lyophilizates Inventor(s): Hutt; Julie A. (Columbus, OH), Palepu; Nageswara R. (Dublin, OH) Assignee(s): Erbamont, Inc. (Dublin, OH) Patent Number: 5,130,305 Date filed: October 15, 1990

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Abstract: A stable rapidly dissoloving lyophilized and hydrated composition of cyclophosphamide and sodium bicarbonate is provided which contains an amount of water which is at least equimolar to the combined amount of cyclophosphamide and sodium bicarbonate in the composition and the weight ratio of cyclophosphamide to sodium bicarbonate is about 1:0.5 to 1:1.5; the composition is preferably prepared from a solution containing at least 1% (W/V) weight sodium bicarbonate. Excerpt(s): The present invention relates to a novel lyophilized composition containing cyclophosphamide and sodium bicarbonate as an excipient. U.S. Pat. No. 4,537,883 to Alexander et al. (Mead Johnson & Co.) discloses various lyophilizates of cyclophosphamide. These lyophilizates are prepared by lyophilizing a solution of cyclophosphamide and one or more excipients and re-hydrating the product such that it contains about 4% moisture. The patent is based upon a comparative study of lyophilizate cakes and the dissolution time for lyophilizates of cyclophosphamide prepared using a number of excipients. The study concludes that the lyophilizate prepared with mannitol gives a better cake and faster dissolution time than the lyophilizates prepared with other excipients. The patent also teaches that the lyophilized cyclophosphamide-mannitol composition exhibits better thermal stability if it contains an equimolar amount of water based on cyclophosphamide. The preferred lyophilizate contains 20 parts cyclophosphamide, 1.25 to 2 parts water and 10 to 85 parts mannitol. Among the excipients evaluated in the patent are mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid. The lyophilizates illustrated in the patent prepared with sodium bicarbonate exhibited dissolution times upon reconstitution of about two minutes or greater. A study of "The Stability of Cyclophosphamide in Lyophilized Cakes" by Kovalcik and Guillory, J. Parenteral Science & Technology, 42, No. 1, 29-37 (1988) discloses sodium bicarbonate lyophilizates prepared using a 1:4 weight ratio of cyclophosphamide to sodium bicarbonate with a 5% water content of total weight of the lyophilizate. The sample cakes showed a 5% loss in potency when left at room temperature for 53 days and 4% loss in potency when stored at room temperature for 117 days. Web site: http://www.delphion.com/details?pn=US05130305__ •

Direct compression cyclophosphamide tablet Inventor(s): Gallian; Claude E. (Newburgh, IN), Williams; Charles (Evansville, IN) Assignee(s): Bristol-Myers Company (New York, NY) Patent Number: 5,047,246 Date filed: September 9, 1988 Abstract: A directly compressible pharmaceutical composition comprising cyclophosphamide and a partially or fully pregelatinized starch is disclosed. The pharmaceutical composition, when directly compressed into a tablet, exhibits unexpected stability when compared to cyclophosphamide in combination with other direct compression vehicles. Excerpt(s): This invention relates to a novel pharmaceutical composition. More particularly, this invention relates to an unexpectedly stable pharmaceutical composition comprising cyclophosphamide and a partially or fully pregelatinized starch, which composition can be directly compressed to form a pharmaceutical tablet. The compressed tablet is one of the oldest and most popular unit dosage forms for medicinal substances. The tablet as a dosage form can be traced to well over 1,000 years

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ago when a procedure for molding solid forms containing medicinal ingredients was recorded. As a result of the introduction of new carriers and compression vehicles, tablets are replacing many forms of pills, powders and capsules. Accordingly, tablets presently represent the largest production volume of all pharmaceuticals. The reasons for the widespread use of tablets are apparent, since tablets facilitate: (1) administration of medication in an accurate dose; (2) fast and accurate dispensing with less chance of error and contamination: (3) ease of administration: (4) administration in a form in which the time and area of contact between the active ingredient and the taste buds are reduced, thus obviating the physiological problems associated with the oral administration of drugs that possess a bitter taste and, in the case of coated tablets, with drugs that possess a disagreeable odor; (5) release of drugs at specific locations in the gastro-intestinal tract to prevent degradation of drugs sensitive to the low pH environment in the stomach, prevent release of drugs that irritate the gastric mucosa in the stomach, and facilitate local action or preferential absorption at specific sites in the tract: (6) enhanced stability by effecting a marked reduction in the surface of the drug exposed to the environment; (7) rapid production; and (8) economy and ease in storage, packaging and shipping. Web site: http://www.delphion.com/details?pn=US05047246__ •

Lyophilized cyclophosphamide Inventor(s): Alexander; Robert L. (Evansville, IN), Bequette; Robert J. (Evansville, IN), Kensler; Terry T. (Evansville, IN), Scott; Joseph A. (Evansville, IN) Assignee(s): Mead Johnson & Company (Evansville, IN) Patent Number: 4,537,883 Date filed: March 13, 1984 Abstract: A lyophilized pharmaceutical solid composition containing cyclophosphamide for reconstitution with water to provide a solution for oral or parenteral administration. This lyophilized cyclophosphamide solid composition demonstrates improved stability, solubility characteristics and enhanced appearance compared with currently available dry powder pre-mix compositions of cyclophosphamide. The lyophilized solid composition contains about 20 parts by weight of cyclophosphamide, about 11/4-2 parts by weight of water and from about 1085 parts by weight of excipient which is comprised mainly of mannitol. Processes for making the composition are disclosed. Excerpt(s): Cyclophosphamide is the generic name for 2-[bis(2chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide monohydrate, a widely used antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide was one example of a group of novel cyclic phosphoric acid ester amides which were disclosed and claimed in U.S. Pat. No. 3,018,302 granted Jan. 23, 1962 to H. Arnold, et al. A related series of compounds bearing substituents on the oxazaphosphorine ring nitrogen was disclosed and claimed in U.S. Pat. No. 3,732,340 granted May 8, 1973 also to H. Arnold, et al. Over the past 20 years a considerable amount of literature concerning cyclophosphamide has accumulated. Most of these references deal mainly with clinical applications of this agent as an antineoplastic drug. Cyclophosphamide has been distributed for much of that time by Mead Johnson & Company under the proprietary name CYTOXAN.RTM. ENDOXAN.RTM. and NEOSAR.RTM. are proprietary names for similar pharmaceutical formulations of cyclophosphamide which are essentially comparable to CYTOXAN.RTM.

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Web site: http://www.delphion.com/details?pn=US04537883__ •

Method for lyophilization of cyclophosphamide and product Inventor(s): Herzyk; Tomaz R. (King of Prussia, PA), Palepu; Nageswara R. (Lansdale, PA) Assignee(s): Erbamont, Inc. (Dublin, OH) Patent Number: 5,418,223 Date filed: April 22, 1994 Abstract: A process for preparing a pharmaceutical preparation consisting essentially of a lyophilized cake of cyclophosphamide monohydrate and a bulking agent which comprises freezing cyclophosphamide, a bulking agent, and water, lyophilizing part of the water, obtaining and melting a supersaturated cyclophosphamide-bulking agent solution, precipitating cyclophosphamide as a hydrated polymorph, refreezing the solution and lyophilizing the water not bound to cyclophosphamide or the bulking agent. Excerpt(s): The present invention relates to the lyophilization of cyclophosphamide. U.S. Pat. No. 4,537,883 to Alexander et al. (Mead Johnson & Co.) discloses various lyophilizates of cyclophosphamide. These lyophilizates are prepared by lyophilizing a solution of cyclophosphamide and one or more excipients and re-hydrating the product such that it contains about 4% moisture. The patent is based upon a comparative study of lyophilizate cakes and the dissolution time for lyophilizates of cyclophosphamide prepared using a number of excipients. The study concludes that the lyophilizate prepared with mannitol gives a better cake and faster dissolution time than the lyophilizates prepared with other excipients. The patent also teaches that the lyophilized cyclophosphamide-mannitol composition exhibits better thermal stability if it contains an equimolar amount of water based on cyclophosphamide. The preferred lyophilizate contains 20 parts cyclophosphamide, 1.25 to 2 parts water and 10 to 85 parts mannitol. Among the excipients evaluated in the patent are mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid. In lyophilizing cyclophosphamide, it is known that cyclophosphamide monohydrate is more stable than anhydrous cyclophosphamide. As a result, a practice has developed wherein in preparing lyophilized pharmaceutical preparations containing cyclophosphamide, the bound water or water of crystallization is removed from the cyclophosphamide in the lyophilizer and a small amount of water is back added to the composition to convert the less stable anhydrous cyclophosphamide product to the more stable monohydrate. This practice is described in U.S. Pat. No. 4,537,883 to Alexander and in T. R. Kovalcik and J. K. Guillory "The Stability of Cyclophosphamide in Lyophilized Cakes," J. Paren. Sci. & Tech., 42, No. 1, p. 29-37 (1988). It is also described in commonly assigned U.S. applications Ser. Nos. 07/597,965 (now U.S. Pat. No. 5,130,305) and 07/583,896, now U.S. Pat. No. 5,066,647). Web site: http://www.delphion.com/details?pn=US05418223__

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Method of reducing cyclophosphamide induced hemorrhagic cystitis Inventor(s): Gordon; Donovan E. (Highland Park, IL), Rice; Deborah (Broadview, IL), Safron; Joseph A. (Grayslake, IL), White; Randy D. (Crystal Lake, IL) Assignee(s): Free Radical Sciences (Cambridge, MA) Patent Number: 5,447,712 Date filed: December 9, 1993 Abstract: A method is provided for reducing side effects caused by chemotherapeutic agents by administering to a patient in need thereof a therapeutically effective amount of a composition including L-2-oxothiazolidine-4-carboxylate specifically for reducing hemorrhagic cystitis in a patient at risk of same. Excerpt(s): The present invention relates generally to the treatment of patients using chemotherapy agents. More specifically, the present invention relates to reducing or preventing side effects caused by chemotherapeutic agents. Cancer can develop in any tissue of any organ at any age. Many cancers detected at an early stage are potentially curable. The principal objectives of cancer screening and early diagnosis are: (1) to decrease cancer mortality; (2) to lead to less radical therapy; and (3) to reduce financial costs. Merck Manual, 16th Edition, 1263, 1269 (1992). Successful therapy must be focused on the primary tumor and its metastases, whether clinically apparent or microscopic. Thus, local and regional therapy, surgery, or radiation must be integrated with systemic therapy (e.g. drugs). Id. at 1275. Web site: http://www.delphion.com/details?pn=US05447712__

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Method of treatment of hormone-unresponsive metastatic prostate cancer Inventor(s): Brandes; Lorne J. (Winnipeg, CA) Assignee(s): University of Manitoba (Winnipeg, CA) Patent Number: 5,432,168 Date filed: December 27, 1993 Abstract: Prostate cancer particularly hormone-unresponsive metastatic prostate cancer, is treated by cyclophosphamide or other normally substantially inactive agent. Potentiation of the anti-cancer activity and amelioration of cyclophosphamideassociated toxicity is achieved by an initial intravenous infusion of DPPE over an approximately one hour period prior to cyclophosphamide treatment. Excerpt(s): The present invention relates to the treatment of prostate cancer. Cancer of the prostate is now the most commonly-diagnosed cancer in males. It is estimated that, in 1993, there will be 110,000 new cases of prostate cancer diagnosed in the United States alone, while 45,000 will die from this disease. Prostate cancer is now the third leading cause of all cancer-specific deaths in men between the ages of 55 and 74. It is projected that by the year 2000, a 90% increase in annual incidence of the disease and a 37% increase in annual mortality rates will be observed. Although prostate cancer may be a relatively indolent neoplasm in the elderly, the overall decrease in life span in patients with this disease is approximately 10 years. Improvement in the treatment of prostate cancer has centered on early detection; in recent years, a screening test (prostate-specific antigen, or PSA), although not entirely specific, has increased the power to diagnose this disease in asymptomatic patients. Treatment of early prostate cancer in men under the age of 65 has focused on radical surgery and/or radiotherapy, but the impact of these

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aggressive approaches on overall survival remains debatable. The approach to treatment of men over the age of 65 historically has been more conservative, and is based on the ablation of testosterone production. This result is achieved by the administration of female hormones (estrogen) or by orchidectomy, often in combination with antiandrogen medication. More recently, luteinizing hormone-releasing hormone (LHRH) agonists have joined the hormonal armamentarium. Web site: http://www.delphion.com/details?pn=US05432168__ •

Method of using 4-(2-(P-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl)phenoxy)ethyl)morpholine with cytostatics Inventor(s): Teelmann; Kampe (Basel, CH) Assignee(s): Hoffmann-La Roche Inc. (Nutley, NJ) Patent Number: 5,242,909 Date filed: October 4, 1991 Abstract: The use of 4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propeny l]phenoxy]ethyl]-morpholine, simultaneously, separately or sequentially in combination with a synergistically effective amount of cyclophosphamide in cancer prophylaxis or therapy for mammary tumors in mammals is described. Excerpt(s): The invention is concerned with the use of 4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro5,5,8,8-tetramethyl-2-napthyl)propenyl] phenoxy]ethyl]-morpholine as an active substance for the manufacture of pharmaceutical preparations for supporting therapy with a cytostatic agent. In another aspect, the invention is concerned with a product containing 4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl ]phenoxy]-ethyl]morpholine and a cytostatic agent as a combination preparation for the simultaneous, separate or sequential use in cancer prophylaxis or therapy particularly for cancers which are sensitive to such a combination. The invention is also concerned with a commercial pack containing as the pharmaceutically active substance 4-[2-[p-[(E)2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl ]phenoxy]ethyl]morpholine together with instructions for its use in combination with a cytostatic agent for the simultaneous, separate or sequential use in cancer prophylaxis or therapy particularly for cancers which are sensitive to such a combination. The invention is also concerned with a method of cancer prophylaxis or therapy in mammals which comprises administering 4-[2-[p-[(E)-2 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)propenyl]phenoxy]ethyl ]morpholine simultaneously, separately or a sequentially in combination with a cytostatic agent particularly for cancers which are sensitive to such a combination. Therapy with cytostatic agents is frequently associated with undesirable effects which have their origin in the toxicity of the cytostatic agent. Examples of such undesirable effects are hair loss, weight loss or inappetence, bone marrow disorders, gastrointestinal disorders, myocardial changes, testicular changes, liver and kidney disorders. It has now been found that these undesirable effects during therapy with cytostatic agents can be reduced or avoided when the compound 4-[2-[p[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propeny l]phenoxy]ethyl]morpholine (referred to hereinafter as "Compound Z") is administered simultaneously or sequentially. Web site: http://www.delphion.com/details?pn=US05242909__

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Process for freeze drying cyclophosphamide Inventor(s): Francis; Daniel L. (Ravenna, OH) Assignee(s): Cetus-Ben Venue Therapeutics (Emeryville, CA) Patent Number: 4,659,699 Date filed: May 21, 1984 Abstract: A two-stage process for freeze-drying an aqueous solution of a dosage amount of cyclophosphamide to yield a hydrate of cyclophosphamide (referred to as "CPA" for brevity), comprises, in a first stage, freeze-drying a solution of CPA in combination with an excipient until the moisture content of the freeze-dried material is less than 2% by wt, based on the amount of anhydrous CPA present; and, in a second stage, rehydrating the freeze-dried material until the moisture content of the product is in the critical range of from about 2% to 7% by wt, based on the net wt of CPA product, it being essential for stability of the product that at least one sugar excipient be present. The process requires that a major amount by weight of the excipient(s) or all of it, be mannitol, optionally with an additional sugar and/or a carboxylic acid, and/or a buffer salt; and, the mannitol is present in an amount at least one-half (0.5 times) as mush as the CPA (anhyd) present. To produce a dosage form of a `plug` or `cake` which is free of flakes and granules, or bubbles on its surface, and/or voids within the product (or "plug"), any of which are individually no greater than 2 mm in equivalent diameter ("equiv. dia."), requires a unique combination of carefully controlled process steps. The preferred CPA product obtained by the process provides a dosage amount of stable freeze-dried and rehydrated CPA as a hydrate which includes at least an equivalent amount by weight, and up to 5 times as much, of mannitol. The dosage amount may include sodium chloride to adjust tonicity, and a buffer salt to maintain pH. Excerpt(s): Pharmaceuticals, biological specimens and foodstuffs are among the most commonly freeze-dried ("lyophilized") materials. Though it would seem relatively easy to achieve desirable results, namely the dry state, by starting with an aqueous solution of a pharmaceutical, then freezing the solution and subliming the resulting ice, it is not. The purpose of freeze-drying is to minimize the changes in the properties of the substance while improving its stability at or near room temperature. Much has been published as to how to do this effectively (See, for example, Edwards Freeze-Drying Handbook, by Terence W. G. Rowe and John W. Snowman, published by Edwards High Vacuum, Crawley, England (1976). The problem is that in one or the other stages of freeze-drying, the material being freeze dried is undesirably altered. A great deal of well-publicized effort has been directed to the freeze-drying of biological materials because of the criticality of the process steps required to obtain satisfactory results (see Freezing and Drying of Biological Materials, edited by O. St. Whitelock, "Annals of the New York Academy of Sciences", Vol 85, Art. 2, pgs 501-734, published by The Academy 1960). A comparable amount of less well-publicized effort has been directed to the freeze-drying of various pharmaceuticals for the twin purposes of maintaining their potency and stability over extended periods of time under ambient conditions, and to provide convenience in dispensing or using the pharmaceuticals. Much attention has been paid, and much effort had been directed, neither too well-publicized, to the importance of presenting a pharmaceutically elegant dosage quantity of a pharmaceutical which must also maintain its potency and stability. In most instances, the freeze-dried pharmaceutical is deposited as a product (or "cake") which adheres to the sides of the vial or other container in which the precursor solution is freeze-dried. As the preferred form of packaging freeze-dried pharmaceuticals is in glass vials or containers, it will immediately be evident that a cake or plug tightly held in a glass

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container, near its bottom, has greater visual appeal than a loose powder, particularly if the powder has a proclivity to dust. When a pharmaceutical defies being successfully freeze-dried, that is, being reduced to a stable pharmaceutically elegant product without deleteriously affecting the physiological properties of the pharmaceutical, it is generally packaged as a dry powder. Web site: http://www.delphion.com/details?pn=US04659699__ •

Reconstitution of dry fill cyclophosphamide Inventor(s): Grab; Frederick L. (Dublin, OH) Assignee(s): Erbamont, Inc. (Dublin, OH) Patent Number: 4,775,533 Date filed: February 24, 1987 Abstract: In a method for reconstituting dry fill cyclophosphamide, the vial volume is at least 50 ml and the headspace is at least 15 ml. Excerpt(s): The present invention relates to dry fill cyclophosphamide and to a method of reconstituting dry fill cyclophosphamide. Cyclophosphamide has been used to inhibit cell growth in the treatment of malignant growths and similar diseases. Clinical tests have proven that cyclophosphamide is effective as an antineoplastic agent. cyclophosphamide is available under the trademark Cytoxan from Bristol-Myers Oncology Division of Bristol-Myers Company. Bristol-Myers supplies Cytoxan in a 20 ml vial for a 200 mg dosage and a 30 ml vial for a 500 mg dosage. The solvent volume recommended for the 200 mg vial is 10 ml while the solvent volume recommended for the 500 mg vial is 25 ml. Web site: http://www.delphion.com/details?pn=US04775533__

•

Retroviral vector capable of transducing the aldehyde dehydrogenase-1 gene and uses of said vector Inventor(s): Dalla-Favera; Riccardo (New York, NY), Gianni; Alessandro Massimo (Milan, IT) Assignee(s): The Trustees of Columbia University in the City of New York (New York, NY) Patent Number: 5,888,820 Date filed: December 1, 1994 Abstract: This invention provides viral and retroviral vectors which comprises a nucleic acid molecule encoding a human cytosolic aldehyde dehydrogenase or a glutamylcysteine synthetase or combinations thereof. Further, this invention provides an isolated mammalian nucleic acid molecule encoding a cytosolic aldehyde dehydrogenase and glutamylecysteine synthetase. In addition, this invention provides a method for reducing the toxic effects of a cyclophosphamide in a subject which comprises replacing the subject's hematopoietic cells with hematopoietic cells having the retroviral vector. Further, this invention provides a method for introducing a selectable marker into a mammalian cell which comprises transfecting the cell with a nucleic acid molecule encoding human cytosolic aldehyde dehydrogenase or glutamylcysteine synthetase. Lastly, this invention provides a method for selecting mammalian cells

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expressing protein of interest which comprises: a) introducing into the cells a nucleic acid molecule comprising a nucleic acid molecule encoding the protein of interest and the nucleic acid molecule encoding human cytosolic aldehyde dehdrogenase: b) culturing the resulting transfected cells; and c) selecting cells which express human cytosolic aldehyde dehdrogenase. Excerpt(s): Recent advances in autologous bone marrow transplant strategies indicate that normal hematopoiesis can be promptly restored in patients treated with myelotoxic agents (drugs or radiation) by re-injection of autologous peripheral blood (CD34.sup.+) "stem cells" (Gianni, et al., Lancet 2:580, 1989). In addition, it has very recently been reported that CD34.sup.+ cells can be transduced in vitro at high efficiency with retroviral vectors expressing specific genes (Bregni, et al., Blood 80:1418, 1992). These technologies open the way to approaches in which the in vitro transduction of specific genes into autologous CD34.sup.+ cells followed by reinoculation into patients can be used to transduce genes of therapeutic significance. This gene therapy approach includes the reconstitution of drug-resistant hematopoietic cells allowing for subsequent treatment with higher dose myelotoxic chemotherapy in cancer patients. This invention provides a vector which comprises a nucleic acid molecule encoding a human cytosolic aldehyde dehydrogenase. In addition, this invention provides a vector which comprises a nucleic acid molecule encoding a human glutamylcysteine synthetase. Web site: http://www.delphion.com/details?pn=US05888820__ •

Treatment of melanoma with a vaccine comprising irradiated autologous melanoma tumor cells conjugated to a hapten Inventor(s): Berd; David (Wyncote, PA) Assignee(s): Thomas Jefferson University (Philadelphia, PA) Patent Number: 5,290,551 Date filed: December 4, 1992 Abstract: The invention is a haptenized tumor vaccine for the treatment of cancer. Treatment of cancer patients with an autologous, vaccine preceded by low dose cyclophosphamide (CY) induces delayed-type hypersensitivity (DTH) to melanoma cells, and in some cases, regression of metastatic tumors. The efficiency of the process has been increased by immunizing with tumor cells conjugated to the hapten such as DNP, TNP or AED.Additional embodiments of the vaccine include: 1) combining the vaccine with immunomodulating drugs, such as, interleukin-2 (IL2); and 2) purifying the active components of the vaccine by extracting antigens from cancer cells to produce a chemically-defined, haptenated vaccine. The treatment may also be extended to include other types of human cancer. Excerpt(s): The invention described herein was made in the course of work under a grant or award from an NIH Cancer Research grant. This invention was disclosed in a Disclosure Document filed Apr. 18, 1990, which is now abandoned. It was theorized in the 1960's that tumor cells bear specific antigens (TSA) which are not present on normal cells and that the immune response to these antigens might enable an individual to reject a tumor. It was later suggested that the immune response to TSA could be increased by introducing new immunological determinants on cells. Mitchison, Transplant. Proc. 2:92-103 (1970). Such a "helper determinant", which can be a hapten, a protein, a viral coat antigen, a transplantation antigen, or a xenogenous cell antigen, could be introduced into a population of tumor cells. The cells would then be injected

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into an individual who would be expected to be tolerant to the growth of unmodified tumor cells. Clinically, the hope was that an immunologic reaction would occur against the helper determinants, as a consequence of which the reaction to the accompanying TSA is increased, and tumor cells which would otherwise be tolerated are destroyed. Mitchison (1970) also suggests several modes of action of the helper determinants including 1) that the unmodified cells are merely attenuated, in the sense that their growth rate is slowed down or their susceptability to immunologic attack increased; 2) that helper determinants merely provide points of attack and so enable the modified cells to be killed by an immune response not directed against TSA; 3) that the helper determinants have an adjuvant action such as binding to an antibody or promoting localization of the cells in the right part of the body for immunization, in particular, in lymph nodes. Web site: http://www.delphion.com/details?pn=US05290551__ •

Use of 4-carboxy-phthalato(1,2-diaminocyclohexane)-platinum (II) and alkali metal salts thereof with cyclophosphamide in alleviating L1210 murine leukemia Inventor(s): Gale; Glen R. (Charleston, SC), Schwartz; Paul (Charleston, SC) Assignee(s): The United States of America as represented by the Department of Health, (Washington, DC) Patent Number: 4,206,207 Date filed: December 22, 1978 Abstract: The Pt compound may be prepared by reacting the known dichloro(1,2diaminocyclohexane)platinum(II) (NSC 194814) with silver nitrate to replace chloro with nitro. Subsequently, benzene tricarboxylic acid is added to form an off-white precipitate (2 hrs, dark, 5.degree. C.) of the desired product which is preferably utilized as the alkali metal salt.The 4-carboxyphthalato(1,2-diaminocyclohexane)platinum(II) and alkali metal salts thereof may be combined in multiple drug regimen with substantially improved yield cures over the parent compound. For example, the compound denoted Pt-307 may be combined in a dual regimen with cyclophosphamide (CY) and in a triple drug regimen of Pt-307 plus cyclophosphamide (CY) and either 5-fluorouracil (5-FU) or hydroxyurea (HU) as the third component.Additionally, the present compound (NSC 271674) has shown superior results in testing for renal toxicity against the parent compound (NSC 119875, cis-dichlorodiamino platinum II) and further the present compound appears to be active against strains of murine leukemia wherein the same NSC 119875 has exhausted its activity. Excerpt(s): 4-Carboxyphthalato(1,2-diaminocyclohexane)platinum(II) (and alkali metal salts thereof) has shown antileukemic activity in mice against murine leukemia L1210. It is effective in dosages of 5-60 mg/kg of body weight and is potentiated in a treatment with cyclophosphamide (CY) (50 mg/kg of body weight) to which may be added 5fluorouracil (5-FU) (75 mg/kg of body weight) or hydroxyurea (HU) (1000 mg/kg of body weight). Some previous platinum chelate compounds show dosage limitation due to renal impairment but the free carboxyl of the present composition offers a possible route of oral injection and absorption by the stomach. The compound may be prepared by reacting the known dichloro(1,2-diaminocyclohexane)platinum(II) (NSC 194814) with silver nitrate to replace chloro with nitro. Subsequently, benzene tricarboxylic acid is added to form an off-white precipitate (2 hrs, dark, 5.degree. C.) of the desired product which is preferably utilized as the alkali metal salt. The 4-carboxyphthalato(1,2diaminocyclohexane)platinum(II) and alkali metal salts thereof may be combined in

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multiple drug regimen with substantially improved yield cures over the parent compound. For example, the compound denoted Pt-307 may be combined in a dual regimen with cyclophosphamide (CY) and in a triple drug regimen of Pt-307 plus cyclophosphamide (CY) and either 5-fluorouracil (5-FU) or hydroxyurea (HU) as the third component. Web site: http://www.delphion.com/details?pn=US04206207__

Patent Applications on Cyclophosphamide As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to cyclophosphamide: •

Animal model for testing immunotherapies of spontaneous metastatic disease Inventor(s): Mokyr, Margalit B.; (Chicago, IL) Correspondence: Darby & Darby P.C.; 805 Third Avenue; New York; NY; 10022; US Patent Application Number: 20010046502 Date filed: February 1, 2001 Abstract: The present invention provides an animal model that can provide information on the effectiveness of postsurgical immunotherapies for recurrence of metastatic disease. In a specific embodiment, this tumor model used mice from which the primary 410.4 mammary carcinoma was surgically excised to assess the therapeutic potential of low-dose cyclophosphamide (CY) followed by vaccination with DNPmodified,.gamma.-irradiated, autologous tumor cells admixed with BCG compared to mice receiving low-dose CY followed by vaccination with unmodified,.gamma.irradiated, autologous tumor cells admixed with BCG, or mice treated with PBS (control group). In this model, therapeutic benefits offered by DNP-modified,.gamma.irradiated, autologous tumor cell vaccine (preceded by low-dose CY) were abrogated completely upon depletion of CD8.sup.+ T-cells, and was improved when the mice were pretreated with a single dose of DNP-modified,.gamma.-irradiated, autologous tumor cells (without BCG) prior to the low-dose CY treatment, and then subjected to vaccination with DNP-modified,.gamma.-irradiated, autologous tumor cells admixed with BCG. Excerpt(s): The present invention relates to an animal model that provides information about the efficacy of an immunotherapy for metastatic disease more accurately than prior animal models. More specifically, the invention permits evaluation of haptenized tumor cell vaccines. An autologous whole-cell vaccine modified with the hapten dinitrophenyl (DNP) has been shown to produce inflammatory responses in metastatic sites of melanoma patients. The survival rates of patients receiving post-surgical adjuvant therapy with DNP-modified vaccine are markedly higher than those reported for patients treated with surgery alone. Intact cells are preferred for the vaccine. U.S. Pat. No. 5,290,551, to David Berd, discloses and claims vaccine compositions comprising haptenized melanoma cells. Melanoma patients who were treated with these cells developed a strong immune response. This response was detected, e.g., in a delayed-

9

This has been a common practice outside the United States prior to December 2000.

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type hypersensitivity (DTH) response to haptenized and non-haptenized tumor cells. More importantly, the immune response to non-haptenized cells has been associated with an increased survival rate of melanoma patients. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Anti-tumor chemotherapy erythropoeitin

by

administration

of

cyclophosphamide

and

Inventor(s): Farrell, Francis; (Doylestown, PA), Thews, Oliver; (Mainz, DE), Vaupel, Peter; (Mainz, DE) Correspondence: Janet E. Reed ,esq; Woodcock Washburn Llp; One Liberty Place 46th FLR.; Philadelphia; PA; 19103; US Patent Application Number: 20030083250 Date filed: October 25, 2001 Abstract: The present invention provides, in one embodiment, methods to treat, prevent the progression of, or facilitate elimination of a malignancy by increasing the supply of red blood cells using erythropoietin in conjunction with administration of an anti-tumor agent. Excerpt(s): PROCRIT.RTM. is the brand name for the Epoetin alfa. In 1990, PROCRIT received market clearance by the FDA for the treatment of anemia in HIV-infected patients on zidovudine (ZDV) therapy (.ltoreq.4200 mg/week) with endogenous serum erythropoietin levels.ltoreq.500 MU/mL. It is also approved for the treatment of anemia in patients with non-myeloid malignancies receiving chemotherapy, in patients with chronic renal failure (pre-dialysis), and for use in elective noncardiac nonvascular surgery to reduce the need for allogeneic blood transfusion during high volume blood loss procedures. In clinical trials to date, Epoetin alfa has been evaluated in normal subjects as well as in subjects with various anemic conditions. Epoetin alfa induces a brisk haematological response in normal human volunteers, provided that adequate supplies of iron are available to support increased hemoglobin synthesis. A majority of trials have investigated the safety and effectiveness of Epoetin alfa in the treatment of chronic renal failure and of anemia in cancer. Other trials have evaluated Epoetin alfa for the treatment of anemia associated with rheumatoid arthritis, prematurity, AIDS, bone marrow transplantation, myelofibrosis, sickle cell anemia, as a facilitator of presurgical autologous blood donation, and as a perisurgical adjuvant. Erythropoietin is currently used to treat anemic subjects who are amenia as a result of insufficient levels of Erythropoietin or who demonstrate a blunted response to Erythropoietin. Erythropoietin is not currently used to treat hemolytic anemia or most form of anemia that results from enhanced rate of clearance of the red blood cells, except for sickle cell anemia and thalycemia. Epoetin alfa is approved for sale in many countries for the treatment of anemia in chronic renal failure (dialysis and predialysis), anemia in zidovudine treated HIV positive patients (US), anemia in cancer patients receiving platinum-based chemotherapy, as a facilitator of autologous blood pre-donation, and as a perisurgical adjuvant to reduce the likelihood of requiring allogeneic blood transfusions in patients undergoing orthopedic surgery. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Composition comprising camptothecin or a camptothecin derivative and an alkylating agent for the treatment of cancer Inventor(s): Bissery, Marie-Christine; (Vitry Sur Seine, FR) Correspondence: Finnegan, Henderson, Farabow,; Garrett & Dunner, L.L.P.; 1300 I Street, N.W.; Washington; DC; 20005-3315; US Patent Application Number: 20010056082 Date filed: March 7, 2001 Abstract: The present invention relates to therapeutic associations for the treatment of cancer, comprising an effective amount of a camptothecin, or a camptothecin derivative, with an effective amount of an alkylating agent, such as melphalan, dacarbazine, or cyclophosphamide, and methods of using such therapeutic associations. Excerpt(s): The present application claims the benefit of U.S. Provisional Application No. 60/190,007, filed Mar. 17, 2000. The present invention relates to therapeutic combinations comprising an effective amount of camptothecin, or a camptothecin derivative such as irinotecan (CPT-11), with an effective amount of an alkylating agent for the treatment of cancer. More specifically, the invention relates to anticancer treatments with associations of camptothecin derivatives such as irinotecan (CPT-11, CAMPTOSAR.RTM.), topotecan, 9-aminocamptothecin, or 9-nitrocamptothecin, and alkylating agents. Such alkylating agents include, inter alia, melphalan (alkeran, L-3{para-[Bis(2-chloroethyl)amino]phenyl}alanine, CB 3025, phenylalanine mustard, LSarcolysine, SK-15673), dacarbazine (DTIC-Dome.RTM., DTIC, dimethyl triazeno imidazole carboxamide; 5-(3,3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide, 9CI, DIC), and cyclophosphamide (CPA, CYTOXAN.RTM., NEOSAR.RTM.). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

CYCLOPHOSPHAMIDE FILM-COATED TABLETS Inventor(s): ENGEL, JURGEN; (ALZENAU, DE), RAWERT, JURGEN; (ALZENAU, DE), SAUERBIER, DIETER; (WERTHER, DE), WICHERT, BURKHARD; (BIELEFELD, DE) Correspondence: Pillsbury Madison & Sutro Llp; Intellectual Property Group; 1100 New York Avenue NW; Ninth Floor East Tower; Washington; DC; 200053918 Patent Application Number: 20010046504 Date filed: June 15, 1999 Abstract: 1. [sic] The invention relates to film-coated tablets with cyclophosphamide as active compound, which in the core comprise cyclophosphamide, one or more fillers, one or more dry binders but no preswollen starch, flow regulators and lubricants.According to a preferred embodiment of the invention, the core of the filmcoated tablet comprises as a filler lactose monohydrate, D-mannitol or CaHPO.sub.4, nonpreswollen cornstarch or microfine cellulose as a dry binder, highly disperse silica as a flow regulator and magnesium stearate, stearic acid, glycerol palmitostearate, polyethylene glycol, talc or glycerol monobeherate [sic] as a lubricant. Excerpt(s): Cyclophosphamide is an agent having a broad antitumor spectrum which has been introduced [sic] in chemotherapy for decades for the treatment of solid tumors such as mastocarcinoma, bronchial carcinoma and hemoblastoses. Until now, on [sic] known pharmaceutical forms have been tablets, coated tablets and mainly lyophilizates with various auxiliaries such as mannitol or urea. EP 0519099 describes tablets

Patents 163

comprising cyclophosphamide and preswollen starch, prepared by a direct tableting process. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for treating tumors by the administration of tegafur, uracil, folinic acid, and cyclophosphamide Inventor(s): Bunnell, Craig A.; (Brookline, MA), Dugan, Terry S.; (Plainsboro, NJ), Ressler-Tatro, Jody; (Kensington, CT), Winer, Eric P.; (Wellesley, MA) Correspondence: Stephen B. Davis; Bristol-Myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20020187956 Date filed: April 19, 2002 Abstract: This invention provides a method of treating a tumor in a warm-blooded animal, including humans, by administering, in combination, an anti-tumor effective amount of tegafur, uracil, folinic acid or pharmaceutically acceptable salt thereof and cyclophosphamide. Excerpt(s): This application claims benefit to provisional application U.S. Ser. No. 60/286,729 filed Apr. 26, 2001. The entire teachings of the referenced applications are incorporated herein by reference. The present invention is directed to the administration to a warm blooded animal including humans of the combination of tegafur, uracil, and folinic acid and its administration with cyclophosphamide for the treatment of tumors. 5-Fluorouracil (5-FU) is a known anti-tumor agent. The combination of 5-fluorouracil and folinic acid is a known treatment for cancer including adenocarcinoma of the female breast. Tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) is a prodrug of 5-fluorouracil. In vivo, 5-fluorouracil is rapidly inactivated by the enzyme dihydropyridine dehydrogenase (DPD). Uracil competitively inhibits DPD metabolism of 5-FU generated from tegafur. Thus, coadministration of uracil with tegafur results in higher exposures of active 5-FU as compared to tegafur alone. It is also known that 5-fluorouracil cannot be administered orally. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Methods for evaluating the ability to metabolize pharmaceuticals and compositions therefor Inventor(s): Colvin, Oliver M.; (Chapel Hill, NC), Guida, Marco; (San Diego, CA), Hall, Jeff; (Carlsbad, CA), Marks, Jeffrey R.; (Hillsborough, NC), Petros, William P.; (Durham, NC), Vredenburgh, James J.; (Chapel Hill, NC) Correspondence: Sheridan Ross PC; 1560 Broadway; Suite 1200; Denver; CO; 80202 Patent Application Number: 20030096251 Date filed: February 26, 2002 Abstract: Methods for detecting variant genes having a polymorphism associated with reduced metabolism of a substrate selected from the group consisting of a CYP3A4 substrate, a CYP3A5 substrate and a GSTM1 substrate in an individual are disclosed. The methods are genotyping methods to identify specific polymorphisms which have been found to be associated with reduced metabolism of chemotherapeutic agents, such

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as cyclophosphamide and BCNU. Also disclosed are novel polymorphic nucleic acid molecules useful in the methods of the invention. Excerpt(s): This application is a continuation-in-part application of U.S. patent application Ser. No. 09/144,367, filed Aug. 31, 1998, which is hereby incorporated by reference in its entirety. This application claims the benefit of Provisional Patent Application Serial No. 60/271,630 filed in the U.S. Patent and Trademark Office on Feb. 26, 2001, which is hereby incorporated by reference in its entirety. The present invention relates to polymorphisms in the cytochrome P450 3A4, cytochrome P450 3A5 and GSTM1 genes and methods for genotyping and phenotyping individuals for such polymorphisms. Cytochrome P450 enzymes are a heme-containing family that play central roles in oxidative, peroxidative and reductive metabolism of numerous endogenous and exogenous compounds, including many pharmaceutical agents. Substances known to be metabolized by P450 enzymes include steroids, bile acids, fatty acids, prostaglandins, leukotrienes, biogenic amines, retinoids, lipid hydroperoxides, phytoalexins, pharmaceuticals, environmental chemicals and pollutants. P450 substrates also include natural plant products involved in flavor, odor and flower color. Many P450 enzymes also have functions in maintaining steady-state levels of endogenous ligands involved in ligand-modulated transcription of genes effecting growth, apoptosis, differentiation, cellular homeostasis, and neuroendocrine functions. The metabolism of foreign chemicals by P450 enzymes can produce toxic metabolites, some of which have been implicated as agents responsible for birth defects and tumor initiation and progression. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Non-lethal methods for conditioning a recipient for bone marrow transplantation Inventor(s): Ildstad, Suzanne T.; (Prospect, KY) Correspondence: Hogan & Hartson Llp; One Tabor Center, Suite 1500; 1200 Seventeenth ST; Denver; CO; 80202; US Patent Application Number: 20030017152 Date filed: April 26, 2002 Abstract: Hematopoietic chimerism induces donor-specific tolerance to solid organ grafts. The clinical application of this technique is limited by the morbidity and mortality of conventional bone marrow transplantation (BMT). Conditioning for engraftment is nonspecific, utilizing myeloablation plus nonspecific immunosuppression. In the present study we have characterized which cells in the recipient hematopoietic microenvironment prevent allogeneic marrow engraftment. Mice defective in production of.alpha.beta.-TCR cells,.gamma.delta.-TCR cells;.alpha.beta.- plus.gamma.delta.-TCR cells; CD8 cells and CD4 cells were transplanted with MHC-disparate allogeneic bone marrow. In normal mice, 500 cGy total body irradiation (TBI) plus cyclophosphamide (200 mg/kg) on day +2 is required for engraftment of allogeneic hematopoietic stem cells (HSC). Mice lacking both.alpha.beta.- and.gamma.delta.-TCR.sup.+ cells engrafted when conditioned with 0 to 300 cGy TBI alone, suggesting that.alpha.beta. plus.gamma.delta. T cells in the host play a critical and non-redundant role in preventing engraftment of allogeneic bone marrow. When mice were conditioned with 300 cGy TBI plus a single dose of cyclophosphamide on day +2, all mice engrafted except for mice defective in production of CD4.sup.+ cells. Moreover, CD8 KO mice engrafted without TBI if administered cyclophosphamide on day +2 relative to the marrow infusion. These

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results suggest that different cell populations in host marrow with different mechanisms of action play a role in the resistance to engraftment of allogeneic bone marrow. Both.alpha.beta.-TCR.sup.+ and.gamma.delta.-TCR.sup.+ T-cells play an important and non-redundant role in the marrow rejection response. In addition, the CD8.sup.+ cell effector function is mechanistically different from that for conventional T-cells and independent of CD4.sup.+ T-helper cells. Targeting of specific recipient cellular populations may permit conditioning approaches to allow mixed chimerism with minimal morbidity. Excerpt(s): This patent application is a continuation-in-part of PCT/USO1/46126, filed Nov. 14, 2001 and entitled "Non-Lethal Methods For Conditioning A Recipient For Bone Marrow Transplantation" and this patent application claims benefit of Provisional Application No. 60/249,048 filed Nov. 14, 2000 and entitled "Non-Lethal Methods For Conditioning A Recipient For Bone Marrow Transplantation". All of the abovereferenced applications are incorporated herein by reference. The present invention relates to non-lethal methods of conditioning a recipient for bone marrow transplantation. In particular, the present invention relates to cell specific conditioning strategies which result in the depletion and more preferably the elimination of.alpha.beta.-,.gamma.delta.-TCR.sup.+ T cells and/or CD8.sup.+ T-cells in the recipient hematopoietic microenvironment through the use of antisense DNA technology, cell type-specific antibodies and/or cell type-specific cytotoxic drugs. The transfer of living cells, tissues, or organs from a donor to a recipient, with the intention of maintaining the functional integrity of the transplanted material in the recipient defines transplantation. Transplants are categorized by site and genetic relationship between the donor and recipient. An autograft is the transfer of one's own tissue from one location to another; a syngeneic graft (isograft) is a graft between identical twins; an allogeneic graft (homograft) is a graft between genetically dissimilar members of the same species; and a xenogeneic graft (heterograft) is a transplant between members of different species. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of docetaxel/doxorubicin/cyclophosphamide in adjuvant therapy Inventor(s): Chakroun, Hichem; (Courbevoie, FR) Correspondence: Ross J. Oehler; Aventis Pharmaceuticals INC.; Route 202-206; Mail Code: D303a; Bridgewater; NJ; 08807; US Patent Application Number: 20040014694 Date filed: May 16, 2003 Abstract: The present invention relates to a new method of adjuvant therapy in the treatment of early breast cancer, comprising administering six cycles of docetaxel, doxorubicin and cyclophosphamide to a patient in need thereof, wherein said dosages have a marked therapeutic effect when compared to other adjuvant therapies. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/380,850, filed May 17, 2002. This invention relates to a novel therapeutic use of a combination of taxotere with other antineoplastic agents in the adjuvant therapy of breast cancer. The present invention relates more specifically to the use of docetaxel in combination with doxorubicin and cyclophosphamide as adjuvant therapy in the treatment of breast cancer, i.e., early stages of breast cancer immediately after diagnoses by routine screening, such as mammography or other commonly used methods.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Vaccine immunotherapy for immune suppressed patients Inventor(s): Hadden, John W.; (Cold Spring Harbor, NY) Correspondence: Kenneth I. Kohn; Kohn & Associates, Pllc; Suite 410; 30500 Northwestern Highway; Farmington Hills; MI; 48334; US Patent Application Number: 20040071658 Date filed: August 8, 2003 Abstract: A method of immunotherapy to treat cancer or a synergistic anti-cancer treatment by administering an effective amount of a natural cytokine mixture (NCM), an effective amount of cyclophosphamide (CY), or an effective amount of indomethacin (INDO), wherein the NCM, CY, or INDO are administered singly or in combinations thereof. An anti-metastatic treatment method by promoting differentiation and maturation of immature dendritic cells in a lymph node; allowing presentation thereof; and preventing development of metastasis. A method of using an NCM as a diagnostic skin test for predicting treatment outcome. A method of pre-treating dendritic cells (DC) and a method of treating monocyte defects characterized by sinus histiocytosis or a negative NCM skin test. Compositions and methods for eliciting an immune response to endogenous or exogenous tumor antigens. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 10/015,123, filed Oct. 26, 2001, which claims the benefit of priority under 35 U.S.C. Section 119(e) of U.S. Provisional Patent Application No. 60/243,912, filed Oct. 27, 2000, both of which are incorporated herein by reference. The present invention relates to vaccine therapy for cancer patients. More specifically, the present invention relates to a vaccine immunotherapy, which immunizes cancer patients, having immune suppression, to both endogenous and exogenous tumor peptides or proteins. It has become increasingly apparent that human cancers have antigens, which, if reacted upon by the host's immune systems, lead to tumor regression. These antigens have been defined by both serological and cellular immune approaches. This has lead to the definition of both B and T cell epitopes (Sahin U, et al, Curr Opin Immunol 9:709-715, 1997; Van der Eynde, B, et al. Curr Opin Immunol 9:684-693, 1997; Wang R F, et al., Immunologic Reviews 170:85-100, 1999). Based upon these results, it has become a goal of cancer immunotherapists to induce regressions of tumors. However, historically, successful efforts have been sporadic and generally minor in frequency and magnitude. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with cyclophosphamide, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “cyclophosphamide” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on cyclophosphamide.

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You can also use this procedure to view pending patent applications concerning cyclophosphamide. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON CYCLOPHOSPHAMIDE Overview This chapter provides bibliographic book references relating to cyclophosphamide. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on cyclophosphamide include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Chapters on Cyclophosphamide In order to find chapters that specifically relate to cyclophosphamide, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and cyclophosphamide using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “cyclophosphamide” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on cyclophosphamide: •

Focal Segmental Glomerulosclerosis Source: in Schena, F.P., ed. Nephrology. New York, NY: McGraw-Hill, Inc. 2001. p. 141148. Contact: Available from McGraw-Hill, Inc. Shoppenhangers Road, Maidenhead, Berkshire SL6 2QL. 44 (0)1628 502700. Fax: +44 (0)1628 635895 E-mail: [email protected]. Website: www.mcgraw-hill.co.uk. PRICE: $79.95; plus shipping and handling. ISBN: 0077095251. Summary: Focal segmental glomerulosclerosis (FSGS) is not a disease but a pathologic lesion, a scarring of a portion of the glomerulus (a group of capillaries that are part of the filtering units of the kidney). This chapter on focal segmental glomerulosclerosis(FSGS) is from a book on nephrology (the study of the kidney and kidney diseases) designed for general practitioners and family care providers that offers strategies for the management of patients with renal (kidney) damage. Among

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glomerular disorders that affect children and young adults, FSGS is the most common disorder leading to end stage renal disease (ESRD). The lesion is more frequent and the severity of the disease is greater in patients of African-American origin. Clinically, the lesions of FSGS can be observed in a wide variety of disorders. In the idiopathic (of unknown cause) variety, there is proteinuria (protein in the urine), hypoalbuminemia (low levels of protein in the blood), and generalized edema (fluid accumulation), together with varying degrees of hypertriglyceridemia and hypercholesterolemia (high levels of fats in the blood). Since FSGS is a histologic diagnosis, a renal biopsy is necessary. The pathogenesis of this disease continues to be elusive; however, in recent years studies point to the role of transforming growth factor beta (TGF-b) in inducing the sclerosis. Most cases of FSGS tend to be resistant to steroid therapy as well as to therapy with alkylating agents such as cyclophosphamide. Controlled trials have documented the efficacy of cyclosporine in inducing a remission of the proteinuria, particularly in children; however, relapses tend to occur upon withdrawal of cyclosporine. In severe edema, intravenous furosemide often is necessary. Antihypertensive (high blood pressure medications) therapy should consist of ACE inhibitors and calcium channel blockers. 2 tables. 15 references. •

Immunosuppressive Strategies for the Pediatric Population Source: in Tejani, A.H. and Fine, R.N., eds. Pediatric Renal Transplantation. New York, NY: Wiley-Liss. 1994. p. 23-49. Contact: Available from John Wiley and Sons, Inc. 1 Wiley Drive, Somerset, NJ 088751272. (800) 225-5945. PRICE: $99.95 (as of 1995). ISBN: 0471591203. Summary: In this chapter, from a medical text about pediatric renal transplantation, the authors discuss immunosuppressive strategies for the pediatric population. Topics include a brief history of immunosuppressive; mechanisms of immunosuppressive drug actions, including corticosteroids, azathioprine, cyclophosphamide, polyclonal antilymphocyte preparations, monoclonal antibodies, and cyclosporine; cyclosporine therapy in the pediatric population; algorithms of drug therapy; and new immunosuppressive agents, including cyclosporine G and IMM-125, FK506, rapamycin, new antiproliferative agents, 15-deoxyspergualin, new monoclonal antibodies, and leflunomide (HWA 486). The authors stress that a rigorous pharmacokinetic approach to the evaluation of multidrug combinations using mathematical models are likely to yield highly selective but nontoxic immunosuppressive regimens. 4 figures. 1 table. 285 references.

•

Conventional Immunosuppressive Drugs Source: in Thomson, A.W. and Starzl, T.E. Immunosuppressive Drugs: Developments in Anti-Rejection Therapy. London, England: Edward Arnold. 1994. p. 1-14. Contact: Available from Little, Brown and Company. Order Department, 200 West Street, Waltham, MA 02154. (800) 343-9204. PRICE: $67.50 (as of 1995). ISBN: 0340569514. Summary: This chapter, from a book on immunosuppressive drugs, summarizes the conventional immunosuppressive drugs and their uses in transplantation. The authors discuss the mechanisms of action and the clinical effectiveness of azathioprine, azathioprine plus corticosteroids, cyclophosphamide substitution for azathioprine, and cyclophosphamide in conjunction with azathioprine. The authors also discuss the complications encountered with each type of drug. The authors conclude with a description of the future of immunosuppression and how that future depends so heavily

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on these basic, conventional immunosuppressive agents. 4 figures. 2 tables. 124 references. •

Immunosuppression Source: Cambridge, MA: Harvard University Press. 1991. 20 p. Contact: Available from Harvard University Press. 79 Garden Street, Cambridge, MA 02138-9983. (617) 495-2577 or (617) 495-2480. PRICE: $24.95 plus shipping and handling. ISBN: 067464235X. Summary: This chapter, from a patient education book about organ transplantation, discusses the role of immunosuppression used to prevent rejection of the transplanted organ. Topics include the balance of specific suppression and non-specific suppression; steroids, including prednisone and methylprenisolone; adjusting dosages of immunosuppressive drugs; side-effects of steroids; the use of azathioprine (Imuran); the use and administration of cyclosporine (Sandimmune); side-effects of cyclosporine; antiT cell antibody treatment; OKT3 (orthoclone) therapy; ATG (Atgam and others) therapy; cyclophosphamide (Cytoxan); radiation therapy used for prevention of organ rejection; actinomycin D (Dactino) therapy; and experimental treatments. The chapter presents detailed medical information about these topics in clear, easy-to-understand language designed for the layperson.

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7.

PERIODICALS AND CYCLOPHOSPHAMIDE

NEWS

ON

Overview In this chapter, we suggest a number of news sources and present various periodicals that cover cyclophosphamide.

News Services and Press Releases One of the simplest ways of tracking press releases on cyclophosphamide is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “cyclophosphamide” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to cyclophosphamide. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “cyclophosphamide” (or synonyms). The following was recently listed in this archive for cyclophosphamide: •

Topotecan after cyclophosphamide active, tolerated in pediatric rhabdomyosarcoma Source: Reuters Industry Breifing Date: May 14, 2004

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•

Myasthenia gravis responds to high-dose cyclophosphamide immune "rebooting" Source: Reuters Industry Breifing Date: January 27, 2003

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High-dose cyclophosphamide benefits patients with refractory SLE Source: Reuters Industry Breifing Date: January 16, 2003

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Pregnancy possible during IV cyclophosphamide therapy Source: Reuters Medical News Date: January 06, 2003

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Low-dose cyclophosphamide regimen shown effective for lupus nephritis Source: Reuters Industry Breifing Date: September 24, 2002

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Adjunctive cyclophosphamide does not deplete HIV-infected cells Source: Reuters Industry Breifing Date: June 12, 2002

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High-dose cyclophosphamide shows promise as aplastic anemia treatment Source: Reuters Industry Breifing Date: October 01, 2001

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Oral cyclophosphamide may have advantages in severe lupus nephritis Source: Reuters Industry Breifing Date: August 20, 2001

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Effects of cyclophosphamide on oocytes influenced by stage of development Source: Reuters Medical News Date: March 30, 2001

•

High-dose cyclophosphamide too toxic for patients with aplastic anemia Source: Reuters Industry Breifing Date: November 07, 2000 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name.

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Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “cyclophosphamide” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “cyclophosphamide” (or synonyms). If you know the name of a company that is relevant to cyclophosphamide, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “cyclophosphamide” (or synonyms).

Academic Periodicals covering Cyclophosphamide Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to cyclophosphamide. In addition to these sources, you can search for articles covering cyclophosphamide that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for cyclophosphamide. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with cyclophosphamide. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.).

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The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to cyclophosphamide: Cyclophosphamide •

Systemic - U.S. Brands: Cytoxan; Neosar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202174.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to cyclophosphamide by using the database managed by the National Organization for Rare Disorders, Inc. (NORD), at http://www.rarediseases.org/. Scroll down the page, and on the left toolbar, click on “Orphan Drug Designation Database.” On this page (http://www.rarediseases.org/search/noddsearch.html), type “cyclophosphamide” (or synonyms) into the search box, and click “Submit Query.” When you receive your results, note that not all of the drugs may be relevant, as some may have been withdrawn from orphan status. Write down or print out the name of each drug and the relevant contact

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information. From there, visit the Pharmacopeia Web site and type the name of each orphan drug into the search box at http://www.nlm.nih.gov/medlineplus/druginformation.html. You may need to contact the sponsor or NORD for further information. NORD conducts “early access programs for investigational new drugs (IND) under the Food and Drug Administration’s (FDA’s) approval ‘Treatment INDs’ programs which allow for a limited number of individuals to receive investigational drugs before FDA marketing approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for cyclophosphamide: •

Mesna http://www.rarediseases.org/nord/search/nodd_full?code=106

•

Amifostine (trade name: Ethyol) http://www.rarediseases.org/nord/search/nodd_full?code=531

If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute10: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

10

These publications are typically written by one or more of the various NIH Institutes.

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•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.11 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:12 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

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NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

11

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 12 See http://www.nlm.nih.gov/databases/databases.html.

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•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway13 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “cyclophosphamide” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 50077 138 1563 131 134 52043

HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.17 Simply search by “cyclophosphamide” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

13

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

14

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists18 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.19 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

18 Adapted 19

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 20 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on cyclophosphamide can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internetbased services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to cyclophosphamide. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to cyclophosphamide. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “cyclophosphamide”:

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Autoimmune Diseases http://www.nlm.nih.gov/medlineplus/autoimmunediseases.html Lupus http://www.nlm.nih.gov/medlineplus/lupus.html Lymphoma http://www.nlm.nih.gov/medlineplus/lymphoma.html Myositis http://www.nlm.nih.gov/medlineplus/myositis.html Vasculitis http://www.nlm.nih.gov/medlineplus/vasculitis.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The NIH Search Utility The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to cyclophosphamide. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://my.webmd.com/health_topics

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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cyclophosphamide. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cyclophosphamide. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about cyclophosphamide. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “cyclophosphamide” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “cyclophosphamide”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “cyclophosphamide” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.

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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “cyclophosphamide” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.21

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

21

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)22: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

22

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

199

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

201

CYCLOPHOSPHAMIDE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 6-Mercaptopurine: An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Ablation: The removal of an organ by surgery. [NIH] Academic Medical Centers: Medical complexes consisting of medical school, hospitals, clinics, libraries, administrative facilities, etc. [NIH] Acantholysis: Separation of the prickle cells of the stratum spinosum of the epidermis, resulting in atrophy of the prickle cell layer. It is seen in diseases such as pemphigus vulgaris (see pemphigus) and keratosis follicularis. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]

Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH]

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Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adjunctive Therapy: Another treatment used together with the primary treatment. Its purpose is to assist the primary treatment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adjuvant Therapy: Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, or hormone therapy. [NIH]

Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU]

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Airways: Tubes that carry air into and out of the lungs. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]

Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylate: To treat with an alkylating agent. [EU] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allogeneic: Taken from different individuals of the same species. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH]

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Amenorrhea: Absence of menstruation. [NIH] Amifostine: A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Aminocamptothecin: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analysis of Variance: A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent

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variable. [NIH] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anemic: Hypoxia due to reduction of the oxygen-carrying capacity of the blood as a result of a decrease in the total hemoglobin or an alteration of the hemoglobin constituents. [NIH] Angiotensin I: The decapeptide precursor of angiotensin II, generated by the action of renin on angiotensinogen. It has limited pharmacologic activity. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Anhydrous: Deprived or destitute of water. [EU] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anoikis: Apoptosis triggered by loss of contact with the extracellular matrix. [NIH] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antibody therapy: Treatment with an antibody, a substance that can directly kill specific tumor cells or stimulate the immune system to kill tumor cells. [NIH] Antidiuretic: Suppressing the rate of urine formation. [EU]

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Antidote: A remedy for counteracting a poison. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antifungals: Drugs that treat infections caused by fungi. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antithymocyte globulin: A protein used to reduce the risk of or to treat graft-versus-host disease. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Apheresis: Components plateletpheresis. [NIH]

being

separated

out,

as

leukapheresis,

plasmapheresis,

Aplastic anaemia: A form of anaemia generally unresponsive to specific antianaemia therapy, often accompanied by granulocytopenia and thrombocytopenia, in which the bone marrow may not necessarily be acellular or hypoplastic but fails to produce adequate numbers of peripheral blood elements. The term actually is all-inclusive and most probably encompasses several clinical syndromes. [EU] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]

Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the

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physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Appendicitis: Acute inflammation of the vermiform appendix. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteritis: Inflammation of an artery. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Asbestos: Fibrous incombustible mineral composed of magnesium and calcium silicates with or without other elements. It is relatively inert chemically and used in thermal insulation and fireproofing. Inhalation of dust causes asbestosis and later lung and gastrointestinal neoplasms. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH]

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Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Aural: Pertaining to or perceived by the ear, as an aural stimulus. [EU] Autacoids: A chemically diverse group of substances produced by various tissues in the body that cause slow contraction of smooth muscle; they have other intense but varied pharmacologic activities. [NIH] Authorship: The profession of writing. Also the identity of the writer as the creator of a literary production. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmune Hepatitis: A liver disease caused when the body's immune system destroys liver cells for no known reason. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autologous tumor cells: Cancer cells from an individual's own tumor. [NIH] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form

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salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenic Amines: A group of naturally occurring amines derived by enzymatic decarboxylation of the natural amino acids. Many have powerful physiological effects (e.g., histamine, serotonin, epinephrine, tyramine). Those derived from aromatic amino acids, and also their synthetic analogs (e.g., amphetamine), are of use in pharmacology. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to

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determine whether disease is present. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bladder: The organ that stores urine. [NIH] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Blister: Visible accumulations of fluid within or beneath the epidermis. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a

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neurotransmitter. [NIH] Breast Neoplasms: Tumors or cancer of the breast. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]

Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Carbonate: Carbonic acid calcium salt (CaCO3). An odorless, tasteless powder or crystal that occurs in nature. It is used therapeutically as a phosphate buffer in hemodialysis patients and as a calcium supplement. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Cancer vaccine: A vaccine designed to prevent or treat cancer. [NIH] Capecitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carboxy: Cannabinoid. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Carcinoma in Situ: A malignant tumor that has not yet invaded the basement membrane of

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the epithelial cell of origin and has not spread to other tissues. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiotoxicity: Toxicity that affects the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Carmustine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]

Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Ceftriaxone: Broad-spectrum cephalosporin antibiotic with a very long half-life and high penetrability to usually inaccessible infections, including those involving the meninges, eyes, inner ears, and urinary tract. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell Extracts: Preparations of cell constituents or subcellular materials, isolates, or substances. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH]

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Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Chemoembolization: A procedure in which the blood supply to the tumor is blocked surgically or mechanically, and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chlorambucil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorda Tympani Nerve: A branch of the facial (7th cranial) nerve which passes through the middle ear and continues through the petrotympanic fissure. The chorda tympani nerve carries taste sensation from the anterior two-thirds of the tongue and conveys parasympathetic efferents to the salivary glands. [NIH] Choriocarcinoma: A malignant tumor of trophoblastic epithelium characterized by secretion of large amounts of chorionic gonadotropin. It usually originates from chorionic products of conception (i.e., hydatidiform mole, normal pregnancy, or following abortion), but can

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originate in a teratoma of the testis, mediastinum, or pineal gland. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] Cladribine: An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH]

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Cloxacillin: A semi-synthetic antibiotic that is a chlorinated derivative of oxacillin. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combined Modality Therapy: The treatment of a disease or condition by several different means simultaneously or sequentially. Chemoimmunotherapy, radioimmunotherapy, chemoradiotherapy, cryochemotherapy, and salvage therapy are seen most frequently, but their combinations with each other and surgery are also used. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols

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C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conflict of Interest: A situation in which an individual might benefit personally from official or professional actions. It includes a conflict between a person's private interests and official responsibilities in a position of trust. The term is not restricted to government officials. The concept refers both to actual conflict of interest and the appearance or perception of conflict. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the

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anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Consolidation therapy: Chemotherapy treatments given after induction chemotherapy to further reduce the number of cancer cells. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Cooperative group: A group of physicians, hospitals, or both formed to treat a large number of persons in the same way so that new treatment can be evaluated quickly. Clinical trials of new cancer treatments often require many more people than a single physician or hospital can care for. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU]

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Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cowpox: A mild, eruptive skin disease of milk cows caused by cowpox virus, with lesions occurring principally on the udder and teats. Human infection may occur while milking an infected animal. [NIH] Cowpox Virus: A species of orthopoxvirus that is the etiologic agent of cowpox. It is closely related to but antigenically different from vaccina virus. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Crystallization: The formation of crystals; conversion to a crystalline form. [EU] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cystitis: Inflammation of the urinary bladder. [EU] Cytarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU]

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Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Dacarbazine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Dactinomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]

De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]

Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diagnostic Services: Organized services for the purpose of providing diagnosis to promote and maintain health. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH]

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Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Diethylcarbamazine: An anthelmintic used primarily as the citrate in the treatment of filariasis, particularly infestations with Wucheria bancrofti or Loa loa. [NIH] Diethylstilbestrol: DES. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] Diphtheria Toxin: A 60 kD single chain protein elaborated by Corynebacterium diphtheriae that causes the sign and symptoms of diphtheria; it can be broken into two unequal fragments, the smaller (A fragment) inhibits protein synthesis and is the lethal moiety that needs the larger (B fragment) for entry into cells. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis. [NIH] Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration

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in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuretic: A drug that increases the production of urine. [NIH] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH]

Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Drug Combinations: Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. It is differentiated from combination drug therapy in which two or more drugs are administered separately for a combined effect. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects

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of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Duodenum: The first part of the small intestine. [NIH] Dysphagia: Difficulty in swallowing. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]

Emollient: Softening or soothing; called also malactic. [EU] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]

Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly

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into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometrium: The layer of tissue that lines the uterus. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enterocolitis: Inflammation of the intestinal mucosa of the small and large bowel. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [NIH] Eosinophilic: A condition found primarily in grinding workers caused by a reaction of the pulmonary tissue, in particular the eosinophilic cells, to dust that has entered the lung. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermoid carcinoma: A type of cancer in which the cells are flat and look like fish scales. Also called squamous cell carcinoma. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epirubicin: An anthracycline antibiotic which is the 4'-epi-isomer of doxorubicin. The compound exerts its antitumor effects by interference with the synthesis and function of DNA. Clinical studies indicate activity in breast cancer, non-Hodgkin's lymphomas, ovarian

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cancer, soft-tissue sarcomas, pancreatic cancer, gastric cancer, small-cell lung cancer and acute leukemia. It is equal in activity to doxorubicin but exhibits less acute toxicities and less cardiotoxicity. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelial ovarian cancer: Cancer that occurs in the cells lining the ovaries. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Evaluable patients: Patients whose response to a treatment can be measured because enough information has been collected. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excrete: To get rid of waste from the body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH]

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Facial: Of or pertaining to the face. [EU] Facial Nerve: The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fanconi anemia: A rare and often fatal inherited disease in which the bone marrow fails to produce red blood cells, white blood cells, platelets, or a combination of these cells. The disease may transform into myelodysplastic syndrome or leukemia. Also called Fanconi's syndrome. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Filler: An inactive substance used to make a product bigger or easier to handle. For example, fillers are often used to make pills or capsules because the amount of active drug is too small to be handled conveniently. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flow Cytometry: Technique using an instrument system for making, processing, and

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displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Freeze Drying: Method of tissue preparation in which the tissue specimen is frozen and then dehydrated at low temperature in a high vacuum. This method is also used for dehydrating pharmaceutical and food products. [NIH] Freeze-dried: A method used to dry substances, such as food, to make them last longer. The substance is frozen and then dried in a vacuum. [NIH] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of action and is used in edema and chronic renal insufficiency. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually

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between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Mucosa: Surface epithelium in the stomach that invaginates into the lamina propria, forming gastric pits. Tubular glands, characteristic of each region of the stomach (cardiac, gastric, and pyloric), empty into the gastric pits. The gastric mucosa is made up of several different kinds of cells. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gemcitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] General practitioner: A medical practitioner who does not specialize in a particular branch of medicine or limit his practice to a specific class of diseases. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational trophoblastic disease: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic tumor, gestational trophoblastic neoplasia, molar pregnancy, or

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choriocarcinoma. [NIH] Gestational trophoblastic neoplasia: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic disease, gestational trophoblastic tumor, molar pregnancy, or choriocarcinoma. [NIH] Gestational trophoblastic tumor: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic disease, gestational trophoblastic neoplasia, molar pregnancy, or choriocarcinoma. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioblastoma multiforme: A type of brain tumor that forms from glial (supportive) tissue of the brain. It grows very quickly and has cells that look very different from normal cells. Also called grade IV astrocytoma. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glossopharyngeal Nerve: The 9th cranial nerve. The glossopharyngeal nerve is a mixed motor and sensory nerve; it conveys somatic and autonomic efferents as well as general, special, and visceral afferents. Among the connections are motor fibers to the stylopharyngeus muscle, parasympathetic fibers to the parotid glands, general and taste afferents from the posterior third of the tongue, the nasopharynx, and the palate, and afferents from baroreceptors and chemoreceptors of the carotid sinus. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic

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(drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadorelin: A decapeptide hormone released by the hypothalamus. It stimulates the synthesis and secretion of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. [NIH] Goserelin: 6-(O-(1,1-Dimethylethyl)-D-serine)-10-deglycinamideluteinizing hormonereleasing factor (pig) 2-(aminocarbonyl)hydrazide. A long-acting gonadorelin agonist. It is used in the treatment of malignant neoplasms of the prostate, uterine fibromas, and metastatic breast cancer. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH]

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Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]

Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Haematemesis: The vomiting of blood. [EU] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] Haematuria: Blood in the urine. [EU] Haemophilia: A haemorrhagic diathesis occurring in two main forms: 1. Haemophilia A (classic haemophilia, factor VIII deficiency), an X-linked disorder due to deficiency of coagulation factor VIII; 2. Haemophilia B (factor IX deficiency, Christmas disease), also Xlinked, due to deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but a different loci, and are characterized by subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. [EU] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of

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health. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic Stem Cell Mobilization: The release of stem cells from the bone marrow into the peripheral blood circulation for the purpose of leukapheresis, prior to stem cell transplantion. Hematopoietic growth factors or chemotherapeutic agents often are used to stimulate the mobilization. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hematuria: Presence of blood in the urine. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin C: A commonly occurring abnormal hemoglobin in which lysine replaces a glutamic acid residue at the sixth position of the beta chains. It results in reduced plasticity of erythrocytes. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH]

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Hemosiderosis: Conditions in which there is a generalized increase in the iron stores of body tissues, particularly of liver and the reticuloendothelial system, without demonstrable tissue damage. The name refers to the presence of stainable iron in the tissue in the form of hemosiderin. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes virus: A member of the herpes family of viruses. [NIH] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hidradenitis: The inflammation of a sweat gland (usually of the apocrine type). The condition can be idiopathic or occur as a result of or in association with another underlying condition. Neutrophilic eccrine hidradenitis is a relatively rare variant that has been reported in patients undergoing chemotherapy, usually for non-Hodgkin lymphomas or leukemic conditions. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histiocytosis: General term for the abnormal appearance of histiocytes in the blood. Based on the pathological features of the cells involved rather than on clinical findings, the histiocytic diseases are subdivided into three groups: Langerhans cell histiocytosis, nonLangerhans cell histiocytosis, and malignant histiocytic disorders. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homodimer: Protein-binding "activation domains" always combine with identical proteins. [NIH]

Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH]

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Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormonal therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called hormone therapy or endocrine therapy. [NIH] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Hospital Administrators: Managerial personnel responsible for implementing policy and directing the activities of hospitals. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hydroxyurea: An antineoplastic agent that inhibits DNA synthesis through the inhibition of ribonucleoside diphosphate reductase. [NIH] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH]

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Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Idarubicin: An orally administered anthracycline antibiotic. The compound has shown activity against breast cancer, lymphomas and leukemias, together with potential for reduced cardiac toxicity. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune Complex Diseases: Group of diseases mediated by the deposition of large soluble complexes of antigen and antibody with resultant damage to tissue. Besides serum sickness and the arthus reaction, evidence supports a pathogenic role for immune complexes in many other systemic immunologic diseases including glomerulonephritis, systemic lupus erythematosus and polyarteritis nodosa. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immune Tolerance: The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. [NIH] Immunity:

Nonsusceptibility

to

the

invasive

or

pathogenic

effects

of

foreign

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microorganisms or to the toxic effect of antigenic substances. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunophenotyping: Process of classifying cells of the immune system based on structural and functional differences. The process is commonly used to analyze and sort Tlymphocytes into subsets based on CD antigens by the technique of flow cytometry. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Immunotoxins: Semisynthetic conjugates of various toxic molecules, including radioactive isotopes and bacterial or plant toxins, with specific immune substances such as immunoglobulins, monoclonal antibodies, and antigens. The antitumor or antiviral immune substance carries the toxin to the tumor or infected cell where the toxin exerts its poisonous effect. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH]

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In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Indolent: A type of cancer that grows slowly. [NIH] Indolent lymphoma: Lymphoma that grows slowly and has few symptoms. [NIH] Indomethacin: A non-steroidal anti-inflammatory agent (NSAID) that inhibits the enzyme cyclooxygenase necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infiltrating cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called invasive cancer. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Influenza: An acute viral infection involving the respiratory tract. It is marked by inflammation of the nasal mucosa, the pharynx, and conjunctiva, and by headache and severe, often generalized, myalgia. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH]

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Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inoperable: Not suitable to be operated upon. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. It is an initiator of cell-mediated immunity. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH]

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Interleukin-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [NIH] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interphase: The interval between two successive cell divisions during which the chromosomes are not individually distinguishable and DNA replication occurs. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestinal Mucosa: The surface lining of the intestines where the cells absorb nutrients. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invasive cancer: Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. Also called infiltrating cancer. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a

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gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isozymes: The multiple forms of a single enzyme. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keratoacanthoma: A benign, non-neoplastic, usually self-limiting epithelial lesion closely resembling squamous cell carcinoma clinically and histopathologically. It occurs in solitary, multiple, and eruptive forms. The solitary and multiple forms occur on sunlight exposed areas and are identical histologically; they affect primarily white males. The eruptive form usually involves both sexes and appears as a generalized papular eruption. [NIH] Kidney Cortex: The outer zone of the kidney, beneath the capsule, consisting of kidney glomerulus; kidney tubules, distal; and kidney tubules, proximal. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kidney Glomerulus: A cluster of convoluted capillaries beginning at each nephric tubule in

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the kidney and held together by connective tissue. [NIH] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Leflunomide: An anticancer drug that works by inhibiting a cancer cell growth factor. Also called SU101. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leucovorin: The active metabolite of folic acid. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid. [NIH] Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Levamisole: An antiparasitic drug that is also being studied in cancer therapy with fluorouracil. [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it

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is longer acting. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Linkages: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Lomustine: An alkylating agent of value against both hematologic malignancies and solid tumors. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Low-grade lymphomas: Lymphomas that tend to grow and spread slowly, including chronic lymphocytic lymphoma and follicular small cleaved cell lymphoma. Also called indolent lymphomas. [NIH] Lubricants: Oily or slippery substances. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lupus Nephritis: Glomerulonephritis associated with systemic lupus erythematosus. It is classified into four histologic types: mesangial, focal, diffuse, and membranous. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen,

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thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Macrophage Colony-Stimulating Factor: A mononuclear phagocyte colony-stimulating factor synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (receptor, macrophage colony-stimulating factor). [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant mesothelioma: A rare type of cancer in which malignant cells are found in the sac lining the chest or abdomen. Exposure to airborne asbestos particles increases one's risk of developing malignant mesothelioma. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mammography: Radiographic examination of the breast. [NIH] Mannitol: A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate.

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Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Mechlorethamine: A vesicant and necrotizing irritant destructive to mucous membranes. It was formerly used as a war gas. The hydrochloride is used as an antineoplastic in Hodgkin's disease and lymphomas. It causes severe gastrointestinal and bone marrow damage. [NIH] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical oncologist: A doctor who specializes in diagnosing and treating cancer using chemotherapy, hormonal therapy, and biological therapy. A medical oncologist often serves as the main caretaker of someone who has cancer and coordinates treatment provided by other specialists. [NIH] Medical Oncology: A subspecialty of internal medicine concerned with the study of neoplasms. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medulloblastoma: A malignant brain tumor that begins in the lower part of the brain and can spread to the spine or to other parts of the body. Medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - melphalan, the racemic mixture - merphalan, and the dextro isomer medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Membranoproliferative: A disease that occurs primarily in children and young adults. Over time, inflammation leads to scarring in the glomeruli, causing proteinuria, hematuria, and sometimes chronic renal failure or end-stage renal disease. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU]

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Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mercaptopurine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesna: A sulfhydryl compound used to prevent urothelial toxicity by inactivating metabolites from antineoplastic agents, such as ifosfamide or cyclophosphamide. [NIH] Mesothelioma: A benign (noncancerous) or malignant (cancerous) tumor affecting the lining of the chest or abdomen. Exposure to asbestos particles in the air increases the risk of developing malignant mesothelioma. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metaphase: The second phase of cell division, in which the chromosomes line up across the equatorial plane of the spindle prior to separation. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methylprednisolone: (6 alpha,11 beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,2dione. A prednisolone derivative which has pharmacological actions similar to prednisolone. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Millimeter: A measure of length. A millimeter is approximately 26-times smaller than an

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inch. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mineralocorticoids: A group of corticosteroids primarily associated with the regulation of water and electrolyte balance. This is accomplished through the effect on ion transport in renal tubules, resulting in retention of sodium and loss of potassium. Mineralocorticoid secretion is itself regulated by plasma volume, serum potassium, and angiotensin II. [NIH] Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitostis). [NIH]

Mitoxantrone: An anthracenedione-derived antineoplastic agent. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH]

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Monotherapy: A therapy which uses only one drug. [EU] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagenicity: Ability to damage DNA, the genetic material; the power to cause mutations. [NIH]

Myalgia: Pain in a muscle or muscles. [EU] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic Syndromes: Conditions in which the bone marrow shows qualitative and quantitative changes suggestive of a preleukemic process, but having a chronic course that does not necessarily terminate as acute leukemia. [NIH] Myelofibrosis: A disorder in which the bone marrow is replaced by fibrous tissue. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [NIH] Myelotoxic: 1. Destructive to bone marrow. 2. Arising from diseased bone marrow. [EU]

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Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myositis: Inflammation of a voluntary muscle. [EU] Nasal Mucosa: The mucous membrane lining the nasal cavity. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of

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antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrocamptothecin: An alkaloid drug belonging to a class of anticancer agents called topoisomerase inhibitors. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Node-positive: Cancer that has spread to the lymph nodes. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma,

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adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nosocomial: Pertaining to or originating in the hospital, said of an infection not present or incubating prior to admittance to the hospital, but generally occurring 72 hours after admittance; the term is usually used to refer to patient disease, but hospital personnel may also acquire nosocomial infection. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Nursing Care: Care given to patients by nursing service personnel. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [NIH] Oncology: The study of cancer. [NIH] Oncology nurse: A nurse who specializes in treating and caring for people who have cancer. [NIH]

Oncolysis: The destruction of or disposal by absorption of any neoplastic cells. [NIH] Oncolytic: Pertaining to, characterized by, or causing oncolysis (= the lysis or destruction of tumour cells). [EU]

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Ondansetron: A competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and it has reported anxiolytic and neuroleptic properties. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [NIH] Osmolarity: The concentration of osmotically active particles expressed in terms of osmoles of solute per litre of solution. [EU] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH]

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Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Papilla: A small nipple-shaped elevation. [NIH] Papillary: Pertaining to or resembling papilla, or nipple. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Partial response: A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. [NIH] Particle: A tiny mass of material. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Care Management: Generating, planning, organizing, and administering medical and nursing care and services for patients. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pelvic: Pertaining to the pelvis. [EU] Pemphigus: Group of chronic blistering diseases characterized histologically by acantholysis and blister formation within the epidermis. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood

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vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perimenopausal: The time of a woman's life when menstrual periods become irregular. Refers to the time near menopause. [NIH] Perioperative: Around the time of surgery; usually lasts from the time of going into the hospital or doctor's office for surgery until the time the patient goes home. [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral stem cell transplantation: A method of replacing blood-forming cells destroyed by cancer treatment. Immature blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are given after treatment to help the bone marrow recover and continue producing healthy blood cells. Transplantation may be autologous (an individual's own blood cells saved earlier), allogeneic (blood cells donated by someone else), or syngeneic (blood cells donated by an identical twin). Also called peripheral stem cell support. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacists: Those persons legally qualified by education and training to engage in the practice of pharmacy. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenobarbital: A barbituric acid derivative that acts as a nonselective central nervous

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system depressant. It promotes binding to inhibitory GABA subtype receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Pheresis: A procedure in which blood is collected, part of the blood such as platelets or white blood cells is taken out, and the rest of the blood is returned to the donor. Also called apheresis. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Plague: An acute infectious disease caused by Yersinia pestis that affects humans, wild rodents, and their ectoparasites. This condition persists due to its firm entrenchment in sylvatic rodent-flea ecosystems throughout the world. Bubonic plague is the most common form. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid

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and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma Exchange: Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (PPF), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]

Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Pneumonitis: A disease caused by inhaling a wide variety of substances such as dusts and molds. Also called "farmer's disease". [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyarteritis Nodosa: A form of necrotizing vasculitis involving small- and medium-sized arteries. The signs and symptoms result from infarction and scarring of the affected organ

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system. [NIH] Polyarthritis: An inflammation of several joints together. [EU] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]

Polyethylene Glycols: Alpha-Hydro-omega-hydroxypoly(oxy-1,2-ethanediyls). Additional polymers of ethylene oxide and water and their ethers. They vary in consistency from liquid to solid, depending on the molecular weight, indicated by a number following the name. Used as surfactants in industry, including foods, cosmetics and pharmaceutics; in biomedicine, as dispersing agents, solvents, ointment and suppository bases, vehicles, tablet excipients. Some specific groups are lauromagrogols, nonoxynols, octoxynols and poloxamers. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyneuritis: Inflammation of several peripheral nerves at the same time. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH]

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Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Preoperative: Preceding an operation. [EU] Primary tumor: The original tumor. [NIH] Primitive neuroectodermal tumors: PNET. A type of bone cancer that forms in the middle (shaft) of large bones. Also called Ewing's sarcoma/primitive neuroectodermal tumor. [NIH] Procarbazine: An antineoplastic agent used primarily in combination with mechlorethamine, vincristine, and prednisone (the MOPP protocol) in the treatment of Hodgkin's disease. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propylene Glycol: A clear, colorless, viscous organic solvent and diluent used in pharmaceutical preparations. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all

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free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostate-Specific Antigen: Kallikrein-like serine proteinase produced by epithelial cells of both benign and malignant prostate tissue. It is an important marker for the diagnosis of prostate cancer. EC 3.4.21.77. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]

Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteoglycans: Glycoproteins which have a very high polysaccharide content. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They

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function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation Chimera: An organism whose body contains cell populations of different genotypes as a result of the transplantation of donor cells after sufficient ionizing radiation to destroy the mature recipient's cells which would otherwise reject the donor cells. [NIH] Radiation oncologist: A doctor who specializes in using radiation to treat cancer. [NIH] Radiation Oncology: A subspecialty of medical oncology and radiology concerned with the

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radiotherapy of cancer. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Randomized Controlled Trials: Clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table. Treatment allocations using coin flips, odd-even numbers, patient social security numbers, days of the week, medical record numbers, or other such pseudo- or quasi-random processes, are not truly randomized and trials employing any of these techniques for patient assignment are designated simply controlled clinical trials. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH]

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Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regional chemotherapy: Treatment with anticancer drugs that is directed to a specific area. [NIH]

Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Research Personnel: Those individuals engaged in research. [NIH] Residual disease: Cancer cells that remain after attempts have been made to remove the cancer. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH]

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Retraction: 1. The act of drawing back; the condition of being drawn back. 2. Distal movement of teeth, usually accomplished with an orthodontic appliance. [EU] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rheumatology: A subspecialty of internal medicine concerned with the study of inflammatory or degenerative processes and metabolic derangement of connective tissue structures which pertain to a variety of musculoskeletal disorders, such as arthritis. [NIH] Ribavirin: 1-beta-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [NIH] Ribonucleoside Diphosphate Reductase: An enzyme of the oxidoreductase class that catalyzes the formation of 2'-deoxyribonucleotides from the corresponding ribonucleotides using NADPH as the ultimate electron donor. The deoxyribonucleoside diphosphates are used in DNA synthesis. (From Dorland, 27th ed) EC 1.17.4.1. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rituximab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] S Phase: Phase of the cell cycle following G1 and preceding G2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. [NIH] Saline: A solution of salt and water. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salvage Therapy: A therapeutic approach, involving chemotherapy, radiation therapy, or surgery, after initial regimens have failed to lead to improvement in a patient's condition. Salvage therapy is most often used for neoplastic diseases. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH]

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Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Sebaceous: Gland that secretes sebum. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [NIH] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU]

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Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH]

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Skin test: A test for an immune response to a compound by placing it on or under the skin. [NIH]

Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smallpox: A generalized virus infection with a vesicular rash. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Security: Government sponsored social insurance programs. [NIH] Socioeconomic Factors: Social and economic factors that characterize the individual or group within the social structure. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Bicarbonate: A white, crystalline powder that is commonly used as a pH buffering agent, an electrolyte replenisher, systemic alkalizer and in topical cleansing solutions. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Soft tissue sarcoma: A sarcoma that begins in the muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters

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distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standardize: To compare with or conform to a standard; to establish standards. [EU] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117 (proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Sterile: Unable to produce children. [NIH]

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Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulants: Any drug or agent which causes stimulation. [NIH] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stomatology: The branch of medical science concerned with the mouth and its diseases. [NIH]

Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclavian: The direct continuation of the axillary vein at the lateral border of the first rib. It passes medially to join the internal jugular vein and form the brachiocephalic vein on each side. [NIH] Subclavian Artery: Artery arising from the brachiocephalic trunk on the right side and from the arch of the aorta on the left side. It distributes to the neck, thoracic wall, spinal cord, brain, meninges, and upper limb. [NIH] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH]

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Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppository: A medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body, suppository bases are solid at room temperature but melt or dissolve at body temperature. Commonly used bases are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. [EU] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suramin: A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU]

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Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systemic therapy: Treatment that uses substances that travel through the bloodstream, reaching and affecting cells all over the body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Talc: A native magnesium silicate. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Taste Buds: Small sensory organs which contain gustatory receptor cells, basal cells, and supporting cells. Taste buds in humans are found in the epithelia of the tongue, palate, and pharynx. They are innervated by the chorda tympani nerve (a branch of the facial nerve) and the glossopharyngeal nerve. [NIH] Tegafur: 5-Fluoro-1-(tetrahydro-2-furanyl)-2,4-(1H,3H)-pyrimidinedione. Congener of fluorouracil with comparable antineoplastic action. It has been suggested especially for the treatment of breast neoplasms. [NIH] Telecommunications: Transmission of information over distances via electronic means. [NIH]

Telemedicine: Delivery of health services via remote telecommunications. This includes interactive consultative and diagnostic services. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Telomere: A terminal section of a chromosome which has a specialized structure and which is involved in chromosomal replication and stability. Its length is believed to be a few hundred base pairs. [NIH] Temozolomide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used

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mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalidomide: A pharmaceutical agent originally introduced as a non-barbiturate hypnotic, but withdrawn from the market because of its known tetratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor alpha from monocytes, and modulates other cytokine action. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thiotepa: A very toxic alkylating antineoplastic agent also used as an insect sterilant. It causes skin, gastrointestinal, CNS, and bone marrow damage. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), thiotepa may reasonably be anticipated to be a carcinogen (Merck Index, 11th ed). [NIH] Thoracic: Having to do with the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thymoma: A tumor of the thymus, an organ that is part of the lymphatic system and is located in the chest, behind the breastbone. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tirapazamine: A drug that makes tumor cells more sensitive to radiation therapy. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tonicity: The normal state of muscular tension. [NIH] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [NIH] Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting

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DNA topoisomerase. [NIH] Total-body irradiation: Radiation therapy to the entire body. Usually followed by bone marrow or peripheral stem cell transplantation. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGFbeta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. [NIH]

Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Transitional cell carcinoma: A type of cancer that develops in the lining of the bladder, ureter, or renal pelvis. [NIH] Translating: Conversion from one language to another language. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH]

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Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trastuzumab: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. Trastuzumab blocks the effects of the growth factor protein HER2, which transmits growth signals to breast cancer cells. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]

Triethylenephosphoramide: An insect chemosterilant and an antineoplastic agent. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trypanosomiasis: Infection with protozoa of the genus Trypanosoma. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tularemia: A plague-like disease of rodents, transmissible to man. It is caused by Francisella tularensis and is characterized by fever, chills, headache, backache, and weakness. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor model: A type of animal model which can be used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive;

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called also neoplasm. [EU] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Unresectable: Unable to be surgically removed. [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urodynamic: Measures of the bladder's ability to hold and release urine. [NIH] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] Urologist: A doctor who specializes in diseases of the urinary organs in females and the urinary and sex organs in males. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vaccinia: The cutaneous and occasional systemic reactions associated with vaccination using smallpox (variola) vaccine. [NIH] Vaccinia Virus: The type species of Orthopoxvirus, related to cowpox virus, but whose true origin is unknown. It has been used as a live vaccine against smallpox. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of vaccinia virus. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH]

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Vaginal: Of or having to do with the vagina, the birth canal. [NIH] Variola: A generalized virus infection with a vesicular rash. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vertebral Artery: The first branch of the subclavian artery with distribution to muscles of the neck, vertebrae, spinal cord, cerebellum and interior of the cerebrum. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vial: A small bottle. [EU] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viraemia: The presence of virus in blood or blood plasma. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH]

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Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Vulgaris: An affection of the skin, especially of the face, the back and the chest, due to chronic inflammation of the sebaceous glands and the hair follicles. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Xanthoma: A tumour composed of lipid-laden foam cells, which are histiocytes containing cytoplasmic lipid material. Called also xanthelasma. [EU] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIVinduced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [NIH]

275

INDEX 6 6-Mercaptopurine, 14, 201 A Abdominal, 10, 201, 238, 251, 252, 261, 272 Abdominal Pain, 10, 201, 272 Ablation, 155, 201 Academic Medical Centers, 21, 201 Acantholysis, 201, 251 Acceptor, 201, 241, 250 Acetylcholine, 201, 213, 248 Actin, 57, 201 Acute leukemia, 17, 21, 45, 201, 224, 246 Acute lymphoblastic leukemia, 45, 46, 73, 85, 201 Acute lymphocytic leukemia, 87, 119, 139, 201 Acute myelogenous leukemia, 46, 201 Acute myeloid leukemia, 86, 136, 201 Acute nonlymphocytic leukemia, 25, 201 Acute renal, 202, 231 Adaptability, 202, 212 Adenocarcinoma, 163, 202, 232, 249 Adjunctive Therapy, 29, 202 Adjuvant Therapy, 21, 99, 125, 160, 165, 202 Adolescence, 52, 202 Adrenal Cortex, 202, 217, 218, 256 Adrenal Glands, 202, 204 Adrenal Medulla, 202, 223, 249 Adrenergic, 43, 202, 221, 223, 267, 272 Adverse Effect, 8, 13, 202, 222, 263 Aerobic, 202, 245, 250 Aerobic Metabolism, 202, 250 Aerobic Respiration, 202, 250 Affinity, 25, 202, 207, 242, 264 Agonist, 202, 221, 229, 248, 268 Airways, 11, 203 Alanine, 150, 162, 203 Albumin, 13, 203, 254 Aldehyde Dehydrogenase, 31, 32, 109, 157, 158, 203 Algorithms, 170, 203, 210 Alimentary, 203, 251 Alkaline, 203, 204, 211 Alkaloid, 125, 203, 211, 215, 248 Alkylate, 31, 149, 203 Alkylating Agents, 6, 52, 60, 149, 162, 170, 203, 211, 212, 213, 219, 268, 272

Alkylation, 56, 112, 149, 203 Allergen, 203, 219, 262 Allogeneic, 61, 81, 82, 85, 86, 103, 109, 161, 164, 165, 203, 229, 231, 252 Allograft, 106, 203 Allylamine, 203, 204 Alopecia, 203 Alpha Particles, 203, 258 Alternative medicine, 175, 203 Amenorrhea, 9, 204 Amifostine, 72, 125, 179, 204 Amine, 148, 204, 232 Amino Acid Sequence, 204, 205, 227 Amino Acids, 150, 204, 205, 207, 209, 224, 227, 251, 255, 257, 263, 270, 272 Aminocamptothecin, 24, 162, 204 Ammonia, 204, 229, 267, 272 Amphetamine, 204, 209 Amyloidosis, 93, 204 Anaemia, 204, 206 Anaesthesia, 204, 236 Anal, 204, 225, 241, 246 Analog, 72, 78, 204, 226 Analogous, 204, 221, 270 Analysis of Variance, 73, 204 Anaphylatoxins, 205, 216 Anatomical, 205, 235, 262 Androgens, 202, 205, 217 Anemia, 71, 82, 161, 205, 226, 246, 274 Anemic, 161, 205 Angiotensin I, 5, 205 Angiotensinogen, 205, 260 Anhydrous, 150, 153, 156, 205 Animal model, 59, 160, 205, 271 Anions, 203, 205, 239, 263 Anoikis, 37, 205 Anthracycline, 99, 205, 219, 223, 234 Antiallergic, 205, 217 Antibacterial, 205, 265 Antibiotic, 205, 212, 215, 219, 221, 223, 224, 234, 265, 268 Antibodies, 4, 8, 43, 70, 135, 165, 170, 205, 230, 231, 234, 245, 254, 259 Antibody therapy, 43, 205 Antidiuretic, 13, 205 Antidote, 206, 240 Antiemetic, 72, 117, 206 Antifungals, 88, 206

276

Cyclophosphamide

Antigen, 11, 26, 30, 36, 43, 75, 158, 202, 205, 206, 216, 219, 232, 234, 235, 236, 243, 262 Antigen-Antibody Complex, 206, 216 Antigen-presenting cell, 206, 219 Anti-inflammatory, 28, 206, 217, 219, 228, 236, 256 Anti-Inflammatory Agents, 206, 217 Antimetabolite, 201, 206, 226, 244, 261 Antineoplastic Agents, 52, 149, 165, 203, 206, 244, 273 Antioxidant, 38, 39, 134, 206 Antiproliferative, 170, 206 Antithymocyte globulin, 84, 100, 109, 206 Antiviral, 5, 206, 235, 237, 251, 261 Anuria, 206, 239 Anxiety, 72, 206 Anxiolytic, 206, 250 Apheresis, 206, 253 Aplastic anaemia, 102, 122, 206 Aplastic anemia, 17, 44, 84, 92, 102, 108, 109, 174, 206 Apoptosis, 16, 17, 26, 30, 37, 43, 58, 70, 71, 88, 164, 205, 206 Appendicitis, 116, 207 Applicability, 54, 207 Aqueous, 31, 133, 149, 156, 207, 209, 218, 233 Arachidonic Acid, 207, 240, 257 Arginine, 150, 151, 153, 205, 207, 248 Arterial, 111, 122, 203, 207, 234, 257, 268 Arteries, 207, 210, 254 Arteriosclerosis, 207, 234 Arteritis, 114, 207 Artery, 207, 258, 266 Asbestos, 207, 242, 244 Aseptic, 118, 207, 250, 266 Aspartic Acid, 148, 207 Assay, 44, 71, 207 Astrocytes, 207, 238 Astrocytoma, 207, 228 Asymptomatic, 7, 10, 154, 207 Atmospheric Pressure, 208, 233 Atrophy, 7, 201, 208 Attenuated, 34, 57, 96, 159, 208 Aural, 12, 208 Autacoids, 208, 236 Authorship, 61, 69, 208 Autoimmune disease, 8, 35, 42, 71, 74, 208, 246, 254 Autoimmune Hepatitis, 88, 208 Autoimmunity, 4, 35, 74, 208

Autologous, 17, 26, 43, 48, 52, 61, 80, 94, 96, 102, 118, 133, 134, 158, 160, 161, 208, 231, 252 Autologous bone marrow transplantation, 52, 208, 231 Autologous tumor cells, 160, 208 Autonomic Nervous System, 208, 267 Autosuggestion, 208, 234 B Bacteria, 205, 206, 208, 209, 223, 231, 244, 259, 262, 265, 270, 272 Bacteriostatic, 208, 224 Bacterium, 208, 231 Barbiturate, 208, 269 Basal cells, 208, 268 Basal Ganglia, 208, 228 Base, 21, 22, 24, 26, 46, 51, 69, 76, 77, 208, 219, 227, 239, 268 Basement Membrane, 4, 209, 211, 224, 240 Basophils, 209, 230 Benign, 5, 209, 230, 239, 244, 247, 257, 259 Beta-Thromboglobulin, 209, 238 Bilateral, 11, 12, 209 Bile, 164, 209, 226, 233, 241, 266 Bile Acids, 164, 209, 266 Bile Acids and Salts, 209 Bilirubin, 203, 209 Biochemical, 9, 36, 39, 44, 50, 57, 59, 133, 206, 209, 226, 239, 240, 252, 263 Biogenic Amines, 164, 209 Biological response modifier, 27, 52, 209, 237 Biological therapy, 209, 230, 243 Biomarkers, 18, 209 Biopsy, 4, 9, 10, 12, 58, 107, 170, 209 Biopsy specimen, 10, 209 Biotechnology, 77, 80, 175, 185, 210 Bladder, 10, 64, 83, 86, 89, 108, 119, 210, 216, 218, 246, 257, 260, 270, 272 Bleomycin, 83, 118, 125, 131, 133, 139, 210 Blister, 210, 251 Blood Coagulation, 210, 211 Blood Glucose, 210, 231 Blood pressure, 5, 8, 10, 170, 210, 234, 245, 264 Blood transfusion, 161, 210 Blood vessel, 210, 212, 213, 217, 223, 228, 231, 239, 242, 244, 252, 264, 269, 273 Blot, 18, 210 Body Fluids, 209, 210, 264, 271 Bolus, 86, 121, 210 Bolus infusion, 210

277

Bowel, 14, 40, 69, 140, 204, 210, 220, 223, 236, 238, 252, 272 Brachytherapy, 210, 238, 239, 259, 274 Bradykinin, 210, 248, 254 Breast Neoplasms, 211, 268 Bronchi, 211, 223 Bronchial, 84, 123, 162, 211, 232 Buccal, 211, 241 Busulfan, 52, 80, 82, 85, 86, 87, 100, 101, 103, 109, 133, 211 C Cachexia, 15, 75, 211 Calcium, 28, 170, 207, 211, 216, 240, 263 Calcium Carbonate, 28, 211 Calcium Channel Blockers, 170, 211 Camptothecin, 162, 211, 239 Cancer vaccine, 26, 211 Capecitabine, 82, 211 Capsules, 152, 211, 221, 225, 228 Carbohydrate, 211, 217, 229, 255 Carboplatin, 24, 75, 95, 102, 105, 107, 108, 117, 122, 133, 136, 138, 211 Carboxy, 159, 211 Carcinogen, 211, 243, 269 Carcinogenesis, 37, 211, 213 Carcinogenic, 203, 211, 237, 249, 256, 266 Carcinoma, 10, 22, 81, 83, 88, 92, 93, 95, 111, 115, 117, 119, 123, 137, 138, 160, 162, 211, 249 Carcinoma in Situ, 10, 211 Cardiac, 39, 48, 86, 95, 106, 122, 203, 212, 223, 227, 234, 247, 266 Cardiopulmonary, 12, 212 Cardiotoxicity, 39, 212, 224 Cardiovascular, 7, 12, 204, 212, 240, 263 Carmustine, 82, 212 Case report, 95, 212, 214 Case series, 136, 212, 214 Causal, 212, 231 Ceftriaxone, 79, 212 Cell Cycle, 16, 149, 212, 214, 224, 258, 261 Cell Death, 30, 37, 39, 77, 149, 206, 212, 224, 247 Cell Differentiation, 212, 263, 265 Cell Division, 149, 208, 212, 218, 224, 230, 238, 244, 245, 253, 256, 262 Cell Extracts, 32, 212 Cell membrane, 211, 212, 219, 253 Cell proliferation, 15, 36, 37, 75, 207, 212, 238, 263 Cell Respiration, 202, 212, 245, 250, 260 Cell Size, 212, 226

Cell Survival, 212, 230 Cell Transplantation, 27, 43, 94, 101, 102, 103, 108, 109, 115, 118, 133, 134, 137, 213, 231 Central Nervous System, 31, 51, 201, 203, 204, 208, 213, 227, 228, 229, 230, 240, 246, 253, 263 Cerebellum, 213, 273 Cerebral, 208, 213, 223, 228 Cerebral hemispheres, 208, 213, 228 Cerebrovascular, 211, 213 Cerebrum, 213, 273 Cervical, 122, 213 Cervix, 93, 213 Chemoembolization, 61, 213 Chemopreventive, 72, 75, 213 Chemotactic Factors, 213, 216 Chemotherapeutic agent, 16, 42, 58, 72, 149, 154, 163, 213, 231 Chimeras, 34, 213 Chlorambucil, 6, 14, 83, 213 Cholesterol, 209, 213, 233, 234, 266, 268 Cholinergic, 213, 248 Chorda Tympani Nerve, 213, 268 Choriocarcinoma, 213, 228 Chromatin, 207, 214, 223, 242 Chromosomal, 17, 46, 214, 261, 268 Chromosome, 18, 86, 214, 230, 241, 261, 262, 268 Chronic, 5, 7, 11, 17, 37, 46, 83, 97, 98, 100, 103, 105, 118, 120, 161, 211, 214, 220, 223, 226, 236, 239, 240, 241, 243, 246, 251, 266, 268, 272, 274 Chronic Disease, 211, 214, 240 Chronic granulocytic leukemia, 214 Chronic myelogenous leukemia, 46, 214 Chronic renal, 7, 161, 214, 226, 243 Cirrhosis, 5, 214 CIS, 10, 148, 159, 214 C-kit receptor, 214, 265 Cladribine, 83, 103, 108, 214 Clear cell carcinoma, 214, 220 Clinical Medicine, 214, 256 Clinical Protocols, 54, 55, 74, 214 Clinical study, 96, 214, 217 Cloning, 210, 214, 237 Cloxacillin, 79, 215 Coagulation, 210, 215, 230, 254 Cofactor, 215, 257 Colchicine, 215, 271 Colitis, 215 Collagen, 3, 209, 215, 217, 225, 254, 256

278

Cyclophosphamide

Colloidal, 203, 215, 263 Colon, 215, 236, 240, 272 Colony-Stimulating Factors, 215, 230 Colorectal, 38, 40, 215 Colorectal Cancer, 38, 40, 215 Combination chemotherapy, 5, 96, 114, 121, 215 Combination Therapy, 5, 215 Combined Modality Therapy, 75, 215 Complement, 26, 205, 215, 216, 254, 262 Complementary and alternative medicine, 131, 143, 216 Complementary medicine, 32, 131, 216 Complete remission, 7, 8, 11, 14, 110, 216, 260 Complete response, 216 Compliance, 10, 32, 51, 55, 216 Computational Biology, 185, 216 Conception, 213, 216, 225, 227, 228, 264, 266 Concomitant, 15, 59, 149, 216 Conflict of Interest, 68, 77, 216 Congestion, 11, 216 Conjugated, 158, 209, 216, 218 Conjunctiva, 216, 236 Connective Tissue, 104, 210, 215, 217, 225, 227, 240, 241, 244, 261, 266, 268 Connective Tissue Cells, 217 Connective Tissue Diseases, 104, 217 Consolidation, 70, 88, 134, 217 Consolidation therapy, 70, 88, 217 Constitutional, 217, 246 Consultation, 62, 217 Contamination, 152, 217 Continuous infusion, 73, 217 Contraindications, ii, 12, 217 Control group, 28, 32, 160, 217 Controlled clinical trial, 21, 40, 217, 259 Cooperative group, 18, 19, 20, 24, 38, 45, 50, 52, 62, 63, 64, 65, 66, 73, 217 Coordination, 28, 45, 48, 55, 64, 65, 69, 213, 217, 246 Cortical, 217, 262 Corticosteroid, 11, 12, 92, 93, 121, 217, 256, 266 Cortisol, 203, 218 Cortisone, 218, 219, 256 Cowpox, 218, 272 Cowpox Virus, 218, 272 Creatinine, 4, 9, 10, 218, 239 Crossing-over, 218, 260 Crystallization, 153, 218

Curative, 17, 35, 43, 59, 218, 269 Cutaneous, 86, 113, 218, 241, 272 Cyclic, 152, 218, 230, 248 Cyclosporine, 5, 6, 8, 10, 13, 14, 48, 57, 71, 93, 170, 171, 218 Cystitis, 10, 28, 136, 137, 139, 154, 218 Cytarabine, 88, 95, 98, 136, 139, 218 Cytochrome, 18, 77, 98, 99, 105, 164, 218 Cytogenetics, 23, 27, 54, 55, 61, 66, 218 Cytokine, 37, 42, 74, 75, 81, 166, 218, 225, 237, 238, 269 Cytomegalovirus, 79, 218 Cytoplasm, 207, 209, 212, 218, 223, 242 Cytosine, 88, 219 Cytostatic, 24, 135, 155, 219 Cytotoxic, 5, 7, 11, 12, 14, 16, 30, 34, 72, 165, 219, 235, 250, 259, 263 Cytotoxic chemotherapy, 219, 250 Cytotoxicity, 16, 43, 75, 99, 149, 203, 214, 219 D Dacarbazine, 162, 219 Dactinomycin, 133, 219 Daunorubicin, 98, 219, 221 De novo, 44, 219 Deamination, 219, 272 Decarboxylation, 209, 219, 232 Decitabine, 109, 219 Degenerative, 219, 232, 261 Deletion, 36, 207, 219 Dendrites, 219, 248 Dendritic, 30, 166, 219, 243 Dendritic cell, 30, 166, 219 Depolarization, 219, 263 Desensitization, 219, 235 Deuterium, 56, 219, 233 Dexamethasone, 87, 89, 98, 104, 111, 117, 120, 139, 219 Diabetes Mellitus, 74, 219, 228, 229, 231 Diagnostic procedure, 147, 175, 219 Diagnostic Services, 219, 268 Diarrhea, 10, 219 Diastole, 220 Diastolic, 108, 220, 234 Diathesis, 220, 230 Diethylcarbamazine, 220, 267 Diethylstilbestrol, 115, 220 Diffusion, 220, 236 Digestion, 203, 209, 210, 220, 238, 241, 266 Digestive system, 220, 246 Digestive tract, 220, 264, 265 Dihydrotestosterone, 220, 260

279

Dimethyl, 162, 220 Diphtheria, 34, 220 Diphtheria Toxin, 34, 220 Diploid, 220, 254 Direct, iii, 9, 16, 35, 151, 163, 177, 214, 220, 221, 260, 266, 267 Disease Progression, 5, 17, 220 Disease-Free Survival, 47, 50, 220 Dissociation, 202, 220, 238 Distal, 221, 239, 258, 261 Diuretic, 221, 226, 242, 264 Docetaxel, 24, 90, 91, 113, 128, 132, 138, 139, 142, 165, 221 Dominance, 44, 221 Dopamine, 204, 221, 248, 253 Dosage Forms, 151, 221 Dose-dependent, 221, 274 Dose-limiting, 28, 221 Double-blind, 114, 117, 118, 221 Drug Combinations, 14, 29, 221 Drug Design, 34, 178, 179, 221 Drug Interactions, 178, 221 Drug Resistance, 16, 26, 29, 53, 54, 221, 222 Drug Tolerance, 221, 222, 269 Drug Toxicity, 36, 222 Duodenum, 209, 222, 266 Dysphagia, 10, 222 E Edema, 6, 12, 13, 170, 222, 226, 247 Effector, 30, 42, 75, 165, 201, 215, 222 Effector cell, 30, 75, 222 Elastin, 215, 217, 222 Elective, 161, 222 Electrolyte, 217, 222, 239, 245, 264 Electrons, 206, 209, 222, 238, 239, 250, 258, 259 Embryo, 212, 222, 236 Embryogenesis, 222, 265 Emesis, 114, 117, 222 Emollient, 222, 229, 249 Enalapril, 48, 222 Encapsulated, 222, 241 Endemic, 222, 265 Endocrine System, 222, 247 Endogenous, 11, 161, 164, 166, 221, 223, 270 Endometrial, 88, 96, 223 Endometrium, 223 Endothelial cell, 41, 223, 238 Endothelium, 223, 248 Endothelium-derived, 223, 248 Endotoxin, 223, 271

End-stage renal, 214, 223, 243 Enterocolitis, 10, 223 Environmental Health, 83, 98, 184, 186, 223 Enzymatic, 56, 209, 211, 216, 223, 232 Eosinophilia, 104, 223 Eosinophilic, 10, 223 Eosinophils, 223, 230 Epidemic, 223, 265 Epidermis, 201, 208, 210, 223, 239, 251, 258 Epidermoid carcinoma, 223, 265 Epinephrine, 202, 209, 221, 223, 248, 249, 272 Epirubicin, 81, 82, 86, 90, 91, 94, 96, 107, 110, 117, 119, 120, 121, 124, 132, 137, 223 Epithelial, 36, 37, 84, 117, 202, 212, 224, 232, 238, 239, 240, 257 Epithelial Cells, 36, 37, 224, 232, 238, 240, 257 Epithelial ovarian cancer, 117, 224 Epithelium, 209, 213, 223, 224, 227 Erythrocytes, 204, 205, 210, 224, 231, 260, 262 Erythromycin, 79, 224 Erythropoietin, 161, 224 Escalation, 102, 224 Esophagus, 220, 224, 252, 266 Estrogen, 111, 155, 224, 262, 268 Estrogen receptor, 111, 224 Evaluable patients, 49, 67, 224 Excipient, 149, 150, 151, 152, 156, 224 Excitation, 224, 226, 248 Excrete, 206, 224, 239 Exogenous, 11, 164, 166, 223, 224 External-beam radiation, 224, 239, 259, 274 Extracellular, 205, 207, 217, 224, 225, 264 Extracellular Matrix, 205, 217, 224, 225 F Facial, 213, 225, 268 Facial Nerve, 225, 268 Family Planning, 185, 225 Fanconi anemia, 84, 225 Fat, 207, 209, 210, 217, 225, 241, 246, 264, 271 Fatigue, 225, 231 Fatty acids, 75, 164, 203, 225, 257 Fetus, 224, 225, 234, 272 Fibroblasts, 41, 217, 225, 238 Fibrosis, 7, 58, 113, 203, 225, 262 Filgrastim, 96, 225 Filler, 162, 225

280

Cyclophosphamide

Filtration, 57, 225, 239 Fixation, 225, 262 Flow Cytometry, 54, 75, 225, 235 Fludarabine, 5, 17, 59, 83, 94, 96, 97, 98, 105, 135, 137, 226 Fluorescence, 226 Fluorescent Dyes, 226 Foam Cells, 226, 274 Folate, 25, 226 Folic Acid, 226, 240 Forearm, 210, 226 Free Radicals, 206, 220, 226 Freeze Drying, 156, 226 Freeze-dried, 156, 226 Furosemide, 170, 226 G Gallbladder, 201, 220, 226 Gamma Rays, 226, 259 Ganglia, 201, 204, 227, 247, 267 Gas, 59, 204, 220, 227, 233, 243, 248, 266 Gastric, 98, 152, 221, 224, 227, 232 Gastric Mucosa, 152, 227 Gastrin, 227, 233 Gastrointestinal tract, 61, 227, 240, 263, 271 Gemcitabine, 17, 24, 75, 99, 139, 227 Gene Expression, 17, 34, 38, 58, 227 Gene Therapy, 30, 50, 62, 74, 98, 99, 101, 158, 227 General practitioner, 169, 227 Genetic Code, 227, 249 Genetics, 22, 26, 54, 61, 74, 82, 218, 221, 227 Genital, 214, 227, 272 Genitourinary, 44, 63, 67, 227, 272 Genotype, 18, 227, 253 Germ Cells, 227, 250, 264, 268 Gestational, 140, 227, 228 Gestational trophoblastic disease, 227, 228 Gestational trophoblastic neoplasia, 140, 227, 228 Gestational trophoblastic tumor, 227, 228 Ginseng, 15, 143, 228 Gland, 202, 214, 218, 228, 232, 241, 251, 253, 257, 262, 266, 269 Glioblastoma, 119, 228 Glioblastoma multiforme, 119, 228 Glioma, 31, 228 Glomerular, 4, 5, 57, 58, 99, 170, 228, 239, 242, 260 Glomerular Filtration Rate, 228, 239, 242 Glomeruli, 5, 14, 57, 58, 228, 243

Glomerulonephritis, 4, 5, 7, 8, 9, 10, 11, 13, 14, 58, 99, 114, 228, 234, 241 Glomerulosclerosis, 6, 9, 169, 228 Glomerulus, 169, 228, 247 Glossopharyngeal Nerve, 228, 268 Glucocorticoid, 11, 219, 228, 256 Glucose, 210, 219, 229, 231, 237, 261, 264 Glucose Intolerance, 219, 229 Glutamate, 229, 253 Glutamic Acid, 226, 229, 231, 248, 256 Glutamine, 137, 142, 229 Glycerol, 162, 229, 253 Glycine, 58, 150, 209, 229, 248, 263 Glycoprotein, 224, 229, 230, 240, 242, 271 Gonad, 229 Gonadal, 59, 229, 266 Gonadorelin, 229 Goserelin, 99, 116, 229 Governing Board, 229, 255 Gp120, 229, 251 Grade, 97, 101, 124, 134, 137, 228, 229 Graft, 9, 33, 59, 100, 165, 206, 229, 230, 235, 246 Graft Rejection, 229, 235 Grafting, 229, 235 Graft-versus-host disease, 33, 59, 206, 230, 246 Granulocyte, 33, 81, 87, 95, 98, 100, 101, 105, 108, 110, 215, 225, 230 Granulocyte Colony-Stimulating Factor, 33, 81, 95, 105, 110, 215, 225, 230 Granulocytopenia, 206, 230 Gravis, 101, 123, 174, 230 Growth factors, 136, 230 Guanine, 31, 60, 230 Guanylate Cyclase, 230, 248 H Haematemesis, 222, 230 Haematological, 161, 230 Haematology, 84, 95, 96, 97, 100, 102, 104, 109, 120, 122, 123, 137, 230 Haematuria, 230 Haemophilia, 95, 230 Hair follicles, 230, 274 Half-Life, 212, 230 Haploid, 230, 253, 254 Haptens, 202, 230 Headache, 230, 236, 271 Health Services, 230, 268 Heart failure, 116, 231 Hematologic malignancies, 23, 27, 60, 64, 71, 81, 133, 137, 231, 241

281

Hematopoiesis, 33, 52, 158, 231 Hematopoietic growth factors, 56, 61, 231 Hematopoietic Stem Cell Mobilization, 89, 231 Hematopoietic Stem Cell Transplantation, 86, 95, 231 Hematopoietic Stem Cells, 16, 44, 164, 231 Hematuria, 5, 7, 10, 11, 231, 243 Hemodialysis, 211, 231, 239 Hemoglobin, 11, 161, 205, 224, 231 Hemoglobin C, 205, 231 Hemoglobinopathies, 227, 231 Hemoglobinuria, 44, 231 Hemolysis, 120, 231 Hemolytic, 161, 231 Hemorrhage, 4, 116, 230, 231, 258 Hemosiderosis, 121, 232 Hepatic, 38, 203, 232 Hepatitis, 4, 5, 107, 232 Hepatocellular, 90, 101, 232 Hepatocellular carcinoma, 90, 101, 232 Hepatocytes, 36, 232 Hereditary, 217, 232 Heredity, 227, 232 Herpes, 29, 34, 41, 232 Herpes virus, 34, 232 Herpes Zoster, 232 Heterogeneity, 58, 70, 202, 232 Heterozygotes, 221, 232 Hidradenitis, 113, 232 Histamine, 205, 209, 232 Histiocytosis, 108, 166, 232 Histology, 109, 232 Homeostasis, 164, 232 Homodimer, 232, 270 Homologous, 218, 227, 232, 262, 267 Homozygotes, 221, 232 Hormonal, 15, 155, 208, 217, 233, 243 Hormonal therapy, 15, 233, 243 Hormone therapy, 202, 233 Hospital Administrators, 76, 233 Humoral, 8, 42, 229, 233 Humour, 233 Hybrid, 57, 233 Hybridization, 39, 233 Hydrogen, 201, 204, 209, 211, 219, 233, 241, 245, 248, 249, 250, 257 Hydrogen Peroxide, 233, 241 Hydrolysis, 214, 233, 253, 255, 257 Hydroxylysine, 215, 233 Hydroxyproline, 215, 233 Hydroxyurea, 128, 148, 159, 233

Hyperbaric, 136, 137, 233 Hyperbaric oxygen, 136, 137, 233 Hypercholesterolemia, 170, 233 Hyperglycemia, 139, 233 Hyperlipidemia, 7, 8, 233 Hyperlipoproteinemia, 234 Hypersensitivity, 11, 79, 158, 161, 203, 219, 234, 240, 261, 262 Hypertension, 5, 7, 211, 222, 230, 234 Hyperthermia, 57, 234 Hypertriglyceridemia, 170, 234 Hypnotic, 208, 234, 269 Hypoxia, 94, 205, 234 Hypoxic, 31, 234 I Iatrogenic, 5, 234 Idarubicin, 52, 138, 234 Idiopathic, 9, 121, 170, 232, 234 Ifosfamide, 28, 56, 58, 60, 73, 82, 88, 93, 104, 112, 125, 136, 139, 234, 244 Imidazole, 162, 232, 234 Immune Complex Diseases, 206, 234, 254 Immune response, 4, 14, 26, 35, 42, 78, 79, 158, 160, 166, 202, 206, 208, 217, 218, 229, 230, 234, 235, 262, 264, 266, 272, 273 Immune Sera, 234, 235 Immune Tolerance, 95, 234 Immunity, 26, 35, 42, 79, 203, 234, 235, 237, 270 Immunization, 159, 235, 262 Immunodeficiency, 36, 136, 235 Immunofluorescence, 10, 235 Immunogenic, 35, 235 Immunologic, 44, 50, 159, 166, 213, 234, 235, 259, 274 Immunology, 23, 45, 49, 61, 73, 74, 90, 93, 104, 105, 202, 226, 235 Immunophenotyping, 46, 235 Immunosuppressant, 201, 203, 226, 235, 244 Immunosuppression, 3, 4, 5, 7, 9, 79, 164, 170, 171, 235, 242, 250 Immunosuppressive, 5, 6, 7, 9, 11, 88, 99, 104, 170, 171, 228, 234, 235, 268 Immunosuppressive Agents, 5, 6, 9, 170, 171, 235 Immunosuppressive therapy, 7, 11, 88, 235 Immunotherapy, 22, 26, 27, 36, 74, 104, 105, 160, 166, 209, 219, 235 Immunotoxins, 235, 259 Impairment, 32, 159, 235

282

Cyclophosphamide

Implant radiation, 235, 238, 239, 259, 274 Implantation, 29, 216, 235 Impotence, 15, 235 In situ, 55, 236 In vitro, 15, 16, 26, 33, 50, 52, 57, 58, 71, 77, 78, 105, 125, 158, 227, 236, 268, 269 In vivo, 15, 27, 33, 35, 39, 41, 50, 57, 58, 77, 78, 105, 139, 163, 227, 236, 242, 268 Incision, 236, 238 Indolent, 96, 111, 114, 134, 154, 236, 241 Indolent lymphoma, 114, 236, 241 Indomethacin, 166, 236 Induction, 12, 30, 57, 58, 69, 75, 95, 105, 122, 139, 205, 217, 236 Infancy, 52, 236 Infarction, 209, 236, 254 Infiltrating cancer, 236, 238 Infiltration, 94, 228, 236 Inflammation, 4, 5, 8, 14, 203, 206, 207, 215, 218, 223, 225, 232, 236, 240, 243, 247, 254, 255, 266, 268, 272, 273, 274 Inflammatory bowel disease, 14, 236 Influenza, 78, 236 Informed Consent, 45, 51, 52, 236 Infusion, 13, 61, 100, 125, 154, 164, 236, 270 Ingestion, 236, 254 Inhalation, 207, 237, 254 Initiation, 20, 32, 164, 237, 270 Initiator, 237 Inner ear, 212, 237 Innervation, 42, 225, 237 Inoperable, 82, 237 Inorganic, 214, 237, 246 Inositol, 44, 237 Insertional, 16, 237 Insight, 37, 44, 237 Insulator, 237, 246 Intensive Care, 3, 237 Interferon, 5, 24, 136, 237, 242 Interferon-alpha, 237 Interleukin-1, 33, 105, 237 Interleukin-12, 33, 237 Interleukin-2, 158, 237 Interleukin-3, 79, 215, 238 Interleukin-8, 33, 238 Interleukins, 235, 238 Internal Medicine, 4, 12, 14, 18, 30, 64, 65, 66, 71, 75, 76, 89, 92, 118, 231, 238, 243, 247, 261 Internal radiation, 238, 239, 259, 274 Interphase, 70, 238

Interstitial, 10, 110, 113, 118, 210, 238, 239, 247, 260, 274 Intestinal, 31, 137, 152, 223, 238 Intestinal Mucosa, 31, 223, 238 Intestine, 209, 210, 215, 238, 240 Intoxication, 124, 238, 274 Intracellular, 211, 236, 238, 243, 248, 263 Intracellular Membranes, 238, 243 Intrahepatic, 38, 116, 238 Intramuscular, 230, 238, 251 Intraperitoneal, 107, 132, 238 Intrinsic, 44, 202, 209, 238 Invasive, 22, 40, 41, 234, 236, 238 Invasive cancer, 40, 236, 238 Ionization, 119, 238 Ionizing, 37, 39, 203, 238, 258, 259 Ions, 209, 220, 222, 233, 238 Irinotecan, 24, 34, 162, 239 Irradiation, 37, 43, 59, 80, 81, 84, 86, 109, 115, 118, 122, 133, 164, 239, 274 Ischemia, 208, 239 Isozymes, 32, 239 K Kb, 184, 239 Keratinocytes, 238, 239 Keratoacanthoma, 99, 239 Kidney Cortex, 58, 239 Kidney Disease, 5, 13, 57, 112, 123, 169, 184, 239 Kidney Failure, 4, 223, 228, 239, 242 Kidney Failure, Acute, 239 Kidney Failure, Chronic, 239 Kidney Glomerulus, 239 Kinetic, 56, 107, 238, 240 L Labile, 215, 240 Laminin, 209, 240 Large Intestine, 215, 220, 238, 240, 260, 264 Latency, 83, 240 Lectin, 240, 243 Leflunomide, 170, 240 Lesion, 169, 239, 240, 241 Lethal, 30, 79, 164, 165, 220, 240 Leucocyte, 100, 240, 242 Leucovorin, 24, 121, 240 Leukaemia, 88, 97, 100, 240 Leukapheresis, 206, 231, 240 Leukopenia, 9, 240, 274 Leukotrienes, 164, 207, 240 Levamisole, 6, 12, 240 Levo, 240, 243 Ligament, 241, 257

283

Ligands, 35, 164, 241 Linkages, 231, 241, 274 Lipid, 35, 134, 164, 207, 226, 229, 241, 246, 271, 274 Lipid Peroxidation, 134, 241 Liposomal, 98, 132, 241 Localization, 159, 241 Localized, 44, 109, 204, 220, 222, 225, 236, 240, 241, 253 Lomustine, 83, 241 Longitudinal study, 28, 241 Low-grade lymphomas, 135, 241 Lubricants, 162, 241 Lupus, 4, 5, 7, 8, 12, 13, 35, 58, 75, 87, 89, 93, 94, 101, 106, 110, 113, 114, 120, 141, 174, 190, 241, 268 Lupus Nephritis, 5, 7, 8, 12, 13, 58, 75, 87, 89, 93, 94, 101, 174, 241 Lymph, 75, 92, 132, 159, 166, 213, 223, 233, 241, 242, 248 Lymph node, 75, 92, 132, 159, 166, 213, 241, 242, 248 Lymphatic, 223, 236, 241, 244, 264, 265, 269 Lymphatic system, 241, 264, 265, 269 Lymphoblastic, 88, 242 Lymphoblasts, 45, 56, 201, 242 Lymphocyte Depletion, 235, 242 Lymphocytes, 35, 72, 75, 206, 219, 235, 237, 238, 240, 241, 242, 247, 265, 268, 269, 274 Lymphocytic, 12, 17, 83, 97, 98, 103, 105, 110, 120, 241, 242 Lymphoid, 5, 45, 46, 53, 73, 84, 96, 205, 240, 242 Lymphoproliferative, 50, 71, 80, 94, 214, 242 Lytic, 242, 273 M Macrophage, 98, 100, 215, 237, 242 Macrophage Colony-Stimulating Factor, 100, 215, 242 Maintenance therapy, 48, 242 Malignancy, 47, 161, 242 Malignant mesothelioma, 242, 244 Malignant tumor, 211, 213, 242, 246, 250, 261 Malnutrition, 203, 208, 211, 242 Mammary, 155, 160, 242, 268 Mammography, 165, 242 Mannitol, 149, 150, 151, 152, 153, 156, 162, 242

Maximum Tolerated Dose, 52, 222, 243 Mechlorethamine, 243, 256 Mediator, 237, 243, 254, 263 Medical oncologist, 18, 62, 243 Medical Oncology, 27, 38, 63, 66, 91, 92, 94, 124, 128, 243, 258 MEDLINE, 185, 243 Medulloblastoma, 31, 243 Melanin, 243, 253, 272 Melanocytes, 243 Melanoma, 27, 68, 158, 160, 243 Melphalan, 31, 52, 87, 138, 162, 243 Membrane, 59, 207, 212, 216, 219, 229, 240, 243, 246, 247, 250, 253, 254, 255, 263, 270 Membrane Proteins, 59, 243 Membranoproliferative, 5, 9, 11, 243 Meninges, 212, 213, 243, 266 Menopause, 243, 252, 255, 256 Menstruation, 204, 243 Mental, iv, 15, 184, 186, 220, 225, 243, 244, 258, 262, 272 Mental Health, iv, 15, 184, 186, 244, 258 Mental Processes, 220, 244, 258 Mentors, 26, 244 Mercaptopurine, 14, 244 Mercury, 226, 244 Mesenchymal, 30, 242, 244 Mesna, 124, 125, 179, 244 Mesothelioma, 61, 242, 244 Metabolite, 28, 38, 78, 220, 240, 244, 256 Metaphase, 70, 244 Metastasis, 166, 244 Methylprednisolone, 7, 11, 28, 87, 94, 98, 104, 111, 244 Microbe, 244, 270 Microorganism, 215, 244, 251, 274 Microscopy, 59, 209, 244 Microtubules, 244, 250 Migration, 33, 244 Millimeter, 134, 244 Mineralization, 28, 245 Mineralocorticoids, 202, 217, 245 Minority Groups, 29, 245 Mitochondria, 39, 245 Mitochondrial Swelling, 245, 247 Mitosis, 207, 245 Mitotic, 221, 224, 245, 273 Mitotic inhibitors, 221, 245 Mitoxantrone, 97, 105, 111, 117, 122, 125, 245 Mobilization, 33, 87, 98, 105, 107, 111, 120, 231, 245

284

Cyclophosphamide

Modeling, 34, 98, 107, 221, 245 Modification, 74, 245, 258, 274 Monitor, 21, 25, 218, 245, 249 Monoclonal, 10, 24, 86, 170, 235, 239, 245, 259, 261, 271, 274 Monoclonal antibodies, 10, 170, 235, 245, 261, 271 Monocyte, 166, 242, 245 Mononuclear, 79, 242, 245, 271 Monotherapy, 109, 246 Morphology, 230, 231, 246 Motility, 236, 246, 263 Motion Sickness, 246, 247 Mucosa, 227, 241, 246, 266 Mucositis, 24, 246 Mucus, 246, 272 Multicenter study, 96, 133, 246 Multidrug resistance, 48, 77, 246 Multiple Myeloma, 68, 80, 87, 89, 95, 96, 102, 104, 105, 110, 120, 123, 133, 138, 246 Multiple sclerosis, 74, 88, 92, 102, 104, 119, 121, 246 Multivariate Analysis, 11, 246 Mutagenic, 60, 72, 203, 246 Mutagenicity, 139, 246 Myalgia, 236, 246 Myasthenia, 101, 123, 174, 246 Mycophenolate mofetil, 5, 7, 8, 10, 13, 59, 246 Myelin, 246 Myelodysplastic Syndromes, 44, 246 Myelofibrosis, 161, 246 Myelogenous, 246 Myeloid Cells, 34, 246 Myeloma, 64, 69, 74, 246 Myeloproliferative Disorders, 50, 209, 246 Myelotoxic, 158, 246 Myocarditis, 96, 106, 220, 247 Myocardium, 247 Myositis, 190, 247 N Nasal Mucosa, 236, 247 Natural killer cells, 237, 247 Nausea, 10, 72, 114, 206, 221, 247, 250, 272 NCI, 1, 19, 25, 27, 40, 63, 74, 76, 183, 214, 247 Necrosis, 81, 206, 228, 236, 247 Neoplasia, 31, 54, 247 Neoplasm, 34, 154, 247, 261, 272 Nephritis, 5, 7, 8, 12, 13, 58, 247 Nephrology, 4, 5, 7, 9, 11, 12, 13, 101, 106, 107, 116, 121, 169, 247

Nephron, 228, 247 Nephropathy, 5, 6, 7, 9, 92, 112, 239, 247 Nephrosis, 57, 247 Nephrotic, 6, 7, 9, 10, 12, 13, 57, 106, 107, 112, 116, 121, 123, 247 Nephrotic Syndrome, 6, 7, 9, 10, 12, 13, 106, 107, 116, 121, 123, 247 Nervous System, 42, 204, 208, 213, 243, 247, 248, 266, 267, 272 Neural, 42, 233, 247 Neuroblastoma, 18, 46, 48, 50, 52, 56, 247 Neuroendocrine, 61, 164, 247 Neuroleptic, 247, 250 Neurologic, 131, 228, 248 Neurology, 55, 73, 101, 104, 248 Neurons, 219, 227, 248, 267 Neurosurgery, 54, 55, 66, 73, 101, 248 Neurotoxic, 28, 248 Neurotoxicity, 28, 60, 248 Neurotransmitter, 201, 207, 211, 221, 229, 232, 248, 249, 263, 266, 267, 272 Neutrons, 203, 239, 248, 258, 259 Neutropenia, 71, 100, 248 Neutrophil, 112, 248 Nicotine, 37, 248 Nitric Oxide, 39, 136, 248 Nitrocamptothecin, 162, 248 Nitrogen, 39, 149, 152, 203, 204, 205, 225, 229, 239, 243, 248, 271 Node-positive, 81, 92, 94, 99, 111, 116, 137, 248 Non-small cell lung cancer, 75, 248 Norepinephrine, 42, 202, 221, 248, 249 Nosocomial, 10, 249 Nuclear, 59, 208, 211, 222, 227, 228, 247, 249 Nuclei, 203, 222, 227, 245, 248, 249, 257 Nucleic acid, 14, 157, 158, 164, 201, 219, 227, 233, 248, 249, 261, 274 Nucleic Acid Hybridization, 233, 249 Nucleus, 207, 208, 209, 214, 218, 219, 223, 226, 242, 245, 248, 249, 256, 257, 261, 266 Nurse Practitioners, 50, 249 Nursing Care, 249, 251 O Ocular, 114, 116, 249 Ointments, 221, 249 Oliguria, 239, 242, 249 Oncogene, 249, 265 Oncogenic, 70, 249, 257, 258 Oncologist, 64, 68, 82, 243, 249 Oncology nurse, 22, 249

285

Oncolysis, 249 Oncolytic, 148, 249 Ondansetron, 114, 250 Oocytes, 174, 250 Opportunistic Infections, 42, 250 Organ Culture, 250, 269 Organ Transplantation, 80, 171, 250 Osmolarity, 243, 250 Osmosis, 13, 250 Osmotic, 13, 122, 203, 245, 250, 263 Osteogenic sarcoma, 250 Osteosarcoma, 27, 49, 250 Outpatient, 25, 250 Ovaries, 224, 250, 263 Ovary, 27, 138, 229, 250, 266 Overall survival, 70, 155, 250 Oxidation, 115, 201, 206, 218, 241, 250 Oxidative metabolism, 59, 202, 240, 250 P P53 gene, 45, 250 Palate, 228, 251, 268 Palliative, 15, 39, 63, 251, 269 Pancreas, 201, 209, 220, 251, 271 Pancreatic, 224, 251 Pancreatic cancer, 224, 251 Papilla, 251 Papillary, 95, 251 Parenteral, 148, 149, 151, 152, 251 Partial remission, 8, 251, 260 Partial response, 251 Particle, 251, 270 Pathogen, 11, 251 Pathologic, 58, 59, 135, 169, 207, 209, 234, 251, 273 Pathologic Processes, 207, 251 Pathophysiology, 17, 251 Patient Care Management, 5, 251 Patient Education, 14, 171, 194, 196, 199, 251 Pelvic, 251, 257 Pemphigus, 94, 114, 201, 251 Peptide, 75, 251, 255, 257 Peptide T, 75, 251 Perception, 216, 251, 262 Perfusion, 61, 234, 251 Pericardium, 252, 268 Perimenopausal, 116, 252 Perioperative, 21, 252 Peripheral blood, 33, 52, 75, 87, 89, 95, 100, 105, 109, 111, 123, 134, 158, 206, 231, 237, 252

Peripheral stem cell transplantation, 252, 270 Peripheral stem cells, 230, 252 Peritoneal, 95, 138, 238, 252 Peritoneal Cavity, 238, 252 Peritoneum, 252, 261 Phagocyte, 242, 252 Pharmaceutical Preparations, 153, 155, 252, 256 Pharmaceutical Solutions, 221, 252 Pharmacists, 18, 22, 252 Pharmacodynamics, 22, 24, 54, 252 Pharmacokinetic, 56, 113, 170, 252 Pharmacologic, 29, 50, 53, 205, 208, 230, 252, 270 Pharynx, 236, 252, 268 Phenobarbital, 105, 252 Phenotype, 33, 58, 82, 88, 253 Phenyl, 162, 253 Phenylalanine, 162, 253, 272 Pheresis, 120, 253 Phospholipases, 253, 263 Phospholipids, 225, 237, 253 Phosphorus, 211, 253 Phosphorylated, 71, 253 Phosphorylation, 57, 253 Physiologic, 202, 230, 243, 253, 259 Physiology, 10, 15, 231, 247, 253 Pigment, 209, 243, 253 Pigmentation, 115, 253 Pilot Projects, 53, 253 Pilot study, 32, 80, 113, 131, 132, 253 Pituitary Gland, 217, 229, 253 Plague, 253, 271 Plants, 203, 207, 228, 229, 240, 246, 249, 253, 261, 270 Plasma cells, 205, 246, 254 Plasma Exchange, 4, 254 Plasma protein, 203, 254, 263 Plasmapheresis, 5, 8, 206, 254 Platelet Activation, 254, 263 Platelet Aggregation, 205, 248, 254 Platelet Factor 4, 238, 254 Platelets, 209, 225, 248, 253, 254, 263, 269 Pleura, 61, 254 Ploidy, 55, 254 Pneumonia, 113, 217, 254 Pneumonitis, 78, 110, 254 Podophyllotoxin, 224, 254 Poisoning, 87, 222, 238, 244, 247, 254 Polyarteritis Nodosa, 4, 234, 254 Polyarthritis, 28, 255

286

Cyclophosphamide

Polyethylene, 149, 162, 255, 267 Polyethylene Glycols, 255, 267 Polymers, 29, 255, 257 Polymorphic, 18, 83, 164, 255 Polymorphism, 163, 255 Polyneuritis, 220, 255 Polypeptide, 204, 215, 233, 255 Polyposis, 215, 255 Polysaccharide, 206, 255, 257 Postmenopausal, 94, 111, 255 Postnatal, 255, 265 Postoperative, 113, 255 Postsynaptic, 255, 263, 267 Potentiates, 42, 237, 255 Potentiation, 154, 255, 263 Practicability, 255, 271 Practice Guidelines, 186, 255 Precancerous, 213, 256 Preclinical, 15, 26, 256 Precursor, 156, 205, 207, 221, 222, 223, 230, 249, 253, 256, 270, 271, 272 Prednisolone, 4, 8, 13, 93, 94, 112, 113, 118, 120, 138, 244, 256 Premenopausal, 99, 116, 256 Preoperative, 71, 113, 139, 256 Primary tumor, 154, 256 Primitive neuroectodermal tumors, 243, 256 Procarbazine, 83, 131, 139, 256 Prodrug, 29, 31, 121, 163, 256 Progesterone, 256, 266 Prognostic factor, 84, 118, 256 Progression, 11, 35, 42, 44, 75, 161, 164, 205, 256, 271 Progressive, 4, 5, 7, 8, 13, 80, 88, 118, 121, 212, 214, 221, 222, 224, 239, 247, 254, 256, 260, 271 Projection, 249, 256 Proline, 215, 233, 256 Promoter, 18, 256 Prone, 32, 134, 256 Prophase, 250, 256, 267 Prophylaxis, 155, 256, 272 Propylene Glycol, 149, 256 Prospective study, 81, 119, 241, 256 Prostaglandins, 164, 207, 236, 257 Prostaglandins A, 236, 257 Prostate, 22, 23, 44, 61, 62, 69, 77, 111, 115, 154, 209, 229, 257, 271 Prostate-Specific Antigen, 154, 257 Protease, 215, 257 Protective Agents, 211, 257

Protein C, 203, 204, 257, 272 Protein S, 14, 210, 220, 224, 227, 257, 269 Proteinuria, 6, 7, 8, 9, 10, 12, 92, 170, 228, 243, 246, 247, 257 Proteoglycans, 209, 257 Proteolytic, 216, 257 Protons, 203, 233, 238, 257, 258 Proto-Oncogene Proteins, 250, 257 Proto-Oncogene Proteins c-mos, 250, 257 Proximal, 36, 59, 221, 239, 258 Psychic, 243, 258, 262 Psychoactive, 258, 274 Psychology, 55, 220, 258 Public Health, 23, 43, 64, 186, 258 Public Policy, 185, 258 Publishing, 10, 11, 14, 77, 258 Pulmonary, 4, 12, 64, 66, 94, 121, 139, 210, 223, 239, 240, 258, 273 Pulmonary Artery, 210, 258, 273 Pulmonary Edema, 239, 258 Purifying, 158, 258 Purpura, 90, 118, 120, 258 Q Quality of Life, 14, 19, 22, 32, 43, 61, 66, 72, 74, 258, 267 Quiescent, 42, 258 R Race, 13, 24, 68, 243, 244, 258 Racemic, 243, 258 Radiation Chimera, 33, 258 Radiation oncologist, 52, 62, 249, 258 Radiation Oncology, 22, 27, 53, 61, 63, 64, 66, 76, 258 Radiation therapy, 20, 34, 45, 55, 86, 171, 202, 224, 233, 238, 239, 259, 261, 269, 270, 274 Radioactive, 230, 233, 235, 238, 239, 245, 249, 259, 274 Radioimmunotherapy, 43, 215, 259 Radiolabeled, 43, 239, 259, 274 Radiology, 23, 55, 66, 96, 258, 259 Radiotherapy, 46, 48, 81, 83, 84, 103, 154, 210, 239, 259, 265, 274 Randomized, 6, 22, 28, 32, 38, 48, 54, 70, 72, 73, 85, 88, 90, 91, 92, 94, 96, 108, 117, 118, 132, 222, 259 Randomized clinical trial, 54, 72, 259 Randomized Controlled Trials, 6, 259 Reactivation, 10, 259 Reactive Oxygen Species, 39, 259 Receptor, 33, 44, 70, 108, 206, 214, 221, 229, 242, 250, 251, 253, 259, 263, 268

287

Recombinant, 101, 260, 273 Recombination, 36, 227, 260 Rectal, 260, 267 Rectum, 215, 220, 227, 236, 240, 257, 260 Recurrence, 70, 160, 260 Red blood cells, 59, 161, 224, 225, 231, 260, 261 Reductase, 42, 98, 244, 260 Refer, 1, 211, 215, 225, 232, 241, 247, 248, 249, 259, 260, 270 Refraction, 260, 265 Refractory, 52, 82, 86, 87, 92, 97, 98, 99, 101, 103, 104, 115, 119, 120, 123, 136, 137, 174, 260 Regional chemotherapy, 61, 260 Registries, 44, 260 Relapse, 5, 6, 9, 11, 13, 14, 45, 52, 53, 73, 122, 260 Remission, 10, 11, 12, 14, 28, 92, 134, 139, 170, 201, 242, 260 Renal failure, 4, 5, 7, 11, 161, 260 Renal pelvis, 260, 270 Renin, 205, 260 Research Personnel, 50, 260 Residual disease, 56, 260 Respiration, 245, 260 Response rate, 17, 119, 136, 260 Retinoid, 22, 260 Retraction, 57, 261 Retroperitoneal, 61, 202, 261 Retrospective, 4, 10, 12, 261 Retroviral vector, 157, 158, 227, 261 Retrovirus, 42, 261 Rhabdomyosarcoma, 53, 73, 124, 135, 173, 261 Rheumatoid, 28, 93, 141, 161, 261 Rheumatoid arthritis, 28, 93, 161, 261 Rheumatology, 28, 93, 105, 106, 110, 112, 114, 116, 118, 120, 125, 261 Ribavirin, 5, 261 Ribonucleoside Diphosphate Reductase, 233, 261 Risk factor, 11, 13, 18, 133, 257, 261 Rituximab, 80, 98, 111, 118, 120, 134, 261 S S Phase, 74, 261 Saline, 254, 261 Salivary, 213, 218, 220, 225, 251, 261 Salivary glands, 213, 218, 220, 225, 261 Salvage Therapy, 102, 215, 261 Saponins, 261, 266

Sarcoma, 48, 49, 61, 73, 112, 125, 256, 261, 264 Schizoid, 262, 274 Schizophrenia, 262, 274 Schizotypal Personality Disorder, 262, 274 Sclerosis, 9, 93, 95, 98, 110, 119, 120, 141, 170, 207, 246, 262 Screening, 33, 36, 61, 154, 165, 214, 262 Sebaceous, 262, 274 Secondary tumor, 244, 262 Secretion, 71, 213, 217, 229, 232, 233, 238, 245, 246, 262, 270 Sedimentation, 262, 271 Segmental, 6, 9, 169, 228, 262 Segmentation, 262 Segregation, 260, 262 Seizures, 7, 228, 262 Selective estrogen receptor modulator, 262, 268 Semen, 257, 262 Semisynthetic, 211, 224, 235, 262 Sensitization, 35, 262 Sepsis, 81, 262 Septic, 3, 207, 262 Sequence Homology, 251, 263 Sequencing, 26, 86, 263 Serine, 229, 257, 258, 263 Serotonin, 209, 248, 250, 263, 271 Serous, 95, 223, 254, 263 Serum, 9, 46, 108, 119, 145, 161, 203, 205, 215, 234, 239, 242, 245, 263, 271 Serum Albumin, 9, 263 Sex Characteristics, 202, 205, 263, 268 Shock, 57, 90, 263, 271 Side effect, 6, 8, 9, 12, 13, 15, 30, 154, 177, 179, 202, 209, 221, 263, 267, 270 Signal Transduction, 37, 70, 237, 263 Signs and Symptoms, 254, 260, 263 Skeletal, 205, 246, 263 Skeleton, 201, 263 Skin test, 166, 264 Small cell lung cancer, 75, 264 Small intestine, 222, 233, 238, 264 Smallpox, 264, 272 Smooth muscle, 203, 205, 208, 211, 217, 226, 232, 264, 266 Social Environment, 258, 264 Social Security, 259, 264 Socioeconomic Factors, 13, 264 Sodium, 13, 149, 150, 151, 153, 156, 245, 264, 267 Sodium Bicarbonate, 150, 151, 153, 264

288

Cyclophosphamide

Soft tissue, 73, 210, 263, 264 Soft tissue sarcoma, 73, 264 Solid tumor, 23, 45, 51, 52, 54, 58, 64, 73, 74, 80, 97, 102, 115, 132, 162, 210, 221, 241, 264 Solvent, 157, 229, 250, 252, 256, 264 Soma, 264 Somatic, 17, 44, 202, 222, 228, 233, 245, 264, 268 Somatic mutations, 17, 264 Sorbitol, 242, 264 Specialist, 191, 264 Specificity, 202, 265 Spectrum, 9, 31, 162, 212, 265 Sperm, 89, 205, 214, 264, 265, 271 Spinal cord, 122, 207, 213, 243, 247, 248, 265, 266, 267, 273 Spleen, 143, 204, 218, 241, 265 Sporadic, 166, 265 Squamous, 84, 223, 239, 248, 265 Squamous cell carcinoma, 84, 223, 239, 248, 265 Squamous cells, 265 Staging, 25, 70, 265 Standardize, 21, 265 Statistically significant, 49, 265 Stem Cell Factor, 33, 214, 265 Stem Cells, 16, 101, 109, 111, 158, 224, 231, 252, 265 Stereotactic, 45, 48, 265 Sterile, 149, 207, 265 Sterility, 266 Steroid, 5, 6, 9, 10, 12, 99, 106, 107, 120, 121, 123, 170, 209, 218, 261, 266 Steroid therapy, 170, 266 Stimulants, 228, 266 Stimulus, 208, 222, 224, 237, 238, 240, 266, 269 Stomach, 152, 159, 201, 220, 224, 227, 233, 247, 252, 264, 265, 266 Stomatology, 27, 266 Strand, 16, 149, 266 Stress, 14, 38, 42, 51, 57, 170, 208, 218, 247, 261, 266 Stromal, 33, 266 Stromal Cells, 34, 266 Subacute, 236, 266 Subclavian, 266, 273 Subclavian Artery, 266, 273 Subclinical, 236, 262, 266 Subcutaneous, 42, 222, 230, 251, 266 Subspecies, 264, 266, 272

Substance P, 224, 244, 262, 266 Substrate, 163, 266, 272 Suction, 225, 266 Superoxide, 39, 267 Supplementation, 28, 59, 137, 267 Supportive care, 53, 267 Suppository, 114, 255, 267 Suppression, 5, 61, 134, 166, 171, 217, 267, 274 Suramin, 24, 267 Survival Rate, 11, 43, 160, 250, 267 Sweat, 232, 267 Sympathetic Nervous System, 42, 208, 248, 267 Sympathomimetic, 204, 221, 223, 249, 267, 272 Symphysis, 257, 267 Synapse, 202, 267, 271 Synaptic, 248, 263, 267 Synaptic Transmission, 248, 267 Synergistic, 15, 19, 26, 42, 61, 105, 139, 166, 267 Systemic lupus erythematosus, 5, 7, 8, 12, 13, 35, 74, 103, 105, 108, 122, 234, 241, 268 Systemic therapy, 154, 268 Systolic, 234, 268 T Tacrolimus, 9, 59, 123, 268 Talc, 162, 268 Tamoxifen, 15, 24, 85, 93, 94, 97, 262, 268 Taste Buds, 152, 268 Tegafur, 163, 268 Telecommunications, 268 Telemedicine, 66, 268 Telomerase, 36, 268 Telomere, 230, 268 Temozolomide, 119, 268 Teratogenic, 203, 268 Terminator, 268, 274 Testicular, 78, 155, 268 Testis, 214, 268 Testosterone, 155, 260, 268 Tetracycline, 42, 268 Thalidomide, 70, 104, 120, 269 Therapeutics, 22, 24, 50, 54, 60, 63, 66, 94, 135, 156, 178, 269 Thermal, 150, 151, 153, 207, 220, 248, 269 Thiotepa, 82, 87, 95, 103, 117, 119, 134, 269 Thoracic, 21, 86, 242, 254, 266, 269 Threonine, 251, 258, 263, 269 Threshold, 234, 269

289

Thrombocytopenia, 206, 269 Thrombosis, 209, 257, 269 Thymoma, 86, 269 Thymus, 143, 235, 241, 242, 269 Thyroid, 269, 272 Thyroxine, 203, 253, 269 Tirapazamine, 115, 269 Tissue Culture, 29, 78, 269 Tolerance, 35, 59, 164, 202, 229, 269 Tonicity, 156, 231, 269 Topical, 233, 264, 269 Topoisomerase inhibitors, 204, 239, 248, 269 Topotecan, 115, 135, 162, 173, 269 Total-body irradiation, 85, 270 Toxicology, 37, 39, 83, 87, 98, 112, 128, 133, 186, 270 Toxin, 44, 220, 223, 235, 269, 270 Transcriptase, 261, 268, 270 Transcription Factors, 38, 270 Transduction, 34, 158, 263, 270 Transfection, 210, 227, 270 Transfer Factor, 235, 270 Transforming Growth Factor beta, 170, 270 Transfusion, 87, 107, 270 Transgenes, 39, 270 Transitional cell carcinoma, 89, 270 Translating, 26, 270 Translation, 224, 270 Translational, 20, 22, 26, 51, 63, 72, 74, 270 Translocation, 18, 224, 271 Transmitter, 201, 207, 221, 243, 249, 271, 272 Trastuzumab, 86, 271 Trauma, 230, 247, 271 Treatment Outcome, 70, 166, 271 Triethylenephosphoramide, 119, 271 Triglyceride, 234, 271 Trypanosomiasis, 267, 271 Tryptophan, 78, 215, 263, 271 Tuberculosis, 241, 271 Tubulin, 46, 244, 271 Tularemia, 79, 271 Tumor marker, 22, 209, 271 Tumor model, 36, 42, 160, 271 Tumor Necrosis Factor, 30, 39, 269, 271 Tumor suppressor gene, 250, 271 Tumour, 81, 249, 271, 274 Tyramine, 209, 272 Tyrosine, 70, 221, 272

U Ulcerative colitis, 118, 236, 272 Unresectable, 86, 272 Uracil, 163, 272 Urea, 162, 239, 267, 272 Uremia, 239, 260, 272 Urethra, 257, 272 Urinary, 86, 108, 122, 212, 218, 227, 249, 272 Urinary tract, 212, 272 Urodynamic, 10, 272 Urogenital, 227, 272 Urologist, 44, 272 Uterus, 213, 223, 227, 228, 243, 250, 256, 272 V Vaccination, 26, 90, 160, 272 Vaccine, 26, 79, 158, 160, 166, 202, 211, 257, 272 Vaccinia, 78, 272 Vaccinia Virus, 78, 272 Vagina, 213, 220, 243, 272, 273 Vaginal, 267, 273 Variola, 272, 273 Vascular, 3, 34, 98, 111, 203, 211, 223, 236, 248, 273 Vasculitis, 5, 11, 14, 111, 113, 190, 254, 273 Vasodilation, 204, 273 Vasodilators, 248, 273 Vector, 29, 34, 42, 157, 158, 237, 270, 272, 273 Vein, 238, 249, 266, 273 Venous, 209, 257, 273 Ventricle, 258, 268, 273 Ventricular, 108, 273 Vertebrae, 265, 273 Vertebral, 122, 273 Vertebral Artery, 122, 273 Veterinary Medicine, 185, 273 Vial, 156, 157, 273 Vinblastine, 110, 271, 273 Vinca Alkaloids, 273 Vinorelbine, 132, 273 Viraemia, 107, 273 Viral, 157, 158, 236, 249, 261, 270, 273, 274 Virulence, 208, 270, 273 Virulent, 78, 273 Virus, 5, 34, 36, 41, 78, 79, 94, 110, 136, 218, 229, 237, 261, 264, 270, 272, 273 Viscera, 264, 273 Visceral, 12, 208, 228, 252, 274 Vitamin A, 129, 237, 260, 274

290

Cyclophosphamide

Vitro, 15, 17, 29, 34, 50, 57, 59, 158, 274 Vivo, 15, 57, 242, 274 Vulgaris, 94, 114, 201, 274 W White blood cell, 12, 201, 205, 214, 225, 230, 240, 241, 242, 245, 246, 247, 248, 253, 254, 274 Withdrawal, 170, 274

X Xanthoma, 121, 274 Xenograft, 27, 205, 271, 274 X-ray, 226, 239, 249, 259, 265, 274 X-ray therapy, 239, 274 Y Yeasts, 253, 274 Z Zidovudine, 161, 274

291

292

Cyclophosphamide