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

MALIGNANT MELANOMA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

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., 1960Malignant Melanoma: 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: 0-497-00701-0 1. Malignant Melanoma-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 malignant melanoma. 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 MALIGNANT MELANOMA ........................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Malignant Melanoma ................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 61 CHAPTER 2. NUTRITION AND MALIGNANT MELANOMA ............................................................ 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Malignant Melanoma ................................................................ 109 Federal Resources on Nutrition ................................................................................................. 113 Additional Web Resources ......................................................................................................... 114 CHAPTER 3. ALTERNATIVE MEDICINE AND MALIGNANT MELANOMA...................................... 115 Overview.................................................................................................................................... 115 National Center for Complementary and Alternative Medicine................................................ 115 Additional Web Resources ......................................................................................................... 121 General References ..................................................................................................................... 123 CHAPTER 4. DISSERTATIONS ON MALIGNANT MELANOMA........................................................ 125 Overview.................................................................................................................................... 125 Dissertations on Malignant Melanoma ..................................................................................... 125 Keeping Current ........................................................................................................................ 125 CHAPTER 5. PATENTS ON MALIGNANT MELANOMA .................................................................. 127 Overview.................................................................................................................................... 127 Patents on Malignant Melanoma .............................................................................................. 127 Patent Applications on Malignant Melanoma .......................................................................... 132 Keeping Current ........................................................................................................................ 139 CHAPTER 6. BOOKS ON MALIGNANT MELANOMA ...................................................................... 141 Overview.................................................................................................................................... 141 Book Summaries: Federal Agencies............................................................................................ 141 Book Summaries: Online Booksellers......................................................................................... 142 Chapters on Malignant Melanoma ............................................................................................ 143 CHAPTER 7. PERIODICALS AND NEWS ON MALIGNANT MELANOMA ........................................ 147 Overview.................................................................................................................................... 147 News Services and Press Releases.............................................................................................. 147 Academic Periodicals covering Malignant Melanoma............................................................... 149 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 151 Overview.................................................................................................................................... 151 U.S. Pharmacopeia..................................................................................................................... 151 Commercial Databases ............................................................................................................... 152 Researching Orphan Drugs ....................................................................................................... 153 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 157 Overview.................................................................................................................................... 157 NIH Guidelines.......................................................................................................................... 157 NIH Databases........................................................................................................................... 159 Other Commercial Databases..................................................................................................... 161 APPENDIX B. PATIENT RESOURCES ............................................................................................... 163 Overview.................................................................................................................................... 163 Patient Guideline Sources.......................................................................................................... 163 Finding Associations.................................................................................................................. 165 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 167 Overview.................................................................................................................................... 167

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Preparation................................................................................................................................. 167 Finding a Local Medical Library................................................................................................ 167 Medical Libraries in the U.S. and Canada ................................................................................. 167 ONLINE GLOSSARIES................................................................................................................ 173 Online Dictionary Directories ................................................................................................... 175 MALIGNANT MELANOMA DICTIONARY .......................................................................... 177 INDEX .............................................................................................................................................. 247

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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 malignant melanoma 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 malignant melanoma, 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 malignant melanoma, 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 malignant melanoma. 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 malignant melanoma, 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 malignant melanoma. 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 MALIGNANT MELANOMA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on malignant melanoma.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and malignant melanoma, 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 “malignant melanoma” (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: •

Amelanotic Melanoma of the Palate: Report of Case Source: Journal of Oral and Maxillofacial Surgery. 59(5): 580-583. May 2001. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Website: www.harcourthealth.com. Summary: Malignant melanoma arises primarily in the skin and represents the leading cause of death from cutaneous malignancy in the United States. Fewer than 1 percent of all reported primary melanomas arise in the oral cavity. The cutaneous form of this lesion normally is highly visible, with irregular borders and dark pigmentation. Rarely, melanoma may present without clinically evident pigmentation (coloration). Termed amelanotic melanoma, these lesions tend to have a worse prognosis because of delayed

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recognition and subsequent treatment. This article reports a case of amelanotic melanoma of the palate. A 68 year old Caucasian female presented with a 2 centimeter nodular lesion on the right soft palate found on routine dental examination. The patient's medical history was significant for a stroke, which resulted in left hemiplegia. She had lost all her teeth from periodontal disease; she had been wearing complete upper and lower dentures for the preceding 15 years. After diagnosis, surgical excision (removal) was performed. The patient did well postoperatively and has undergone successful prosthetic rehabilitation. The surgical margins were clear of disease, and the patient remains disease free at 1 year. The authors note that because oral cavity melanomas are extremely rare, it is difficult to determine the optimum method of staging, prognosis, and treatment. 3 figures. 17 references. •

Spontaneous Regression of Cutaneous Melanoma with Subsequent Metastasis Source: Journal of Oral and Maxillofacial Surgery. 60(5): 588-591. May 2002. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Website: www.harcourthealth.com. Summary: There has been a four-fold increase in the incidence of cutaneous malignant melanoma during the past 25 years. However, the ratio of expected deaths from melanoma to new melanoma cases has actually decreased steadily during this time period, largely as a result of increased public awareness leading to earlier diagnosis and treatment. The relationship between malignant melanoma and melanocytic nevi (pigmented skin blemishes, present at birth) is well recognized; more than 80 percent of patients with melanoma reported a change in a preexisting nevus as the initial sign of their disease. This article presents the case of a patient with an apparent spontaneous regression of a presumed malignant melanoma that arose from a longstanding cutaneous melanocytic nevus followed by the development of a regional lymph node metastasis (spread of the cancer). The authors describe the patient's multimodal therapy with wide surgical excision of the gross lesion, noting that this offers the most favorable opportunity for locoregional control and, therefore, prolonged disease-free survival. 6 figures. 16 references.

Federally Funded Research on Malignant Melanoma The U.S. Government supports a variety of research studies relating to malignant melanoma. 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 malignant melanoma. 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 2

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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animals or simulated models to explore malignant melanoma. The following is typical of the type of information found when searching the CRISP database for malignant melanoma: •

Project Title: A MOUSE MODEL FOR UV-INDUCED JUNCTIONAL MELANOMA Principal Investigator & Institution: Noonan, Frances P.; Professor; Immunology; George Washington University 2121 I St Nw Washington, Dc 20052 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Cutaneous malignant melanoma (CMM), already notorious for its highly aggressive behavior and its recalcitrance to currently available therapeutics is one of the the fastest increasing cancers in the USA. Recent studies have provided compelling evidence for a significant underlying genetic basis for CMM, as well as an initiating role for sunlight exposure in its etiology. The functional relationship, however, between genes and environment in the pathogenesis of melanoma is virtually unknown. Until now, research on this deadly disease has been badly hampered by the lack of an animal model which adequately recapitulates human disease. We have developed a new transgenic mouse model for UV-induced melanoma which, for the first time, shows an etiology, histopathology and molecular pathogenesis remarkably similar to human CMM. In this proposal, we seek to characterize and further validate this model which shows great promise for melanoma investigations. Preliminary data to date have demonstrated that a single neonatal burning dose of UV exposure is necessary and sufficient to induce highly penetrant cutaneous melanoma, arising in apposition to epidermal elements with a junctional morphology and a molecular pathogenetic profile remarkably reminiscent of human melanoma. Specifically, the UV responsiveness and waveband dependence of this model will be established, the role of critical genetic alterations in the tumor suppressor loci Ink4a and p53 occurring in early lesions and in malignant tumors will be investigated using an in vivo genetic approach, and we propose to establish if UV-induced immune alterations play a fundamental role in the early pathogenesis of disease in this model. We anticipate that these studies will provide the major basis for development of this system for application in the design of preventive strategies and therapeutic interventions and for further investigations of the fundamental biology of cutaneous malignant melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ACTIVE SPECIFIC IMMUNOTHERAPY FOR MELANOMA Principal Investigator & Institution: Morton, Donald L.; Surgeon-In-Chief; John Wayne Cancer Institute 2200 Santa Monica Blvd Santa Monica, Ca 90404 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The long-term objective of this grant has been the development of effective therapeutic vaccines against malignant melanoma. The Project's focus is the evaluation of a living irradiated polyvalent melanoma cell vaccine (PMCV). This project has four Specific Aims: 1) We will conduct a multicenter randomized Phase III trial in AJCC Stage III melanoma to test the hypothesis that PMCV plus BCG has superior activity in prolonging disease free and overall survival when compared to placebo plus BCG as a post surgical adjuvant. 2) Determine the immune response that optimally correlates with the clinical outcome of PMCV recipients enrolled in the Phase III trial. Our goal is to develop an immune response model that can serve as a prototype for monitoring vaccine therapy in patients with melanoma. 3) Determine whether the immune response against tumor-associated antigens can be enhanced by combining PMCV immunotherapy with cytokines that are effective vaccine

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adjuvants for inducing tumor rejection responses in animal models, such as GMCSF and IL-12 and whether manipulation of co-stimulatory molecules on melanoma cells can enhance immmunogenicity. 4) To determine whether new tumor markers can be used to detect subclinical metastatic melanoma and quantitate the response to adjuvant therapy. We hypothesize that these new techniques will be useful in predicting the outcome of adjuvant therapy for melanoma patients who have no clinical evidence of disease following sugery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADRENAL STEROID--IMMUNE INTERACTIONS Principal Investigator & Institution: Miller, Andrew H.; Professor; Psychiatry and Behavioral Scis; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-APR-1989; Project End 30-NOV-2003 Summary: The long term objectives of this competitive renewal of a Research Scientist Development Award (K02 series) are designed to provide the applicant with scientific training in viral immunology using experimental murine infections and to extend knowledge gained from this work to a clinical context. Training in viral immunology will be achieved by conducting a collaborative research project with Dr. Christine Biron, a viral immunologist at Brown University, examining interactions between adrenal steroids (or glucocorticoids) and the immune system during viral infections. Work with Dr. Biron over the previous project period has 1) demonstrated an IL-6-dependent pathway for the induction of endogenous glucocorticoids during infection with murine cytomegalovirus (MCMV), 2) characterized effects of viral infection on the receptors for glucocorticoids and 3) revealed the contribution of endogenous glucocorticoids to protection against lethality in MCMV infection via negative regulation of tumor necrosis factor (TNF)alpha. Specific aims for the proposed research plan are 1) to further investigate the mechanisms by which viral infections activate neuroendocrine pathways, 2) to determine how immune signals are translated into neuroendocrine signals in the central nervous system, 3) to determine how neuroendocrine signals are received by target immune tissues (e.g., at the level of the glucocorticoid receptor) and 4) to examine the impact of the neuroendocrine system on specific immune responses to the virus including both cellular and cytokine responses. In addition, to develop skills in clinical research, information from the basic science studies will be integrated into an examination of the impact of the type I interferon (IFN), IFNalpha, on neuroendocrine function and behavior in patients undergoing high dose IFNalpha therapy for malignant melanoma. INFalpha is an important early cytokine in viral infections and has been shown to induce glucocorticoids and IL-6 in humans. Moreover, IFNalpha has been associated with glucocorticoid receptor changes in patients with HIV infection. The INFalpha project will also examine whether antidepressants, which the applicant has found facilitate glucocorticoid receptor function, will increase glucocorticoid-mediated negative feedback on proinflammatory cytokines including TNFalpha and thereby reduce the toxicity associated with high dose cytokine (IFNalpha) exposure. Finally, the applicant will serve as a primary mentor in an HIV/AIDS clinical research training program and extend examination of adrenal steroid-immune interactions to patients with HIV infection. Further understanding of neuroendocrine- immune interactions in viral infections will provide the foundation for developing new therapeutic strategies to limit the immunologic and behavioral morbidity of viral diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AN INTELLIGENT MELANOMA DIAGNOSTIC TRAINING SYSTEM Principal Investigator & Institution: Crowley, Rebecca S.; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 21-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): This project will determine whether the welldescribed paradigm of the model-tracing Intelligent Tutoring System can be adapted to create a multimedia, knowledge-based, medical training system. We propose to develop the Melanoma Diagnostic Training System, a virtual-slide based tutor for pathology residents. The system is designed to provide instruction in detection, classification, and reporting of Malignant Melanoma and other melanocytic skin lesions. Melanocytic lesions are a difficult area of histologic cancer diagnosis. False negative and false positive diagnoses of Melanoma can result in significant morbidity and mortality, and are among the most commonly litigated pathology case types. New advances in treatment of Melanoma have placed an increasing responsibility on the pathologist to identify and report on a range of histologic prognostic indicators. We propose to develop a diagnostic training system in this domain using the paradigm of the Intelligent Tutoring Systems (ITS). ITS are computer-based systems that provide individualized instruction by incorporating models of expert performance and dynamically building a unique student model for each user. ITS can be highly effective in systems that simulate real-world tasks, enabling students to work through case-based scenarios as the ITS offers guidance, points out errors and organizes the curriculum to address the needs of that individual learner. As part of the project, we will develop a library of whole-slide digital images of melanocytic lesions and melanoma, each with a gold-standard diagnosis. System development will be accompanied by a controlled, randomized laboratory evaluation in which we will examine the effect of the system on accuracy of detection, classification, and reporting using pre-test and post-test methods. In the final year of the project, we will deploy the system across multiple sites in the Pennsylvania Cancer Alliance Bioinformaties Consortium, and evaluate acceptance and use of the system using surveys, interviews, and log-file analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANALYSIS OF BREAST/MELANOMA MULTIPLE PRIMARY CANCERS Principal Investigator & Institution: Ward, Michelle Renee.; Pediatrics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 12-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): The proposed project is centered on cancer susceptibility gene discovery. This project is based on the hypothesis that a subset of individuals with multiple primary cancers has an underlying susceptibility gene mutation that is common to all tumors in that individual. Earlier studies using population-based tumor registries have demonstrated an increased risk of melanoma as a second malignancy in women diagnosed with breast cancer. Conversely, an increased risk of breast cancer has been demonstrated in women who have been previously diagnosed with melanoma. This bi-directional increased risk of a second malignancy deserves further attention and is suggestive of a common mechanism as the etiology of these two tumors. To this end, we intend to define and characterize a population of women who have been diagnosed with both breast cancer and melanoma. Outside of defined syndromes, little had been documented regarding multiple primary cancers. What data exist strongly support the hypothesis that women with multiple primary

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cancers are more likely to harbor germline susceptibility alleles than those with a single malignancy. We hypothesize that women with the multiple primary cancers, breast and melanoma, represent a clinically significant variation in disease phenotype for one of the known candidate genes. We will screen this population for germline and somatic mutations in genes known to be involved in cancer predisposition or progression. In addition, we will use array-based comparative genomic hybridization (aCGH) to identify the critical genetic changes that are necessary to transform normal melanocytes or breast epithelium into cells with malignant potential. A DNA-based microarray platform using bacterial artificial chromosomes (BACs) containing human genomic DNA representative of the entire genome at 1-2 Mb intervals, will be utilized to define regions of chromosomal gain and loss using DNA from breast and melanoma tumors both from a single individual as well as versus matched sporadic tumors. The overall objective of this proposal is the identification of additional cancer susceptibility genes, which will enable the study of the genes themselves and advance our understanding of the etiology of breast cancer and malignant melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI-MELANOMA IMMUNE RESPONSES IN MELANOMA DEVELOPMENT Principal Investigator & Institution: Vachon, Celine M.; Assistant Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2004 Summary: Melanoma incidence and mortality have been rapidly increasing over the past fifty years, and the disease remains a public health burden. Although much research has been conducted in developing novel systemic treatments for melanoma, none have been very effective. With the molecular identification of cytotoxic T lymphocyte (CTL) responses to melanoma tumor antigens, many promising new trials are targeting the up-regulation of these responses in therapy for advanced melanomas. However, the natural history of the CTL anti-melanoma immune response in melanoma is not known. We propose to investigate the role of primary anti-melanoma immune responses in melanoma development. This cross-sectional study will examine the antimelanoma CTL immune response across stage of disease, including patients with benign nevi, atypical nevi, and stage 0-IV melanomas. Ninety-eight cases will be enrolled with malignant melanoma diagnosed at the Mayo Clinic over a two-year time period. We will also ascertain 30 patients with a diagnosis of aytpical nevus and 30 patients with a benign nevus removed at the Mayo Clinic during this same time period and who have a similar age distribution as the cases. Participants will complete a structured self-administered questionnaire soliciting sun-exposure, medical and lifestyle history, and provide a blood sample for analyses. All melanoma cases and patients with benign and atypical nevi will undergo central pathology review. Furthermore, immune responses to the gp100, MART-1, and tyrosinase melanoma-specific peptides will be examined using tetramer, ELISPOT and RT-PCR techniques. The epidemiologic risk factor information will allow for adjustment of known melanoma risk factors in our primary analyses as well as investigating associations of these risk factors with antimelanoma immune response. We have assembled an interdisciplinary research team for this study to create an outstanding research resource. In summary, we will characterize the role of primary anti-tumor CTL immune responses in melanoma development. This should greatly contribute to our understanding of the natural history and immunobiology of human melanoma, allowing for the development of rational immunotherapeutics.

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

Project Title: ARGININE DEIMINASE AS AN ANTI-CANCER THERAPY Principal Investigator & Institution: Clark, Mike A.; Phoenix Pharmacologics, Inc. Astecc Facility #a-217 Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 20-AUG-1999; Project End 31-MAR-2003 Summary: The distinctive arginine requirement of hepatocellular carcinomas and malignant melanomas provides the basis for a new potential chemotherapy. Just as acute lymphocytic leukemia cells require asparagine and E. coli asparaginase enzyme can be used to effect a cure for this disease, we propose using a mycoplasma derived arginine deiminase (ADI) to treat hepatocellular carcinoma and malignant melanomas. As a result of Phase I funding we have discovered a method where by ADI can be formulated with polyethylene glycol (PEG) such that it has a much longer circulating half-life in mice and is less immunogenic. When ADI formulated with PEG is injected into mice it selectively reduces the plasma levels of arginine and starves human melanomas and hepatocellular carcinomas implanted into these animals. This treatment is also being tested in dogs with spontaneous melanoma (under an INAD received from the FDA) and is quickly being proven to be an effective means of treating spontaneous melanoma with very few, if any, side effects. We have requested and received an Orphan Drug Designation for this project and in a Pre-IND meeting with the FDA and the Orphan drug Office, delineated the experiments needed to file a Phase I IND to permit human testing of this drug. The studies proposed in this grant reflect the FDA requirements and when completed will allow for the testing of ADI formulated with PEG in humans. The studies proposed include the validation of the process used to make (under GMP conditions) 3 lots of ADI-PEG, characterize these lots with validated procedures, obtain pharmacodynamic and pharmacokinetic data that will allow allometric modeling of the predicted human dosing and perform the necessary immunological and toxicological testing needed for this project to progress into human clinical testing. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ARGININE DEPRIVATION: A TARGETED THERAPY FOR MELANOMA Principal Investigator & Institution: Feun, Lynn G.; Medicine; University of MiamiMedical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2004; Project Start 06-AUG-2004; Project End 31-JUL-2007 Summary: (provided by applicant): Malignant melanoma is usually resistant to drug therapy which historically has been non-selective in action and often very toxic. A novel approach is to target a specific defect found in melanoma cells. We and others have shown that exposure of melanoma cells to arginine deiminase (ADI), an enzyme that catalyzes the hydrolysis of arginine to citrulline, results in apoptotic cell death. This unique sensitivity to ADI is primarily due to the fact that melanoma cells, unlike normal cells, do not express argininosuccinate synthetase (ASS) and hence are unable to synthesize arginine. Transfection of ASS cDNA confers resistance to AD1, further confirming that lack of ASS expression is critical for ADI sensitivity. We formulated a pegylated form of ADI (ADI-PEG20) to reduce immunogenicity and to increase the halflife. ADI-PEG20 has shown significant antitumor activity in vivo with low toxicity. We have completed a Phase I trial of ADI-PEG20 in advanced melanoma. Remarkably, 5/10 patients had partial response when treated at a dose >160 IU/m2, a dose that depleted

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plasma arginine to non detectable levels for >7 days. No > grade 2 toxicity was observed. Interestingly, two patients who did not respond had ASS expression in their tumors. In this application, we plan to conduct a Phase II trial to confirm the antitumor activity in advanced melanoma as outlined in specific aim 1. In specific aim 2, we will assay ASS in tumor samples by immunohistochemistry and RT-PCR prior and after treatment to assess whether ASS expression can be a predictor for tumor response, and whether de-repression of ASS occurs at relapse. In specific aim 3, we will investigate the possible mechanism of apoptotic cell death by ADI-PEG20. In addition, the possible mechanism(s) of resistance will be examined by using an in-vitro cell line made resistant to ADI-PEG20 and by using de-novo resistant cell lines derived from tumors at time of treatment failure. In order to optimize future use of ADI-PEG20, we will investigate whether pharmacological manipulation can induce/repress ASS expression. Our goal is to improve the treatment outcome of melanoma while minimizing toxicity by targeting a specific defect in melanoma cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOREACTOR FOR ENHANCED T-CELL BASED THERAPY OF MELANOMA Principal Investigator & Institution: Smith, Douglas M.; Aastrom Biosciences, Inc. Box 376 Ann Arbor, Mi 48105 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 30-NOV-2004 Summary: (provided by applicant): Malignant melanoma is a significant and deadly form of cancer worldwide. Emerging evidence has shown that melanoma cells express tumor-associated antigens that are specifically recognized by the immune system. Melanoma antigen-specific T-lymphocytes can be isolated from the tumors of late stage cancer patients or induced by active vaccination using well-characterized tumor peptide epitope vaccines. Adoptive transfer therapy of autologous tumor infiltrating lymphocytes (TILs) has been shown to mediate durable regression of malignant melanoma in particular patients. Furthermore, ex vivo antigen-specific expansion of autologous T-cells from vaccinated patients is a promising approach to increase the potency and frequency of tumor antigen specific T-cells for adoptive immunotherapy. However, current culture methods for ex vivo lymphocyte expansion to produce billions of T-cells for patient therapy are costly, labor intensive and consist of multiple manual open-process steps which are difficult to implement for wider patient delivery without specialized facilities under increasingly stringent regulatory requirements. In addition, prolonged culture of T-cells leads to replicative senescence with loss of biological function and therapeutic activity. Aastrom Biosciences, Inc. is developing a novel clinical scale bioreactor system for production of cells for human cell therapy using closed system automation and continuous single-pass perfusion technologies. The primary goal of this Phase I proposal is to demonstrate the feasibility of using the AastromReplicell/TM Cell Production System to expand highly active melanoma tumor antigen specific T-lymphocytes from patients' tumors or apheresis cells of vaccinated donors for immunotherapy against malignant melanoma. Multiple culture parameters for both antigen-independent and selective melanoma peptide driven T-cell expansion processes will be implemented and evaluated in the clinical scale bioreactor system. The beneficial effect of single-pass perfusion for potentially improved biological function and replicative capabilities of T-lymphocytes when compared to conventional methods will be defined. A closed automated bioreactor system will fulfill a large unmet clinical demand for consistent, reliable and reproducible T-cell production under stringent

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regulatory conditions with improved immunologic and therapeutic potency for immunotherapy of cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL RELEVANCE OF MICROMETASTASES IN MELANOMA Principal Investigator & Institution: Ghossein, Ronald A.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: The candidate is a diagnostic surgical pathologist whose immediate research goals are the detection and molecular characterization of circulating tumor cells (CTC) and micrometastases in solid tumors, especially in malignant melanoma (MM). His long term goals are the 1) development of these molecular tests into clinically relevant prognostic markers and 2) an in depth analysis of the mechanisms of metastases in solid tumors. Memorial Sloan-Kettering Cancer Center has the clinical and laboratory facilities appropriate for the development of junior faculty members into independent researchers, and for the conduct of this type of research. There is a need for better prognostic markers in advanced MM. The objectives of this proposal are to assess the prognostic significance of CTC and bone marrow (BM) micrometastases in patients with advanced melanoma (i.e patients with melanoma >4mm thickness, with lymph node or distant metastases). Blood and BM from 250 patients with advanced melanoma who were rendered surgically free of disease will be tested for CTC and micrometastases using reverse transcriptase po1yrnerase chain reaction (RT PCR) for the presence of tyrosinase, MART1/Melan-A and GAGE mRNAs. The test data will be correlated with outcome and other clinico-pathologic parameters - The investigators will also study the variation in blood RT PCR results in relation to serial sampling and its prognostic significance. The expression of these markers will be also studied in the primary tumors and metastatic tissue deposits by immunohistochemistry and RT PCR. This latter tissue data will be correlated with the RT PCR tests for CTC and BM micrometastases in order to study how these markers are modified during the metastatic process. This will increase our understanding of the metastatic process in MM, and provide new prognostic markers aimed at better stratifying and therefore more accurately treat MM patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--ENVIRONMENT /GENE INTERACTIONS Principal Investigator & Institution: Chen, Suzie; Associate Professor; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 088545635 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Description (provided by applicant): This core was created in 1994 under the name "Biotransformation and Toxicity of Environmental Chemicals." The name was changed to Environment-Gene Interactions in April 2000, reflecting the expansion into new areas and the appointment of Dr. Suzie Chen as the Director. Dr. P. Thomas remains in the leadership of the Core as Co-Director. The core includes 16 investigators from 6 different departments at Rutgers University and 6 departments at RWJMS. The collective funding for this group of investigators is 12.8 million dollars. This number includes peer review grants, contracts, and cooperative agreements. The research interest of the core members falls into the following ten areas of research and collaboration: 1) chemopreventive activities and other dietary compounds; 2) regulation of xenobioticmetabolizing

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enzymes; 3) genetic polymorphisms of metabolizing enzymes Lambert; 4) detection of phytoestrogens from environmental samples; 5) P53 mutations in skin carcinogenesis; 6) mouse model for esophageal carcinoma; 7) mouse model of malignant melanoma; 8) genomic stability; 9) mutagenesis and environmental carcinogenesis; and 10) animal models. The core goals are, 1) to identify and study genes involved in cellular response to environmental exposure; 2) to characterize the alterations of the gene expression resulting from host responses to environmental factors; 3) to identify important genetic polymorphisms associated with environmental response genes; and 4) to elucidate functionally important environmental response genes in a variety of model systems, from yeast to mammals. The future plans for the core include enhancement of use of genomic and proteomic approaches, develop and increase intracore interaction and to extend studies in animal models to humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MOLECULAR EPIDEMIOLOGY AND ECOGENETICS Principal Investigator & Institution: Spitz, Margaret R.; Professor and Chair; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002 Summary: The overall goal of this research core is to develop and validate genetic markers for cancer susceptibility. By incorporating molecular genetics and cytogenetics into population studies, the investigators hope to gain insights into the complex interactions between genetic and environmental determinants of cancer. Of particular interest are the low penetrance genes that may modulate one's response to environmental exposures and contribute to the etiology of sporadic cancers. Specific aims include maintaining and expanding communication and scientific interaction among Core and other Center members, as well as non-Center members; strengthen current and promote future research activities in the area of genetic susceptibility to environmental disease; stimulate and facilitate intra- and inter-Core grant renewals and new investigators-initiated grant proposals; and serve in consultative and collaborative roles across research and facility cores to include concept development, study design, human tissue procurement and environmental data collection. Major areas of research focus in this Core encompass: 1) the assessment of phenotypic markers of DNA damage and repair as markers of susceptibility to carcinogenesis, 2) the evaluation of polymorphisms in select metabolic and DNA repair genes and DNA adducts in the etiology of lung, bladder, breast, and pancreatic cancers, and 3) the development of statistical models for cancer risk assessment by combining biomarkers and for genotypephenotype and surrogate-tissue marker correlation. Intra-Core 4 and inter-Core collaborative studies being conducted or completed include the following: 1) a casecontrol study of lung cancer examining cytogenetic and molecular determinants of tobacco carcinogenesis, 2) a study of genetic and environmental determinants, including phytoestrogen intake, of prostate cancer progression, 3) a genetic epidemiologic study of gliomas in relation to family history and genetic susceptibility markers, 4) a study of microsatellite instability and the risk of bilateral breast cancer, 5) a study of genetic polymorphisms, epidemiologic risk factors and differences in breast cancer survival among different ethnic groups, 6) a study of DNA adducts, P53 mutation spectrum, oxidative DNA damage and breast cancer risk among premenopausal women, 7) a study of molecular genetics of hereditary nonpolyposis colorectal cancer, 8) a study of modifier genes that influence age-associated risk of colorectal cancer, 9) two studies evaluating environmental and genetic determinants of advanced prostate cancer, 10) studies of second malignancies after treatment for hairy cell leukemia, acute myelocytic

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leukemia, 11) a study of cutaneous malignant melanoma and non-melanoma skin cancer, 12) a study of linkage and linkage disequilibrium, methods for traits, 13) a study of genetic susceptibility of bladder cancer, 14) a study of mutagen sensitivity and progression in Barrett's esophagus, 15) a study of the genetic, hormonal and behavioral determinants of obesity, 16) a pilot study of breast and colorectal cancers among Egyptians and organochlorine pesticides exposures, and 17) a pilot study to examine associations of mutagen sensitivity, oxidative damage and DNA adducts in lung cancer. The stated long term goal of this Core is to develop a validated risk model for cancer, such as lung cancer, to take into account simultaneously the effects of numerous genetic and environmental factors and the nature of subgroups (women, never-smokers, young subjects, ethnic minorities, etc). Future plans include the use of funds from the Tobacco Settlement for the State of Texas to establish an archival laboratory for the long-term storage and tracking of biological specimens and a centralized genotyping core. It also plans to expand in the area of nutritional epidemiology, and in its molecular epidemiologic studies to include brain and lymphoid malignancies. Future plans also include the development of a genotyping chip, in collaboration with Genometrix, expansion of the CRED website and implementation of multivariate statistical analysis to the large database that will be generated by incorporating chip technologies into studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--PATHOLOGY AND TISSUE BANK Principal Investigator & Institution: Mckee, Phillip; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The purpose of the Tissue and Pathology and Core, which will be located within the Departments of Pathology at Brigham and Women's Hospital, Massachusetts General Hospital, and the Beth Israel Deaconess Medical Center, is to provide to all SPORE investigators with: 1. Research pathology services including expert diagnosticians to confirm diagnoses and ensure consistency in reporting of all human tissue samples utilize by researchers and provide technical and laboratory facilities including a comprehensive range of resource such as immunohistochemistry and in situ hybridization for both frozen and paraffin-embedded material, in situ hybridization, fluorescence based flow cytometry and microscopy for quantitative and qualitative analysis of cell surface and intracellular molecules, computer assisted image analysis, digital imaging, and laser capture microdissection. These facilities will provide SPORE investigators with essential services for diagnosis confirmation and the evaluation of new markers, probes and antibodies. The Core will contain the appropriate equipment, reagents, and technical expertise to provide the services using the facilities described above. Personnel in the Pathology Core will be available to advise investigators on technical aspects of the Core facilities in addition to help with interpretation of results. 2. A Tissue/Blood Repository/Virtual Tissue Bank, including collection, and storage of fresh tissue samples and collection, processing and storage of blood and blood components from patients with malignant melanoma, congenital nevi, cutaneous T-cell lymphoma, cutaneous squamous cell carcinoma, and vascular tumors enrolled in the SPORE-related projects. The Virtual Tissue Bank will link the extensive resources of the Dana Farber/Harvard Cancer Center-associated hospitals. The investigators will therefore be provided with ready access to a wide range of related clinical material with associated clinical information. In the context of all access to a wide range of related clinical material with associated clinical information. In the context of all human tissues,

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there will be close collaboration between the Tissue and Pathology Core and the Clinical Data Management Core which will assume responsibility for providing and maintaining the clinical databases for Management Core which will assume responsibility for providing and maintaining the clinical databases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DENDRITIC CELLS, HEAT SHOCK PROTEINS AND TUMOR IMMUNITY Principal Investigator & Institution: Banchereau, Jacques F.; Director; Baylor Research Institute 3434 Live Oak St, Ste 125 Dallas, Tx 75204 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 28-FEB-2005 Summary: (Applicant's Abstract) Our long-term goal is to develop new vaccination strategies in humans with an emphasis on anti-tumor immunity. The unique ability of dendritic cells (DC) to induce and sustain immune responses makes them optimal candidates for vaccination protocols. Yet, optimal strategies for the delivery of antigen(s) to human DCs still need to be identified. Recent studies demonstrate that DCs efficiently capture apoptotic cells and present MHC class I and class II-restricted epitopes. Thus, the use of tumor cell bodies as source of antigens in DC-based vaccination offers a novel strategy that allows presentation of both CTL and T helper epitopes. Our own studies show that naive CD8+ T cells can be induced to differentiate into melanoma-specific CTL when primed by DCs loaded with killed allogeneic melanoma cells. Yet, T cells require several rounds of stimulation for the tumor specific responses to be established. Therefore, it is of great importance to identify the means of increasing tumor cell immunogenicity. Because the purified heat shock proteins, gp96 and hsp7O, have been shown to play a critical role in tumor rejection in mice, it is likely that the expression level as well as the type of hsps expressed in tumor cell bodies will determine their immunogenicity. We propose that: Immunogenicity of tumor cell bodies is determined by their expression of heat shock proteins and we propose to analyze the immunogenicity of cell bodies from lines induced to overexpress hsp70 or gp96. Using human malignant melanoma as a model we will: (1) Determine whether loading DCs with tumor bodies overexpressing hsp70 or gp96 enhances TAA presentation to melanoma specific T cell lines/clones. (2) Determine whether loading DCs with tumor bodies overexpressing hsp 70 or gp96 enhances their capacity to prime naive T cells. (3) Determine whether loading DCs with tumor bodies overexpressing hsp70 or gp96 skews their capacity to prime CD4 T cells. (4) Determine whether hsp70 and gp96 account for the differential priming activity of cell bodies. These studies will permit us to produce an altered melanoma cell line, with enhanced immunogenicity, that will be used to generate tumor cell bodies to load onto DCs for vaccination protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MELANOMA

DEVELOPMENT

OF

INHIBITORS

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B-RAF

TO

TREAT

Principal Investigator & Institution: Birnberg, Neal C.; Mercury Therapeutics. Inc. 2E Gill St Woburn, Ma 01801 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JUL-2004 Summary: (provided by applicant): The goal of this Phase I proposal is to develop a novel small molecule anti-cancer therapeutic to treat malignant melanoma. The strategy will be to screen for inhibitors of a mutant form of the protein kinase B-Raf. It has recently been reported that the V599E mutation in B-Raf is present in over half of all

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human malignant melanomas, and causes constitutive activation of the MAP kinase signal transduction pathway, promoting continuous cell proliferation. If detected early, malignant melanoma, as a cancer of the skin, has a high cure rate when surgically excised before it metastasizes. Metastatic melanoma, in contrast, is a highly aggressive and later stage disease that is virtually incurable. While the incidence of all cancers in the U.S. has shown a net decrease of 7.1% over the last six years, the incidence of melanoma has increased by 24.8% during that same time period, demonstrating a growing need for an effective therapy. An anti-cancer drug which targets mutant B-Raf protein kinase has the potential to cause a paradigm shift in the way malignant melanoma is currently treated, particularly metastatic disease. The goals for this proposal is to I) Discover at least five B-Raf kinase inhibitors or lead series from a high throughput screen; ii) Identify at least two compounds with biological activity that inhibit the MAP kinase signal transduction pathway in two human melanoma cell lines; and iii) Identify at least one cellular active that inhibits proliferative activity or reduces viability of a V599E B-Raf expressing melanoma cell line, and test for differential growth inhibition between normal human and B-Raf mutant tumor cell lines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DORMANCY VERSUS PROGRESSION OF HUMAN PRIMARY MELANOMA Principal Investigator & Institution: Kerbel, Robert S.; Director; Sunnybrook & Women's Coll Hlth Scis Ctr S132 Toronto, on M4n 3M5 Timing: Fiscal Year 2002; Project Start 01-JUN-1992; Project End 31-DEC-2002 Summary: (adapted from the investigator's abstract) The majority of primary cutaneous melanomas go through a prolonged period of dormant growth before acquiring malignant properties. Unlike most other primary tumors, however, this dormancy stage is visible in melanomas, subdermal/orthotopic injection of human melanoma cell lines, obtained from different stages of disease progression, into nude mice. Thus, whereas almost all advanced stage primary or metastatic-derived cell lines give rise to progressively small slow-growing, plaque-like lesions -- similar to radial growth phase (RGP) or thin vertical growth phase (VGP) tumors in humans. Using various methods, e.g. retroviral insertional mutagenesis or gene transfection, this applicant has recently succeeded in isolating tumorigenic variants from a number of such early-stage primary melanomas. These cell lines present an outstanding opportunity to study the basis of pre-malignant melanoma dormancy and the reasons for its termination. First, (based on their recent results), they believe there are three major interconnected factors which govern primary melanoma dormancy. These are: (i) sensitivity to inhibitory controls mediated by several cytokines, including IL-6; (ii) a deficient capacity of melanoma cells to survive in a multicellular growth context; (iii) a deficient ability to induce angiogenesis; Second, overcoming these 'defects' results in acquisition of overt malignant growth characteristics. Third, genetic alterations thought to be involved in the progression of melanomas, such as loss of p21WAF1 or p16INK4, do so by affecting several, or all three phenotypes simultaneously (i.e., cell proliferation, survival, and angiogenesis). Examination of these hypotheses comprise the three specific aims of the research program. The proposed research will shed new light on what is probably the most crucial stage of melanoma progression, but which, thus far, has received little experimental scrutiny because of the lack of appropriate experimental models. It may also serve as a model for factors influencing premalignant-primary tumor dormancy in other types of cancer where access to early-stage lesional material is severely limited, or non-existent.

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

Project Title: EASTERN COOPERATIVE ONCOLOGY GROUP Principal Investigator & Institution: Atkins, Michael B.; Director; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 12-MAY-1999; Project End 30-APR-2004 Summary: Beth Israel Deaconess Medical Center (BIDMC) resulted from the 1996 merger of the Beth Israel and New England Deaconess Hospitals, two neighbors and major Harvard Medical School institutions in the Longwood Medical Area. The BIDMC faculty, together with newly recruited long-time Boston-based ECOG members now includes an exceptional group of committed clinical cancer researchers. Serving as the principal tertiary/academic resources of the CareGroup Network, BIDMC has a natural and ready-made ECOG network to add to its long tradition of excellence in cancer care as well as both clinical and basic science research. BIDMC is home to nationally recognized centers of special expertise including the Joint Center for Radiation (JCRT), liver and other solid-organ transplantation, AIDS and related malignancies, breast cancer/women's health, malignant melanoma, medical informatics and clinical trials methodology, cytokine and biologic therapy. The Harvard Institute of Medicine (H.I.M.) Located nearby provides outstanding research scientists and laboratory-based components for cooperative group translational research. BIDMC joined ECOG as an affiliate of Vanderbilt University in May 1997. From May '97-October '97, as an affiliate, BIDMC entered 36 cases. Based on this strong activity and a fully satisfactory site visit in September '97, BIDMC was granted Main Member Institution status in October '97 and approved to apply for an ECOG Core Grant in January 1998. From October '97 to December '97, as a main institution, BIDMC enrolled 19 patients to ECOG studies. To date, in 1998 BIDMC has accrued 33 patients, making the total accrual for May '97 to May '98 equal to 88 patients. We are committed to conducting laboratory and clinical research in the ECOG specified areas of cancer prevention, diagnosis, and treatment and have demonstrated high levels of patient accrual in the past and have the potential for even greater contributions, group science, and patient enrollment in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELUCIDATING THE SURVIVIN PATHWAY IN MELANOMA Principal Investigator & Institution: Grossman, Douglas; Dermatology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: (Taken from the applicant's abstract): The long-term goal of this project is to understand how apoptosis influences the development and growth of malignant melanoma (MM). Preliminary studies indicate that survivin, a newly recognized inhibitor of apoptosis, is broadly expressed in human nevi, MM lesions and melanoma cell lines, but not in normal melanocytes. A four-year mentored program is proposed to investigate the hypothesis that expression of survivin is an important early step in the transformation from normal melanocyte to melanoma and represents a potential therapeutic target in MM. This program will incorporate both didactic and research training in three general areas: apoptosis, melanocyte and melanoma biology, and adenoviral-mediated gene transfer. The training will be guided by a mentor (Dario Altieri, M.D.), 2 collaborators (Ruth Halaban, Ph.D., Alfred Bothwell, Ph.D.), and an advisory committee of 5 additional senior scientists with expertise in these areas. Three specific aims are proposed. First, modulation of survivin expression and function will be

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studied in cultured human melanocytes in vitro. Melanocytes will be stimulated by UV radiation and growth factors to induce survivin expression, and the effects of (adenoviral-mediated) survivin expression on apoptosis resistance, proliferation, dendricity and melanogenesis will be examined. Second, mechanisms of survivin inhibition of apoptosis in nevi and melanoma cells will be investigated. Nevus cells will be transfected with survivin antisense and a dominant negative survivin point mutant to block survivin function. Melanoma cell lines expressing these antagonists under the control of a tetracycline-regulated promoter will be used to investigate the timing of apoptosis and identify the intracellular target(s) of survivin action. Third, an in vivo model will be developed using these cell lines in SCID mice to study the role of survivin in melanoma tumor development. In addition, survivin antagonists will be directly targeted to tumors using adenoviruses. The proposed studies promise to elucidate the mechanisms of apoptosis regulation in MM, and may identify new molecular approaches for the therapeutic intervention in cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENHANCING TUMOR VACCINES WITH CO-STIMULATORY MOLECULES Principal Investigator & Institution: Kaufman, Howard L.; Associate Professor; Surgery; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 16-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): The identification of tumor-associated antigens recognized by T-cells and a better understanding of how these T-cells are activated has renewed interest in the use of tumor vaccines for the treatment of cancer. The two signal hypothesis of T-cell activation states that T-cells require both an antigen-dependent signal delivered by HLA restricted epitopes and an antigen-independent signal delivered by co-stimulatory molecules. In fact, the lack of co-stimulatory molecule expression by tumor cells predicts that T-cells may be suppressed at sites of active tumor growth. This application seeks to understand the potential role of introducing costimulatory molecules into growing tumors as a method for enhancing local and systemic T-cell responses against the tumor. Recombinant poxviruses have been utilized to express human genes because of their stability, replication accuracy, and strong immunostimulant properties. The first aim is to study a recombinant vaccinia virus expressing the human B7.l co-stimulatory molecule in a dose escalation phase I trial in patients with malignant melanoma. The vaccine will be administered monthly as a direct intra-tumoral injection in an effort to activate tumor-infiltrating lymphocytes and evaluate the effects on systemic immunity. Patients will be evaluated for toxicity, clinical response, and systemic immune response by IFN-gamma ELISPOT assay. The second aim is to evaluate a novel recombinant vaccinia virus expressing three co-stimulatory molecules (B7.1, ICAM-1, and LFA-3), which has been superior to vaccinia-B7.l in preclinical studies. This vaccine will be tested in a similar dose escalation phase I clinical trial with similar endpoints. The third aim will be to evaluate the local effects of the vaccine through quantitative real-time PCR of fine needle aspirates taken from injected tumor lesions. Completion of these aims will demonstrate the safety and immunological effects of direct tumor injection of recombinant vaccinia viruses expressing costimulatory molecules. This may have important implications for the future design of tumor vaccines in melanoma and other settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EXPRESSION PATHWAYS IN MELANOMA PROGRESSION FOR DIAGNOSIS AND PROGNOSIS Principal Investigator & Institution: Elder, David E.; Wistar Institute Philadelphia, Pa 191044268 Timing: Fiscal Year 2002 Summary: The total mortality from malignant melanoma continues to rise despite partially successful efforts at control of risk factors and at early diagnosis. Two stages of melanoma have been identified by the University of Pennsylvania's Pigmented Lesion Group in a model based on the analysis of stepwise tumor progression. In the first stage, radial growth phase, the lesion ay be invasive but is non-tumorigenic and metastasis does not occur. In the second stage, vertical growth phase, there is tumorigenic growth in the mesenchyme to form a mass lesion. Metastasis occurs with a probability that can be estimated on the basis of a multivariable prognostic mode. Growth in the mesenchyme appears to correlate with changes in cell surface adhesion molecular expression as judged by studies in cell lines, in experimental animals, and by limited univariate analysis of marker expression in frozen sections of human melanomas. A matrix adhesion subunit, beta3 integrin, two cell adhesion molecules, MUC18, the costimulatory molecule ICAM-1, an other integrins including alpha2beta1, alpha4beta1 and alpha5beta1, appear to be among the most highly expressed and/or specific tumor progression markers for melanoma. The Group has access to archival paraffinembedded blocks and/or microscopic slides of the melanomas from more than 3000 prospectively registered and followed patients who have been entered into a clinical database. This unique pathology resource together with newly developed immunohistochemical methods will allow the group to test for the first time in a robust analysis the hypothesis that expression of adhesion molecules correlates with survival in cases of human melanoma evaluated in situ. The finding that a marker correlates with survival suggests that it represents a molecule of importance to the metastatic phenotype, which in turn may prompt the exploration of therapeutic possibilities. Further, such markers may be of value in the development of new prognostic models that will add to the accuracy of survival prediction for therapeutic decision-making and the planning of therapeutic trials. Finally, as clinicians remove increasing numbers of clinically problematical pigmented lesions, pathologists are faced with increasingly difficult diagnostic problems. Tumor progression antigens, if they can be studied in routine archival material, could provide the basis for useful diagnostic tests. This project represents a logical continuation and extension of our previous basic science work into the clinical arena, and it is well connected to the studies of adhesion molecules in the projects of M Herlyn and D Speicher, and to the evaluation of new antibodies that will be produced in these projects and in that of D Herlyn. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUSOGENIC MEMBRANE GLYCOPROTEINS FOR CANCER GENE THERAPY Principal Investigator & Institution: Vile, Richard G.; Consultant; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: The goal of this project is to exploit the highly potent cytotoxic properties of a novel class of genes, called Fusogenic Membrane Glycoproteins (FMG), for the gene therapy of cancer. Many viruses kill their target cells by causing cell fusion through binding of the viral envelope protein on an infected cell with its cellular receptor on

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neighboring cells. The result is the formation of large, multi-nucleated syncytia which eventually become non-viable and die. We have used gene transfer of the cDNAs of three different types of FMG to tumor cells. The cytotoxicities of these FMG were consistently greatly superior to that of conventional suicide genes and the local bystander killing effects were at least one log greater than those of the HSVtk/Ganciclovir system. FMG tested so far kill target cells via non-apoptotic mechanisms with the concomitant induction of immune stimulatory signals such as heat shock proteins. We now hypothesize that these properties of FMG-mediated tumor cell killing can be exploited, and enhanced, to generate more effective gene therapies for cancer. We will characterize in detail the mechanisms by which FMG gene transfer leads to cell death to understand what regulates the efficiency of syncytial killing and how to improve it for therapeutic purposes.We will investigate how the mechanisms of syncytial killing can be enhanced in vivo to stimulate potent immune responses against tumor metastases. This will be done by constructing vectors in which additional immune stimulatory genes, such as GM-CSF, are co-expressed with FMG and by generating FMG-induced tumor cell-dendritic cell hybrids for anti-tumor vaccination. We propose to make a series of viral vectors to transfer the cDNAs of different FMG into tumor cells to identify the most effective FMG for the gene therapy of the target disease, in this case malignant melanoma. Finally, we will construct retroviral and adenoviral vectors which incorporate tight transcriptional regulatory elements to allow targeting of FMG expression to melanoma cells to increase the safety of these potent genes for progression to clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR HUMAN MALIGNANT MELANOMA Principal Investigator & Institution: Grimm, Elizabeth A.; Professor and Section Head; Introgen Therapeutics, Inc. 2250 Holcombe Blvd Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 02-JUL-2001; Project End 30-JUN-2003 Summary: (Applicant's Description) Melanoma is the most malignant of skin cancers. In the USA, the incidence of melanoma is increasing more rapidly than any other cancer. Melanoma is the most frequently occurring cancer in women from the ages of 25-30, and has recently replaced leukemia as responsible for the most lost work hours in the United States. Currently there is no approved therapy that achieves more that a 20% response rate. Therefore, better therapies for malignant melanoma are urgently needed. Introgen Therapeutics is developing a novel anti-tumor gene therapeutic, Ad-mda7, and has demonstrated it's anti-tumor potential against breast and lung cancer cell lines. Here, we propose to perform proof-of-principle experiments to evaluate the efficacy of Ad-mda7 in melanoma. Growth inhibition studies will be performed using human melanoma cell lines in vitro and, if successful, will progress to evaluate Ad-mda7 in vivo using human melanoma xenografts. If these first aims are successful, we will test Ad-mda7 alone and in combination with conventional chemotherapeutic agents using metastatic tumor models. At the end of this Phase I STTR, we plan to have gathered the necessary efficacy data to proceed to safety studies and IND filing in a Phase II STTR, based on clinical trial testing of Ad-mda7. PROPOSED COMMERCIAL APPLICATION: Ad-mda7 is a gene therapy drug to be tested as a novel therapeutic for the treatment of malignant melanoma. Malignant melanoma is a dire skin cancer with few available treatment options. The incidence of melanoma and malignant melanoma is increasing. Approximately 41,000 people are predicted to diagnosed with melanoma this year, with more than 7,000 deaths resulting from this disease. The studies outlined here will guide the preclinical development of Ad-mda7 for melanoma. Subsequent Phase II studies will

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evaluate the therapeutic potential of Ad-mda7 in clinical trials with the goal of submission of a BLA to the FDA and subsequent marketing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC PREDICTORS FOR DNA REPAIR PHENOTYPE IN CMM Principal Investigator & Institution: Wei, Qingyi; Professor; Epidemiology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2009 Summary: (provided by applicant): Cutaneous malignant melanoma (CMM) is the most serious form of skin cancer. Sunlight has for a long time been suspected to cause CMM. It is predicted that the incidence of CMM will continue to increase as a result of the continuous decrease in the concentration of stratospheric ozone and increased leisure time for sunlight-related recreations such as sunbathing, which will increase exposure to solar ultraviolet (UV) B radiation responsible for inducing DNA damage in humans. Our recently completed case-control study provides evidence that low DNA repair for UV-induced DNA damage (as measured by a host-cell reactivation (HCR) assay) may contribute to sporadic CMM in the general population. These seven xeroderma pigmentosum (XP) genes (i.e., XPA, XPB/excision repair cross-complementing group 3 (ERCC3), XPC, XPD/ERCC2, XPE/damaged DNA-binding protein (DDB1), XPF/ERCC4 and XPG/ERCC5)code for core proteins involved in the nucleotide excision repair (NER) pathway that effectively repairs UV-damaged DNA including photoproducts such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs). Our preliminary data suggest that a combined genotype of XPC and XPD predicts DNA repair phenotype as measured by the HCR assay. We propose to identify a combination of functional polymorphisms of these seven NER genes that predicts DNA repair phenotype in CMM using a case series analysis. Our specific Aims are: Aim 1. To accrue a case series of 800 incident CMM with blood sample collection and to develop a comprehensive database of complete assessment of epidemiological risk factors, whole body skin examination, and genotypic and phenotypic biomarkers for the NER. Aim 2. To determine phenotypic and genotypic characteristics of NER in these CMM patients; and Aim 3. To determine the correlation between DNA repair genotype and phenotype and identify a combined NER pathway genotype that best predicts the DNA repair phenotype. These aims are achievable, because it is biologically plausible that DRC may be determined by genetic polymorphisms of genes that participate in NER, which is measured by DRC. Our preliminary data have shown that individuals with suboptimal DRC are at risk of developing CMM and that a combined genotype of three polymorphisms of XPC and XPD is a reasonable predictor of the DRC phenotype. Because the phenotypic DNA repair assay requires cell cultures with viable cells and is too labor-intensive for large molecular epidemiological studies, it is important to identify genotypic markers that predict such DNA repair phenotype so that they can be used for future screening for individuals with genetic susceptibility to development of CMM in the general population. When the combined NER genotype representing genetic susceptibility to CMM is identified and is confirmed in the general population, it may have a significant impact on primary prevention of CMM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENOME WIDE APPROACH TO MELANOMA CLASSIFICATION Principal Investigator & Institution: Flotte, Thomas J.; Director; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115

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Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-AUG-2003 Summary: (provided by applicant): The incidence of malignant melanoma is increasing worldwide at rates that have been reported to be between 3 and 7 percent. In the United States, the incidence of melanoma is rising faster than any other malignancy. The overall goal of this project is to evaluate whether gene expression profiling can provide additional diagnostic and prognostic information for patients with malignant melanoma. Despite decades of attempts to identify clinical and histological features that would be useful in predicting which lesions were going to metastasize, only limited success can be claimed. The measured thickness (the Breslow measurement) and the presence or absence of ulceration are the strongest predictors of outcome for localized disease. The identification of patients with a high risk of metastasis is important for the surgical management of the patient as well as to determine which patients should be admitted to clinical trials of adjuvant agents as these become available. A comprehensive knowledge of the genes expressed by melanoma may be helpful in management of these patients. The specific aims are as follows: 1. To use genome-wide gene expression using microarray technology of human metastatic melanoma and congenital nevi in tissue specimens to identify candidates for accurate prognostication of melanoma patients with localized disease (Stages I and II). 2. Develop in situ hybridization assays for the candidate genes identified in Specific Aim 1. The assays will be validated both on from the tissues used in Specific Aim 1 as well as specimens from additional patients. 3. In situ hybridization will be utilized to examine tissue sections of primary melanomas. The pattern of involvement of the primary tumors will be correlated with clinical outcome. The results will be correlated with known prognostic factors to determine if the information provides additional prognostic information. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENOMIC-WIDE KINASE SEQUENCING OF PEDIATRIC BRAIN TUMORS Principal Investigator & Institution: Roberts, Thomas M.; Professor of Pathology; DanaFarber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2004; Project Start 15-JUL-2004; Project End 30-JUN-2009 Summary: (provided by applicant): Pediatric cancers of neural ectodermal origin are the most common solid tumor in children and are now the most common cause of cancerrelated death in children. The goal of this grant is to define drugable targets for two of the most common pediatric cancers of the central nervous system - malignant medulloblastoma and low-grade astrocytoma. Neither of these tumors exhibits gross chromosomal instability that characterizes malignant astrocytomas in adults. Both tumors are generally wild type for the tumor suppressor genes most commonly mutated in adult CNS cancers - p53, RB and PTEN. On the other hand, upregulated kinase activity has been associated with poor outcome or increased metastatic potential in these tumors. The hypothesis of this grant is that the malignant phenotype for medulloblastoma and also for low-grade astrocytoma reflects a gain-of-function mutation within a single protein kinase (or a small number of kinases) unique to each tumor type. Recent insights into the genetics of malignant melanoma suggest that this hypothesis is reasonable. We have assembled a tripartite team in 1) Pediatric Oncology/Neuro Pathology, 2) Molecular Biology/Bioinformatics and 3) Signal Transduction/Drug Discovery that makes the hypothesis testable and our goal achievable. Our study plan has three aims: (1) to isolate DNA for mutation analysis from at least 15 medulloblastoma and 15 low-grade astrocytomas a year for three years. (2) to identify mutations in all tyrosine kinases and all serine/threonine and lipid kinases

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Malignant Melanoma

involved in oncogenic signaling pathways. Towards this end, we will sequence roughly 4000 exons, covering the entire coding sequences of tyrosine kinases and of all oncogenic serine/threonine kinases as well as key portions of the remaining serine/threonine kinases and type 1 PI3 kinases, (3) to characterize the biochemical activity and biological activity of the mutant kinases. Mutant kinases will be subjected to a battery of analytical tests to see if the mutation increases the specific activity of the kinase in vitro or in cells. Finally, we will determine if the mutation increases the transformation potential of the kinase. The research will lead to a new generation of selective therapeutics for children with brain cancer. Since cancers of children are often "informative" in a larger context, it is likely that these medicines will find use for more frequent adult cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST/TUMOR INTERACTIONS IN IMMUNOTHERAPY OF PROSTATE CA Principal Investigator & Institution: Ratliff, Timothy L.; Andersen-Hebbeln Professor; Urology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 05-MAR-2001; Project End 28-FEB-2006 Summary: (Applicant's Abstract) Prostate cancer is the most common visceral cancer and the second leading cause of death from cancer in men in the United States. Metastatic prostate cancer is treated in a palliative manner by androgen ablation. The appearance of hormone-independent cancer denotes cancer progression for which no curative treatment is available. Immunotherapy offers an approach for the development of treatments of an otherwise untreatable cancer. However, even though new technology has provided superior activation of antitumor immune responses, the therapeutic benefit of treating previously diagnosed cancer has not proven efficacious. Recent studies demonstrate that many tumor recognition antigens are normal, nonmutated antigens common to normal cells of similar histological type. Furthermore, in recent immunotherapy trials activation of immunity to antigens on malignant melanoma cells induced an autoimmune response to normal melanocytes. These data show that tumor cells and normal parenchymal cells share common self-determinants that are recognized by the immune system. Such responses are tightly regulated to prevent the development of autoimmune disease. The applicant has performed immunotherapy studies in a prostate cancer model using the non-replicative canarypox virus, ALVAC, as an immune-activating gene delivery system. Treatment of prostate tumors with ALVAC cytokine recombinant induced antitumor activity but also activated immunoregulatory mechanisms that inhibited the immune effector events necessary for the elimination of cancers. The studies outlined in this application will characterize the immmunoregulation induced by immunotherapy of prostate cancer and will determine the relationship between the identified tumor escape mechanisms and the regulation of immunity to self antigens expressed on normal prostate cells. To this end the following specific aims are proposed: (1) Characterization of the CD8+ T cell regulation observed after ALVAC cytokine treatment. This will include: a) Determination of functional characteristics of the regulatory phenomenon induced by cytokine-secreting RM-1 tumor cell vaccines, b) Determination of phenotypic characteristics of the CD4+ regulatory T cell, and c) Characterization of the inhibition of CD8+ T cell function after the in vivo administration of ALVAC cytokine recombinants; (2) Determination of the effects of ALVAC cytokine treatment on CD8+ T cell activation in vivo. This will include: a) Characterization of the effects of ALVAC cytokine treatment on CD8+ T cell activation and b) Characterization of the regulation of CD8+ T

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cell activation in a transgenic tumor system. The studies proposed in this application address a PRIORITY ONE research objective described in the "Report of the Prostate Cancer Progress Review Group". These studies address the specific recommended action that requested support for ".research that emphasizes specific cell-cell interactions between and among developing epithelial cells.and inflammatory cells". Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF A MELONOMA SUSCEPTIBILTY GENE AT 1P22 Principal Investigator & Institution: Brown, Kevin M.; Translational Genomics Research Inst 400 N 5Th St, Ste 1600 Phoenix, Az 85004 Timing: Fiscal Year 2004; Project Start 22-APR-2004; Project End 21-APR-2007 Summary: (provided by applicant): Cutaneous malignant melanoma (CMM) incidence is rising, accounting for approximately 4% of cancer diagnoses in U.S. Recently, a novel CMM susceptibility locus was identified on chromosome 1 (1p22). To identify this gene Aim 1, we will use a multidisciplinary approach to comprehensively identify, prioritize, and screen genes within the critical region. We will construct a custom oligonucleotide microarray with probes representing all evolutionarily conserved sequence at 1p22 and assay expression in melanocytes and melanoma cell lines to identify all expressed genes in the region. We will use these arrays for CGH to screen for deletions in familial CMM patients and sporadic melanoma cell lines. We will SNP-genotype our families and perform a linkage disequilibrium based association study to narrow the 1p22 critical region. Based on these experiments, we will prioritize 1p22 candidates for highthroughput mutation screening. Once the CMM susceptibility gene is identified, we will look for genotype-genotype correlation, testing the hypothesis that Iow-penetrance genetic CMM risk factors act as modifiers to the penetrance of 1p22 mutations (Aim 2). Finally, we will determine the prevalence of 1p22 mutations in sporadic melanoma cell lines and tumors (Aim 3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFICATION OF CRITICAL DERMOSCOPIC FEATURES Principal Investigator & Institution: Stoecker, William V.; Adjunct Assistant Professor; Stoecker & Associates 1702 E 10Th St Rolla, Mo 65401 Timing: Fiscal Year 2003; Project Start 23-SEP-2003; Project End 29-FEB-2004 Summary: (provided by applicant): Malignant melanoma, with an estimated growth in incidence of about 6% per year for decades, causes considerable loss of life. Yet melanoma can be easily cured if detected early. Digital dermoscopy has shown promise for more accurate detection, particularly at an early stage. Recent conferences have highlighted a general agreement on definition of dermoscopic features and moderate agreement on the most useful structural features. Automatic detection of these specific structures that are critical for early diagnosis and are used in various dermoscopic diagnostic algorithms would be desirable. Yet little work has been published on automatic detection of any specific dermoscopic structures. In addition, diagnostic accuracy of digital dermoscopic systems is limited by the failure of systems to properly separate the lesion from the background in a significant number of cases. Although specific colors figure prominently in the definition of the most critical dermoscopic structures, little work has been done on finding the specific regions in the color space where melanoma colors are located, particularly with reference to the surrounding skin. This proposal seeks to improve performance of digital dermoscopy systems by 1)

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Malignant Melanoma

finding borders with greater accuracy 2) developing an algorithm that uses a threedimensional representation of a probability density function to specify melanoma colors via cluster methods and fuzzy logic techniques 3) identifying critical structural features including brown globules, abrupt border cutoff, granularity, regression, and pigment asymmetry with high accuracy 4) developing a clinical interface for acquisition of images within the clinic 5) developing a web-tool for interactive analysis of images. Key features of the research include dermatopathology confirmation of specific structures and the use of relative color analysis. If successful, specific algorithms would be shared with the growing number of dermatologists using digital dermoscopy. In Phase II, further testing of the algorithms and development of a fast interface would be undertaken. A commercial package combining the software components would be made available for a popular combination digital camera-light head. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMAGING MALIGNANT MELANOMA WITH RADIOLABELED ALPHA-MSH PEPTIDE ANALOGS Principal Investigator & Institution: Quinn, Thomas P.; Assistant Professor; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (Revised Abstract) (provided by applicant): This application outlines a research effort to develop and evaluate radiolabeled peptides for malignant melanoma imaging. Malignant melanoma is a serious public health problem due to an increase in its incidence and resistance to conventional chemotherapeutics and external beam radiation therapy. Early detection is critical for proper therapeutic management. There is a clear need to develop new and efficacious imaging and therapeutic agents. Our laboratory has developed a new class of metal-cyclized peptide (CCMSH) that target the a-MSH receptor present on melanoma cells. The CCMSH peptides will be radiolabeled with 99mTc, 111In for SPECT and 64Cu for PET imaging of melanoma in murine and human melanoma mouse models. Mice bearing solid tumors and metastatic melanoma in the lungs will be imaged at various times during the course of their disease to determine the detection sensitivity and specificity of the radiolabeled peptides. Micro SPECT and micro PET imaging studies will also be compared to determine the optimal combination of peptide, radionuclide and detection modality for melanoma imaging. The CCMSH imaging agents are envisioned to be part of a matched pair strategy for melanoma imaging and therapy in which the same melanoma targeting vector (CCMSH) can be radiolabeled with radioisotopes that possess imaging or therapeutic properties. We also plan to employ bacteriophage (phage) display technology to discover new melanoma targeting vectors. The random peptide libraries, displaying 5150 peptides per particle, will be selected in human melanoma bearing mice for tumor targeting peptides. In vivo selection strategy should closely simulate the complex targeting environment an imaging agent encounters thus allowing us to select superior melanoma avid phage. We propose to use the tumor avid phage particles themselves as targeting agents in a pretarget approach. The tumor avid phage will be conjugated with <10 copies of Neutravidin per particle. Neutravidin phage will be injected into tumor bearing mice and allowed to localize to the tumor or clear the body over a period of day(s). Indium-111 labeled DTPA-biotin will be injected intravenously and the animals will be imaged over a period of several hours. Pretarget phage imaging will allow us to take advantage of the power of in vivo selection with polyvalent peptide display while not suffering the partitioning consequences of a large radiolabeled molecule. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Principal Investigator & Institution: Borejdo, Julian; Molecular Biology Immunology; University of North Texas Hlth Sci Ctr Fort Worth, Tx 761072699

and

Project Title: IMAGING MELANIN IN MELANOCYTES

Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant): The long-term goal is early diagnosis of malignant melanoma. It is proposed to test a possibility that malignant transformation modifies physical characteristics of melanin. Physical characteristics will be monitored by fluorescence. It is proposed to compare fluorescence of melanin from normal cells with fluorescence of melanin from a series of melanoma cell lines with varying degrees of aggressiveness. Fluorescence will be collected from a small number of molecules by a modified confocal microscope. Fluorescence of a few molecules should be an accurate indicator of early events of malignant transformation, because it it is not averaged over the entire population of melanins in a melanocyte. Confocal microscope is the instrument of choice when attempting to measure fluorescence of a small number of molecules. However, a commercial instrument is unable to detect less than about 1000 molecules. To decrease this number, the sensitivity is increased by replacing vacuum tubes with semiconductor detectors and by processing signal digitally. Preliminary results show that this modification improves sensitivity by two orders of magnitude. Fluorescence of melanin is induced by the absorption of infrared light. Three parameters of fluorescence - its intensity, lifetime and spectrum -- are measured simultaneously. The method is important because it can be extended to measurements on skin samples in situ. The modifications are relatively simple, inexpensive and not tied to a specific brand of instrument. It is expected that the method will find application in a small diagnostic laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE AND COLON CANCER IN BLACKS AND WHITES Principal Investigator & Institution: Keku, Temitope O.; Associate Professor; Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The long-term goals of this project are to define the interactions between insulin resistance, genetic and environmental risk factors in the etiology of colon cancer and to achieve further career development training for the applicant in molecular epidemiology and bioinformatics. Dr. Keku, the applicant, is an Assistant Professor at UNC. Her mentors are Drs. Robert Millikan and Kay Lund. Dr. Millikan is an established molecular epidemiologist. He is the Principal Investigator of the Carolina Breast Cancer Study and also part of an international collaboration investigating the interactions between sunlight and genetic factors in the etiology of malignant melanoma. Dr. Lund is a Professor of Molecular Biology and Physiology and an expert on the IGF system as it relates to GI disease. They propose a mentored career training for Dr. Keku in molecular epidemiology and bioinformatics utilizing the resources at the UNC School of Public Health and the Department of Cell and Molecular Physiology in the School of Medicine. The study proposed as part of the mentored career development training is a case-control study of insulin resistance (insulin/IGF) and colon cancer in African Americans and whites. Colon cancer is the most common gastrointestinal malignancy in the United States. The rise in the incidence and mortality of colon cancer in African Americans poses a serious public health problem. The specific

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Malignant Melanoma

aims of this study are: 1)To examine the association between insulin/IGF axis and colon cancer in African American and white subjects with and without colon cancer. 2) To evaluate the role of genetic polymorphisms in the insulin/IGF axis and their relationship to colon cancer and associated risk factors. 3) To examine the association between the insulin/IGF-axis and factors related to insulin resistance in African American and white subjects with and without colon cancer. The proposed study will utilize available specimens and measurements from a population based case-control study of colon cancer (NCI R01 CA66635). We will use plasma and DNA specimens to determine insulin, IGF-I, IGF-II, IGFBP-1, IGFBP-3, glucose and C-peptide levels and for genotyping assays respectively. The results of the laboratory assays will be merged with lifestyle/dietary information and analyzed for associations. The proposed project will advance the understanding of the role of insulin resistance in colon cancer among African Americans and whites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERLEUKIN 2 + HISTAMINE VERSUS INTERLEUKIN 2 IN ADVANCE MALIGNANT MELANOMA Principal Investigator & Institution: Oratz, Ruth; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: KIT GROWTH CONTROL OF MELANOCYTIC TUMORS Principal Investigator & Institution: Grichnik, James M.; Associate Professor; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: Malignant melanoma, a deadly skin cancer, is the result of the unregulated proliferation of melanocytes. Therapeutic approaches targeting specific proliferation pathways may be useful for the treatment of melanocytic tumors. We have shown that in human skin, cytokine stimulation of melanocytes with cell factor (SCF) cause melanocyte proliferation, while inhibition of the SCF receptor, KIT, results in melanocyte loss. This is the only cytokine pathway that has been shown to have the pharmacologic capacity to control melanocyte homeostasis within human skin; however, it is not clear how pharmacologic manipulation of this pathway will affect benign and malignant melanocytic neoplasias. Our objective is to determine the extent to which the KIT pathway controls growth and maintenance of melanocytes in benign and malignant tumor types in vivo, and to develop an in vitro system suitable for the study of KIT pathway in melanocytes and melanoma cell lines. We developed a xenografting technique that allow us to engraft human skin, nevi, and early melanoma tissues on immunodeficient mice. The xenografts can be maintained long term and allow for pharmacologic manipulation of human skin without potential risks to the patient. We have demonstrated that SCF drives melanocytic proliferation in the human skin grafts and that the changes reflect those seen at the SCF injection site in patients who have received recombinant SCF in phase one trails. Further, we have demonstrated that inhibition of KIT with K44.2, a specific inhibitory antibody, results in melanocyte loss. We intend to utilize the pharmacologic treatment of human xenografted tissue to determine the role of the SCF/KIT pathway on the growth and maintenance of benign and malignant melanocytic tumors. Potential mechanisms by which this pathway elicits

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its effects will be studied with a focus on proliferation, apoptosis, and differentiation status. In order to study the mechanism by which KIT-inhibition results in melanocyte loss and the mechanisms of KIT resistance, which may be present in advanced melanomas, a KIT- sensitive culture system will be developed by growth factor, substrate attachment, cell co-culture, and media modifications. This culture system will allow us to evaluate the direct effect of KIT inhibition on individual melanocytes and melanoma cells and to potentially determine whether it is possible to reactivate SCF/KIT pathway dependence in resistant tumor lines. The proposed experiments will define to what extent manipulation of the KIT pathway will be useful for the therapeutic treatment of proliferative melanocytic disease processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LYMPHOKINES ON METASTATIC MALIGNANT MELANOMA Principal Investigator & Institution: Valentine, Frederick T.; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MALIGNANT MELANOMA: REGULATION BY AP-2 AND PAR-2 Principal Investigator & Institution: Bar-Eli, Menashe; Professor; Cancer Biology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-APR-1999; Project End 31-AUG-2007 Summary: (provided by applicant): The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP, metastatic phenotype) are not very well-defined. Recent work from this laboratory demonstrated that this transition is associated with loss of expression of the AP-2 transcription factor. We showed that lack of expression of AP-2 in metastatic melanoma cells resulted in deregulation of the c-KIT and MCAM/MUC18 genes, both of which are involved in the progression of human melanoma. Moreover, inactivation of w.t. AP-2 in primary cutaneous melanoma cells by dominant-negative AP-2 (AP-2B gene) resulted in an increase in their tumorigenicity and metastatic potential in vivo due to upregulation of MMP-2. Loss of AP-2 expression was also observed in advanced primary of melanoma patients indicating that loss of AP-2 is a crucial event in the progression of human melanoma. In an effort to identify other target genes regulated by AP-2, here we provide evidence of an inverse correlation between the expression of AP2 and the thrombin receptor (PAR-1) in metastatic melanoma cells. Regulation of PAR-1 by AP-2 in melanoma cells is demonstrated in vitro and in vivo, thus providing a unique link between the coagulation system and the progression of human melanoma. Recent evidence suggests that thrombin receptor plays an important role in metastasis of human melanoma. PAR-1 is a unique G-coupled protein receptor that belongs to the protease activated receptor family. Activation of PAR-1 can result in upregulation of gene products involved in adhesion (integrins), invasion (MMP's) and angiogenesis (IL8, VEGF, uPA, PDGF and bFGF). The hypothesis to be tested in this proposal is that loss of AP-2 results in upregulation of PAR-1 which correlates with the malignant phenotype of human melanoma. To test this hypothesis we now propose to: 1) determine how AP-2 regulates PAR-1 expression; 2) to analyze AP-2 and PAR-1 expression in tumor specimens from melanoma patients and; 3) to study how activation of PAR-1 contributes to the metastatic phenotype in human melanoma. Understanding the mechanisms by

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Malignant Melanoma

which PAR-1 is activated may lead to new techniques to inhibit melanoma invasion and metastasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF DIETARY MODULATION OF MELANOMA INVASION Principal Investigator & Institution: Meadows, Gary G.; Dorothy O. Kennedy Professor & Director,; Pharmaceutical Sciences; Washington State University 423 Neill Hall Pullman, Wa 99164 Timing: Fiscal Year 2002; Project Start 20-JUL-1999; Project End 30-APR-2004 Summary: The incidence of malignant melanoma continues to increase, and often is associated with metastasis. Once metastasis occurs, it is virtually incurable. The goal of this project is to discover the mechanism by which melanoma metastasis occurs so that we can disrupt this fatal process. We already demonstrated that restricting tyrosine (Tyr) and phenylalanine (Phe) in the diet dramatically inhibits metastasis, more than doubles survival time of mice with metastatic B16BL6 melanoma, and alters the invasive and metastatic phenotype of B16BL6 melanoma cells. Inhibition of invasion and metastasis can be replicated after culture of cells in vitro under Tyr/Phe-deprived conditions. We propose to examine the mechanism underlying the inhibition of invasion. Preliminary data indicate that Tr/Phe restriction induces G0/G1 cell cycle arrest, decreases attachment to a group of constituents of the cell matrix known collectively as heparan sulfate proteoglycans (HSPG), and decreases invasion through reconstituted extracellular matrix (Matrigel), and growth factor reduced Matrigel in melanoma cells. Meanwhile, this deprivation also decreases some functional proteins, such as 1) focal adhesion kinase (FAK) expression and phosphorylation, 2) Ras and cRaf-1 expression, 3) cyclin D1 expression, and 4) secretion of tissue plasminogen activation (tPa), urokinase plasminogen activator (uPA) and metalloproteases )(MMPs) 2 and 9. We hypothesize that the inhibition of FAK expression and activation along with decreased Ras and c-Raf-1 signaling pathways accounts for the anti-invasive effect of Tyr/Phe restriction in melanoma cells. Biochemical and molecular approaches will be used to examine the following specific aims: 1) Determine what role(s) FAK protein plays in the attachment of melanoma cells to HSPG and invasion through HSPG (using in vitro techniques, comparing cells deprived of specific amino acids with cells grown in complete media); 2) Determine whether the inhibition of Tyr phosphorylation of FAK by amino acid deprivation in melanoma cells is Src Try kinase specific; 3) Determine the role of the Ras of the Ras/Raf/Erk signaling plays in synthesis and secretion of plasminogen activators (Pas) and MMPs in melanoma cells as influenced by amino acid deprivation; and 4) Determine the effect of anti-Ras and anti- cyclin D1 treatment on invasion. This study will enhance knowledge of the mechanisms underlying the antiinvasion activity of Tyr/Phe restriction. Understanding the connection between antiadhesion and anti-signaling effects by Tyr/Phe deprivation will provide a sound rationale for designing new therapeutic approaches to slow or block progression of highly invasive and metastatic melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TOXICITY

MECHANISMS

OF

PSORALEN-INDUCED

REPRODUCTIVE

Principal Investigator & Institution: Diawara, Moussa M.; Colorado State UniversityPueblo 2200 Bonforte Blvd Pueblo, Co 81001

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Timing: Fiscal Year 2002; Project Start 25-AUG-1981; Project End 30-JUN-2006 Summary: (provided by applicant): The psoralens are naturally occurring plant metabolites found in common fruit and vegetable crops. Synthetic forms of 8methoxypsoralen (xanthotoxin or methoxsalen) and 5-methoxypsoralen (bergapten) are widely used as drugs in skin photochemotherapy and have been used as tanning activators in many sunscreen preparations. Unfortunately, the use of psoralens in skin photochemotherapy has been shown to have major side effects, for example malignant melanoma. Recent studies have shown that these compounds can also have reproductive effects in rats. Therefore, these chemicals could also represent a risk for infertility or birth defects in humans. The main goal of the study proposed herein is to better characterize xanthotoxin-induced reproductive toxicity in female and male rats. The central hypothesis is that xanthotoxin produces reproductive effects by disrupting the hypothalamo-pituitary axis, and the alternate hypothesis is that this compound targets gonadal function, resulting in alteration of pregnancy outcome. Xanthotoxin will be administered orally or by injection in male and female Wistar rats during acute and subchronic tests. Its effects will also be observed in tissue culture and in vitro experiments. Its impact on secretion of reproductive hormones, gene expression, and gonadal function will also be determined. The Specific Aims are to: I) investigate the direct effect of xanthotoxin dosing on the hypothalamo/pituitary/gonadal axis in female and male rats; II) investigate the direct effect of xanthotoxin dosing on gonadal function in female and male rats; and III) investigate the role of the male in xanthotoxininduced pregnancy effects. The results of the proposed study will help 1) establish the role of the hypothalamo-pituitary axis in the response of the reproductive system to environmental insults such as xanthotoxin, 2) provide dramatic insight into the potential reproductive toxicity of the psoralens in the female and male reproductive systems; 3) better understand gender differences in the response of the male and female reproductive systems to xenobiotic exposures; and 4) reduce the risk in men and women who are exposed to therapeutic (medicinal use), dietary (produce handling and/or consumption), cosmetic (sunscreen use), or occupational (agricultural or industrial work) psoralens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELANOMA AND ALLELIC VARIATION IN THE MCIR GENE Principal Investigator & Institution: Kanetsky, Peter A.; Assistant Professor; Biostatistics and Epidemiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 06-SEP-2000; Project End 31-AUG-2005 Summary: (Applicant's Description) One of my academic career goals is to develop molecular and genetic epidemiologic research to identify etiologic factors associated with pigmented lesions, including cutaneous malignant melanoma and multiple primary melanoma (MPM). Determination of susceptibility genes for melanoma can facilitate identification of those at increased risk for disease and may result in increase public and individual efforts of prevention and early detection. The potential impact of these measures is great, as melanoma incidence has reached epidemic proportions and mortality due to melanoma has slowly increased over the past decades. The Preventive Oncology Academic Award will give me an opportunity to become a competent melanoma molecular epidemiologist. To this end, I will advance my academic understanding of melanoma through further education in the basic sciences, molecular biology/epidemiology, genetics, and clinical decision making. Practical experience will be gained through participation in molecular laboratory biology, with a focus on

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Malignant Melanoma

methodologies used in molecular epidemiology. Two research projects are proposed to explore the association of a candidate susceptibility gene and development of melanoma. Mutations in the candidate gene of interest, the melanocortin-1 receptor (MC1R), may affect melanin synthesis, resulting in an increased potential for cellular DNA damage that may lead to melanocytic carcinogenesis. The goals of the first study are i) to determine the number and types of gene variants among persons with MPM and single cutaneous melanoma (SCM), and ii) to test whether these mutations play a role in the subsequent development of MPM. The results will contribute greatly to the epidemiologic literature on candidate susceptibility genes associated with melanoma and will help focus primary and secondary prevention for persons at increased risk for secondary, primary melanomas. The second project evaluates whether allelic variants in the MC1R gene explain the pattern of melanoma in families prone to melanoma. Result from this project may provide valuable insight into the genetic predisposition to melanoma seen in some families, and may lead to more efficient mechanisms of primary prevention and clinical follow-up within these families. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELANOMA CELL SURFACE PROTEOGLYCANS IN METASTASIS Principal Investigator & Institution: Mc Carthy, James B.; Professor; Lab Medicine and Pathology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: (Adapted from the investigator's abstract) Melanoma chondroitin sulfate proteoglycan (MCSP), also known as high molecular weight melanoma associated antigen (HMW-MAA) is large, highly antigenic cell surface proteoglycan that is dramatically upregulated in melanoma. MCSP is being actively pursued as a target for melanoma vaccine development due to its restricted expression and antigenic properties. Despite its potential clinical importance, relatively little is known about the role of MCSP in melanoma progression. Previous studies have implicated MCSP in adhesion, motility, or cellular growth control. He presents data to demonstrate that inhibition of MCSP expression by anti-sense oligonucleotides inhibits tumor invasion and growth in soft agar in vitro. He has demonstrated that MCSP functions as an adhesion molecule, in part by enhancing the activity of a4b1 integrin, a mediator of tumor invasion and arrest. In addition, he has identified a novel signaling pathway stimulated by MCSP. Activation of MCSP leads to the rapid association and tyrosine phosphorylation of p130cas, an adapter protein implicated in tumor motility and invasion. This signaling pathway also involves the association of MCSP with cdc42, a rho-family GTPase that mediates filopodial formation, cell motility and growth. Furthermore, Ack-1, a tyrosine kinase that associates with active (i.e., GTP bound) cdc42, is required for MCSP induced tyrosine phosphorylation of p130cas. Collectively the data are consistent with a model in which MCSP enhances tumor growth and invasion by sequestering intracellular components of a signaling complex in response to an external stimulus. In this application he will further define that signaling complex and study its importance for melanoma growth, invasion and metastasis. Additionally, although the MCSP sequence is published, it has not previously been cloned. He has recently amplified the full-length coding sequence for MCSP by RT-PCR of human melanoma mRNA and are in the process of expressing it in transfected melanoma cells which lack MCSP. This clone will enable them to examine the structural and functional relationships between MCSP, its extracellular stimuli, and its intracellular signal transduction. He proposes three specific aims: 1. To evaluate the importance of MCSP

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expression and function in the growth, invasion and metastasis of malignant melanoma cells. 2. To delineate the mechanism of Ack-1 in MCSP induced tyrosine phosphorylation of p130cas and to study this mechanism in the survival, growth and metastasis of malignant melanoma cells. 3. To define functional domains of the MCSP core protein required for signaling and melanoma growth, invasion and metastasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELANOMA CHEMOPREVENTION Principal Investigator & Institution: Dellavalle, Robert P.; Dermatology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The incidence of cutaneous malignant melanoma is rising faster than any other cancer in the US. 1 in 74 Americans will develop melanoma, more than 45,000 cases will be diagnosed, and more than 7,500 Americans will die from melanoma this year. Effective prevention of melanoma will not only save lives, but will also decrease the estimated one billion dollars spent annually treating melanoma in the US. There is currently no recognized chemoprevention for melanoma. Two large, randomized, placebo-controlled clinical trials, the VA-HIT Study utilizing gemfibrozil, and the AFCAPS Study utilizing lovastatin, have each reported an association of lipidlowering medication therapy with statistically significant lower melanoma incidence rates. Lovastatin inhibits melanoma cell growth in tissue culture, and mice Jed lovastatin develop lower lung metastases following tail vein injection with mouse B16 melanoma cells. More recently low concentrations of atorvastatin have been reported to specifically induce apoptosis and inhibit migration of human A375 melanoma cells but not cultured melanocytes. To investigate the unconventional hypothesis that lipid-lowering medications might prevent melanoma, a case-control study will be conducted utilizing Veterans Administration (VA) databases to answer the following question: Do persons who have developed cutaneous malignant melanoma have a history of less lipidlowering medication exposure than persons who are spared the disease? The answer to this question will help determine whether more expensive and labor intensive randomized prospective clinical trials of potentially teratogenic lipid-lowering medications should be initiated in persons at high risk of developing melanoma. Robert Dellavalle, MD, Ph.D., is an Assistant Professor of Dermatology at the University of Colorado Health Sciences Center and a staff dermatologist at the Denver VA medical center He is committed to a career in academic dermatology and public health. His current career goals are completing a Masters of Science in Public Health and becoming an independent researcher in skin cancer prevention and control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MELANOMA IN P16INK4A AND P19ARF DEFICIENT MICE Principal Investigator & Institution: Sharpless, Norman E.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-AUG-2002 Summary: (provided by applicant): Malignant melanoma (MM) is a singular challenge to modern oncology as it is one of the few human cancers in which the age-adjusted incidence has increased throughout the last decade, and it is notoriously refractory to therapy. The genetics of MM in humans suggest two general classes of lesions, receptor tyrosine kinase (RTK) activation, and deletion of the Ink4a/Arf locus at 9p21. Mice with melanocyte specific overexpression of H-Ras (a signaling intermediate of several RTKs)

32

Malignant Melanoma

and Ink4a/Arf loss have been previously shown to develop melanoma with high penetrance and short latency. The Ink4a/Arf locus, conserved in mouse and humans, encodes two distinct proteins, p16INK4a and p19ARF, both of which regulate critical tumor suppressor pathways, and each may play a substantive role in human melanoma. Mutational analysis of human tumors and melanoma- prone kindreds clearly establish p16INK4a as a suppressor of melanoma formation, while the role of p19ARF in human tumors is less clear. Previous work in the mouse, however, shows p19ARF, through its regulation of p53, to be a critical tumor suppressor gene in a wide range of tissues. I propose to define genetically the relative importance of these two proteins in murine melanoma using two novel but as of yet uncharacterized strains of knockout mice. Using standard gene targeting techniques coupled with CRE recombinase mediated excision of the remnant selectable marker (PGK-Neo), I have produced two independent knockout (KO) strains with specific deletion of either p16INK4a or p19ARF. The work described in this proposal involves the characterization in vitro and in vivo of the p16INK4a specific KO, with a particular emphasis on melanocyte biology and melanoma formation. To c o mplement the in vivo analysis of the effect of p16INK4a loss on tumorigenesis, I will cross the p16INK4a KO to a p53-deficient background to look for increased tumor formation and change in tumor spectrum. Melanocyte growth from both p16INK4a and p19ARF null mice will be characterized in vitro, with particular emphasis on their relative transformability. Finally, I will attempt to develop a well-defined murine model of melanoma by crossing the p16INK4a and p19ARF specific KO mice to H-RAS overexpressing mice, in the hope of establishing which of the proteins, or perhaps both, is the critical mediator of melanoma susceptibility in mice in vivo. Such a model could then serve as a foundation for future studies of melanoma progression and therapy, and the results of this work will have implications for the treatment of human MM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELANOMA NRAS/BRAF MUTATIONS: A POPULATION-BASED STUDY Principal Investigator & Institution: Thomas, Nancy E.; Dermatology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Melanoma, which is rapidly increasing in incidence, remains a potentially fatal disease with poor medical treatment options and controversial methods of prevention. Because of the increasing burden of this disease and its lethality, improved methods of prevention, early diagnosis and treatment are expected to be of increasing importance. NRAS and BRAF, mediators in the RAS-RAFMEK-ERK-MAP cell signaling pathway, are the most commonly mutated oncogenes thus far described for melanoma. However, despite the identification of these mutations in primary human melanomas, the frequency and mutational spectrum of NRAS and BRAF mutations in melanoma have not been fully characterized and there is a critical gap in the knowledge base regarding the association of these mutations with heterogeneity, precursor lesions, risk, and prognosis in melanoma. The specific aims of this study are to: (1) determine the population-based frequency and mutational spectrum of NRAS and BRAF somatic alterations in primary cutaneous invasive melanoma and their associations with histologic subtype and potential precursor lesions, and (2) determine associations between NRAS and BRAF mutational phenotypes and known prognostic indicators and risk factors. For this study, a group of approximately 300 consecutive patients with malignant melanoma in North Carolina in

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the year 2000 has been assembled. Complete epidemiologic data, pathology, and tumor blocks have been obtained for these patients. NRAS and BRAF somatic mutations will be detected and characterized using the highly sensitive technique of single strand conformational polymorphism (SSCP) analysis combined with direct sequencing of PCR products. The population-based frequency of these mutations will be determined and compared between pathologically distinct subtypes of melanoma (superficial spreading, lentigo maligna, nodular, and acral lentiginous). In melanoma samples associated with a nevus, this component will be analyzed separately for mutations using laser capture microdissection. Mutational phenotype will be associated with subtype, potential precursor lesions, risk factors, and prognostic indicators. The data derived from this study is expected to clarify the role of NRAS and BRAF in the development, progression and heterogeneity of melanoma, ultimately leading to better prevention, classification and treatment. Elucidation of how these mutations might arise in relationship to environmental and hereditary factors should result in more evidence-based recommendations for risk factor avoidance. In addition, understanding how mutations arise in relationship to precursors should provide information regarding which potential precursors should be removed. This study is also expected to lead to identification of new hemotherapeutic targets and more efficient testing of inhibitors for NRAS and BRAF signaling, which have recently been developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELANOMA PROTEINS IN SERUM AND URINE Principal Investigator & Institution: Tjoelker, Larry W.; Macrogenics, Inc. Rockville, Md 20850 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2005 Summary: (provided by applicant): The overall objective of this proposal is to identify, in serum and urine samples from melanoma patients, specific marker proteins or patterns of protein expression, which are diagnostic of cancer. As with many malignancies, early detection is critical for successful treatment of melanoma. Recent innovations in mass spectrometry make it a powerful technology that has the potential to revolutionize the identification of diagnostic markers for cancer. We aim to use this technology to identify diagnostic proteomic patterns in samples from melanoma patients. To that end, the following specific aims are proposed: 1. Perform mass spectrometry experiments on serum samples from three melanoma patients and three normal controls. 2. Perform mass spectrometry experiments on urine samples from three melanoma patients and three normal controls. 3. For additional biomarker discovery, samples will be fractionated with additional procedures (glycosylation capture and affinity matrices such as Protein A and dye chromatography) prior to mass spectrometry. 4. Confirm biomarker expression with a larger panel of 15 melanoma samples by an alternative method (e.g. Western blots or ELISA for markers with available antibodies or enzymatic activity for characterized enzymes). Relative expression levels of newly identified proteins will also be compared with known melanoma markers such as lactate dehydrogenase. Preliminary proteomic experiments described herein demonstrate that proteins characteristic of different physiological conditions can be identified using isotope-coded affinity tags (ICAT) coupled with tandem mass spectrometry. The specific aims of this proposal will apply this technology to identification of early markers of malignant melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Malignant Melanoma

Project Title: MELANOMA: INTERACTIONS

MICROENVIRONMENT

AND

ONCOGENE

Principal Investigator & Institution: Powell, Marianne Broome.; Sr. Research Scientist; Radiation Oncology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2006 Summary: Malignant melanoma is a very aggressive disease with a high propensity for metastatic spread and chemotherapeutic resistance. Expression of mutated ras has been observed in 15-25 percent of melanomas and premalignant lesions. However the frequency of ras mutations is likely an underestimate of the contribution of aberrant signaling through ras since alterations in anyone of the numerous positive and negative effectors of Ras can result in a similar phenotype as activated ras. Past studies have shown that an expression of activated Ha-ras is necessary for the development of melanoma in several transgenic mouse models. As a key regulator of growth factor and stress signals, ras leads to activation of multiple effector pathways such as Raf/MEK/Erk, phosphoinositide 3-kinase/PDK/Akt, and Ra1GDS. The hypothesis to be explored in this project is that activation of the PI3-OH kinase/PDK/Akt pathway is critical for the malignant progression and metastatic spread of melanoma. To address this hypothesis, we will introduce ras mutants that discriminate between effector pathways. Mutations in the effector binding loop eliminate the ability of ras to bind and specifically activate certain downstream components of the ras network. Ras constructs will be introduced into melanocytes and each pathway will be examined for its effects on the transformed phenotype, activation of downstream effector functions, and the development and progression of melanoma both in cell culture, transplanted cells, and in transgenic mice. Specific aims to address this hypothesis are: 1) to characterize the effect of activated PI 3- kinase pathway melanocyte transformation in cell cultures; 2) to develop and characterize transgenic mice in which we have targeted expression of the ras loss-of-function mutants, C40 and S35, and activated Akt and Raf to melanocytes and; 3) to study the in vivo effect of activation of PI-3 kinase pathway on melanoma progression and metastatic disease. We will study effect of an activated PI3 kinase pathway on histopathology of the tumors, on regulating the tumor response to stress signals, a hypoxic environment and UV exposure, and on the development of metastatic disease. Comparisons will be made with single transgenic mice and double transgenic mice on an INK4a-/- background (a melanoma susceptibility marker) and by exposing the transgenic mice on a C3H background to the carcinogen, DMBA. These studies will provide new models for studying the cancer biology of melanoma and provide new models that will be used to evaluate of new, potential therapeutic agents and identify new molecular targets for intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AWARD

PATIENT-ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Florell, Scott R.; Dermatology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The goal of this project is to determine the role of p16, a tumor-suppressor gene in the retinoblastoma cell-cycle regulation pathway, in familial melanoma kindreds. Malignant melanoma is the most lethal of the skin cancers, and unlike most malignancies, often affects younger patients in their third and fourth decades. Several risk factors have been associated with melanoma, including sun

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exposure, genetic predisposition, total number of nevi present on an individual, and characteristics of nevi. The overall proportion of cutaneous melanoma attributable to genetic predisposition is reported to be about 10- 15%, but evaluation of cancer incidence data from the Utah Population Database suggests that the fraction of melanoma occurring in a familial setting may be as high as 30%. The applicant proposes to re-examine members of Utah melanoma kindreds, first studied 15 years ago at the UUSM, that helped establish the presence of a melanoma susceptibility locus on 9p21 and later confirm the association of p16 mutations with familial melanoma. A five-year mentored program is proposed to investigate the global hypothesis that carriage of a germline p16 mutation results in measurable clinical, histologic, and cellular changes that lead to familial susceptibility to melanoma. This program will incorporate both didactic and research training and will be guided by a research oversight committee composed of four established scientists at the UUSM and the Huntsman Cancer Institute. Three specific aims are proposed. First, clinical differences between carriers and non-carriers of a p16 mutation will be examined in the Familial Melanoma Research Clinic (FMRC) at the Huntsman Cancer Institute. Kindred members studied 15 years ago will be re-examined to measure differences in photodamage, number of nevi, size of nevi, characteristics of nevi, and distribution of nevi among p16 carrier and noncarrier kindred members. Second, I will determine whether p16 mutation carriage results in decreased senescence or apoptosis of nevus cells utilizing B-galactosidase levels and TUNEL staining, respectively. Third, I will determine whether nevi and melanomas from p16 mutation carriers have acquired additional mutations that could lead to increased risk of malignant transformation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: META-ANALYSIS OF MELANOMA AND NEVI Principal Investigator & Institution: Van Beek, Marta J.; Epidemiology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-JUL-2002 Summary: The incidence of cutaneous malignant melanoma is increasing faster than any other cancer in the United States. Since early diagnosis and intervention are important in potentially altering the course of malignant melanoma, attention has focused on identifying individuals at high risk. According to the medical literature, there is a correlation between quantitative measures of nevi and risk of melanoma. The goal of this proposal is to conduct research pertinent to melanoma by combining relative risk estimates and their variances from previously conducted studies. The strengths and consistency of the observed associations will be examined through a large meta-analysis of nevi counts (total body and site-specific) and the relation to melanoma. Eventually, the strength and consistency of the relative risk estimates (RRs) may focus the selection of measures in a planned case-control study or direct future clinical or laboratory investigations. Moreover, a quantitative review of relative risk (RRs) estimates will help identify high-risk populations, and may guide future cancer prevention efforts within the community. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MELANOMA

MOLECULAR

DETERMINANTS

OF

BRAIN

METASTATIC

Principal Investigator & Institution: Marchetti, Dario; Comparative Biomedical Scis; Louisiana State Univ A&M Col Baton Rouge Office of Sponsored Programs Baton Rouge, La 70803

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Malignant Melanoma

Timing: Fiscal Year 2003; Project Start 01-JUL-2001; Project End 28-FEB-2006 Summary: (Adapted from the investigator's abstract) Mechanisms responsible for malignant melanoma progression to highly aggressive brain-metastatic disease remain largely unknown. We have previously demonstrated that certain neurotrophins (NT) and their receptor p75 TR modulate the invasion of melanoma cells to the brain and the activity of an enzyme, called heparanase. This enzyme is a key determinant for the successful degradation of the tumor-surrounding extracellular matrix (ECM): heparanase degrades heparan sulfate proteoglycans (HSPGs), which are important ECM components, at sites within HS linear chains. Our hypothesis is that NT/p75NTR play important roles in melanoma brain invasion and that NT-regulated heparanase is critical in the metastatic melanoma progression being a potential target for antimetastasis drugs. The objective of this application is to determine p75NTR function as a molecular determinant of brain metastases formation and the role of heparanase in invasion and angiogenesis. We selected melanoma cells with low/high p75NTR expression and generated a monoclonal antibody against human heparanase that inhibits its enzymatic activity and experimental metastases formation. In addition, we have access to the recently cloned human heparanase, related probes, and novel important enzyme inhibitors. Our specific aims are: 1. To define p75NTR as a molecular determinant of brain-metastatic melanoma cells, which will be accomplished by modifying p75NTR gene expression and analysis of p75NTR variants for their organ colonizing abilities in nude mice, in particular to the brain. 2. To characterize NT-regulated heparanase gene expression at specific steps of metastasis in malignant melanoma, which will be accomplished by studying the distribution and mechanisms of human heparanase to test the precise function of heparanase in the multistep process of melanoma metastasis. 3. To determine the role of heparanase in angiogenesis, which will be accomplished by relating angiogenic molecules and models to heparanase functionality by using purified enzyme and HS substrates subpopulations from corresponding HSPGs. We anticipate that the results of our proposed research will fundamentally advance the field of brain tumors biology and metastatic ECM processing. Of significance, they are expected to provide new targets for preventive and therapeutic interventions that will be particularly important to the growing numbers of persons who have malignant melanoma, and are experiencing the "urgency" of the melanoma problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PATHOGENESIS OF MALIGNANT MELANOMA Principal Investigator & Institution: Chin, Lynda; Assistant Professor of Adult Oncology; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: Genetic basis of malignant melanoma is poorly understood. Progress in our understanding of the pathogenesis of malignant melanoma and in the design of therapeutic modalities has been significantly hampered by the lack of a bona fide animal model. In this proposed study, transgenic and knockout mouse technology will be utilized to construct a mouse model for malignant melanoma. Commonly encountered melanoma-associated genetic lesions will be analyzed in vitro to dissect their molecular functions and their causal roles in disease will be validated in vivo. Specifically, I will focus on the differential roles of p15 INK4b, P16INK4a and p19ARF as well as activated H-rasva112 in development of malignant melanoma. My working hypothesis is that loss of both gene products of the INK4a gene, (namely p16INK4a and p19ARF), are important, but not sufficient, in development of malignant melanoma, that p15INK4b does not play a key role in melanoma pathogenesis, and that additional genetic events

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such as RAS activation may be necessary to achieve full malignant transformation of melanocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOUSE MODEL OF MALIGNANT MELANOMA Principal Investigator & Institution: Depinho, Ronald A.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-MAR-2004 Summary: The significance and impact of melanoma as a disease entity can not be understated. Despite the long history of clinical and molecular efforts directed towards this disease, surprisingly little is known about the precise genetic lesions leading to melanoma and even less is known with regard to how these few genetic lesions relate to disease classification or progression. Significant progress on both the basic and clinical fronts could be achieved through the production of an accurate mouse model of malignant melanoma that faithfully reproduces disease progression on the pathological and molecular levels. This proposal attempts to refine and validate further an established mouse model of cutaneous melanoma. To achieve this goal, mice will be engineered to possess several genetic lesions commonly observed in human melanomas, including activated MET, EGF receptors as well as disruption of the p16INK4a, PTEN and possibly Mxi1 genes. Evolving gene expression patterns and genomic changes at various tumor stages will be extensively cataloged as a means of validation. This refined model of melanoma should serve to advance our understanding of melanoma biology as well as to provide a system for melanoma gene discovery. The latter will include a combination of CGH, genome wide LOH, genetic mapping of susceptibility loci and candidate gene mutational analyses. The use of these melanoma mice in preclinical testing are outlined as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MURINE P73 IN TUMORIGENESIS Principal Investigator & Institution: Mckeon, Frank D.; Professor; Cell Biology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-JUN-1998; Project End 31-JUL-2002 Summary: Convergence of data from biology and medicine has implicated p53 in the suppression of a wide range of human cancers. In collaboration with the investigator's colleague Daniel Caput of Sanofi, they have characterized p73, protein with considerable homology to the transcriptional activation, DNA binding, and oligomerization domains of p53. Significantly, the human p73 gene is located at chromosome 1p36.3, a region frequently deleted in human cancers such as neuroblastoma, colonrectal carcinoma, ductile breast carcinoma, and melanoma. The investigators' initial studies have shown that p73 interacts with p53 and can transactivate p53 target genes. However, p73 apparently differs from p53 in that it is not induced by radiation and genotoxic drugs, which activate p53. Therefore it is likely that p73 functions cannot be simply extrapolated from those attributed to p53. As many of p53's functions have been realized through the analysis of its loss of function, the investigator has generated mice lacking one or both copies of p73 through targeted disruption and has found that, unlike p53 deficient mice, those lacking p73 show profound defects in growth, development of the nervous system, and function of the immune system. The investigators will use these mice and cell lines derived from them to ask what role p73 plays in proliferation, cell cycle control, and regulation of the

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Malignant Melanoma

immune system. The investigators will further assess the physiological significance of p73 and p53 interactions by analyzing mice deficient in both genes for effects on tumorigenesis and developmental control In addition, they will generate mouse strains with combined defects in p73 and other genes implicated in 1p36-associated tumors, specifically the APC gene in colon cancer, p16INK4 in malignant melanoma, and NMyc overexpression in neuroblastoma. These experiments aim to take full advantage of the murine system for assaying the effects of a specific and defined set of genetic lesions, and should allow them to probe the interactions of p73 with other genes in pathways of tumorigenesis. Together with their ongoing analysis of human tumors, these murine models should offer important insights into p73 function in development and human disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NATURAL PRODUCT ANTITUMOR INDUCERS OF APOPTOSIS Principal Investigator & Institution: Molinski, Tadeusz F.; Professor; Chemistry; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant) Natural products are represented among clinically useful antitumor agents. The general goal of this project is to find and identify small molecules that can manipulate function of proteins and other receptors relevant to cancer. Answers to critical questions related to mechanism and site of action of cytotoxic compounds are now desired much earlier in the progression from compound discovery to clinical trial. Truly novel chemotherapeutic agents that are most likely to attract interest are cytotoxic or cytostatic compounds that exhibit activity against solid tumors and also target novel points of intervention in the sequence of events in oncogenesis. Natural products that induce apoptosis in transformed proliferating tumor cells may lead to tumor cell-specific suppressive agents that are useful as cancer chemotherapeutic drugs. Drug-induced apoptosis involves cell-cycle specific events mediated by a family of genes and gene products including p53 and Bcl-2 that may constitute a novel target for cancer chemotherapy. Apoptosis has important implications in the clinical outcome of cancer chemotherapy, not only for arresting tumor growth, but also for solid tumor regression by channeling the disposal of apoptotic tumor cells without problematic inflammatory responses. Pure cytotoxic and cytostatic natural products will be isolated from invertebrates collected from sites of unique marine biodiversity based on bioassayguided purification. Active compounds will be prioritized based on activity against HCT-116 (colon tumor) and CCRF-CEM (T-cell leukemia), MCF-7 (breast), PC-3 (prostate), SK-MEL-5 (malignant melanoma), A549 (lung carcinoma), and HL-60 (promyelocytic) tumor cell lines. Prioritized cytotoxic compounds that also induce apoptosis in PC-3 and MCF-7 will be evaluated further by cell flow cytometry and drug profiling using DNA-microarray technology to determine the involvement of genes in cell-cycle arrest related to drug-induced apoptotic events. Promising new leads that emerge from this evaluation will be advanced to in vivo trials in animal models to ascertain their potential usefulness as leads in development of novel anticancer drugs active against human solid tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW APPROACHES TO SURGICAL TREATMENT BASED UPON PATHOLOGY OF MALIGNANT MELANOMA Principal Investigator & Institution: Cochran, Alistair J.; Professor of Pathology and Surgery; John Wayne Cancer Institute 2200 Santa Monica Blvd Santa Monica, Ca 90404 Timing: Fiscal Year 2002 Summary: Project I covers the pathology activities essential to the conduct of the Trial. Quality assurance is provided by expert review of all primary tumors from patients entering the Trial, all sentinel/non-sentinel node material from Learning Phase cases and 20% of sentinel modes from Trial Phase cases. To assure uniformity of pathology in the Trial a videotape is provided to all pathologists involved, and annual meetings are held. Dr. Cochran provides help-line support and specific consultation as required. We proposed a detailed study of the amount of distribution of micrometastic and occult melanoma in regional nodes against survival. We will assess whether the sentinel node tumor burden can predict the need for completion lymphadenectomy. We will investigate the frequency and extent of immune modulation of sentinel nodes and relate this to outcome and extent of tumor penetration of the regional nodes. We will undertake a major study to determine whether our present sampling is sufficient. We will assess whether molecular biological techniques improve the accuracy of nodal evaluation over immunohistochemistry. We will continue to develop techniques to allow microscopic confirmation a node is sentinel. We will evaluate the accuracy of our newly developed prognostic models to determine their accuracy on an individual patient basis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL ANTI-OXIDANT CATALYST TO TREAT IL-2 TOXICITY Principal Investigator & Institution: Southan, Garry J.; Inotek Pharmaceuticals Corporation Suite 419E Beverly, Ma 01915 Timing: Fiscal Year 2003; Project Start 14-MAR-2003; Project End 31-AUG-2004 Summary: (provided by applicant): IL-2 biotherapy of refractory malignancies may produce cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. These host responses include a massive capillary leak syndrome, manifested as non-cardiogenic pulmonary edema and consequent respiratory failure. There is now substantial evidence that the inflammatory process to IL-2 biotherapy is mediated by profound alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion, and their reaction product peroxynitrite. An effective anti-inflammatory treatment would reduce the toxicity of IL-2 treatment and encourage increased use of this highly promising antineoplastic therapy. To address this unmet need, Inotek is developing a novel class of ultrapotent peroxynitrite decomposition catalysts. The lead compound, the metalloporphyrin INO-1080, is dramatically protective in experimental models of systemic inflammatory shock. The investigators propose to establish "proof-of-principle" that INO-1080 reduces the hemodynamic biochemical, and histopathologic alterations in an experimental model of IL-2 biotherapy. First, the investigators will ensure that INO-1080 does not adversely impact the anti-tumor activity of IL-2. They will carry out these investigations in a murine model of pulmonary metastasis by syngeneic melanoma cells. Second, they will document in a large animal model that INO-1080 ameliorates shock and tissue injury induced by IL-2. The investigators will utilize a well-established ovine model of IL-2 induced shock. The investigators expect INO-1080 will reduce tissue injury, capillary leak, pulmonary hypertension, lipid peroxidation, and nitrotyrosine formation, and

40

Malignant Melanoma

attenuate the loss of systemic vascular resistance. Confirmation of efficacy, coupled with evidence that INO-1080 does not adversely impact on the anti-tumor activity of IL-2, would justify clinical testing in population with refractory malignant melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORAL MELANOMA: ALPHA V BETA 3 EXPRESSION AND METASTASIS Principal Investigator & Institution: Ramos, Daniel M.; Associate Professor; Stomatology; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 30-JUN-2005 Summary: (Adapted from the Investigator's Abstract): Malignant melanoma of the oral cavity is almost always fatal. The proposed work focuses on two stages in melanoma progression: invasion and metastasis, during which melanoma cells interact with the extracellular matrix primarily through integrin receptors. The vitronectin receptor alphavbeta3 is expressed by vertically invasive and metastatic cutaneous melanoma but is absent from superficial spreading melanoma and normal melanocytes in vivo. In the murine K1735 melanoma, highly metastatic cells express alphavbeta3, but not the alphavbeta5 vitronectin receptor, while poorly metastatic cells express alphavbeta5 but not alphavbeta3. Adhesion of alphavbeta3, but not alphavbeta5, to vitronectin results in the activation of FAK, c-Src, and pMAP kinase-signaling molecules implicated in cell motility and gene expression - and in increased expression of matrix metalloproteinase-2 (MMP-2). This study addresses the following questions: 1) Does expression of alphavbeta3 or alphaVbeta5 correlate with oral melanoma metastasis? Human biopsy specimens will be evaluated by immunohistochemistry and in situ hybridization for expression of alphavbeta3 or alphavbeta5. 2) Does expression of alphavbeta3 correlate with metastatic potential in murine melanoma cells? K1735 cells with differing metastatic potential will be used to generate additional metastatic variants by both transoral and hind-flank injection. The resulting tumors and variant cell lines will be evaluated for expression of alphavbeta3 and for activation of FAK, pMAP kinase, and expression of MMP-2. 3) Will overexpression of alphavbeta3 confer the metastatic phenotype to poorly metastatic melanoma cells? Poorly metastatic cells expressing beta3 by retroviral transduction will be evaluated for invasive and metastatic behavior. The effect on metastasis of expressing a constitutively active Src will also be evaluated. 4) Will decreasing alphavbeta3 receptor expression, or suppressing its function, alter the invasive and metastatic potential of melanoma cells? beta3 expression in highly metastatic cells will be reduced by both antisense and dominant negative strategies. Also, human beta3 will be expressed in poorly invasive melanoma cells, and its function suppressed by function-blocking antibody to human beta3. Finally, whether expression of a dominant-negative c-Src in a highly metastatic cell line decreases metastasis will be determined. Understanding the role beta3 plays in oral melanoma invasion and metastasis may lead to novel prognostic indicators and development of new treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHWAYS FROM GENOTYPE AND ENVIRONMENT TO MELANOMA Principal Investigator & Institution: Hayward, Nicholas K.; Queensland Institute of Medical Research Herston Brisbane Qld, 4006

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Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 29-SEP-2006 Summary: The incidence of cutaneous malignant melanoma has increased dramatically in white-skinned populations throughout the world over past decades. The Australian state of Queensland has the highest incidence of melanoma in the world with lifetime incidences of 1 in 13 males and 1 in 16 females. While these rates are almost five times those in the USA, the shape of the age-specific incidence curve is almost the same in the two populations, suggesting similar causal factors. Over the past 20 years we have conducted several large-scale studies into the molecular genetics and genetic epidemiology of melanoma and its risk factors, particularly nevus density and pigmentation. We shall follow up a population-based sample of 1,912 melanoma families to update survival status and risk factor information, and to obtain DNA from all melanoma cases and a sample of unaffected relatives, and do likewise in studies of melanoma in children (under l4y), adolescents (14-19y) and older men (over 50y). 3,440 family members of twins for whom we have nevus counts and 600 controls will also be included in the total of 6,248 DNA samples for molecular analysis. We shall sequence the CDKN2A and P genes in 100 subjects of diverse melanoma risk and pigmentation, and type all subjects for single-nucleotide polymorphisms (SNPs) in these and other genes of the cell cycle (CDKN2B, CDK4), and pigmentation (MCI R) pathways. We shall perform within-family and case-control analyses for association of melanoma risk variables including status, age-at-onset, survival and severity, with SNPs and environmental risk factors, stratified by familial risk. Similar analyses will be conducted for mediating variables such as nevus density, freckling, and pigmentation. We shall test for gene-gene interactions (epistasis) between SNPs of cell-cycle genes and pigmentation axis genes, and for gene-environment interactions of SNPs with measured environmental risk factors, on melanoma risk variables. We shall also test whether melanoma in childhood or adolescence can be solely explained by the same risk factors that operate in adults or whether they carry rare alleles in cell cycle or pigmentation genes. Finally, segregation-association analysis will test whether familial aggregation for melanoma can be completely explained by our measured risk factors. In addition, we shall fine map a major locus affecting nevus density linked to CDKN2A, and extend a 10cM genome scan to 900 twin families (about 1100 sib pairs) so we can use sib pair linkage analysis to locate loci influencing nevus density, freckling, pigmentation phenotypes, and other risk factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE 2 STUDY OF ANTI VEGF ANTIBODY IN MELANOMA Principal Investigator & Institution: Carson, William E.; Professor; Surgery; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: (Provided by applicant) The incidence of malignant melanoma is rising faster than that of any other cancer, yet treatment options for patients with advanced disease remain limited. The development of agents that inhibit tumor vascularization represent a novel approach to the treatment of these cancers. Tumors secrete a number of factors that stimulate the formation of new vessels, and two important molecules in this regard are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Given this fact, we feel it is logical to explore combinations of antiangiogenic drugs in an attempt to achieve greater anti-tumor activity. We have received NCI approval to conduct a randomized phase II trial of recombinant anti-human VEGF (Bevacizumab) alone or in combination with low-dose interferon-alpha (IFN-a) (Aim 1). Bevacizumab prevents the binding of VEGF to receptors on endothelial cells and has

42

Malignant Melanoma

shown activity in colon, breast, lung, and prostate cancer. Low-dose IFN-a inhibits the elaboration of bFGF and has been successfully used to treat infantile hemangiomas. We hypothesize that co-administration of Bevacizumab and low-dose IFN-a will lead to maximal inhibition of new vessel formation in patient tumors and that this will result in improved response rates and increased time to disease progression. Patients with metastatic malignant melanoma will receive Bevacizumab at 10 mg/kg IV every 14 days and will be randomized to receive either no additional treatment or concurrent IFN-a at 1 MU/m2 SC daily. In Aim 2, we will conduct a series of correlative studies designed to elucidate the mechanisms that contribute to the anti-tumor actions of these drugs. Patient blood samples will be drawn just prior to the administration of Bevacizumab and procured for serum and peripheral blood mononuclear cells. Serum levels of VEGF and bFGF will be analyzed by ELISA. In addition, we will perform tumor biopsies prior to the initiation of therapy and immediately following the 6th dose of Bevacizumab. Tumors will be analyzed for vascularity (CD31 and CD34), levels of angiogenic factors, as well as the presence of apoptotic cells. Given the prevalence of accessible tumor deposits in melanoma patients, we feel we will be able to successfully biopsy a majority of patients enrolled in this study. This approach represents one of the few trials to employ combinations of anti-angiogenic drugs and an aggressive plan for tumor sampling. Information gained from this trial will help us to understand the mechanism of action of anti-angiogenic drugs and help us to plan future studies in melanoma and other solid tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE II EVALUATION OF IV MELPHALAN (L PAM) AND WBH FOR MALIGNANT MELANOMA Principal Investigator & Institution: Robins, H I.; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHASE II STUDY OF TEMOZOLOMIDE (SCH52365) PRIOR TO RADIATION THERAPY Principal Investigator & Institution: Agarwala, Sanjiv; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002 Summary: This is a multinational, multicenter, open label Phase II study designed to determine the efficacy and safety of Temozolomide (SCH 52365) in the treatment of patients who have brain metastases from malignant melanoma not requiring immediate radiation therapy, previously untreated for this presentation of brain metastases, except for steroids, & who may or may not have received previous chemotherapy for the treatment of malignant melanoma. It is anticipated that 10 patients will enter this study at the University of Pittsburgh Cancer Institute. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHOSPHORYLATABLE MONOCLONAL ANTIBODIES FOR TUMOR THERAPY Principal Investigator & Institution: Clark, William A.; Pbl Biomedical Laboratories 131 Ethel Rd W, Ste 6 Piscataway, Nj 08854

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Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-AUG-2004 Summary: (provided by applicant): The long-term objectives of this proposal are to develop an efficient, effective, safe, convenient and economical monoclonal antibodies (MAbs) labeled with radioactive phosphate for therapy of cancers. Many chemical labeling procedures are currently used, but all these methods inactivate the antibodies to a significant extent (20 - 70 percent). The technology described in this proposal avoids this serious problem and has many advantages over the current methods. The specific aims of this proposal, designed to achieve the objectives and demonstrate the extraordinary advantages of this technology over other procedures, are: 1) Examine the in vivo distribution of [32P]radiolabeled MAbs in athymic mice bearing human tumors; 2) Evaluate the efficacy of MAbs labeled with this new technology compared to a common chemical method in arresting tumor growth; 3) Develop reagent, production, and finished product assays and protocols in preparation for clinical trials; 4) Use the new technology to develop one additional MAb to broaden the range of cancers targeted by this new procedure from adenocarcinomas in general (colon, breast, ovarian, lung, pancreatic, prostate cancers), to malignant melanoma. This work should benefit the larger population of patients and be useful to many companies developing MAbs for the treatment and detection of cancers. PROPOSED COMMERCIAL APPLICATION: PBL has developed two potential [32P] labeled MAbs as clinical candidates for therapy of adenocarcinomas. Our novel phosphorylation technology circumvents a number of the drawbacks of conventionally radiolabeled MAb therapy. The extensive advantages of PBL's phosphorylation technology can be exploited for virtually any anticancer MAb in development, in clinical trials, or already in use, including MAbs designed to treat human melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PILOT--METHYLATION PROFILES OF TUMOR SUPPRESSOR GENES IN SKIN CANCERS Principal Investigator & Institution: Gazdar, Adi F.; Professor; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: Specific aims: Aim 1. Collect skin tumors (approximately 40 squamous cell (SCC) and basal cell (BCC) carcinomas (approximately 40 each) and malignant melanomas (MM)(approximately 20). Skin tags will be collected from sun exposed (approximately 50) and non exposed (approximately 25) skin of adults. Aim 2. We will select a panel of 15 tumor suppressor genes involved in growth cycle regulation, apoptosis, cell adhesion, differentiation, tissue invasion and metastasis and which are known to be down regulated in many tumor types by aberrant gene methylation of promoter regions. We will determine the methylation profile of our tumor and skin samples. Aim 3. We will compare and contrast the methylation patterns of the major forms of skin cancer and between sun exposed and non exposed skin samples. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MELANOMA

POLARIZATION

SENSITIVE

OCT

FOR

DETECTION

OF

Principal Investigator & Institution: Gulsen, Gultekin; Assistant Researcher; Ctr for Functional Onco-Imaging; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004

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Malignant Melanoma

Summary: (provided by applicant): Optical Coherence Tomography (OCT) is a recently developed imaging technology, which permits in-situ, real-time, non-invasive, noncontact, cross-sectional imaging of micron-scale structures in biological tissues and as such seems to be a suitable modality for the study of skin cancer. The development of polarization sensitive optical coherence tomography (PS-OCT) permits the acquisition additional information on the polarization properties of tissue carried by the reflected light. Malignant melanoma, a form of skin cancer, is increasing in incidence at the most rapid rate of all cancers. Yet detection of melanoma visually, even by experts in melanoma, has only 60-80% sensitivity. Thus, new methods of analyzing suspicious skin lesions in vivo are urgently needed. In this proposed study, we will construct a PS-OCT system to distinguish between normal, benign and malignant tissues. The PS-OCT system will control the polarization state of the light incident upon the sample. By measuring the reflectivity of light returning in particular polarization states we will obtain the Mueller matrix that provides complete representation of the polarization properties of the sample. During the first year of this project, we will complete construction and refinement of a high speed PS-OCT system by using a rapid scan optical delay line. In the second year, a transgenic mouse model will be used in conjunction with PS-OCT to study multistage melanoma carcinogenesis and differentiation of benign and 1 malignant lesions. This transgenic mouse model uses tyrosinase promoter to target expression of the mutated human T24 Ha-ras oncogene, as previously developed by Dr. Powell who will serve as a consultant in the second year. The overall goals of developing a system capable of determining benign from malignant pigmented lesions will be achieved through the following specific aims: (1) develop PSOCT instrumentation, (2) compare PS-OCT and histology to differentiate benign from malignant lesions. Successful completion of this pilot project will further the development of a practical and inexpensive device that can be used to differentiate benign from malignant lesions of the skin. Thus this research will have the potential to improve patient care and reduce the human and economical cost of melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGNOSTIC MARKERS FOR ASSESSMENT OF TREATMENT EFFICACY OF MELANOMA Principal Investigator & Institution: Hoon, Dave S B.; Member and Director; John Wayne Cancer Institute 2200 Santa Monica Blvd Santa Monica, Ca 90404 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): One of the major problems in managing malignant melanoma is predicting the course of disease progression after removal of the primary tumor. Our main hypothesis is that molecular markers can be used for analysis of tumors and blood as surrogates to predict disease progression and outcome, and treatment efficacy well in advance of clinicopathological events. Malignant melanoma progression occurs from accumulation of multiple genetic aberrations that result in progressive genetic instability. In order to translate the detection and prognostic value of these changes efficiently, analysis must be conducted on specimens from well-defined retrospective and prospective clinical trials. Validation of the molecular results will allow better disease stratification and management of malignant melanoma. In the previous grant period we developed multimarker RTPCR assays to identify blood prognostic molecular markers (PMMs) and demonstrated that they could be useful as potential surrogates of subclinical disease progression, and to predict disease recurrence. We will continue to develop new informative PMMs for blood in this proposal. Our hypothesis is that quantitative levels of PMMs which include melanoma-

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associated antigens (MAAs) and cellular physiologic factors influencing tumor progression/metastasis in melanoma tumors can also be used as surrogates of disease outcome and the efficacy of active-specific immunotherapy (vaccine). Our hypothesis is that DNA markers in primary and metastatic melanoma can also be used as PMMs. We have identified several DNA markers that have shown potential clinicopathological utility. In this renewal we will focus on assessing paired primary/metastatic melanomas to develop different types of PMMs to complement the blood RT-PCR assay as correlates to disease progression and outcome, and treatment failure. The Aims of the project are as follows: 1) Development and assessment of new mRNA PMMs for assessing melanoma patients' tumor and blood; 2) Development and assessment of DNA markers in melanoma tumors as prognostic indicators of disease progression and outcome; and 3) Validation of the clinical and pathological utility of RNA and DNA molecular markers in melanomas from patients entered in the multicenter PMCV Phase III clinical trial. The Aims will take advantage of the JWCI's large melanoma patient referral and comprehensive follow up to provide resources to develop and assess PMMs. The Aims will also take advantage of the randomized multicenter vaccine trial's archived and prospectively collected specimens to validate the PMMs. Identification of molecular markers for melanoma at different stages of disease progression will allow us to develop an "applicable" molecular progression model to aid in management decisions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONS

REGULATION

OF

CHEMOKINE

MEDIATED

LEUKOCYTE

Principal Investigator & Institution: Richardson, Micheler R.; Associate Professor; Biochemistry; Meharry Medical College 1005-D B Todd Blvd Nashville, Tn 37208 Timing: Fiscal Year 2002; Project Start 01-JUN-1996; Project End 31-JAN-2007 Summary: (provided by the applicant): Chemokines are inflammatory mediators of the chemotactic and cytotoxic functions of a large variety of cells including neutrophils, monocytes, eosinophils, basophils and lymphocytes. These functions are initiated through interaction with specific cell surface G-protein coupled receptors (GPCRs). Most chemokines activate more than one receptor on leukocytes. The hypothesis that underlies this application is that since multiple chemokines are present at sites of inflammation, the chemokine receptors activities must be tightly regulated to prevent tissue damage. We have developed a cellular model, a rat basophilic leukemia cell line (RBL-2H3), in which chemokine receptors can be singly or multiply expressed to display many leukocytes activities. These studies have provided striking evidence that these receptors cross-regulate each other?s function at multiple steps. Signal duration and protein kinase C (PKC) activation have been shown to be critical for receptor crossregulation. Studies in phagocytes and mouse models of peritoneal and skin inflammation have shown a complexity of cross-regulation among interleukin-8 (IL-8) and RANTES. This complexity likely reflects the ability of these chemokines to activate multiple receptors in leukocytes. The overall objective of this application is to elucidate the mechanism(s) of cross-regulation among the receptors for IL-8 (CXCR1 and CXCR2) and RANTES (CCR1 and CCR5) and to identify specific molecular targets in the signaling pathways, which modulate their ability to mediate and undergo crossdesensitization. Mechanisms of cross-desensitization will be investigated by determining the role of different protein kinase C (PKC) isozymes in receptor crossphosphorylation. The hypothesis that arrestin-mediated receptor internalization modulate signal duration will also be tested in beta arrestin deficient mice. Chemokines

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Malignant Melanoma

are involved in many acute and chronic inflammatory diseases such as rheumatoid arthritis, emphysema, cystic fibrosis, chronic bronchitis and bronchiectasis and proliferation of tumor malignant melanoma cells. Understanding the molecular mechanisms governing the regulation of chemokine will aid in understanding the control of inflammation as well as the etiology of many inflammatory disorders. These studies will also identify specific targets for the development of therapeutic drugs for the modulation of inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RHOC/GALR2 IN THE METASTASIS OF OROPHARYNGEAL CANCERS Principal Investigator & Institution: Henson, Bradley; Periodontics; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: This proposal is submitted pursuant to the application for a Mentored Clinical Scientist Development Award by Bradley S. Henson, D.D.S. This award will enable the applicant to complete his graduate education and training in the Oral Health Sciences Ph.D. Program at the University of Michigan School of Dentistry. The objectives of this application are to optimize current animal models of metastasis for head and neck squamous cell carcinoma (HN SCC) and investigate the role of two candidate proteins, rhoC and galanin receptor 2 (GALR2), in the spread of this disease. Last year, in the US alone, there were an estimated 30,200 newly diagnosed cases of oropharyngeal cancer [2]. Limited prognostic predictability and late detection for individual tumors, based on histopathology and existing staging protocols, results in disfiguring and debilitating surgical, chemotherapeutic and radiotherapeutic interventions. A major determinant of prognosis in HN SCC is metastatic transformation. RhoC, a member of the rho family of GTPases, has been implicated in metastatic potential in cancers of the breast and pancreas, and in malignant melanoma. It is likely that the rho GTPase family plays an important role in regulating cell movement during metastatic transformation, by configuring the actin cytoskeleton for motility through the formation of stress fibers. Rho has been shown to be downstream of galanin receptor 2 (GALR2). GALR2 binds galanin, a 30 amino acid neuropeptide, and has been implicated in small cell lung carcinoma. Overexpression or activating mutations of GALR2 may be important in the tumorigenesis of oropharyngeal SCC. Furthermore, mutations or alterations of expression of GA LR2, leading to activation of rhoC in the same tumor cell population may be an important determinant of aggressive, metastatic tumor behavior. The specific hypothesis to be investigated here is that upregulation or an activating mutation of rhoC and/or GALR2 facilitates metastasis of oropharyngeal SCC. In order to begin to address this hypothesis, we propose to: (1) investigate the role of rhoC in oropharyngeal cancer metastasis, (2.) determine whether overexpression or an activating mutation of GALR2, leads to a more aggressive, metastatic tumor phenotype and to determine if this signaling occurs via rho activation, and (3.) optimize current murine models used to study human o ropharyngeal S CC and develop primary and metastatic oral cancer cell lines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RNA PULSED DENDRITIC CELLS AS IMMUNOTHERAPY FOR MELANOMA Principal Investigator & Institution: Kalady, Matthew F.; Surgery; Duke University Durham, Nc 27710

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Timing: Fiscal Year 2002; Project Start 01-MAY-2002 Summary: Malignant melanoma remains a formidable challenge to patients, physicians, and scientists. Although surgical resection serves as the primary therapy and is often curative, melanoma recurs both locally and at distant sites. Unfortunately, current adjuvant therapies have not improved the dismal prognosis associated with regional and metastatic disease. This research focuses on the use of immunotherapy to treat micrometastatic and recurrent melanoma. Information gained through this preclinical research will be applied to developing an effective clinical melanoma vaccine. Immunologic rejection of tumor cells is mediated by cytotoxic T-lymphocytes (CTL) which recognize specific tumor- associated antigens (TAA). Antigen presenting cells, such as dendritic cells (DC), have been shown to generate an antigen-immunologic response both in vitro and in vivo after priming with TAA. Current research and clinical trials are underway at this institution loading of DC with tumor lysates and TAA peptides. This research project will attempt to optimize the CTL response against melanoma by methodologically studying the methods used to prime DC with tumor RNA induce unexpectedly potent tumor-specific CTL responses. Specifically, DC will be isolated through leukopheresis from patients with melanoma in whom tumor cell lines can be established. The DC from these patients will be primed with total tumor RNA from the patients' own tumor, or primed with combinations of previously isolated RNA for melanoma-specific TAA such as MART-1, MAGE-3, tumor, or primed with combinations of previously isolated RNA for melanoma-specific TAA such as MART-1, MAGE-3, tumor, or primed with combinations of previously isolated RNA for melanoma-specific TAA such as MART-1, MAGE-3, tyrosinase, and gp100. The primed dendritic cells will be incubated with CTL. These CTL will subsequently be mixed with melanoma cell lines and the percentage of lysed cells will be quantified using a chromium release assay. The antigen that yields the greatest cytoxicity will then by directly tested against the current method of pulsing dendritic cells with protein yields the greater cytotoxicity will then be directly tested against the current method of pulsing dendritic cells with protein lysates and peptides. Data gained from this preclinical work will guide future uses of vaccine development in the clinic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE CARCINOGENESIS

OF

AHR/ARNT

SIGNALING

PATHWAY

IN

Principal Investigator & Institution: White, Lori A.; Biochemistry and Microbiology; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Malignant melanoma is on the rise in industrialized nations. Indeed, the incidence of mortality related to melanoma has increased by 34% in the United States from 1973-1992. However, there are few effective treatments developed for melanoma. We propose that the aryl hydrocarbon receptor (AhR) pathway plays a role in melanoma progression through the activation of matrix remodeling enzymes. We have chosen to use 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the agent to activate the AhR- pathway. TCDD and related polycyclic and halogenated aromatic hydrocarbons (PAH/HAH) are ubiquitous environmental contaminants that are the unintentional by-products of industrial combustion. TCDD is ideal for examination of the AhR pathway in melanoma for three reasons: (1.) skin is a target tissue for TCDD-activation of the AhR pathway; (2.) and TCDD is not metabolized; and (3) TCDD is non-mutagenic, and therefore the effects we observe should be directly related to activation of the AhR pathway. We hypothesize that

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Malignant Melanoma

TCDD-activation of the AhR/Arnt pathway stimulates melanoma progression by altering expression of the genes involved in matrix remodeling, specifically the matrix metalloproteinases (MMPs). MMP activity is necessary for cell migration through matrix barriers, and expression of these enzymes correlates with aggressive and invasive tumors. Our preliminary data in melanoma cells demonstrate that both non-invasive and invasive melanoma lines are responsive to TCDD, and invasive melanoma cells express MMPs in response to TCDD exposure. Further, we also show increased invasiveness of melanoma cells when treated with TCDD. This suggests that TCDD directly increases melanoma invasion by activating matrix degradation. Therefore, the specific aims for this proposal are: (1.) Elucidate the molecular mechanism mediating TCDD-induced expression of MMPs in melanoma cell lines. (2.) Elucidate the role of the AhR in TCDD-induced changes in MMP expression in melanoma. (3.) Demonstrate the role of the AhR pathway in melanoma migration and invasion using an in vitro invasion assay. (4.) Using a three-dimensional skin model system, determine the role of cell-cell interaction on AhR-activation of MMP expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF FRZB-1 IN CHICK MELANOGENESIS Principal Investigator & Institution: Burrus, Laura W.; Assistant Professor; Biology; San Francisco State University 1600 Holloway Ave San Francisco, Ca 941321722 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 31-AUG-2004 Summary: (provided by applicant): During vertebrate embryogenesis, neurons and glia of the peripheral nervous system as well as pigment cells (melanocytes) descend from a common progenitor cell, the neural crest cell. The specification of neural crest cell fates must be exquisitely controlled in order to ensure the proper development of the peripheral nervous system and pigment cells. Recently, it has been shown that ectopic expression of secreted Wnt signals causes an increase in the number of pigment cells accompanied by a decrease in the number of neurons and glia, suggesting that Wnt signals play an important role in lineage segregation. However, as Wnts are normally expressed during neurogenic and gliogenic specification, it seems likely that additional layers of regulation are required in order for Wnts to specifically participate in the specification of melanogenic lineages. The expression of Frzb-1, a secreted antagonist of Wnt activity, in the neural tube during neurogenic and gliogenic specification, but not during melanogenic specification, suggests the possibility that Frzb-1 plays an important role in the regulation of lineage. We propose to test the hypothesis that Frzb-1 is sufficient and necessary for the inhibition of melanogenesis in avian embryos. If our hypothesis is correct, our results will contribute to an understanding of cell lineage specification during embryonic development. In addition, as the inappropriate regulation of Wnt activity has been implicated in malignant melanomas, our studies will help identify important regulatory circuits that may play a role in the genesis or progression of malignant melanomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF IDO IN MALIGNANCY Principal Investigator & Institution: Munn, David H.; Associate Professor; Pediatrics; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Established tumors create a condition of immunologic unresponsiveness toward their own antigens (functional tolerance) which

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constitutes a major barrier to successful immunotherapy of cancer. New therapeutic strategies are needed that specifically target this important but poorly understood problem. One mechanism by which antigen-presenting cells (APCs) can inhibit T cell responses, and hence create tolerance, is through tryptophan catabolism via the enzyme indoleamine 2,3-dioxygenase (IDO). Malignant melanoma and other human tumors recruit large numbers of IDO-expressing APCs into tumor-draining lymph nodes. The applicants hypothesize that presentation of tumor-derived antigens by IDO expressing APCs contributes to the pathologic tolerance toward tumor antigens found in malignancy. In Aim #1 the applicants will test the hypothesis that IDO-dependent mechanisms block the development of protective immune responses at the time of prophylactic immunization with tumor antigens. This will be accomplished by administration of the IDO-inhibitor drug 1-methyl-[D]-tryptophan to mice receiving immunization with irradiated B16F10 tumor cells or defined antigenic peptides, and by the use of antigen-pulsed dendritic cells from IDO-transgenic and IDO-knockout mice. In Aim #2 the applicants will test the hypothesis that T cells encountering antigen in tumor-draining lymph nodes are forced into IDO-mediated cell-cycle arrest in mid-G1, with consequent failure of clonal expansion and inability to develop CTL activity. Using an established-tumor model, the applicants will combine 1-methyl-[D]-tryptophan with vaccination to test the hypothesis that IDO-dependent mechanisms inhibit T cell responses to therapeutic immunization. The proposed studies will provide insight into the role of IDO as a tolerogenic mechanism in the pathogenesis of malignancy, and will test the efficacy of 1-methyl-[D]-tryptophan as a therapeutic intervention designed to block this pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF L1-CAM IN MELANOMA PROGRESSION AND AGIOGENESIS Principal Investigator & Institution: Montgomery, Anthony M.; Pediatrics; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2003; Project Start 01-MAR-1996; Project End 31-JUL-2008 Summary: (provided by applicant): Cell adhesion molecules have a profound influence on cancer development, effectively promoting or repressing the development of malignant disease. L1 (or L1-CAM) is a neural cell adhesion molecule that is overexpressed in neuroectodermal tumors. In malignant melanoma, L1-expression correlates with the development of metastatic disease. Recent evidence suggests that L1 may promote the vascularization of tumors and facilitate melanoma cell survival and invasion. The objective is to define the role of L1 in melanoma progression. This work will address a significant gap in our knowledge and will determine whether L1 is a suitable target for therapeutic intervention. There are three aims: AIM #1: L1 is proposed to result in the activation of signaling pathways that induce a highly motile and invasive phenotype in malignant melanoma. Induction of this phenotype is. further proposed to result from direct co-operation between L1 and integrins. This aim will test the hypothesis that direct L1-integrin interaction results in the activation of signaling pathways that promote melanoma cell motility, invasion, and gene transcription. Based on preliminary data, emphasis will be placed on interactions with the 'progression related' integrin alphavbeta3 and on the contribution of the mitogen-activated protein kinase (MAPK) pathway. AIM#2: Animal studies will directly assess the contribution of L1 to melanoma survival, growth, and metastasis. Metastasis will be evaluated in an experimental pulmonary metastasis model, while tumor cell survival and growth will be assessed in the dermal microenvironment. Further studies will test the hypothesis

50

Malignant Melanoma

that L1 can promote metastasis by stabilizing tumor-platelet interactions or by promoting migration across the host vasculature. AIM #3: The goal is to demonstrate that L1 cleavage products contribute to the vascularization of malignant melanoma. We have identified two L1 fragments that are released by melanoma cells as a result of Iosttranslational cleavage. These cleavage products will be tested for proangiogenic activity and for their ability to promote tumor vascularization. Proangiogenic mechanisms will be identified. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF TETRASPAN GLYCOPROTEINS (CD63) IN HIV ENTRY Principal Investigator & Institution: O'brien, William A.; Professor; Internal Medicine; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2003; Project Start 15-DEC-2002; Project End 30-NOV-2005 Summary: (provided by applicant): HIV infection of primary human cells typically requires interaction with both the primary receptor CD4 and a chemokine coreceptor, either CCR5 or CXCR4. There may be additional cellular factors involved in determining the efficiency of HIV entry, however, which may explain (in part) the marked differences in susceptibility to HIV infection among primary cells from different donors. During studies to identify H1V cofactors in macrophages (Mphi), we found that four independently generated monoclonal antibodies (mAb) to a tetraspan membrane glycoprotein, CD63, could block HIV entry into Mphi, but not T-cells. The function of CD63 is not well understood, but another tetraspan protein, CD81, has been proposed as a receptor for Hepatitis C virus, and CD9 has been implicated in infection by feline immunodeficiency virus (FIV). CD63 has previously been recognized as a platelet activation marker, as well as a marker for malignant melanoma, both seemingly unrelated to retroviral infection. Our experiments will investigate the role of CD63 in HIV entry into MO). These studies may lead to development of novel antiretroviral therapies targeting HIV entry. We will pursue these Aims over four years: Specific Aim 1. To test the hypothesis that CD63 has a specific role in facilitating HIV entry into Mphi, we will identify potential mechanisms of CD63-mediated HIV entry. Experiments will be prioritized based on initial studies that more precisely identify the step of HIV entry involved in anti-CD63 inhibition, directing initial studies toward late entry events, such as the role of CD63 in CD4 turnover or virus/receptor endocytosis and signal transduction, or early events, such as anti-CD63 interactions at the cell surface including binding and CCR5-dependent entry pathways. Specific Aim 2. To test the hypothesis that cell-specific differences between HIV target cells affect the role of CD63 in facilitating HIV entry. We will control for and test effects of various levels of receptor/coreceptor/CD63 expression and activation markers on susceptibility to antiCD63 inhibition in primary CD4+ cells. We will also test cell line models of anti-CD63 inhibition, which would facilitate cell manipulation and the consistency of inhibitory effects in these studies. Specific Aim 3. To test the hypothesis that infection of Mphi by diverse primary HIV-1 strains can be inhibited by anti- CD63 mAb. This will include both subtype B and non-subtype B strains, including some that exclusively use CCR5 as a coreceptor for efficient infection (R5), as well as dual-tropic strains that use either CXCR4 or CCR5 (R5X4), and X4 strains able to replicate in Me. Achieving these Aims will provide important new insights into the mechanism of HIV-1 entry, and may well provide important new targets for antiretroviraI therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF THE P34CDC2 RELATED PITSLRE PROTEIN KINASES Principal Investigator & Institution: Nelson, Mark A.; Professor; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 30-APR-2006 Summary: Description (Adapted from the investigator's abstract): Recurring alterations of chromosome 1 represent the most frequent site of structural chromosome abnormalities across all human solid tumors, including human cutaneous malignant melanoma. In melanoma, breakpoints involving chromosome 1 often accumulate at 1p36. The two genes encoding the PITSLRE protein kinases, Cdc2L1 and Cdc2L2, are localized to chromosome band region 1p36. The PITSLRE protein kinases are part of the p34cdc2 supergene family. Several lines of evidence suggests that some of the PITSLRE protein kinases isoforms are involved in apoptotic signal transduction. We have demonstrated deletion of Cdc2L alleles in melanoma. We can also show that the p110 isoform of PITSLRE is cleaved by caspases to a smaller p46 isoform. The p46 isoform retains kinase activity but appears to change its substrate specificity. There is also a difference in the sensitivity of melanoma cells (with wildtype and mutant Cdc2L alleles) to apoptotic stimuli. Thus, the principal hypothesis to be tested is that the caspaseprocessed PITSLRE isoform functions as a downstream effector in apoptotic signaling pathways and that disruption of PITSLRE protein kinase function plays a functional role in melanoma development by deregulating controlled cell death. The three specific aims are: (1) To study the timing of Cdc2L gene (PITSLRE) alteration during melanoma tumor progression using PCR-SSCP and direct DNA sequencing. Archival sporadic melanoma cases from various histological stages of melanoma are analyzed for mutations of specific regions within the Cdc2L1 gene. In addition familial melanoma kindreds linked to 1p are also investigated for Cdc2L1 gene alterations. (2) To isolate and characterize the substrate for the caspase processed PITSLRE isoform using yeast two hybrid methodology and (3) To elucidate the biological function of Cdc2L gene inactivation by generating Cdc2L1 deficient mice. An increased understanding of the critical gene alterations that give rise to the development and progression of melanoma may lead to genetic markers for melanoma. Defining the importance of Cdc2L1 alterations may be used to identify interesting subpopulations. Genetic changes of Cdc2L1 also may have prognostic value when considered in tandem with clinical data. Finally, increased understanding of biological role of Cdc2L may lead to new and innovative strategies to treat melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SENTINEL NODE BIOPSY:A MULTIMEDIA PATIENT GUIDE Principal Investigator & Institution: Brink, Susan G.; Principal; Healthmark Multimedia, Llc 1828 L St Nw, Ste 250 Washington, Dc 20036 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): HealthMark Multimedia proposes a Phase I SBIR for a multimedia education and decision-support for patients considering a SNB for breast cancer, melanoma, and other cancers where this is a possible diagnostic procedure. Initially proposed as a diagnostic tool for malignant melanoma, the SNB is gaining acceptance for breast cancer and other cancers. There are few patient education materials for those considering a SNB. This product will focus on the procedure, anatomy and physiology behind the techniques, survival data as well as contraindications. In Phase I, we will develop patient information for breast cancer SNB. A limited function prototype will be tested with women with breast cancer eligible for

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SNB. Prototype test results will be used to fine-tune the content and approach for Phase II. In Phase II, the product will be expanded to include information on the role of SNB for other cancers (e.g. head & neck, gastrointestinal, urologic and skin). After completion, effectiveness of the interactive guide in helping cancer patients compare their biopsy options, examine risks and benefits, discuss them with their physician and come to a decision will be determined. The final Phase II product will be monetized as a joint venture with Anne Arundel Hospital. PROPOSED COMMERCIAL APPLICATIONS: There is currently no multimedia education for patients considering a sentinel node biopsy. As the procedure becomes more widespread and used for a variety of cancers, this product will be of interest to physicians and surgeons practicing in hospitals and cancer clinics throughout the US. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SKIN CANCER PREVENTION IN A PEDIATRIC POPULATION Principal Investigator & Institution: Crane, Lori A.; Associate Professor; Preventive Med and Biometrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 15-SEP-1997; Project End 31-MAY-2007 Summary: (provided by applicant): About 1 in 90 American children born in the late 1990's will develop malignant melanoma in their lifetimes. Sun exposure in childhood appears to be the most important preventable risk factor for this disease. This study will continue to follow a previously enrolled cohort (n=728) that participated in a randomized trial of a provider-delivered sun protection intervention while children were between the ages of 0 and 3 years. The study will also enroll an additional 900 children who are part of the same birth cohort from 1998. Subjects in both the original cohort and new cohort will be randomly assigned to intervention and control groups; the intervention group will receive a series of tailored newsletters aimed at increasing sun protection over a 3-year intervention period. This tailored intervention is based on the Precaution Adoption Process Model, which focuses on increasing personal perceptions of risk. The effectiveness of the intervention in increasing sun protection of children will be evaluated through telephone surveys of parents at four time-points (upon enrollment and 1, 2, and 3 years later), and through skin exams of all children at the same time-points. Skin exams will provide objective measures of sun exposure using spectrophotometry, assessment of freckling, and enumeration of moles (nevi). This evaluation will assess the long-term effectiveness of the previous provider delivered intervention, the effectiveness of the tailored intervention as a "booster" to the provider intervention, and the effectiveness of the tailored intervention alone. The study also includes a longitudinal study of mole development, which will assess the relationships between sun exposure, "host traits" (such as skin, hair, and eye color, tendency to burn vs. tan, tendency to freckle), and development of nevi, the strongest predictor for malignant melanoma. The study also includes a cost analysis, which will focus on the costs associated with intervention delivery, behavior change, and mole avoidance. If this intervention proves to be effective in increasing sun protection of children, cost and efficiency will be key factors in dissemination and adoption of the intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SKIN SELF EXAMINATION FOR EARLY DETECTION OF MELANOMA Principal Investigator & Institution: Weinstock, Martin A.; Professor; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923

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Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 28-FEB-2004 Summary: ABSTRACT=Malignant melanoma is a major public health problem for which early detection is critical. Melanoma incidence and mortality have increased over the past several decades. Prognosis is critically dependent on the depth of the primary lesion at the time of initial surgical excision. Hence, monthly thorough skin examination (SSE) by the general public for the purpose of early detection, before deep invasion, is one promising approach for reducing melanoma mortality which has been promoted with increasing vigor in recent years. However, strategies for increasing the practice of SSE have not been rigorously evaluated, nor have the effects of SSE interventions on health care resource use. The investigators propose to conduct a 3-group randomized trial of interventions for increasing SSE use. The participants will be recruited from primary care physician offices. The experimental interventions tested will include written materials, cues, aids, and a videotape given at baseline and tailored feedback reports at 2 and 6 months. One of the two experimental interventions will include faceto-face counseling at baseline and a follow-up phone call 2 weeks later. The control intervention will include materials and a videotape on healthy dietary habits. Assessments will be conducted at 2, 6, and 12 months after the initial intervention. The primary outcome variable will be performance of at least one SSE during the two months prior to the assessment. The investigators will also assess the number of visits to health care providers for skin problems since the prior assessment, and the procedures performed by the provider because of those skin problems. Upon completion of this project, the investigators will have developed an intervention package suitable for dissemination, and will have evaluated its efficacy in improving performance of SSE, as well as its potential effect on health care resource use. The knowledge and experiment thus gained will aid the continuing efforts to encourage SSE and reduce melanoma mortality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SPECTROSCOPIC HOME-DETECTION OF MELANOMA Principal Investigator & Institution: Noto, John; President; Scientific Solutions, Inc. 55 Middlesex St Chelmsford, Ma 01863 Timing: Fiscal Year 2004; Project Start 01-SEP-2004; Project End 28-FEB-2005 Summary: (provided by applicant): This research aims to reduce the mortality rate associated with melanoma by development of a low-cost, non-invasive, optical biopsy device that can be used effectively by individuals with no particular medical expertise, in a home setting. Skin Cancer is the most common cancer and melanoma its most fatal form. It is estimated that there will be 91,900 new cases of malignant melanoma and 7600 melanoma deaths in the United States during 2003. Melanoma can be cured if it is diagnosed and treated when the tumor is thin and has not deeply invaded the skin. However, if a melanoma is not removed at its early stages, cancer cells may grow downward from the skin surface, invading healthy tissue. Unfortunately, many melanomas are detected too late and result in significant morbidity and mortality. A need exists to develop a low cost consumer based melanoma detection device. The goal is to establish early and effective detection of melanoma for the largest population possible, through the network of the commercial marketplace. The study is premised on the understanding that the melanoma mortality rate is directly proportional to stage that is detected and the age of patient tumors prior to detection and excision. The project is motivated by recent research indicating that malignant melanoma has unique elastic scattering characteristics in the visible spectral region when compared with dysplastic and benign naevi, or with normal skin. The methodology is to clinically identify discrete

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spectral regions that, when sampled with a simple optical device born of recent innovation in fiber optic, illumination, and detection technology, can reproduce cancerous skin tumor identification with specificity and sensitivity comparable to more costly and cumbersome full-spectrum techniques. Clinical training of the commercial product is accomplished by clinical correlation with histopathological diagnosis. The initiative is accomplished through collaborative expertise in electro-optics, clinical dermatology, bio-medical optics, and medical device commercialization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TANNING BED USE AMONG UI STUDENTS Principal Investigator & Institution: Dennis, Leslie Epidemiology; University of Iowa Iowa City, Ia 52242

K.;

Assistant

Professor;

Timing: Fiscal Year 2003; Project Start 02-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Ultraviolet (UV) radiation is the major etiologic risk factor implicated in the development of cutaneous malignant melanoma (CMM) and in precursor lesions such as nevi (common moles). There is concern that sunlamp or tanning bed use may also be related to CMM, either directly or indirectly by prolonging sun exposure after tanning. Considering the apparent enormous popularity of sunlamp and tanning bed use, it seems imperative to describe tanning bed habits among young persons. Many studies have shown that nevi are good markers of risk for CMM. We will examine nevi, as an early outcome or surrogate for CMM, in college students. We propose to survey college students about their attitudes and use of tanning beds, sunless tanning products, and sunscreen. We will also ask about history of sunburns, recent UV exposure, and potential UV exposure based on places of residence along with the potential confounding effects of sun sensitivity (tendency to burn, inability to tan, skin color, hair color, eye color and freckling). This will be accomplished via a cross-sectional study conducted in fraternity and sorority students. This convenience sample will likely be at higher socioeconomic status and disposable income than other students. Higher socioeconomic status has been related to an increased CMM risk. Such students may also have increased use of tanning beds and sunless tanning products. We will conduct this baseline survey after Spring Break. The specific aims are as follows: 1) to describe the attitudes towards and prevalence of tanning bed, sunless tanning product, and sunscreen use in fraternity and sorority students, 2) to examine the risk of nevi with the previously mentioned factors in students, and 3) to compare mean differences in exposed and unexposed skin color after Spring Break between students who use tanning beds before Spring Break and those who do not. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TOPICAL RETINOIDS FOR CHEMOPREVENTION OF MELANOMA Principal Investigator & Institution: Cattaneo, Maurizio V.; Ivrea, Inc. 216 Ricciuti Dr Quincy, Ma 02169 Timing: Fiscal Year 2003; Project Start 01-JUN-2000; Project End 31-MAR-2005 Summary: (provided by applicant): Malignant melanoma's incidence is increasing by 2.7% annually even as most other cancers are experiencing a decline in incidence. The long-term objective of this project is to commercialize a topical formulation containing retinoic acid (ATRA) for subjects with dysplastic nevi at a higher risk of developing malignant melanoma. However, ATRA is highly irritating to the skin. Several topical delivery systems have been shown to reduce ATRA-induced skin irritation. Phase I studies have shown that the biopolymer chitosan acts as a topical delivery system for

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ATRA. In this Phase II SBIR study we propose to: (1) standardize the topical formulation containing the ATRA/chitosan delivery system according to our IND 60,073, (2) test the long-term toxicity and irritation of the formulation in both rodents and non-rodents species according to FDA 21 CFR, Part 58, (3) determine whether 6 months of topical ATRA/chitosan will result in a significant clinical improvement of dysplastic nevi, and/or a decrease in the dysplasia grade, and/or a change in the expression of proliferation biomarkers, by performing a multicenter controlled clinical trial involving 16 dysplastic nevi subjects using Internet-based randomization, electronic data capture, coordination and monitoring, and pre and post study clinical and histological assessment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSCRIPTIONAL DEVELOPMENT

REGULATION

OF

MELANOCYTE

Principal Investigator & Institution: Hornyak, Thomas J.; Dermatology; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-MAY-2005 Summary: (provided by applicant): The long-term objective of this application is to understand how transcription factors control the development of neural crest-derived pigment cells, or melanocytes, in the vertebrate embryo. By acting at the level of the nucleus and binding to defined DNA elements on promoter or enhancer regions of genes, transcription factors have the ability to interact with the basal transcriptional machinery to activate or repress transcription. Transcription of entire sets of genes can be influenced by the actions of individual transcription factors, leading to the activation or repression of gene programs that have the ability to determine major characteristics of a developing cell. Genetic and biochemical data from well-established murine coat color mutants and from patients with congenital disorders of pigmentation all support the important role of transcription factors in promoting the proper development of the melanocyte, a cell which not only confers pigment to the skin and hair, but also promotes the proper development of the eye and inner ear as well. The specific aims of this proposal are to understand the function of the transcription factors Mitf and Pax3 in melanocyte development and to determine how the misexpression of a basic helix-loophelix transcription factor in melanocyte precursors affects both melanocyte development and differentiation. Achieving these aims, using a combination of techniques with transgenic animals, primary cultures of neural crest cells, and molecular methods of gene expression analysis, will enhance findings from previous work that has been performed in this field and will help elucidate the mechanisms whereby transcription factors known to be crucial to the development of the melanocytic lineage function during development. They will also help determine how factors known to perturb melanocyte development and differentiation act in this role. The results of these experiments have the potential to contribute to our understanding of the etiology of certain genetic disorders of pigmentation, the regulation of normal pigmentation, and the genesis of proliferative melanocytic lesions with substantial morbidity such as large congenital melanocytic nevi and malignant melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT AND MOLECULAR ANALYSIS OF ATYPICAL NEVI Principal Investigator & Institution: Becker, Dorothea; Professor of Pathology; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

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Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2004 Summary: (adapted from the investigator's abstract) The overall objective of this proposal is to determine whether systemic treatment with the biologic agent, interferon a2a, will modulate the molecular, immunologic, histopathologic, and clinical features of atypical nevi, which are the known precursors and risk markers of malignant melanoma. In the setting of familial melanoma, the presence of atypical nevi is associated with a nearly 100% risk of developing primary melanoma by age 70. Likewise, in the case of sporadic melanomas, between 40-60% of them develop from preexisting atypical nevi. Furthermore, patients with a clinical history of primary melanoma and two or more atypical nevi are at an 8-fold greater risk of developing a second primary melanoma. Thus, in light of the rising incidence and mortality rate of melanoma, it is not only imperative to find and implement strategies that will help cure patients with metastatic disease but also to prevent the progression of atypical nevi to malignant melanoma. We recently demonstrated that direct gene targeting of bFGF/FGFR-1 in human melanomas causes their growth arrest and regression as a result of blocked melanoma proliferation and intratumoral angiogenesis. In addition, we documented expression of these two genes in the dermal nevocytic and stromal compartments of atypical nevi. The results of recent clinical trials provided evidence that IFNa has a significant therapeutic impact on metastatic melanoma, leading in 1995 to an FDA approval of IFNa as the first agent for adjuvant therapy of high-risk melanoma. While IFNa is known to be a potent antiviral, antiproliferative and immunomodulating agent, recent studies have shown that IFNa also functions as a strong angiogenesis inhibitor by blocking bFGF mRNA and protein in human malignancies. Given these findings, we propose to determine whether the biological, histopathological and clinical features of melanoma precursor lesions can be modulated by systemic treatment with low-dose IFNa-2a in patients who have a clinical history of melanoma and multiple atypical nevi. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TUMOR ANGIOGENESIS INHIBITIION BY SYSTEMIC GENE DELIVERY Principal Investigator & Institution: Dow, Steven W.; Associate Professor; Clinical Sciences; Colorado State University-Fort Collins Fort Collins, Co 80523 Timing: Fiscal Year 2002; Project Start 11-AUG-2000; Project End 31-JUL-2005 Summary: The overall goal of this project is to assess systemic delivery of angiostatic genes as a means of inhibiting tumor antiogenesis. The specific objectives are to compare two methods of systemic gene delivery and two angiostatic genes for their ability to inhibit angiogenesis and tumor growth, using both experimental tumor models (mice) and hypothesis that sustained systemic production of an angiostatic factor by in vivo gene delivery can inhibit angiogenesis in animals with established tumors. The rationale for this proposal is that sustained in vivo expression of angiostatic genes by systemic non-viral gene delivery techniques may be a more effective and practical approach to angiogenesis inhibition than repeated parenteral injections of purified proteins. Two endogenous angiostatic factors (endostatin and angiostatin), that have both demonstrated impressive antitumor activity in vivo, will be evaluated. The objective of this proposal will be accomplished using three specific aims: (1) compare the effectiveness of intravenous versus intramuscular gene delivery in murine tumor models; (2) determine optimal DNA doses for intravenous and intramuscular gene delivery in dogs; and (3) assess antiangiogenic activity and tumor responses to systemic endostatin gene therapy in dogs with malignant melanoma. The results of these studies,

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which include assessment of angiogenic markers and treatment outcomes in a pertinent large animal tumor model, will provide a clinically realistic evaluation of this novel approach to inhibition to tumor angiogenesis. Such an approach may be broadly applicable to therapeutic modulation of aniogenesis in general, using genes or combinations of genes that either inhibit or stimulate angiogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TUMOR SUPPRESSORS IN SPONTANEOUS AND UV-INDUCED MELANOMA MODELS Principal Investigator & Institution: Nairn, Rodney S.; Professor of Carcinogenesis; Southwest Texas State University San Marcos, Tx 786664616 Timing: Fiscal Year 2002 Summary: Heredity can be a strong predisposing factor in the development of cutaneous malignant melanoma (CMM), a deadly cancer which is increasing in incidence. Although UV radiation is generally believed to play a role in CMM, the role of excessive sunlight exposure in the etiology of melanoma is controversial. Ozone depletion, predicted to increase UVB radiation incident to the earth's surface, may increase the risk of CMM in the human population. However, UVA ration represents a much greater component of sunlight than increasing melanoma incidence in humans, it is crucial to develop and test hypotheses that correlate excessive sunlight exposure with genetic factors underlying melanoma susceptibility can be recognized and potentially isolated are necessary. In this project, the genetic diversity generated by the hybridization of different Xiphophorus species will be exploited to develop and analyze several new experimental melanoma models, with the goal of identifying genetic determinants of spontaneous and HIV-induced tumorigenesis. The investigation of UVinduced melanoma formation in Xiphophorus melanoma models will establish UV action spectra for melanomagenesis, and for UV-induced DNA damage and repair in Xiphophorus tissues and cell lines. Experiments to examine the roles of oncogenes (Xmrk) and tumor suppressor genes (CDKN2X, p53) in melanoma in these models will address hypothesis regarding whether Xmrk over-expression is a common feature of Xiphophorus melanomas. Several hypotheses address the roles of suppressor genes in these tumor models will be developed, including whether suppressor gene dysfunction is determined by methylation patterns, promoter differences, or structural alterations. These studies will contribute to an understanding of how dominant oncogenes and tumor suppressor genes contribute to tumorigenesis in the unique Xiphophorus models, but are also directly relevant to understanding melanoma formation in humans, because of the evidence implicating CDKN2 as a human melanoma susceptibility gene. Investigation of CDKN2X, p53, and DNA damage in these unique model organisms will advance our understanding of the molecular etiology of melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: USE OF AAPC FOR MELANOMA ADOPTIVE IMMUNOTHERAPY Principal Investigator & Institution: Schneck, Jonathan P.; Associate Professor; Pathology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2009 Summary: (provided by applicant): While adoptive immunotherapy holds promise as a treatment for malignant melanoma, development has been impeded by the lack of a reproducible and economical method for generating therapeutic numbers of antigenspecific CTL. Our preliminary data demonstrate that an artificial Antigen-Presenting

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Cell (aAPC), made by coupling HLA-Ig and anti-CD28 to beads, can reliably induce and expand antigen-specific CTL from healthy donors to a variety of different antigens. This raises the possibility that HLA-Ig can be used to replace standard dendritic cell based ex vivo expansion of antigen-specific CTL. Therefore the potential exists to use HLA-Igbased aAPC as a viable method for induction, expansion and activation of clinical grade melanoma-specific T cells in the treatment of metastatic melanoma. In this study we propose to demonstrate functional efficacy of HLA-Ig based aAPC for inducing and expanding anti-tumor specific CTL from patients with metastatic melanoma. Specifically we propose to optimize aAPC stimulation of Mart-1 specific CTL by optimizing aAPC structure and the duration of stimulation. T cell activation requires delivery of a combination of signals through the T cell receptor (Signal 1) and through co-stimulatory molecules (Signal 2) such as engagement of CD28 by B7. The efficacy of the various formulations of aAPC, with variable ratios of signal 1 to signal 2 as well as different type of signal 2, will be determined. In vitro expanded Mart1-specific CTL will be studied for in vivo function in murine models, including a human/SCID model and possibly the murine A2-transgenic mice using adoptively transferred CTL. Efficacy of CTL treatments is likely to be augmented by transferring CTL populations directed at multiple antigenic epitopes. Therefore we will analyze the ability to induce/expand CTL specific for the melanoma associated, A2-restricted subdominant epitopes gpl00, NYESO-1 and tyrosinase. Effective immunotherapy will be augmented by also having melanoma-specific CD4 T cells. Our preliminary data indicates that using biotinylated class II-based aAPC or autologous DC, we can generate gpl00 melanoma specific CD4 cells. We propose to further develop the biotinylated class II HLA-based aAPC and to generate class II-lg-based aAPC for stimulation of melanoma specific class II-restricted CD4 T cells and analyze the importance of having both melanoma specific CD8 and CD4 T cells in the in vivo models. These studies will help evaluate the role of aAPC as a potential approach to adoptive immunotherapeutic for the treatment of metastatic melanoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UV INDUCIBLE INHIBITION IN MELANOMA Principal Investigator & Institution: Ronai, Ze'ev A.; Professor; Ruttenberg Cancer Center; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 05-MAY-1993; Project End 31-JAN-2006 Summary: (Applicant's abstract) Proteolysis plays an important role in regulating cellular proliferation, differentiation and stress response. Studies supported by the current funding period have established and characterized JNK targeting of the ubiquitination and degradation of c-Jun, AFT2, JunB, and p53. In all cases JNK targeting takes place in non-stressed cells when the targeted protein is non-phosphorylated. Upon stress, the phosphorylation of JNK substrates renders them protected from JNK targeting. Since the duration and magnitude of activities elicited by key regulatory proteins is determined by the delicate balance between protein protection from- or targeting for- degradation, our competing renewal application focuses on mechanisms that underlie the protection of stress regulatory proteins from ubiquitination and degradation. Most recent studies from our laboratory have focused on SUMO-1 - an ubiquitin-like protein that is conjugated to a rapidly growing number of substrates. In these preliminary studies, we have established, using the model of Mdm2 E3 ubiquitin ligase, that protein sumoylation (conjugating a single SUMO-1 molecule via respective E1 and E2 to target protein) is key to its stabilization. Further, our studies establish that

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Mdm2 sumoylation takes place on the same lysine residue that is otherwise ubiquitinated. Importantly, sumoylation of Mdm2 increases its ubiquitin ligase activity. These findings provide the foundation for our working hypothesis, which proposes that SUMO-1 modification of ubiquitin ligase proteins, using Mdm2 as a model, is a key regulatory event in its stability and ubiquitin ligase activity. Our proposed studies are aimed at understanding the mechanisms that regulate Mdm2 sumoylation as opposed to ubiquitination both in normal and transformed cells, using malignant melanoma as a model. Accordingly, we propose to: (1) Identify the effects of post-translational modifications on Mdm2 sumoylation, Mdm2 self-ubiquitination, and on Mdm2-targeted ubiquitination of p53; (2) Determine the contribution of Mdm2-associated proteins to its sumoylation and ubiquitin ligase activities. (3) Test the hypothesis that Mdm2 sumoylation contributes to its oncogenic potential. (4) Determine binding sites for Ubc9 and UbcH5b - E2 for SUMO-1 and ubiquitin, respectively. Identify RING finger proteins that share the same structural motifs. (5) Identify (via computer modeling and experimental approaches) minimal size fragments from Mdm2 (or its regulatory proteins) that would attenuate its sumoylation or E3 ligase activities. In all, our proposed studies will establish the mechanism underlying Sumo-conjugation to Mdm2, its significance to the biology of this oncogene and develop reagents that alter Mdm2 sumoylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VALIDATION OF TRANSILLUMINATION AND THE NEVOSCOPE Principal Investigator & Institution: Mullani, Nizar A.; Translite, Llc Suite 150 Sugar Land, Tx 77478 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-SEP-2004 Summary: (provided by applicant): Skin cancer is the most common of all cancers and melanoma is a deadly skin cancer that accounts for over 75% of all the skin cancer deaths in the United States. The incidence of melanoma is rising at approximately 3% per year. Early detection of melanoma results in 95% cure rate. But, early detection of melanoma is difficult because of the subtle changes that differentiate a malignant melanoma from a benign mole. Better methods to detect these subtle changes, and more frequent screening for skin cancer, will significantly improve the early detection of melanoma and possibly reduce the number of deaths caused by this disease. Early detection of melanoma requires better methods for examining subtle changes in the pigmentation of the suspicious moles. Side-transillumination, whereby light is directed into the skin from around the suspicious mole, is a new method that makes the skin translucent so that the subsurface structures can be examined with clarity. This technique is used in a prototype device called the Nevoscope and has the potential for improving the early detection of skin cancers such as melanoma and basal cell carcinoma. The goal of this research project is to validate the use of sidetransillumination for the detection of melanoma by comparing its detection accuracy to the established oil epiluminescence method. The second goal of the research project is to develop a commercial model of the Nevoscope for clinical use by the dermatologists that would be easy to use and affordable. The clinical validation study will digitally image 240 skin lesions suspicious for malignancy using the oil-based imaging and the side-transillumination imaging in the same lesion. Two dermatologists that are blinded to the patient history, and who will make a diagnosis based on a semi quantitative scoring method, will read these images. Diagnostic accuracy for melanoma will be computed for the two methods based on pathology-determined diagnosis of the excised lesion. The long-term goal of this research is to validate the side-transillumination

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method and develop the Nevoscope device into a commercial product for improved early diagnoses of skin cancers. 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 “malignant melanoma” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for malignant melanoma in the PubMed Central database: •

A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells. by Aoyama A, Chen WT.; 1990 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54942

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A distinct octamer-binding protein present in malignant melanoma cells. by Cox PM, Temperley SM, Kumar H, Goding CR.; 1988 Dec 9; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=338995

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Expression of Ia-like antigens on cultured human malignant melanoma cell lines. by Winchester RJ, Wang CY, Gibofsky A, Kunkel HG, Lloyd KO, Old LJ.; 1978 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=393154

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Fibroblasts from patients with hereditary cutaneous malignant melanoma are abnormally sensitive to the mutagenic effect of simulated sunlight and 4nitroquinoline 1-oxide. by Howell JN, Greene MH, Corner RC, Maher VM, McCormick JJ.; 1984 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=344789

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Genetic predisposition of transgenic mouse melanocytes to melanoma results in malignant melanoma after exposure to a low ultraviolet B intensity nontumorigenic for normal melanocytes. by Larue L, Dougherty N, Mintz B.; 1992 Oct 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=50166

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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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Human malignant melanoma cell line (HMV-II) for isolation of influenza C and parainfluenza viruses. by Moriuchi H, Oshima T, Nishimura H, Nakamura K, Katsushima N, Numazaki Y.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=267894

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In vitro studies of 2,4-dihydroxyphenylalanine, a prodrug targeted against malignant melanoma cells. by Morrison ME, Yagi MJ, Cohen G.; 1985 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397686

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Poliovirus vaccine vectors elicit antigen-specific cytotoxic T cells and protect mice against lethal challenge with malignant melanoma cells expressing a model antigen. by Mandl S, Sigal LJ, Rock KL, Andino R.; 1998 Jul 7; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20956

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Prostaglandin D2 formation by malignant melanoma cells correlates inversely with cellular metastatic potential. by Fitzpatrick FA, Stringfellow DA.; 1979 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=383471

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The role of MHC class I glycoproteins in the regulation of induction of cell death in immunocytes by malignant melanoma cells. by Fishman D, Irena B, Kellman-Pressman S, Karas M, Segal S.; 2001 Feb 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29327

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Tissue-specific expression of an anti-ras ribozyme inhibits proliferation of human malignant melanoma cells. by Ohta Y, Kijima H, Ohkawa T, Kashani-Sabet M, Scanlon KJ.; 1996 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=145712

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Upregulation of HMG1 Leads to Melanoma Inhibitory Activity Expression in Malignant Melanoma Cells and Contributes to Their Malignancy Phenotype. by Poser I, Golob M, Buettner R, Bosserhoff AK.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152547

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 malignant melanoma, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “malignant 6

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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melanoma” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for malignant melanoma (hyperlinks lead to article summaries): •

A case of "red face": a clue to early detection of malignant melanoma? Author(s): Tamir E, Brenner S. Source: Skinmed. 2003 September-October; 2(5): 272. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14705600

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A CD4+, HLA-DR7-restricted T-helper lymphocyte clone recognizes an antigen shared by human malignant melanoma and glioma. Author(s): Somasundaram R, Swoboda R, Caputo L, Lee A, Jackson N, Marincola FM, Guerry D, Herlyn D. Source: International Journal of Cancer. Journal International Du Cancer. 2003 April 10; 104(3): 362-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12569560

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A nonepidermal, primary malignant melanoma arising in a giant congenital melanocytic nevus 40 years after partial surgical removal. Author(s): Streams BN, Lio PA, Mihm MC, Sober AJ. Source: Journal of the American Academy of Dermatology. 2004 May; 50(5): 789-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15097968

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A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma. Author(s): Khorana AA, Rosenblatt JD, Sahasrabudhe DM, Evans T, Ladrigan M, Marquis D, Rosell K, Whiteside T, Phillippe S, Acres B, Slos P, Squiban P, Ross M, Kendra K. Source: Cancer Gene Therapy. 2003 April; 10(4): 251-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679797

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A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Author(s): Smalley KS. Source: International Journal of Cancer. Journal International Du Cancer. 2003 May 1; 104(5): 527-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12594806

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A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Author(s): Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Bui BN, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre ME, De Gislain C, Bensadoun RJ, Clavel M. Source: Melanoma Research. 2003 February; 13(1): 97-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12569292

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A prospective study of cutaneous adverse events induced by low-dose alphainterferon treatment for malignant melanoma. Author(s): Guillot B, Blazquez L, Bessis D, Dereure O, Guilhou JJ. Source: Dermatology (Basel, Switzerland). 2004; 208(1): 49-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14730237

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A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. Author(s): Veierod MB, Weiderpass E, Thorn M, Hansson J, Lund E, Armstrong B, Adami HO. Source: Journal of the National Cancer Institute. 2003 October 15; 95(20): 1530-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14559875

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A retrospective observational study of primary cutaneous malignant melanoma patients treated with excision only compared with excision biopsy followed by wider local excision. Author(s): McKenna DB, Lee RJ, Prescott RJ, Doherty VR. Source: The British Journal of Dermatology. 2004 March; 150(3): 523-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030337

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Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma? Author(s): Blake J, Ziman MR. Source: Histology and Histopathology. 2003 April; 18(2): 529-39. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12647804

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Abnormal uterine bleeding as a presenting sign of metastasis to the endometrium in a patient with a history of cutaneous malignant melanoma. Author(s): Berker B, Sertcelik A, Kaygusuz G, Unlu C, Ortac F. Source: Gynecologic Oncology. 2004 April; 93(1): 252-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15047246

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Absence of HER2 overexpression in metastatic malignant melanoma. Author(s): Inman JL, Kute T, White W, Pettenati M, Levine EA. Source: Journal of Surgical Oncology. 2003 October; 84(2): 82-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502781

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Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity. Author(s): Bosserhoff AK, Stoll R, Sleeman JP, Bataille F, Buettner R, Holak TA. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2003 November; 83(11): 1583-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615412

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Adjuvant interferon alfa treatment for patients with malignant melanoma stimulates transporter proteins associated with antigen processing and proteasome activator 28. Author(s): Abuzahra F, Heise R, Joussen S, Dreuw A, Merk H, Zwadlo-Klarwasser G, Baron JM. Source: The Lancet Oncology. 2004 April; 5(4): 250. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15050957

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Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. Author(s): Hancock BW, Wheatley K, Harris S, Ives N, Harrison G, Horsman JM, Middleton MR, Thatcher N, Lorigan PC, Marsden JR, Burrows L, Gore M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 1; 22(1): 53-61. Epub 2003 December 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14665609

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Adrenal glands metastases from malignant melanoma. Laparoscopic bilateral adrenalectomy. Author(s): Carlini M, Lonardo MT, Boschetto A, Carboni F, Appetecchia M, Tropea F, Santoro E. Source: J Exp Clin Cancer Res. 2003 March; 22(1): 141-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12725334

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Agonists of peroxisome proliferator-activated receptor gamma inhibit cell growth in malignant melanoma. Author(s): Mossner R, Schulz U, Kruger U, Middel P, Schinner S, Fuzesi L, Neumann C, Reich K. Source: The Journal of Investigative Dermatology. 2002 September; 119(3): 576-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12230498

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An unusual association of malignant melanoma and small cell lung cancer: case report. An eleven-year-follow-up. Author(s): Bruno G, Coppola M, Eleuteri E, Barucco M, Molfetta R, Bruno A, Angelini L. Source: Clin Ter. 2003 July-August; 154(4): 271-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14618946

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Anorectal malignant melanoma: treatment with surgery or radiation therapy, or both. Author(s): Moozar KL, Wong CS, Couture J. Source: Canadian Journal of Surgery. Journal Canadien De Chirurgie. 2003 October; 46(5): 345-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14577706

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Bartholin's gland carcinoma, malignant melanoma and other rare tumours of the vulva. Author(s): Finan MA, Barre G. Source: Best Practice & Research. Clinical Obstetrics & Gynaecology. 2003 August; 17(4): 609-33. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12965135

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Baseline staging in cutaneous malignant melanoma. Author(s): Hafner J, Schmid MH, Kempf W, Burg G, Kunzi W, Meuli-Simmen C, Neff P, Meyer V, Mihic D, Garzoli E, Jungius KP, Seifert B, Dummer R, Steinert H. Source: The British Journal of Dermatology. 2004 April; 150(4): 677-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15099363

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Basic studies on gene therapy of human malignant melanoma by use of the human interferon beta gene entrapped in cationic multilamellar liposomes. 1. Morphology and growth rate of six melanoma cell lines used in transfection experiments with the human interferon beta gene. Author(s): Benga G. Source: Journal of Cellular and Molecular Medicine. 2001 October-December; 5(4): 402-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12067474

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Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy. Author(s): Hakansson A, Gustafsson B, Abdiu A, Krysander L, Hakansson L. Source: Cancer Immunology, Immunotherapy : Cii. 2003 April; 52(4): 249-54. Epub 2003 March 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12669250

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Bcl-2 overexpression prevents apoptosis induced by ceramidase inhibitors in malignant melanoma and HaCaT keratinocytes. Author(s): Raisova M, Goltz G, Bektas M, Bielawska A, Riebeling C, Hossini AM, Eberle J, Hannun YA, Orfanos CE, Geilen CC. Source: Febs Letters. 2002 April 10; 516(1-3): 47-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959101

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Behavior of malignant melanoma with tonsil metastasis. Author(s): Tueche SG. Source: Annales De Medecine Interne. 2002 March; 153(2): 136-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12037497

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Benign lymphoid infiltrate of the iris simulating a malignant melanoma. Author(s): Sharma MC, Shields CL, Shields JA, Eagle RC Jr, Demirci H, Wiley L. Source: Cornea. 2002 May; 21(4): 424-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11973396

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Bilateral multifocal chorioretinopathy in a woman with cutaneous malignant melanoma. Author(s): Palmowski AM, Haus AH, Pfohler C, Reinhold U, Allgayer R, Tilgen W, Ruprecht KW, Thirkill CE. Source: Archives of Ophthalmology. 2002 December; 120(12): 1756-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12470158

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Binding of rabbit immunoglobulins to melanoma cells: a pitfall in the immunohistochemical study of malignant melanoma. Author(s): van den Oord JJ, Delabie J. Source: Virchows Archiv : an International Journal of Pathology. 2001 April; 438(4): 4213. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11355181

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Biochemotherapy of metastatic malignant melanoma. On down-regulation of CD28. Author(s): Hakansson A, Hakansson L, Gustafsson B, Krysander L, Rettrup B, Ruiter D, Bernsen MR. Source: Cancer Immunology, Immunotherapy : Cii. 2002 November; 51(9): 499-504. Epub 2002 August 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12357321

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Biochemotherapy of metastatic malignant melanoma. Predictive value of tumourinfiltrating lymphocytes. Author(s): Hakansson A, Gustafsson B, Krysander L, Hjelmqvist B, Rettrup B, Hakansson L. Source: British Journal of Cancer. 2001 December 14; 85(12): 1871-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11747328

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Blue naevus with satellitosis mimicking malignant melanoma. Author(s): Sahin MT, Demir MA, Yoleri L, Can M, Ozturkcan S. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2001 November; 15(6): 570-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11843220

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Blue nevus with satellitosis mimicking malignant melanoma. Author(s): del Rio E, Vazquez Veiga HA, Suarez Penaranda JM. Source: Cutis; Cutaneous Medicine for the Practitioner. 2000 May; 65(5): 301-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10826091

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Bolus followed by continuous infusion interleukin-2 in patients with metastatic malignant melanoma and kidney cancer previously treated with interleukin-2. Author(s): Quan WD Jr, Quan FM. Source: Cancer Biotherapy & Radiopharmaceuticals. 2003 August; 18(4): 535-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503947

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Boron neutron capture therapy (BNCT) for malignant melanoma with special reference to absorbed doses to the normal skin and tumor. Author(s): Fukuda H, Hiratsuka J, Kobayashi T, Sakurai Y, Yoshino K, Karashima H, Turu K, Araki K, Mishima Y, Ichihashi M. Source: Australas Phys Eng Sci Med. 2003 September; 26(3): 97-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14626847

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BRAF alterations are associated with complex mutational profiles in malignant melanoma. Author(s): Daniotti M, Oggionni M, Ranzani T, Vallacchi V, Campi V, Di Stasi D, Torre GD, Perrone F, Luoni C, Suardi S, Frattini M, Pilotti S, Anichini A, Tragni G, Parmiani G, Pierotti MA, Rodolfo M. Source: Oncogene. 2004 August 5; 23(35): 5968-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15195137

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BRAF gene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility: the Italian Melanoma Intergroup Study. Author(s): Casula M, Colombino M, Satta MP, Cossu A, Ascierto PA, Bianchi-Scarra G, Castiglia D, Budroni M, Rozzo C, Manca A, Lissia A, Carboni A, Petretto E, Satriano SM, Botti G, Mantelli M, Ghiorzo P, Stratton MR, Tanda F, Palmieri G; Italian Melanoma Intergroup Study. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 January 15; 22(2): 286-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722037

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Brain metastases of malignant melanoma showing unbalanced whole arm chromosomal translocations der (8; 14) (q10; q10) and der (11; 15) (q10; q10) in a Japanese patient. Author(s): Takahashi T, Kazama Y, Shimizu H, Yoshimoto M, Tsujisaki M, Imai K. Source: Intern Med. 2001 September; 40(9): 956-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11579965

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Bullous malignant melanoma: an unusual differential diagnosis of a hemorrhagic friction blister. Author(s): Vogt T, Brunnberg S, Hohenleutner U, Landthaler M. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2003 January; 29(1): 102-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12534522

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Can different genetic changes characterize histogenetic subtypes and biologic behavior in sporadic malignant melanoma of the skin? Author(s): Poetsch M, Dittberner T, Woenckhaus C. Source: Cellular and Molecular Life Sciences : Cmls. 2003 September; 60(9): 1923-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14523552

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Capsaicin regulates vascular endothelial cell growth factor expression by modulation of hypoxia inducing factor-1alpha in human malignant melanoma cells. Author(s): Patel PS, Yang S, Li A, Varney ML, Singh RK. Source: Journal of Cancer Research and Clinical Oncology. 2002 September; 128(9): 4618. Epub 2002 August 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12242509

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Case report: magnetic resonance imaging of vaginal malignant melanoma. Author(s): Kim H, Jung SE, Lee EH, Kang SW. Source: Journal of Computer Assisted Tomography. 2003 May-June; 27(3): 357-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12794599

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CD95/Fas signaling in human melanoma cells: conditional expression of CD95L/FasL overcomes the intrinsic apoptosis resistance of malignant melanoma and inhibits growth and progression of human melanoma xenotransplants. Author(s): Eberle J, Fecker LF, Hossini AM, Wieder T, Daniel PT, Orfanos CE, Geilen CC. Source: Oncogene. 2003 December 11; 22(57): 9131-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668794

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Clinical and histologic features of level 2 cutaneous malignant melanoma associated with metastasis. Author(s): Shaw HM, McCarthy WH, Scolyer RA. Source: Cancer. 2002 August 1; 95(3): 671-2; Author Reply 672-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209764

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Clinical protocol. Immunization of patients with malignant melanoma with autologous CD34(+) cell-derived dendritic cells transduced ex vivo with a recombinant replication-deficient vaccinia vector encoding the human tyrosinase gene: a phase I trial. Author(s): Di Nicola M, Carlo-Stella C, Anichini A, Mortarini R, Guidetti A, Tragni G, Gallino F, Del Vecchio M, Ravagnani F, Morelli D, Chaplin P, Arndtz N, Sutter G, Drexler I, Parmiani G, Cascinelli N, Gianni AM. Source: Human Gene Therapy. 2003 September 20; 14(14): 1347-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14503969

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Clinical significance of sentinel lymph node involvement in malignant melanoma. Author(s): Liszkay G, Peley G, Sinkovics I, Peter I, Orosz Z, Fejos Z, Horvath B, Koves I, Gilde K, Kasler M. Source: Pathology Oncology Research : Por. 2003; 9(3): 184-7. Epub 2003 October 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530813

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Coexpression of bone sialoprotein (BSP) and the pivotal transcriptional regulator of osteogenesis, Cbfa1/Runx2, in malignant melanoma. Author(s): Riminucci M, Corsi A, Peris K, Fisher LW, Chimenti S, Bianco P. Source: Calcified Tissue International. 2003 September; 73(3): 281-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14667142

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Combined endoscopic and open inguinal dissection for malignant melanoma. Author(s): Schneider C, Brodersen JP, Scheuerlein H, Tamme C, Lippert H, Kockerling F. Source: Langenbeck's Archives of Surgery / Deutsche Gesellschaft Fur Chirurgie. 2003 March; 388(1): 42-7. Epub 2003 March 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12690479

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Comparison of diagnostic accuracy for cutaneous malignant melanoma between general dermatology, plastic surgery and pigmented lesion clinics. Author(s): Osborne JE, Chave TA, Hutchinson PE. Source: The British Journal of Dermatology. 2003 February; 148(2): 252-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12588376

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Comparison of DNA ploidy status and DNA ploidy-related parameters in malignant melanoma tissue microarrays and full sections. Author(s): Korabiowska M, Cordon-Cardo C, Buschmann N, Stachura J, Fischer G, Brinck U. Source: Human Pathology. 2004 July; 35(7): 887-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15257554

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Contribution of whole body F-18-FDG-PET and lymphoscintigraphy to the assessment of regional and distant metastases in cutaneous malignant melanoma. A pilot study. Author(s): Klein M, Freedman N, Lotem M, Marciano R, Moshe S, Gimon Z, Chisin R. Source: Nuklearmedizin. 2000; 39(3): 56-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10834191

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Cost-effectiveness of interferon-alpha2 as adjuvant therapy in malignant melanoma. Author(s): Lafuma A, Grob JJ. Source: Expert Opinion on Pharmacotherapy. 2003 March; 4(3): 343-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12614186

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Current and future directions in the treatment of metastatic malignant melanoma. Author(s): Baron JM, Heise R, Merk HF, Abuzahra F. Source: Current Medicinal Chemistry. Anti-Cancer Agents. 2003 November; 3(6): 393-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529447

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Cutaneous malignant melanoma in association with mycosis fungoides. Author(s): Evans AV, Scarisbrick JJ, Child FJ, Acland KM, Whittaker SJ, Russell-Jones R. Source: Journal of the American Academy of Dermatology. 2004 May; 50(5): 701-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15097953

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Cutaneous malignant melanoma: the great simulator. Author(s): Cruz J, Reis-Filho JS, Lopes JM. Source: International Journal of Surgical Pathology. 2003 January; 11(1): 35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12598916

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Cytokine gene single nucleotide polymorphisms and susceptibility to and prognosis in cutaneous malignant melanoma. Author(s): Howell WM, Turner SJ, Theaker JM, Bateman AC. Source: European Journal of Immunogenetics : Official Journal of the British Society for Histocompatibility and Immunogenetics. 2003 December; 30(6): 409-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675394

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Cytopathology of malignant melanoma in conventional and liquid-based smears. Author(s): Morrison C, Young DC, Wakely PE Jr. Source: American Journal of Clinical Pathology. 2002 September; 118(3): 435-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12219786

Studies

71

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Cytotoxic T cell induction against human malignant melanoma cells using HLA-A24restricted melanoma peptide cocktail. Author(s): Akiyama Y, Maruyama K, Nara N, Mochizuki T, Yamamoto A, Yamazaki N, Kawashima I, Nukaya I, Takesako K, Yamaguchi K. Source: Anticancer Res. 2004 March-April; 24(2B): 571-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15160996

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Dacarbazine but not temozolomide induces phototoxic dermatitis in patients with malignant melanoma. Author(s): Treudler R, Georgieva J, Geilen CC, Orfanos CE. Source: Journal of the American Academy of Dermatology. 2004 May; 50(5): 783-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15097966

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Death receptor-independent apoptosis in malignant melanoma induced by the smallmolecule immune response modifier imiquimod. Author(s): Schon MP, Wienrich BG, Drewniok C, Bong AB, Eberle J, Geilen CC, Gollnick H, Schon M. Source: The Journal of Investigative Dermatology. 2004 May; 122(5): 1266-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15140231

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Dermatological perspectives of malignant melanoma. Author(s): Swetter SM. Source: The Surgical Clinics of North America. 2003 February; 83(1): 77-95, Vi. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691451

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Descriptive epidemiology of cutaneous malignant melanoma. Analyses of German Cancer Registry data. Author(s): Stang K, Stang A, Stegmaier C, Ziegler H, Eisinger B, Stabenow R, Jockel KH. Source: Stud Health Technol Inform. 2000; 77: 139-42. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11187529

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Desmoplastic malignant melanoma of the lip: a report of 6 cases and review of the literature. Author(s): Hui JI, Linden KG, Barr RJ. Source: Journal of the American Academy of Dermatology. 2002 December; 47(6): 863-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12451370

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Desmoplastic malignant melanoma of the lower lip presenting as herpetic lesions. Author(s): Moulton MS, Bratton T, Rosdeutscher JD. Source: Otolaryngology and Head and Neck Surgery. 2004 February; 130(2): 268-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14990927

72

Malignant Melanoma

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Detection of intraepidermal malignant melanoma in vivo by confocal scanning laser microscopy. Author(s): Busam KJ, Charles C, Lohmann CM, Marghoob A, Goldgeier M, Halpern AC. Source: Melanoma Research. 2002 August; 12(4): 349-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12170184

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Detection of mitochondrial DNA alterations in plasma of malignant melanoma patients. Author(s): Takeuchi H, Fujimoto A, Hoon DS. Source: Annals of the New York Academy of Sciences. 2004 June; 1022: 50-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15251939

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Detection of telomerase RNA in the plasma of patients with breast cancer, malignant melanoma or thyroid cancer. Author(s): Novakovic S, Hocevar M, Zgajnar J, Besic N, Stegel V. Source: Oncol Rep. 2004 January; 11(1): 245-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654933

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Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Author(s): Butterfield LH, Ribas A, Dissette VB, Amarnani SN, Vu HT, Oseguera D, Wang HJ, Elashoff RM, McBride WH, Mukherji B, Cochran AJ, Glaspy JA, Economou JS. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 March; 9(3): 998-1008. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631598

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Difference between real and perceived power of dermoscopical methods for detection of malignant melanoma. Author(s): Schiffner R, Wilde O, Schiffner-Rohe J, Stolz W. Source: European Journal of Dermatology : Ejd. 2003 May-June; 13(3): 288-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804992

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Differential expression of thrombospondin 2 in primary and metastatic malignant melanoma. Author(s): Kunz M, Koczan D, Ibrahim SM, Gillitzer R, Gross G, Thiesen HJ. Source: Acta Dermato-Venereologica. 2002; 82(3): 163-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12353704

Studies

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Differentiating benign nevi from malignant melanoma using DNA microdensitometry and karyometry and maturation: a zonal comparison, correlation and multivariate analysis. Author(s): Li LX, Crotty KA, Palmer AA, Kril JJ, Stankovic R, Scolyer RA, McCarthy SW. Source: Anal Quant Cytol Histol. 2002 August; 24(4): 234-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12199325

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Discrimination of benign common nevi from malignant melanoma lesions by use of features based on spectral properties of the wavelet transform. Author(s): Wiltgen M, Gerger A, Wagner C, Bergthaler P, Smolle J. Source: Anal Quant Cytol Histol. 2003 October; 25(5): 243-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14603721

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DNA repair gene XRCC3 241Met variant is not associated with risk of cutaneous malignant melanoma. Author(s): Duan Z, Shen H, Lee JE, Gershenwald JE, Ross MI, Mansfield PF, Duvic M, Strom SS, Spitz MR, Wei Q. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2002 October; 11(10 Pt 1): 1142-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12376526

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Does sunlamp use increase the risk of cutaneous malignant melanoma? Author(s): Cattaruzza MS. Source: Archives of Dermatology. 2000 March; 136(3): 389-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12102095

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Down-regulation of a novel actin-binding molecule, skeletrophin, in malignant melanoma. Author(s): Takeuchi T, Heng HH, Ye CJ, Liang SB, Iwata J, Sonobe H, Ohtsuki Y. Source: American Journal of Pathology. 2003 October; 163(4): 1395-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14507647

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Downregulation of tapasin expression in progressive human malignant melanoma. Author(s): Dissemond J, Kothen T, Mors J, Weimann TK, Lindeke A, Goos M, Wagner SN. Source: Archives of Dermatological Research. 2003 June; 295(2): 43-9. Epub 2003 March 28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682852

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Malignant Melanoma

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Downregulation of the retinoblastoma gene expression in the progression of malignant melanoma. Author(s): Korabiowska M, Ruschenburg I, Betke H, Stachura J, Schlott T, Cardo CC, Brinck U. Source: Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology. 2001; 69(5): 274-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107345

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Dynamic lymphoscintigraphy and image fusion of SPECT and pelvic CT-scans allow mapping of aberrant pelvic sentinel lymph nodes in malignant melanoma. Author(s): Kretschmer L, Altenvoerde G, Meller J, Zutt M, Funke M, Neumann C, Becker W. Source: European Journal of Cancer (Oxford, England : 1990). 2003 January; 39(2): 17583. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12509949

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Early diagnosis of malignant melanoma: Proposal of a working formulation for the management of cutaneous pigmented lesions from the Melanoma Cooperative Group. Author(s): Ascierto PA, Palmieri G, Botti G, Satriano RA, Stanganelli I, Bono R, Testori A, Bosco L, Daponte A, Caraco C, Chiofalo MG, Melucci MT, Calignano R, Tatangelo F, Cochran AJ, Castello G; Melanoma Cooperative Group. Source: International Journal of Oncology. 2003 June; 22(6): 1209-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738985

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Echographic follow-up of malignant melanoma of the choroid after brachytherapy with 106Ru. Author(s): Novak-Andrejcic K, Jancar B, Hawlina M. Source: Klinische Monatsblatter Fur Augenheilkunde. 2003 December; 220(12): 853-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704943

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Effect of public education aimed at early diagnosis of malignant melanoma: cohort comparison study. Author(s): MacKie RM, Bray CA, Leman JA. Source: Bmj (Clinical Research Ed.). 2003 February 15; 326(7385): 367. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12586670

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Efficient palliation of haemorrhaging malignant melanoma skin metastases by electrochemotherapy. Author(s): Gehl J, Geertsen PF. Source: Melanoma Research. 2000 December; 10(6): 585-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11198481

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EGF +61 gene polymorphism and susceptibility to and prognostic markers in cutaneous malignant melanoma. Author(s): McCarron SL, Bateman AC, Theaker JM, Howell WM. Source: International Journal of Cancer. Journal International Du Cancer. 2003 November 20; 107(4): 673-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520709

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Elemental sulphur and alkali elutable melanin detected in oral melanosis and malignant melanoma by energy-filtering transmission electron microscopy. Author(s): Nagai N, Lee YJ, Nagaoka N, Gunduz M, Nakano K, Nojima T, Tsujigiwa H, Gunduz E, Siar CH, Nagatsuka H. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2002 September; 31(8): 481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220356

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Epidemiology of malignant melanoma. Author(s): Desmond RA, Soong SJ. Source: The Surgical Clinics of North America. 2003 February; 83(1): 1-29. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691448

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Epidermotropic metastatic malignant melanoma with a pedunculated appearance. Author(s): Hayashi H, Kawashima T, Hosokawa K, Kiyohara T, Kobayashi H, Ohkawara A, Shimizu H. Source: Clinical and Experimental Dermatology. 2003 November; 28(6): 666-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616838

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Eruptive multiple lentigo-maligna-like lesions in a patient undergoing chemotherapy with an oral 5-fluorouracil prodrug for metastasizing colorectal carcinoma: a lesson for the pathogenesis of malignant melanoma? Author(s): Bogenrieder T, Weitzel C, Scholmerich J, Landthaler M, Stolz W. Source: Dermatology (Basel, Switzerland). 2002; 205(2): 174-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12218237

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European approach to adjuvant treatment of intermediate- and high-risk malignant melanoma. Author(s): Eggermont AM, Gore M. Source: Seminars in Oncology. 2002 August; 29(4): 382-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12170441

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Evaluation of combined gene regulatory elements for transcriptional targeting of suicide gene expression to malignant melanoma. Author(s): Rothfels H, Paschen A, Schadendorf D. Source: Experimental Dermatology. 2003 December; 12(6): 799-810. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14714561

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Evaluation of the proliferation marker MIB-1 in the prognosis of cutaneous malignant melanoma. Author(s): Hazan C, Melzer K, Panageas KS, Li E, Kamino H, Kopf A, Cordon-Cardo C, Osman I, Polsky D. Source: Cancer. 2002 August 1; 95(3): 634-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209757

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Excision margins in high-risk malignant melanoma. Author(s): Hurt MA. Source: The New England Journal of Medicine. 2004 May 27; 350(22): 2305-6; Author Reply 2305-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15168421

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Excision margins in high-risk malignant melanoma. Author(s): Hellman S. Source: The New England Journal of Medicine. 2004 May 27; 350(22): 2305-6; Author Reply 2305-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15163784

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Excision margins in high-risk malignant melanoma. Author(s): Thomas JM, Newton-Bishop J, A'Hern R, Coombes G, Timmons M, Evans J, Cook M, Theaker J, Fallowfield M, O'Neill T, Ruka W, Bliss JM; United Kingdom Melanoma Study Group; British Association of Plastic Surgeons; Scottish Cancer Therapy Network. Source: The New England Journal of Medicine. 2004 February 19; 350(8): 757-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14973217

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Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype. Author(s): Varney ML, Li A, Dave BJ, Bucana CD, Johansson SL, Singh RK. Source: Clinical & Experimental Metastasis. 2003; 20(8): 723-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713106

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Extensive locoregional malignant melanoma transformation in a patient with oculodermal melanocytosis. Author(s): Baroody M, Holds JB. Source: Plastic and Reconstructive Surgery. 2004 January; 113(1): 317-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707653

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Extensive pigmented villonodular synovitis with markedly pigmented lymphadenopathy and its implication for differential diagnosis with malignant melanoma. Author(s): Wang S, Stewart JM, Ross MI, Prieto VG. Source: Annals of Diagnostic Pathology. 2003 April; 7(2): 95-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12715334

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Extrascleral extension of choroidal malignant melanoma following transpupillary thermotherapy. Author(s): Singh AD, Rundle PA, Berry-Brincat A, Parsons MA, Rennie IG. Source: Eye (London, England). 2004 January; 18(1): 91-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14707980

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Eyewall resection for a uveal malignant melanoma under local anesthesia. Author(s): Hwang YS, Chen SN, Chao AN. Source: Chang Gung Med J. 2002 December; 25(12): 850-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12635843

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Fas and Fas ligand: expression and soluble circulating levels in cutaneous malignant melanoma. Author(s): Redondo P, Solano T, VAzquez B, Bauza A, Idoate M. Source: The British Journal of Dermatology. 2002 July; 147(1): 80-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12100188

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Fas-induced apoptosis in human malignant melanoma cell lines is associated with the activation of the p34(cdc2)-related PITSLRE protein kinases. Author(s): Ariza ME, Broome-Powell M, Lahti JM, Kidd VJ, Nelson MA. Source: The Journal of Biological Chemistry. 1999 October 1; 274(40): 28505-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10497214

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Fatal transfer of malignant melanoma from multiorgan donor to four allograft recipients. Author(s): Stephens JK, Everson GT, Elliott CL, Kam I, Wachs M, Haney J, Bartlett ST, Franklin WA. Source: Transplantation. 2000 July 15; 70(1): 232-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10919612

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Favourable outcome of giant malignant melanoma of the conjunctiva despite poor prognostic features. Author(s): Malik KP, Dadeya S, Gulliani BP, Gupta VS. Source: Can J Ophthalmol. 2003 August; 38(5): 397-400. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956282

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FDG PET for mucosal malignant melanoma of the head and neck. Author(s): Goerres GW, Stoeckli SJ, von Schulthess GK, Steinert HC. Source: The Laryngoscope. 2002 February; 112(2): 381-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11889401

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Fine needle aspiration cytology of malignant melanoma of soft parts: a case report and literature review. Author(s): Hombal SM. Source: Cytopathology : Official Journal of the British Society for Clinical Cytology. 2000 February; 11(1): 61-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10714378

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Fine-needle aspiration cytology of desmoplastic malignant melanoma metastatic to the parotid gland: case report and review of the literature. Author(s): Chhieng DC, Cangiarella JF, Waisman J, Cohen JM. Source: Diagnostic Cytopathology. 2000 February; 22(2): 97-100. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10649519

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Flow and video-imaging cytometry--usefulness of DNA ploidy measurements in diagnosis of malignant melanoma. Author(s): Skowronek J, Karas Z, Krenz RM, Warchol JB. Source: Advances in Experimental Medicine and Biology. 2001; 495: 435-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11774606

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Fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in malignant melanoma. Diagnostic comparison with conventional imaging methods. Author(s): Krug B, Dietlein M, Groth W, Stutzer H, Psaras T, Gossmann A, Scheidhauer K, Schicha H, Lackner K. Source: Acta Radiologica (Stockholm, Sweden : 1987). 2000 September; 41(5): 446-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11016764

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Follow up for cutaneous malignant melanoma. Author(s): Williams HC. Source: The British Journal of Dermatology. 1999 October; 141(4): 762-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10583143

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Followup of primary malignant melanoma of the prostate. Author(s): Wang CJ. Source: The Journal of Urology. 2001 July; 166(1): 214. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11435865

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Follow-up recommendations for patients with American Joint Committee on Cancer Stages I-III malignant melanoma. Author(s): Poo-Hwu WJ, Ariyan S, Lamb L, Papac R, Zelterman D, Hu GL, Brown J, Fischer D, Bolognia J, Buzaid AC. Source: Cancer. 1999 December 1; 86(11): 2252-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10590365

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Foramen magnum metastatic malignant melanoma. Author(s): Pai SB, Krishna KN. Source: Neurology India. 2003 March; 51(1): 79-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865527

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Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. Author(s): Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 March 15; 22(6): 1118-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15020614

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Frequent loss of p16 protein expression and high proliferative activity (Ki-67) in malignant melanoma from black Africans. Author(s): Vuhahula E, Straume O, Akslen LA. Source: Anticancer Res. 2000 November-December; 20(6C): 4857-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11205232

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Frozen section investigation of the sentinel node in malignant melanoma and breast cancer. Author(s): Tanis PJ, Boom RP, Koops HS, Faneyte IF, Peterse JL, Nieweg OE, Rutgers EJ, Tiebosch AT, Kroon BB. Source: Annals of Surgical Oncology : the Official Journal of the Society of Surgical Oncology. 2001 April; 8(3): 222-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11314938

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Fulminant intravascular disseminating malignant melanoma mimicking acute leukemia. Author(s): Trefzer U, Schlegel C, Sterry W, Spath-Schwalbe E, Possinger K, Denkert C. Source: Blood. 1999 August 15; 94(4): 1483-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10484637

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Functional polymorphism in EGF gene and malignant melanoma. Author(s): Rees J. Source: Lancet. 2002 August 17; 360(9332): 570. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12241682

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Future perspectives on malignant melanoma. Author(s): Leong SP. Source: The Surgical Clinics of North America. 2003 April; 83(2): 453-6, X. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12744619

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Gamma knife radiosurgery for malignant melanoma brain metastases. Author(s): Seung SK, Sneed PK, McDermott MW, Shu HK, Leong SP, Chang S, Petti PL, Smith V, Verhey LJ, Wara WM, Phillips TL, Larson DA. Source: Cancer J Sci Am. 1998 March-April; 4(2): 103-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9532412

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Gamma probe guided biopsy of the sentinel node in malignant melanoma: a multicentre study. Author(s): Harlow SP, Krag DN, Ashikaga T, Weaver DL, Meijer SJ, Loggie BW, Tanabe KK, Whitworth P Jr, Kuhn J, Kusminsky R, Carp NZ, Gadd M, Rawlings M Jr, Slingluff CL Jr. Source: Melanoma Research. 2001 February; 11(1): 45-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11254115

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Gamma-detecting probe used intraoperatively to locate the sentinel lymph node in patients with malignant melanoma. Author(s): Sugranes G, Vidal-Sicart S, Piulachs J, Bombuy E, Pons F, Castel T, Rull R, Herranz R, Visa J. Source: The European Journal of Surgery = Acta Chirurgica. 2001 August; 167(8): 581-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11716443

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Ganglioneuroblastic differentiation in a primary cutaneous malignant melanoma. Author(s): Grayson W, Mare LR. Source: The American Journal of Dermatopathology. 2003 February; 25(1): 40-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544099

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Gender differences in rising trends in cutaneous malignant melanoma in Spain, 197598. Author(s): Nieto A, Ruiz-Ramos M, Abdel-Kader L, Conde M, Camacho F. Source: The British Journal of Dermatology. 2003 January; 148(1): 110-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12534603

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Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma. Author(s): Palmer K, Moore J, Everard M, Harris JD, Rodgers S, Rees RC, Murray AK, Mascari R, Kirkwood J, Riches PG, Fisher C, Thomas JM, Harries M, Johnston SR, Collins MK, Gore ME. Source: Human Gene Therapy. 1999 May 20; 10(8): 1261-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10365657

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Gene transfer of a soluble receptor of VEGF inhibits the growth of experimental eyelid malignant melanoma. Author(s): Shiose S, Sakamoto T, Yoshikawa H, Hata Y, Kawano Y, Ishibashi T, Inomata H, Takayama K, Ueno H. Source: Investigative Ophthalmology & Visual Science. 2000 August; 41(9): 2395-403. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10937546

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Gene-based therapy of malignant melanoma. Author(s): Schadendorf D. Source: Seminars in Oncology. 2002 October; 29(5): 503-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12407515

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General practitioner excision of malignant melanoma. Author(s): English JS. Source: The British Journal of Dermatology. 1998 October; 139(4): 759. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9892938

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Generalized and mucosal melanosis associated with ultra-late recurrence of malignant melanoma. Author(s): Friedman T, Friedman M, Weitzen R, Scapa E. Source: Endoscopy. 2002 April; 34(4): 352. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11932801

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Generalized melanosis in metastatic malignant melanoma: the possible role of DOPAquinone metabolites. Author(s): Tsukamoto K, Furue M, Sato Y, Takayama O, Akasu R, Ohtake N, Wakamatsu K, Ito S, Tamaki K, Shimada S. Source: Dermatology (Basel, Switzerland). 1998; 197(4): 338-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9873171

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Generation of blood-derived dendritic cells in dogs with oral malignant melanoma. Author(s): Catchpole B, Stell AJ, Dobson JM. Source: Journal of Comparative Pathology. 2002 February-April; 126(2-3): 238-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11945016

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Genetic and environmental factors in cutaneous malignant melanoma. Author(s): Bressac-de-Paillerets B, Avril MF, Chompret A, Demenais F. Source: Biochimie. 2002 January; 84(1): 67-74. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11900878

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Genetic and epigenetic alterations of the APC gene in malignant melanoma. Author(s): Worm J, Christensen C, Gronbaek K, Tulchinsky E, Guldberg P. Source: Oncogene. 2004 July 1; 23(30): 5215-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15133491

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Germline 657del5 mutation in the NBS1 gene in patients with malignant melanoma of the skin. Author(s): Debniak T, Gorski B, Cybulski C, Jakubowska A, Kurzawski G, Lener M, Mierzejewski M, Masojc B, Medrek K, Kladny J, Zaluga E, Maleszka R, Chosia M, Lubinski J. Source: Melanoma Research. 2003 August; 13(4): 365-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883362

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Germline mutation and large deletion analysis of the CDKN2A and ARF genes in families with multiple melanoma or an aggregation of malignant melanoma and breast cancer. Author(s): Debniak T, Gorski B, Scott RJ, Cybulski C, Medrek K, Zowocka E, Kurzawski G, Debniak B, Kadny J, Bielecka-Grzela S, Maleszka R, Lubinski J. Source: International Journal of Cancer. Journal International Du Cancer. 2004 July 1; 110(4): 558-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15122588

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Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Author(s): Lens MB, Dawes M. Source: The British Journal of Dermatology. 2004 February; 150(2): 179-85. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996086

Studies

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Growth inhibition of human malignant melanoma transfected with the human interferon-beta gene by means of cationic liposomes. Author(s): Kageshita T, Mizuno M, Ono T, Matsumoto K, Saida T, Yoshida J. Source: Melanoma Research. 2001 August; 11(4): 337-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11479421

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Guess what! Metastatic malignant melanoma of the leg from a warty acral amelanotic malignant melanoma. Author(s): Virgili A, Corazza M. Source: European Journal of Dermatology : Ejd. 2001 November-December; 11(6): 591-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11701418

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Halo naevus or malignant melanoma? A case report. Author(s): Mandalia MR, Skillman JM, Cook MG, Powell BW. Source: British Journal of Plastic Surgery. 2002 September; 55(6): 512-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12479428

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HDM2 protein overexpression and prognosis in primary malignant melanoma. Author(s): Polsky D, Melzer K, Hazan C, Panageas KS, Busam K, Drobnjak M, Kamino H, Spira JG, Kopf AW, Houghton A, Cordon-Cardo C, Osman I. Source: Journal of the National Cancer Institute. 2002 December 4; 94(23): 1803-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12464652

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Hematospermia as the presenting symptom of metastatic malignant melanoma of unknown primary origin. Author(s): Meng MV, Werboff LH. Source: Urology. 2000 August 1; 56(2): 330. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10925109

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Heparan sulfate-like proteoglycans mediate adhesion of human malignant melanoma A375 cells to P-selectin under flow. Author(s): Ma YQ, Geng JG. Source: Journal of Immunology (Baltimore, Md. : 1950). 2000 July 1; 165(1): 558-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10861096

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Heparan sulphate epitope-expression is associated with the inflammatory response in metastatic malignant melanoma. Author(s): Bernsen MR, Smetsers TF, van de Westerlo E, Ruiter DJ, Hakansson L, Gustafsson B, Van Kuppevelt TH, Krysander L, Rettrup B, Hakansson A. Source: Cancer Immunology, Immunotherapy : Cii. 2003 December; 52(12): 780-3. Epub 2003 September 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680194

84

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Heterogeneity of HLA-G gene transcription and protein expression in malignant melanoma biopsies. Author(s): Paul P, Cabestre FA, Le Gal FA, Khalil-Daher I, Le Danff C, Schmid M, Mercier S, Avril MF, Dausset J, Guillet JG, Carosella ED. Source: Cancer Research. 1999 April 15; 59(8): 1954-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10213506

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Heterogenous S-100B protein expression patterns in malignant melanoma and association with serum protein levels. Author(s): Banfalvi T, Udvarhelyi N, Orosz Z, Gergye M, Gilde K, Timar J. Source: Oncology. 2003; 64(4): 374-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759535

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High dose inhalation interleukin-2 therapy for lung metastases in patients with malignant melanoma. Author(s): Enk AH, Nashan D, Rubben A, Knop J. Source: Cancer. 2000 May 1; 88(9): 2042-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10813715

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High frequency of tetraploidy detected in malignant melanoma of Japanese patients by fluorescence in situ hybridization. Author(s): Satoh S, Hashimoto-Tamaoki T, Furuyama J, Mihara K, Namba M, Kitano Y. Source: International Journal of Oncology. 2000 October; 17(4): 707-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10995881

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High levels of sFas and PBMC apoptosis before and after excision of malignant melanoma--case report. Author(s): Alecu M, Coman G, Danaila L. Source: Roum Arch Microbiol Immunol. 2002 October-December; 61(4): 267-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15055260

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High prevalence of the G101W germline mutation in the CDKN2A (P16(ink4a)) gene in 62 Italian malignant melanoma families. Author(s): Mantelli M, Barile M, Ciotti P, Ghiorzo P, Lantieri F, Pastorino L, Catricala C, Torre GD, Folco U, Grammatico P, Padovani L, Pasini B, Rovini D, Queirolo P, Rainero ML, Santi PL, Sertoli RM, Goldstein AM, Bianchi-Scarra G; Societa Italiana Dermatologia; Gruppo Italiano Studi Epidemiologici in Dermatologia. Source: American Journal of Medical Genetics. 2002 January 22; 107(3): 214-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11807902

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High-dose chemotherapy with autologous stem-cell transplantation in patients with pretreated advanced malignant melanoma. Author(s): Schrader AJ, Atzpodien J. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2000 October; 11(10): 1361-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11106128

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High-dose interferon versus GM2 vaccine in high-risk malignant melanoma. Author(s): Wilson K. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 December 1; 19(23): 4350. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11731522

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Histologic classification of tumor-infiltrating lymphocytes in primary cutaneous malignant melanoma. A study of interobserver agreement. Author(s): Busam KJ, Antonescu CR, Marghoob AA, Nehal KS, Sachs DL, Shia J, Berwick M. Source: American Journal of Clinical Pathology. 2001 June; 115(6): 856-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11392882

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Histopathologic features of malignant peripheral nerve sheath tumor are not restricted to metastatic malignant melanoma and can be found in primary malignant melanoma also. Author(s): Diaz-Cascajo C, Hoos A. Source: The American Journal of Surgical Pathology. 2000 October; 24(10): 1438-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11023110

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hMLH1 and hMSH2 gene mutations are present in radial growth-phase cutaneous malignant melanoma cell lines and can be induced further by ultraviolet-B irradiation. Author(s): Hussein MR, Wood GS. Source: Experimental Dermatology. 2003 December; 12(6): 872-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14714570

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Hormone replacement therapy and malignant melanoma: to prescribe or not to prescribe? Author(s): Durvasula R, Ahmed SM, Vashisht A, Studd JW. Source: Climacteric : the Journal of the International Menopause Society. 2002 June; 5(2): 197-200. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12051116

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How to diagnose malignant melanoma. Author(s): Oliviero MC. Source: The Nurse Practitioner. 2002 February; 27(2): 26-7, 31-5; Quiz 36-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11858584

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Human malignant melanoma cells release a factor that inhibits the expression of smooth muscle alpha-actin. Author(s): Okamoto-Inoue M, Nakayama J, Hori Y, Taniguchi S. Source: Journal of Dermatological Science. 2000 August; 23(3): 170-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10959042

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Hypertriglyceridaemia following adjuvant interferon-alpha treatment in two patients with malignant melanoma. Author(s): Junghans V, Runger TM. Source: The British Journal of Dermatology. 1999 January; 140(1): 183-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10215802

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Identification of the sentinel lymph node in patients with malignant melanoma: what are the reasons for mistakes? Author(s): Vidal-Sicart S, Pons F, Puig S, Ortega M, Vilalta A, Martin F, Rull R, Palou JM, Castel T. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2003 March; 30(3): 362-6. Epub 2002 December 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634963

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Ileal malignant melanoma presenting as a mass with aneurysmal dilatation: a case report. Author(s): Kim W, Baek JM, Suh YJ, Jeon HM, Kim JA. Source: Journal of Korean Medical Science. 2004 April; 19(2): 297-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15082908

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Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma. Author(s): Bong AB, Bonnekoh B, Franke I, Schon MP, Ulrich J, Gollnick H. Source: Dermatology (Basel, Switzerland). 2002; 205(2): 135-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12218228

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Immune response in blood and tumour tissue in patients with metastatic malignant melanoma treated with IL-2, IFN alpha and histamine dihydrochloride. Author(s): Jorkov AS, Donskov F, Steiniche T, Ternesten-Bratel A, Naredi P, Hellstrand K, Hokland M. Source: Anticancer Res. 2003 January-February; 23(1B): 537-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12680142

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Immunohistochemical determination of HER-2/neu in malignant melanoma. Author(s): Potti A, Hille R, Koch M. Source: Anticancer Res. 2003 September-October; 23(5A): 4067-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666720

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Immunohistochemical determination of vascular endothelial growth factor (VEGF) overexpression in malignant melanoma. Author(s): Potti A, Moazzam N, Tendulkar K, Javed NA, Koch M, Kargas S. Source: Anticancer Res. 2003 September-October; 23(5A): 4023-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666713

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Immunohistochemical study of melanocytic differentiation antigens in cutaneous malignant melanoma. A comparison of six commercial antibodies and one noncommercial antibody in nodular melanoma, superficially spreading melanoma and lentigo maligna melanoma. Author(s): Kocan P, Jurkovic I, Boor A, Dudrikova K, Krajcar R, Benicky M, Kromydaki A. Source: Cesk Patol. 2004 April; 40(2): 50-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15233017

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Immunotherapy of malignant melanoma. Author(s): Kadison AS, Morton DL. Source: The Surgical Clinics of North America. 2003 April; 83(2): 343-70. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12744613

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Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Author(s): Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW. Source: Nature. 2001 January 11; 409(6817): 207-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11196646

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Incidence of and survival from malignant melanoma in Scotland: an epidemiological study. Author(s): MacKie RM, Bray CA, Hole DJ, Morris A, Nicolson M, Evans A, Doherty V, Vestey J; Scottish Melanoma Group. Source: Lancet. 2002 August 24; 360(9333): 587-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12241928

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Increased expression of VEGF-receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma. Author(s): Straume O, Akslen LA. Source: Angiogenesis. 2003; 6(4): 295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15166498

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Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. Author(s): Ugurel S, Rappl G, Tilgen W, Reinhold U. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 January 15; 19(2): 577-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11208853

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Increased serum levels of 5-S-cysteinyldopa and intercellular adhesion molecule-1 in a patient with a uterine amelanotic metastasis from a primary vaginal malignant melanoma. Author(s): Suenaga Y, Katabuchi H, Okamura H, Kageshita T, Ono T. Source: Gynecologic Oncology. 1999 January; 72(1): 107-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9889040

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Influence of fast lymphatic drainage on metastatic spread in cutaneous malignant melanoma: a prospective feasibility study. Author(s): Maza S, Valencia R, Geworski L, Sandrock D, Zander A, Audring H, Drager E, Winter H, Sterry W, Munz DL. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2003 April; 30(4): 538-44. Epub 2003 February 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12582814

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Instrumental measurements of skin color and skin ultraviolet light sensitivity and risk of cutaneous malignant melanoma: a case-control study in an Italian population. Author(s): Brenner AV, Lubin JH, Calista D, Landi MT. Source: American Journal of Epidemiology. 2002 August 15; 156(4): 353-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12181106

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Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma. Author(s): Lotem M, Shiloni E, Pappo I, Drize O, Hamburger T, Weitzen R, Isacson R, Kaduri L, Merims S, Frankenburg S, Peretz T. Source: British Journal of Cancer. 2004 February 23; 90(4): 773-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14970852

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Intraparenchymal nevus cell aggregates in lymph nodes: a possible diagnostic pitfall with malignant melanoma and carcinoma. Author(s): Biddle DA, Evans HL, Kemp BL, El-Naggar AK, Harvell JD, White WL, Iskandar SS, Prieto VG. Source: The American Journal of Surgical Pathology. 2003 May; 27(5): 673-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12717252

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Intratumoral cisplatin/adrenaline injectable gel for the treatment of patients with cutaneous and soft tissue metastases of malignant melanoma. Author(s): Oratz R, Hauschild A, Sebastian G, Schadendorf D, Castro D, Brocker EB, Orenberg EK. Source: Melanoma Research. 2003 February; 13(1): 59-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12569286

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Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials. Author(s): Lens MB, Dawes M. Source: The Lancet Oncology. 2003 June; 4(6): 359-64. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788409

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It's time for a "change" in our approach to early detection of malignant melanoma. Author(s): Zaharna M, Brodell RT. Source: Clinics in Dermatology. 2003 September-October; 21(5): 456-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678725

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Ki67 antigen and PCNA proliferation markers predict survival in anorectal malignant melanoma. Author(s): Ben-Izhak O, Bar-Chana M, Sussman L, Dobiner V, Sandbank J, Cagnano M, Cohen H, Sabo E. Source: Histopathology. 2002 December; 41(6): 519-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12460204

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L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma. Author(s): Fogel M, Mechtersheimer S, Huszar M, Smirnov A, Abu-Dahi A, Tilgen W, Reichrath J, Georg T, Altevogt P, Gutwein P. Source: Cancer Letters. 2003 January 28; 189(2): 237-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12490317

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Laminin, hyaluronan, tenascin-C and type VI collagen levels in sera from patients with malignant melanoma. Author(s): Burchardt ER, Hein R, Bosserhoff AK. Source: Clinical and Experimental Dermatology. 2003 September; 28(5): 515-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950343

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Late malignant melanoma after treatment of rhabdomyosarcoma of the orbit during childhood. Author(s): Lumbroso L, Sigal-Zafrani B, Jouffroy T, Levy C, Rodriguez J, Desjardins L. Source: Archives of Ophthalmology. 2002 August; 120(8): 1087-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12149065

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Late recurrence of malignant melanoma presenting as peritoneal "carcinomatosis". Author(s): Lee EY, Heiken JP, Huettner PC. Source: Abdominal Imaging. 2003 March-April; 28(2): 284-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12592480

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Lectin binding to cutaneous malignant melanoma: HPA is associated with metastasis formation. Author(s): Thies A, Moll I, Berger J, Schumacher U. Source: British Journal of Cancer. 2001 March 23; 84(6): 819-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11259098

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Lichenoid tissue reaction in malignant melanoma: a potential diagnostic pitfall. Author(s): Dalton SR, Baptista MA, Libow LF, Elston DM. Source: American Journal of Clinical Pathology. 2002 May; 117(5): 766-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12090426

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Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis. Author(s): Achen MG, Williams RA, Minekus MP, Thornton GE, Stenvers K, Rogers PA, Lederman F, Roufail S, Stacker SA. Source: The Journal of Pathology. 2001 February; 193(2): 147-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11180159

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Locally recurrent malignant melanoma characteristics and outcomes: a singleinstitution study. Author(s): Wildemore JK 4th, Schuchter L, Mick R, Synnestvedt M, Elenitsas R, Bedrosian I, Czerniecki BJ, Guerry D 4th, Lessin SR, Elder DE, Bucky LP. Source: Annals of Plastic Surgery. 2001 May; 46(5): 488-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11352421

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Locoregional cutaneous metastases of malignant melanoma and their management. Author(s): Wolf IH, Richtig E, Kopera D, Kerl H. Source: Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. 2004 February; 30(2 Pt 2): 244-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871216

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Locoregional cutaneous metastasis in patients with therapeutic lymph node dissection for malignant melanoma: risk factors and prognostic impact. Author(s): Kretschmer L, Preusser KP, Neumann C. Source: Melanoma Research. 2002 October; 12(5): 499-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12394192

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Long-term prognostic significance of HSP-70, c-myc and HLA-DR expression in patients with malignant melanoma. Author(s): Ricaniadis N, Kataki A, Agnantis N, Androulakis G, Karakousis CP. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2001 February; 27(1): 88-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11237497

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Long-term survival of a female patient with primary malignant melanoma of the urethra. Author(s): Rikaniadis N, Konstadoulakis MM, Kymionis GD, Tsibloulis B, Peveretos P, Karakousis CP. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 1998 December; 24(6): 607-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9870741

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Long-term survival of dogs with advanced malignant melanoma after DNA vaccination with xenogeneic human tyrosinase: a phase I trial. Author(s): Bergman PJ, McKnight J, Novosad A, Charney S, Farrelly J, Craft D, Wulderk M, Jeffers Y, Sadelain M, Hohenhaus AE, Segal N, Gregor P, Engelhorn M, Riviere I, Houghton AN, Wolchok JD. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 April; 9(4): 1284-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684396

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Loss of beta-catenin expression is associated with disease progression in malignant melanoma. Author(s): Osborne JE. Source: The British Journal of Dermatology. 2002 June; 146(6): 1104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072090

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Low molecular weight heparin treatment for malignant melanoma: a pilot clinical trial. Author(s): Wojtukiewicz MZ, Kozlowski L, Ostrowska K, Dmitruk A, Zacharski LR. Source: Thrombosis and Haemostasis. 2003 February; 89(2): 405-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12574822

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Low-dose adjuvant interferon for stage III malignant melanoma. Author(s): Inman JL, Russell GB, Savage P, Levine EA. Source: The American Surgeon. 2003 February; 69(2): 127-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12641352

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Low-dose IFN-gamma induces tumor MHC expression in metastatic malignant melanoma. Author(s): Propper DJ, Chao D, Braybrooke JP, Bahl P, Thavasu P, Balkwill F, Turley H, Dobbs N, Gatter K, Talbot DC, Harris AL, Ganesan TS. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 January; 9(1): 84-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538455

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Lymph node dissection for clinically evident lymph node metastases of malignant melanoma. Author(s): Meyer T, Merkel S, Gohl J, Hohenberger W. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2002 June; 28(4): 424-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12099654

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Lymphatic density and metastatic spread in human malignant melanoma. Author(s): Shields JD, Borsetti M, Rigby H, Harper SJ, Mortimer PS, Levick JR, Orlando A, Bates DO. Source: British Journal of Cancer. 2004 February 9; 90(3): 693-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14760386

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Lymphoscintigraphy and intraoperative gamma probe-directed sentinel lymph node mapping in patients with malignant melanoma. Author(s): Liu SH, Chang WC, Kao PF, Lo YF, Yang CH, Tsai CC, Tzen KY. Source: J Formos Med Assoc. 2004 January; 103(1): 41-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15026857

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Malignant melanoma 2003: predisposition, diagnosis, prognosis, and staging. Author(s): Carlson JA, Slominski A, Linette GP, Mysliborski J, Hill J, Mihm MC Jr, Ross JS. Source: American Journal of Clinical Pathology. 2003 December; 120 Suppl: S101-27. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15298147

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Malignant melanoma involving the ovary: a clinicopathologic and immunohistochemical study of 23 cases. Author(s): Gupta D, Deavers MT, Silva EG, Malpica A. Source: The American Journal of Surgical Pathology. 2004 June; 28(6): 771-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15166669

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Malignant melanoma metastatic to the liver. A cytomorphologic comparative study to identify reproducible diagnostic criteria. Author(s): De Las Casas LE, Gokden M, Baker SJ, Korourian S, Hermonat PL, You H, Miranda RN, Shalkham JE, O'Brien LA, Mukunyadzi P. Source: Acta Cytol. 2004 January-February; 48(1): 32-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14969178

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Malignant melanoma occurring at the periphery of a giant congenital naevus previously treated with laser therapy. Author(s): Woodrow SL, Burrows NP. Source: The British Journal of Dermatology. 2003 October; 149(4): 886-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14616388

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Malignant melanoma of the conjunctiva metastasising to the parotid gland. Author(s): Cuthbertson F, Luck J, Rose S. Source: The British Journal of Ophthalmology. 2003 November; 87(11): 1428-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609854

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Malignant melanoma of the vagina: report of two cases. Author(s): Mishra M, Chawla SC, Chawla S, Basu SM, Tata R. Source: Indian J Pathol Microbiol. 2003 January; 46(1): 71-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15027730

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Malignant melanoma: it pays to be a woman. Author(s): Mashiah J, Brenner S. Source: Skinmed. 2003 May-June; 2(3): 183-7. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14673297

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Management of in-transit metastases from cutaneous malignant melanoma. Author(s): Hayes AJ, Clark MA, Harries M, Thomas JM. Source: The British Journal of Surgery. 2004 June; 91(6): 673-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15164434

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Massive and isolated metastases to spleen of uveal malignant melanoma. Author(s): Tas F, Ustuner Z, Buyukbabani N, Tenekeci N, Topuz E. Source: Retina (Philadelphia, Pa.). 2004 February; 24(1): 170-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15076966

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Metastatic malignant melanoma presenting as a cavernous sinus syndrome. Author(s): Harkness KA, Manford MR. Source: Journal of Neurology. 2004 February; 251(2): 224-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14991360

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Metastatic malignant melanoma. Author(s): Meric JB, Rixe O, Khayat D. Source: Drugs Today (Barc). 2003; 39 Suppl C: 17-38. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14988744

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Neoadjuvant radiotherapy in anorectal malignant melanoma. Author(s): Uner A, Kilic D, Mentes BB, Egehan I, Dursun A. Source: Int J Clin Pract. 2003 January-February; 57(1): 65-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12587948

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Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma. Author(s): Ribatti D, Vacca A, Ria R, Marzullo A, Nico B, Filotico R, Roncali L, Dammacco F. Source: European Journal of Cancer (Oxford, England : 1990). 2003 March; 39(5): 666-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12628847

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Neuropsychiatric complications associated with interferon-alpha-2b treatment of malignant melanoma. Author(s): Okereke OI. Source: Psychosomatics. 2002 May-June; 43(3): 237-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12075040

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New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance. Author(s): Spiro T, Liu L, Gerson S. Source: Forum (Genova). 2000 July-September; 10(3): 274-85. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11007934

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New diagnostic techniques in staging in the surgical treatment of cutaneous malignant melanoma. Author(s): Cobben DC, Koopal S, Tiebosch AT, Jager PL, Elsinga PH, Wobbes T, Hoekstra HJ. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2002 November; 28(7): 692-700. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12431464

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Newly established clear cell sarcoma (malignant melanoma of soft parts) cell line expressing melanoma-associated Melan-A antigen and overexpressing C-MYC oncogene. Author(s): Moritake H, Sugimoto T, Asada Y, Yoshida MA, Maehara Y, Epstein AL, Kuroda H. Source: Cancer Genetics and Cytogenetics. 2002 May; 135(1): 48-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12072203

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No evidence to support delay in excision of malignant melanoma. Author(s): Coldiron B. Source: Archives of Dermatology. 2000 October; 136(10): 1269-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11030779

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Nodal detection in malignant melanoma of the vagina using laparoscopic ultrasonography. Author(s): Siu SS, Lo KW, Chan AB, Yu MY, Cheung TH. Source: Gynecologic Oncology. 2004 March; 92(3): 985-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984972

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Novel immunologic approaches to the management of malignant melanoma. Author(s): Weber JS, Aparicio A. Source: Current Opinion in Oncology. 2001 March; 13(2): 124-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11224710

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Novel therapeutic agents under investigation for malignant melanoma. Author(s): Pavlick AC, Adams S, Fink MA, Bailes A. Source: Expert Opinion on Investigational Drugs. 2003 September; 12(9): 1545-58. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943498

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Observational study of type of surgical training and outcome of definitive surgery for primary malignant melanoma. Author(s): MacKie RM, Bray CA, Hole DJ. Source: Bmj (Clinical Research Ed.). 2002 November 30; 325(7375): 1276-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12458246

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On the effect of biochemotherapy in metastatic malignant melanoma: an immunopathological evaluation. Author(s): Hakansson A, Hakansson L, Gustafsson B, Krysander L, Rettrup B, Ruiter D, Bernsen MR. Source: Melanoma Research. 2003 August; 13(4): 401-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883367

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Orbital inflammation in a patient with extrascleral spread of choroidal malignant melanoma. Author(s): Goh AS, Francis IC, Kappagoda MB, Filipic M. Source: Clinical & Experimental Ophthalmology. 2001 April; 29(2): 97-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11341456

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Orbital malignant melanoma: the 2002 Sean B Murphy lecture. Author(s): Shields JA, Shields CL. Source: Ophthalmic Plastic and Reconstructive Surgery. 2003 July; 19(4): 262-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12878873

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Outcome of surgical treatment for primary malignant melanoma of the female urethra. Author(s): DiMarco DS, DiMarco CS, Zincke H, Webb MJ, Keeney GL, Bass S, Lightner DJ. Source: The Journal of Urology. 2004 February; 171(2 Pt 1): 765-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713806

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Outpatient biochemotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic malignant melanoma: results of two phase II cytokine working group trials. Author(s): Flaherty LE, Atkins M, Sosman J, Weiss G, Clark JI, Margolin K, Dutcher J, Gordon MS, Lotze M, Mier J, Sorokin P, Fisher RI, Appel C, Du W. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 July 1; 19(13): 3194-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11432886

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Outpatient experience with moderate dose bolus interleukin-2 in metastatic malignant melanoma and kidney cancer. Author(s): Quan WD Jr, Quan FM. Source: Journal of Immunotherapy (Hagerstown, Md. : 1997). 2003 May-June; 26(3): 28690. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12806282

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Overexpression of pigment epithelium-derived factor decreases angiogenesis and inhibits the growth of human malignant melanoma cells in vivo. Author(s): Abe R, Shimizu T, Yamagishi S, Shibaki A, Amano S, Inagaki Y, Watanabe H, Sugawara H, Nakamura H, Takeuchi M, Imaizumi T, Shimizu H. Source: American Journal of Pathology. 2004 April; 164(4): 1225-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039211

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Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma. Author(s): Thies A, Schachner M, Moll I, Berger J, Schulze HJ, Brunner G, Schumacher U. Source: European Journal of Cancer (Oxford, England : 1990). 2002 September; 38(13): 1708-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175686

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Oxidative stress in malignant melanoma and non-melanoma skin cancer. Author(s): Sander CS, Hamm F, Elsner P, Thiele JJ. Source: The British Journal of Dermatology. 2003 May; 148(5): 913-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12786821

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Patient age in Spitz nevus and malignant melanoma: implication of Bayes rule for differential diagnosis. Author(s): Vollmer RT. Source: American Journal of Clinical Pathology. 2004 June; 121(6): 872-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15198360

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Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Author(s): Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, Kristeleit H, Polychronis A, Pandha H, Muller GW, Stirling DI, Zeldis J, Dalgleish AG. Source: British Journal of Cancer. 2004 March 8; 90(5): 955-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14997189

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Pigmented metastasis of breast carcinoma mimicking malignant melanoma. Author(s): Garcia-F-Villalta MJ, Adrados M, Dauden E, Fraga J, Garcia-Diez A. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 2004 March; 18(2): 223-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009313

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Primary malignant melanoma of the cervical spinal nerve root. Author(s): Kwon SC, Rhim SC, Lee DH, Roh SW, Kang SK. Source: Yonsei Medical Journal. 2004 April 30; 45(2): 345-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119011

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Primary malignant melanoma of the rectum: CT findings in eight patients. Author(s): Kim KW, Ha HK, Kim AY, Kim TK, Kim JS, Yu CS, Park SW, Park MS, Kim HJ, Kim PN, Kim JC, Lee MG. Source: Radiology. 2004 July; 232(1): 181-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15220501

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Primary malignant melanoma of the right colon. Author(s): Avital S, Romaguera RL, Sands L, Marchetti F, Hellinger MD. Source: The American Surgeon. 2004 July; 70(7): 649-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15279192

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Primary malignant melanoma of the vagina. Poor response to radical surgery and adjuvant therapy. Author(s): Moros ML, Ferrer FP, Mitchell MJ, Romeo JA, Lacruz RL. Source: European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2004 April 15; 113(2): 248-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15063970

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Progression in cutaneous malignant melanoma is associated with distinct expression profiles: a tissue microarray-based study. Author(s): Alonso SR, Ortiz P, Pollan M, Perez-Gomez B, Sanchez L, Acuna MJ, Pajares R, Martinez-Tello FJ, Hortelano CM, Piris MA, Rodriguez-Peralto JL. Source: American Journal of Pathology. 2004 January; 164(1): 193-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14695333

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Prolapsed intraocular aspergilloma masquerading as malignant melanoma. Author(s): Thomas PA, Geraldine P. Source: Indian J Ophthalmol. 2004 June; 52(2): 172-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15283231

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Psychosocial factors related to the correspondence of recipient and provider perceptions of social support among patients diagnosed with or at risk for malignant melanoma. Author(s): Lichtenthal WG, Cruess DG, Schuchter LM, Ming ME. Source: Journal of Health Psychology. 2003 November; 8(6): 705-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670205

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Quality of life in patients with malignant melanoma participating in a phase I trial of an autologous tumour-derived vaccine. Author(s): Cohen L, Parker PA, Sterner J, De Moor C. Source: Melanoma Research. 2002 October; 12(5): 505-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12394193

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Quantification of cathepsin D in plasma of patients with malignant melanoma. Author(s): Westhoff U, Fox C, Otto FJ. Source: Anticancer Res. 1998 September-October; 18(5B): 3785-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9854496

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Radiation dose as a risk factor for malignant melanoma following childhood cancer. Author(s): Guerin S, Dupuy A, Anderson H, Shamsaldin A, Svahn-Tapper G, Moller T, Quiniou E, Garwicz S, Hawkins M, Avril MF, Oberlin O, Chavaudra J, de Vathaire F. Source: European Journal of Cancer (Oxford, England : 1990). 2003 November; 39(16): 2379-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14556931

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Re: A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. Author(s): Boniol M, Autier P, Dore JF. Source: Journal of the National Cancer Institute. 2004 February 18; 96(4): 335-6; Author Reply 336-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14970286

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Re: A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. Author(s): Lazovich D, Sweeney C, Weinstock MA, Berwick M. Source: Journal of the National Cancer Institute. 2004 February 18; 96(4): 335; Author Reply 337-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14970285

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Re: Rowland NH and Schnetler JF. Primary malignant melanoma arising in the dorsum of the tongue. Author(s): Harrington KJ, Nutting CM, Archer DJ. Source: The British Journal of Oral & Maxillofacial Surgery. 2004 February; 42(1): 78-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14706312

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Reassessing the role of lymphatic mapping and sentinel lymphadenectomy in the management of cutaneous malignant melanoma. Author(s): Perrott RE, Glass LF, Reintgen DS, Fenske NA. Source: Journal of the American Academy of Dermatology. 2003 October; 49(4): 567-88; Quiz 589-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14512901

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Recurrent malignant melanoma 51 years after the diagnosis of ocular melanoma. Author(s): Sangueza OP. Source: The American Journal of Dermatopathology. 2004 June; 26(3): 257-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15166521

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Reliability of identification of 655 sentinel lymph nodes in 263 consecutive patients with malignant melanoma. Author(s): Ariyan S, Ariyan C, Farber LR, Fischer DS, Flynn SD, Truini C. Source: Journal of the American College of Surgeons. 2004 June; 198(6): 924-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15194074

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Risk factors for cutaneous malignant melanoma among aircrews and a random sample of the population. Author(s): Rafnsson V, Hrafnkelsson J, Tulinius H, Sigurgeirsson B, Olafsson JH. Source: Occupational and Environmental Medicine. 2003 November; 60(11): 815-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14573711

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Risk of second primary cancers, other than melanoma, in an Italian population-based cohort of cutaneous malignant melanoma patients. Author(s): Crocetti E, Carli P. Source: European Journal of Cancer Prevention : the Official Journal of the European Cancer Prevention Organisation (Ecp). 2004 February; 13(1): 33-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15075786

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Role of imprint cytology in the intraoperative evaluation of sentinel lymph nodes for malignant melanoma. Author(s): Hocevar M, Bracko M, Pogacnik A, Vidergar-Kralj B, Besic N, Zgajnar J. Source: European Journal of Cancer (Oxford, England : 1990). 2003 October; 39(15): 21738. Erratum In: Eur J Cancer. 2004 March; 40(5): 780. Hocevat M [corrected to Hocevar M]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522375

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Screening of inhibitors of human telomerase reverse transcriptase in a cultured malignant melanoma cell line. Author(s): Hu S, Liao SK, Pang JH, Chen MC, Chen CH, Hong HS. Source: The British Journal of Dermatology. 2004 February; 150(2): 388-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996129

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Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma. Author(s): Valencak J, Heere-Ress E, Kopp T, Schoppmann SF, Kittler H, Pehamberger H. Source: European Journal of Cancer (Oxford, England : 1990). 2004 February; 40(3): 35864. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14746853

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Selective sentinel lymphadenectomy for malignant melanoma. Author(s): Leong SP. Source: The Surgical Clinics of North America. 2003 February; 83(1): 157-85, Vii. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691454

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Sentinel lymph nodes in malignant melanoma: extended histopathologic evaluation improves diagnostic precision. Author(s): Abrahamsen HN, Hamilton-Dutoit SJ, Larsen J, Steiniche T. Source: Cancer. 2004 April 15; 100(8): 1683-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15073857

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Sentinel node mapping in patients with malignant melanoma using melanoma Tc99m colloidal rhenium sulfide. Author(s): Weiss M, Kunte C, Schmid RA, Konz B, Dresel S, Hahn K. Source: Clinical Nuclear Medicine. 2003 May; 28(5): 379-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702933

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Serum interleukin-6 concentrations as predictive factor of time to progression in metastatic malignant melanoma patients treated by biochemotherapy: a retrospective study. Author(s): Mouawad R, Rixe O, Meric JB, Khayat D, Soubrane C. Source: Cytokines, Cellular & Molecular Therapy. 2002; 7(4): 151-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14660055

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Small interfering RNA targeting bcl-2 sensitizes malignant melanoma. Author(s): Wacheck V, Losert D, Gunsberg P, Vornlocher HP, Hadwiger P, Geick A, Pehamberger H, Muller M, Jansen B. Source: Oligonucleotides. 2003; 13(5): 393-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15000830

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Spindle cell malignant melanoma metastatic to the breast from a pigmented lesion on the back. A case report. Author(s): Mayayo Artal E, Gomez-Aracil V, Mayayo Alvira R, Azua-Romeo J, Arraiza A. Source: Acta Cytol. 2004 May-June; 48(3): 387-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15192956

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Surgical treatment of malignant melanoma. Author(s): Essner R. Source: The Surgical Clinics of North America. 2003 February; 83(1): 109-56. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691453

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Survival and prognostic factors in patients with brain metastases from malignant melanoma. Author(s): Meier S, Baumert BG, Maier T, Wellis G, Burg G, Seifert B, Dummer R. Source: Onkologie. 2004 April; 27(2): 145-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138346

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Tattoo pigment in lymph nodes mimicking metastatic malignant melanoma. Author(s): Friedman T, Westreich M, Mozes SN, Dorenbaum A, Herman O. Source: Plastic and Reconstructive Surgery. 2003 May; 111(6): 2120-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12711995

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Ten-year experience of carbon dioxide laser ablation as treatment for cutaneous recurrence of malignant melanoma. Author(s): Gibson SC, Byrne DS, McKay AJ. Source: The British Journal of Surgery. 2004 July; 91(7): 893-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15227697

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The Ets-1 transcription factor is involved in the development and invasion of malignant melanoma. Author(s): Rothhammer T, Hahne JC, Florin A, Poser I, Soncin F, Wernert N, Bosserhoff AK. Source: Cellular and Molecular Life Sciences : Cmls. 2004 January; 61(1): 118-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704859

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The impact of immunohistochemistry on sentinel node biopsy for primary cutaneous malignant melanoma. Author(s): Ross GL, Shoaib T, Scott J, Camilleri IG, Gray HW, MacKie R, Soutar DS. Source: British Journal of Plastic Surgery. 2003 March; 56(2): 153-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12791361

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The role of molecular staging in malignant melanoma. Author(s): Prichard RS, Dijkstra B, McDermott EW, Hill AD, O'Higgins NJ. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2003 May; 29(4): 306-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12711281

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The staging of malignant melanoma and the Florida Melanoma Trial. Author(s): Reintgen DS, Jakub JW, Pendas S, Swor G, Giuliano R, Shivers S. Source: Annals of Surgical Oncology : the Official Journal of the Society of Surgical Oncology. 2004 March; 11(3 Suppl): 186S-91S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15023749

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Treatment of primary malignant melanoma of the esophagus with endoscopic injection of interferon-beta combined with systemic chemotherapy: a case report. Author(s): Sakamoto H, Uedo N, Iishi H, Higashino K, Ishihara R, Mitani K, Narahara H, Tatsuta M, Mano M, Ishiguro S. Source: Gastrointestinal Endoscopy. 2003 May; 57(6): 773-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12739558

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Treatment options for choroidal malignant melanoma: a case report featuring transpupillary thermotherapy. Author(s): Riley T, Harshman D. Source: Optometry. 2004 February; 75(2): 103-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14989502

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Two new trifunctional antibodies for the therapy of human malignant melanoma. Author(s): Ruf P, Jager M, Ellwart J, Wosch S, Kusterer E, Lindhofer H. Source: International Journal of Cancer. Journal International Du Cancer. 2004 February 20; 108(5): 725-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14696099

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Tyrosinase expression in malignant melanoma, desmoplastic melanoma, and peripheral nerve tumors. Author(s): Xu X, Zhang PJ, Elder DE. Source: Archives of Pathology & Laboratory Medicine. 2003 September; 127(9): 1083-4; Author Reply 1084-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12951966

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Ultrasonographic detection of regional lymph node metastases in patients with intermediate or thick malignant melanoma. Author(s): Brountzos EN, Panagiotou IE, Bafaloukos DI, Kelekis DA. Source: Oncol Rep. 2003 March-April; 10(2): 505-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12579298

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Ultraviolet radiation and cutaneous malignant melanoma. Author(s): Jhappan C, Noonan FP, Merlino G. Source: Oncogene. 2003 May 19; 22(20): 3099-112. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12789287

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Uncommon manifestations of common malignancies: case 3. Malignant melanoma arising from a spinal nerve root. Author(s): Naing A, Messina JL, Vrionis FR, Daud AI. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 August 1; 22(15): 3194-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15284274

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Unusual aspects of melanoma. Case 1. Jejunal malignant melanoma: intestinal or unknown primary? Author(s): Montella L, Vardanega A, Farruggio A, Bonciarelli G. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 February 15; 22(4): 743-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966100

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Update on the systemic treatment of malignant melanoma. Author(s): Lawson DH. Source: Seminars in Oncology. 2004 April; 31(2 Suppl 4): 33-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15124132

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Upregulation of HMG1 leads to melanoma inhibitory activity expression in malignant melanoma cells and contributes to their malignancy phenotype. Author(s): Poser I, Golob M, Buettner R, Bosserhoff AK. Source: Molecular and Cellular Biology. 2003 April; 23(8): 2991-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12665595

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Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 and type 2 in stage I malignant melanoma. Author(s): Stabuc B, Markovic J, Bartenjev I, Vrhovec I, Medved U, Kocijancic B. Source: Oncol Rep. 2003 May-June; 10(3): 635-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684636

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Use of serum 5-S-CD and S-100B protein levels to monitor the clinical course of malignant melanoma. Author(s): Banfalvi T, Gilde K, Gergye M, Boldizsar M, Kremmer T, Otto S. Source: European Journal of Cancer (Oxford, England : 1990). 2003 January; 39(2): 164-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12509947

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Use of tamoxifen in the treatment of malignant melanoma. Author(s): Lens MB, Reiman T, Husain AF. Source: Cancer. 2003 October 1; 98(7): 1355-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508820

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Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9067 patients from 11 case-control studies. Author(s): Huncharek M, Kupelnick B. Source: American Journal of Public Health. 2002 July; 92(7): 1173-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12084704

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Vaccination for malignant melanoma: recent developments. Author(s): Jager D, Jager E, Knuth A. Source: Oncology. 2001; 60(1): 1-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11150901

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Value of frozen-section analysis of sentinel lymph nodes for primary cutaneous malignant melanoma. Author(s): Stojadinovic A, Allen PJ, Clary BM, Busam KJ, Coit DG. Source: Annals of Surgery. 2002 January; 235(1): 92-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11753047

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Variability of chromosomes in the VUP permanent cell line derived from uveal malignant melanoma. Author(s): Vrba M, Cihalova V, Juraskova V. Source: Neoplasma. 2002; 49(3): 184-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12098005

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Vascular endothelial growth factor expression in malignant melanoma: prognostic versus diagnostic usefulness. Author(s): Bayer-Garner IB, Hough AJ Jr, Smoller BR. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 1999 August; 12(8): 770-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463478

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Very late cerebral metastasis from malignant melanoma. Author(s): Puca A, Vari R, Carbone A. Source: British Journal of Neurosurgery. 1998 February; 12(1): 63-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11013654

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Vitamin D and systemic cancer: is this relevant to malignant melanoma? Author(s): Osborne JE, Hutchinson PE. Source: The British Journal of Dermatology. 2002 August; 147(2): 197-213. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12174089

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Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma. Author(s): Hutchinson PE, Osborne JE, Lear JT, Smith AG, Bowers PW, Morris PN, Jones PW, York C, Strange RC, Fryer AA. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 February; 6(2): 498-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10690530

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Vogt-Koyanagi-Harada syndrome associated with cutaneous malignant melanoma: an 11-year follow-up. Author(s): Aisenbrey S, Luke C, Ayertey HD, Grisanti S, Perniok A, Brunner R. Source: Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie. 2003 December; 241(12): 996-9. Epub 2003 November 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14618342

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Vulvar malignant melanoma associated with human papillomavirus DNA: report of two cases and review of literature. Author(s): Rohwedder A, Philips B, Malfetano J, Kredentser D, Carlson JA. Source: The American Journal of Dermatopathology. 2002 June; 24(3): 230-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12140440

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Vulvar malignant melanoma following radiotherapy for cervical cancer. Author(s): Mendilcioglu I, Zorlu CG, Pestereli HE, Karaveli S, Trak B. Source: Melanoma Research. 2002 October; 12(5): 521-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12394195

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Wearing sunglasses--a risk factor for the development of cutaneous malignant melanoma? Author(s): Krengel S. Source: International Journal of Dermatology. 2002 March; 41(3): 191-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12010351

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What is the diagnosis? Uveal malignant melanoma. Author(s): Kato K. Source: Ann Nucl Med. 2003 October; 17(7): Front Cover, 612. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14651364

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What is there to find in malignant melanoma re-excision specimens? Author(s): Kirkham N. Source: Histopathology. 1998 June; 32(6): 566-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9675598

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Wnt ligand expression in malignant melanoma: pilot study indicating correlation with histopathological features. Author(s): Pham K, Milovanovic T, Barr RJ, Truong T, Holcombe RF. Source: Molecular Pathology : Mp. 2003 October; 56(5): 280-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14514922

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Xanthogranulomas with inconspicuous foam cells and giant cells mimicking malignant melanoma: a clinical, histologic, and immunohistochemical study of three cases. Author(s): Busam KJ, Rosai J, Iversen K, Jungbluth AA. Source: The American Journal of Surgical Pathology. 2000 June; 24(6): 864-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10843290

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XPD gene polymorphism and host characteristics in the association with cutaneous malignant melanoma risk. Author(s): Baccarelli A, Calista D, Minghetti P, Marinelli B, Albetti B, Tseng T, Hedayati M, Grossman L, Landi G, Struewing JP, Landi MT. Source: British Journal of Cancer. 2004 January 26; 90(2): 497-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735199

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Zilascorb(2H), a low-toxicity protein synthesis inhibitor that exhibits signs of anticancer activity in malignant melanoma. Author(s): Semb KA, Aamdal S, Mette E, Ingvar C, Gullaksen N, Osmundsen K. Source: Anti-Cancer Drugs. 1998 October; 9(9): 797-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9840726

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CHAPTER 2. NUTRITION AND MALIGNANT MELANOMA Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and malignant melanoma.

Finding Nutrition Studies on Malignant Melanoma 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 “malignant melanoma” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

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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 “malignant melanoma” (or a synonym): •

A unique in vivo assessment of 4-[10B]borono-L-phenylalanine in tumour tissues for boron neutron capture therapy of malignant melanomas using positron emission tomography and 4-borono-2-[18F]fluoro-L-phenylalanine. Author(s): Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan. Source: Ishiwata, K Shiono, M Kubota, K Yoshino, K Hatazawa, J Ido, T Honda, C Ichihashi, M Mishima, Y Melanoma-Res. 1992 September; 2(3): 171-9 0960-8931

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An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. Author(s): Institute of Pathology, Charite Hospital, Berlin, Germany. Source: Denkert, Carsten Siegert, Antje Leclere, Anja Turzynski, Andreas Hauptmann, Steffen Clin-Exp-Metastasis. 2002; 19(1): 79-85 0262-0898

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Changes in MR of malignant melanomas induced by glucose and fructose. A clinical and experimental investigation. Author(s): Department of Ophthalmology, Uppsala University, Sweden. Source: Naeser, P Thuomas, K A Roberto, A Larsson, B S Acta-Radiol. 1991 May; 32(3): 206-9 0284-1851

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Combined treatment of advanced malignant melanoma with coumarin and cimetidine. A phase II study. Source: Pedersen, L Rose, C Langvad, E Cancer-Immunol-Immunother. 1987; 24(2): 1789 0340-7004

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Differentiation of human malignant melanoma cells that escape apoptosis after treatment with 9-nitrocamptothecin in vitro. Author(s): Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA. [email protected] Source: Pantazis, P Chatterjee, D Han, Z Wyche, J Neoplasia. 1999 August; 1(3): 231-40 1522-8002

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Effective local control of malignant melanoma by intratumoural injection of a betaemitting radionuclide. Author(s): Department of Diagnostic Radiology, Yonsei University College of Medicine, Seoul, Korea. Source: Lee, J D Yang, W I Lee, M G Ryu, Y H Park, J H Shin, K H Kim, G E Suh, C O Seong, J S Han, B H Choi, C W Kim, E H Kim, K H Park, K B Eur-J-Nucl-Med-MolImaging. 2002 February; 29(2): 221-30 1619-7070

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Heterogeneity of cytokine production by human malignant melanoma cells. Author(s): Dermatology Service, Veterans Affairs Medical Center, Portland, Oregon 97207. Source: Armstrong, C A Tara, D C Hart, C E Kock, A Luger, T A Ansel, J C ExpDermatol. 1992 July; 1(1): 37-45 0906-6705

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Histopathology studies in human malignant melanomas of the choroid after unsuccessful treatment with 106Ru/106Rh ophthalmic applicators. Author(s): Augenklinik Universitat Leipzig, Federal Republic of Germany. Source: Klaus, H Lommatzsch, P K Fuchs, U Graefes-Arch-Clin-Exp-Ophthalmol. 1991; 229(5): 480-6 0721-832X

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Hyperthermic limb perfusion for malignant melanoma and soft tissue sarcoma. Author(s): Department of Surgery, University of Heidelberg, FRG.

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Source: Kettelhack, C Kraus, T Hupp, T Manner, M Schlag, P Eur-J-Surg-Oncol. 1990 August; 16(4): 370-5 0748-7983 •

In vivo targeting of malignant melanoma by 125Iodine- and 99mTechnetium-labeled single-chain Fv fragments against high molecular weight melanoma-associated antigen. Author(s): The Restoration of Appearance and Function Trust Institute of Plastic Surgery, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom. Source: Kang, N Hamilton, S Odili, J Wilson, G Kupsch, J Clin-Cancer-Res. 2000 December; 6(12): 4921-31 1078-0432

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Inhibition of the fibroblast growth factor receptor 1 (FGFR-1) gene in human melanocytes and malignant melanomas leads to inhibition of proliferation and signs indicative of differentiation. Author(s): Department of Medicine, University of Pittsburgh, Pennsylvania 15261. Source: Becker, D Lee, P L Rodeck, U Herlyn, M Oncogene. 1992 November; 7(11): 230313 0950-9232

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Long-term follow-up of proton irradiated malignant melanoma by glucose-fructose enhanced magnetic resonance imaging. Author(s): Department of Diagnostic Radiology, Linkoping University, Sweden. Source: Thuomas, K A Naeser, P Acta-Ophthalmol-Scand. 1997 February; 75(1): 17-21 1395-3907

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Metastatic malignant melanoma treated with procarbazine, vincristine and lomustine (POC). Source: Repetto, L Grimaldi, A Ardizzoni, A Sertoli, M R Rosso, R Chemioterapia. 1987 February; 6(1): 63-5 0392-906X

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Myelodysplastic syndrome following treatment of malignant melanoma with vincristine, ACNU, and dacarbazine. Author(s): Department of Dermatology, Kumamoto University, Japan. Source: Kageshita, T Kuribayashi, N Ono, T J-Dermatol. 2000 March; 27(3): 178-80 03852407

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Phase II trials of flavone acetic acid in advanced malignant melanoma and colorectal carcinoma. Author(s): CRC Department of Medical Oncology, University of Glasgow, UK. Source: Kerr, D J Maughan, T Newlands, E Rustin, G Bleehen, N M Lewis, C Kaye, S B Br-J-Cancer. 1989 July; 60(1): 104-6 0007-0920

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Prevention of early recurrence of high risk malignant melanoma by coumarin. Irish Melanoma Group. Author(s): Byrnes Research Centre, Beaumont Hospital, Dublin, Eire. Source: Thornes, D Daly, L Lynch, G Browne, H Tanner, A Keane, F O'Loughlin, S Corrigan, T Daly, P Edwards, G et al. Eur-J-Surg-Oncol. 1989 October; 15(5): 431-5 07487983

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Primary malignant melanoma of the esophagus treated by esophagectomy and systemic chemotherapy. Author(s): Department of Surgery I, Nippon Medical School, Tokyo, Japan. [email protected] Source: Matsutani, T Onda, M Miyashita, M Hagiwara, N Akiya, Y Takubo, K Yamashita, K Sasajima, K Dis-Esophagus. 2001; 14(3-4): 241-4 1120-8694

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Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and

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Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. Author(s): Department of Surgical Oncology, University Hospital, Groningen, The Netherlands. Source: Koops, H S Vaglini, M Suciu, S Kroon, B B Thompson, J F Gohl, J Eggermont, A M Di Filippo, F Krementz, E T Ruiter, D Lejeune, F J J-Clin-Oncol. 1998 September; 16(9): 2906-12 0732-183X •

Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. Author(s): Department of Surgery, Sahlgrenska Hospital, Goteborg, Sweden. Source: Hafstrom, L Rudenstam, C M Blomquist, E Ingvar, C Jonsson, P E Lagerlof, B Lindholm, C Ringborg, U Westman, G Ostrup, L J-Clin-Oncol. 1991 December; 9(12): 2091-4 0732-183X

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Silver staining of nucleolar organizer regions in malignant melanoma and melanotic nevi. Author(s): Division of Tissue Pathology, Institute of Medical & Veterinary Science, Adelaide, South Australia. Source: Leong, A S Gilham, P Hum-Pathol. 1989 March; 20(3): 257-62 0046-8177

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The cellular oncogene EWS/activating transcription factor 1 is unable to activate adenovirus-borne promoters: implications for cytotoxic prodrug therapy of malignant melanoma of soft parts. Author(s): Department of Biology, Hong Kong University of Science and Technology, Kowloon, China. Source: Lung, R W Lee, K A Cancer-Gene-Ther. 2000 March; 7(3): 396-406 0929-1903

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The herbal medicine sho-saiko-to inhibits the growth of malignant melanoma cells by upregulating Fas-mediated apoptosis and arresting cell cycle through downregulation of cyclin dependent kinases. Author(s): Department of Immunology, Nagoya University School of Medicine, Nagoya 466-8550, Japan. Source: Liu, W Kato, M Akhand, A A Hayakawa, A Takemura, M Yoshida, S Suzuki, H Nakashima, I Int-J-Oncol. 1998 June; 12(6): 1321-6 1019-6439

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The treatment of disseminated malignant melanoma with special reference to the role of interferons, vinca alkaloids and tamoxifen. Author(s): Department of Medicine, University of Witwatersrand Medical School, Johannesburg, South Africa. Source: Bezwoda, W R Cancer-Treat-Revolume 1997 January; 23(1): 17-34 0305-7372

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Therapy of metastatic malignant melanoma using Xomazyme Mel, a murine monoclonal anti-melanoma ricin A chain immunotoxin. Author(s): Biotherapeutics of San Francisco, Inc., Oakland, CA 94606. Source: Spitler, L E Mischak, R Scannon, P Int-J-Rad-Appl-Instrum-B. 1989; 16(6): 625-7 0883-2897

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Thermal neutron capture therapy of malignant melanoma using 10B-monoclonal antibodies: in vitro and in vivo analysis. Author(s): Department of Dermatology, School of Medicine, Kobe University, Japan. Source: Komura, A Nakagawa, T Ichihashi, M Mishima, Y Melanoma-Res. 1992 JanFebruary; 1(5-6): 397-403 0960-8931

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Treatment of advanced malignant melanoma with coumarin and cimetidine: a pilot study. Author(s): Division of Hematology/Oncology, University of Kentucky Medical Center, Lexington 40536-0084. Source: Marshall, M E Butler, K Cantrell, J Wiseman, C Mendelsohn, L CancerChemother-Pharmacol. 1989; 24(1): 65-6 0344-5704

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Treatment of metastatic malignant melanoma with dacarbazine, vindesine and cisplatin. Author(s): Department of Medical Oncology, Metaxas Memorial Cancer Hospital, Piraeus, Greece. Source: Pectasides, D Yianniotis, H Alevizakos, N Bafaloukos, D Barbounis, V Varthalitis, J Dimitriadis, M Athanassiou, A Br-J-Cancer. 1989 October; 60(4): 627-9 00070920

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Unexpected cytokines in serum of malignant melanoma patients during sequential biochemotherapy. Author(s): Department of Cancer Biology University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA. Source: Grimm, E A Smid, C M Lee, J J Tseng, C H Eton, O Buzaid, A C Clin-Cancer-Res. 2000 October; 6(10): 3895-903 1078-0432

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/

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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

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CHAPTER 3. ALTERNATIVE MEDICINE AND MALIGNANT MELANOMA Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to malignant melanoma. 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 malignant melanoma 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 “malignant melanoma” (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 malignant melanoma: •

(+)-Tiliarine, a selective in vitro inhibitor of human melanoma cells. Author(s): Seal T, Mukherjee B. Source: Phytotherapy Research : Ptr. 2002 September; 16(6): 596-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12237824

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A clinical trial of intravenous vinorelbine tartrate plus tamoxifen in the treatment of patients with advanced malignant melanoma. Author(s): Feun LG, Savaraj N, Hurley J, Marini A, Lai S. Source: Cancer. 2000 February 1; 88(3): 584-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10649251

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A phase II study of biochemotherapy for the treatment of metastatic malignant melanoma.

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Author(s): Gibbs P, Iannucci A, Becker M, Allen J, O'Driscoll M, McDowell K, Williams P, Rosse P, Murphy J, Gonzalez R. Source: Melanoma Research. 2000 April; 10(2): 171-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10803718 •

A Phase II trial of vinorelbine tartrate in patients with disseminated malignant melanoma and one prior systemic therapy: a Southwest Oncology Group study. Author(s): Whitehead RP, Moon J, McCachren SS, Hersh EM, Samlowski WE, Beck JT, Tchekmedyian NS, Sondak VK; Southwest Oncology Group. Source: Cancer. 2004 April 15; 100(8): 1699-704. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15073859

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A structured psychiatric intervention for patients with malignant melanoma: Fawzy et al. (1990b). Author(s): Payne D. Source: Advances in Mind-Body Medicine. 2001 Winter; 17(1): 21-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11270055

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Acceptance by Swedish users of a multimedia program for primary and secondary prevention of malignant melanoma. Author(s): Lindholm LH, Isacsson A, Slaug B, Moller TR. Source: Journal of Cancer Education : the Official Journal of the American Association for Cancer Education. 1998 Winter; 13(4): 207-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9883779

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Adjuvant therapy of malignant melanoma. Author(s): Molife R, Hancock BW. Source: Critical Reviews in Oncology/Hematology. 2002 October; 44(1): 81-102. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12399001

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Adjuvant therapy of malignant melanoma: is there a choice? Author(s): Retsas S. Source: Critical Reviews in Oncology/Hematology. 2001 November; 40(2): 187-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11682325

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Apoptotic effects of ginsenoside Rh2 on human malignant melanoma A375-S2 cells. Author(s): Fei XF, Wang BX, Tashiro S, Li TJ, Ma JS, Ikejima T. Source: Acta Pharmacologica Sinica. 2002 April; 23(4): 315-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11931705

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Binding of mistletoe lectins to cutaneous malignant melanoma: implications for prognosis and therapy. Author(s): Thies A, Pfuller U, Schachner M, Horny HP, Molls I, Schumacher U. Source: Anticancer Res. 2001 July-August; 21(4B): 2883-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11712781

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Changes in immunological parameters after combination adjuvant therapy with intravenous DTIC, ACNU, and VCR, and local injection of IFN-beta (DAV + IFN-beta therapy) into malignant melanoma. Author(s): Umeda T, Aoki K, Yokoyama A, Ohara H, Hayashi O, Tanaka K, Nishioka K. Source: The Journal of Dermatology. 1998 September; 25(9): 569-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9798342

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Combination chemotherapy with docetaxel and irinotecan in metastatic malignant melanoma. Author(s): Tas F, Camlica H, Kurul S, Aydiner A, Topuz E. Source: Clin Oncol (R Coll Radiol). 2003 May; 15(3): 132-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801051

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Cutaneous malignant melanoma and sun exposure in Spain. Author(s): Espinosa Arranz J, Sanchez Hernandez JJ, Bravo Fernandez P, GonzalezBaron M, Zamora Aunon P, Espinosa Arranz E, Jalon Lopez JI, Ordonez Gallego A. Source: Melanoma Research. 1999 April; 9(2): 199-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10380943

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Cutaneous malignant melanoma in children. Author(s): Vandeweyer E, Sales F, Deraemaecker R. Source: European Journal of Pediatrics. 2000 August; 159(8): 582-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10968235

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Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A randomised phase III trial. Author(s): Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmstrom P, Andersson R, Karlsson M, Willman K, Wist E, Bjelkengren G, Westberg R. Source: European Journal of Cancer (Oxford, England : 1990). 1998 August; 34(9): 136874. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9849419

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Differentiation of human malignant melanoma cells that escape apoptosis after treatment with 9-nitrocamptothecin in vitro. Author(s): Pantazis P, Chatterjee D, Han Z, Wyche J.

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Source: Neoplasia (New York, N.Y.). 1999 August; 1(3): 231-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10935478 •

Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma. A prospective study. Author(s): Nieder C. Source: Cancer. 1999 September 1; 86(5): 900-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463993

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Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Author(s): Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, Carlini P, Boni C, Di Sarra S. Source: Cancer. 1999 April 1; 85(7): 1599-605. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10193952

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Genistein enhances the cisplatin-induced inhibition of cell growth and apoptosis in human malignant melanoma cells. Author(s): Tamura S, Bito T, Ichihashi M, Ueda M. Source: Pigment Cell Research / Sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society. 2003 October; 16(5): 470-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12950722

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Inefficacy of vindesine monotherapy in advanced stage IV malignant melanoma patients previously treated with other chemotherapeutic agents. Author(s): Emmert S, Zutt M, Haenssle H, Neumann C, Kretschmer L. Source: Melanoma Research. 2003 June; 13(3): 299-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777986

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Interferon-alpha-induced activation of signal transducer and activator of transcription proteins in malignant melanoma. Author(s): Carson WE. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1998 September; 4(9): 2219-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9748142

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Investigation of the growth and metastasis of malignant melanoma in a murine model: the role of supplemental vitamin A. Author(s): Weinzweig J, Tattini C, Lynch S, Zienowicz R, Weinzweig N, Spangenberger A, Edstrom L.

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Source: Plastic and Reconstructive Surgery. 2003 July; 112(1): 152-8; Discussion 159-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12832888 •

L-methionine supplementation accelerates tumour growth and shifts the phospholipid derivative pattern in a murine model of malignant melanoma. A proton HRMAS NMR spectroscopy study. Author(s): Demidem A, Morvan D, Papon J, Madelmont JC. Source: Iarc Sci Publ. 2002; 156: 423-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12484228

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Malignant melanoma: effects of a brief, structured psychiatric intervention on survival and recurrence at 10-year follow-up. Author(s): Fawzy FI, Canada AL, Fawzy NW. Source: Archives of General Psychiatry. 2003 January; 60(1): 100-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12511177

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Malignant melanoma: treatments emerging, but early detection is still key. Author(s): Masci P, Borden EC. Source: Cleve Clin J Med. 2002 July; 69(7): 529, 533-4, 536-8 Passim. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12109636

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Myelodysplastic syndrome following treatment of malignant melanoma with vincristine, ACNU, and dacarbazine. Author(s): Kageshita T, Kuribayashi N, Ono T. Source: The Journal of Dermatology. 2000 March; 27(3): 178-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10774145

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Phase II study of paclitaxel and carboplatin for malignant melanoma. Author(s): Hodi FS, Soiffer RJ, Clark J, Finkelstein DM, Haluska FG. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2002 June; 25(3): 283-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12040289

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Phase II trial of Paclitaxel and Dacarbazine with filgrastim administration in advanced malignant melanoma. Author(s): Feun LG, Savaraj N, Hurley J, Marini A. Source: Cancer Investigation. 2002; 20(3): 357-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12025231

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Primary malignant melanoma of the esophagus treated by esophagectomy and systemic chemotherapy. Author(s): Matsutani T, Onda M, Miyashita M, Hagiwara N, Akiya Y, Takubo K, Yamashita K, Sasajima K.

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Source: Diseases of the Esophagus : Official Journal of the International Society for Diseases of the Esophagus / I.S.D.E. 2001; 14(3-4): 241-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11869329 •

Primary malignant melanoma of the oral mucosa. Author(s): Rapidis AD, Apostolidis C, Vilos G, Valsamis S. Source: Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. 2003 October; 61(10): 1132-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586846

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Results of treatment of choroidal malignant melanoma with high-dose-rate strontium-90 brachytherapy. A retrospective study of 46 patients treated between 1983 and 1995. Author(s): Missotten L, Dirven W, Van der Schueren A, Leys A, De Meester G, Van Limbergen E. Source: Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie. 1998 March; 236(3): 164-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9541818

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Risk of cutaneous malignant melanoma in relation to use of sunbeds: further evidence for UV-A carcinogenicity. Author(s): Westerdahl J, Ingvar C, Masback A, Jonsson N, Olsson H. Source: British Journal of Cancer. 2000 May; 82(9): 1593-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10789730

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Systemic chemotherapy in the treatment of malignant melanoma. Author(s): Lens MB, Eisen TG. Source: Expert Opinion on Pharmacotherapy. 2003 December; 4(12): 2205-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14640919

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Ten-year survival in advanced malignant melanoma following treatment with interferon and vindesine. Author(s): Iqbal M, Marshall E, Green JA. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2000 April; 11(4): 483-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10847471

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The herbal medicine Sho-saiko-to inhibits growth and metastasis of malignant melanoma primarily developed in ret-transgenic mice. Author(s): Kato M, Liu W, Yi H, Asai N, Hayakawa A, Kozaki K, Takahashi M, Nakashima I.

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Source: The Journal of Investigative Dermatology. 1998 October; 111(4): 640-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9764846 •

The herbal medicine sho-saiko-to inhibits the growth of malignant melanoma cells by upregulating Fas-mediated apoptosis and arresting cell cycle through downregulation of cyclin dependent kinases. Author(s): Liu W, Kato M, Akhand AA, Hayakawa A, Takemura M, Yoshida S, Suzuki H, Nakashima I. Source: International Journal of Oncology. 1998 June; 12(6): 1321-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9592193

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The role of religious and spiritual beliefs in coping with malignant melanoma. Author(s): Holland JC, Passik S, Kash KM, Russak SM, Gronert MK, Sison A, Lederberg M, Fox B, Baider L. Source: Psycho-Oncology. 1999 January-February; 8(1): 14-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10202779

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The role of religious and spiritual beliefs in coping with malignant melanoma: an Israeli sample. Author(s): Baider L, Russak SM, Perry S, Kash K, Gronert M, Fox B, Holland J, KaplanDenour A. Source: Psycho-Oncology. 1999 January-February; 8(1): 27-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10202780

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Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen, or vindesine plus tamoxifen: a prospective randomized study. Author(s): Cocconi G, Passalacqua R, Foladore S, Carlini P, Acito L, Maiello E, Marchi M, Gebbia V, Di Sarra S, Beretta M, Bacchi M. Source: Melanoma Research. 2003 February; 13(1): 73-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12569288

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Unexpected cytokines in serum of malignant melanoma patients during sequential biochemotherapy. Author(s): Grimm EA, Smid CM, Lee JJ, Tseng CH, Eton O, Buzaid AC. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 October; 6(10): 3895-903. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11051235

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/

The following is a specific Web list relating to malignant melanoma; 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 Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Prostate Cancer Source: Healthnotes, Inc.; www.healthnotes.com Skin Cancer Source: Integrative Medicine Communications; www.drkoop.com Uveitis Source: Integrative Medicine Communications; www.drkoop.com

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Herbs and Supplements Melatonin Source: Healthnotes, Inc.; www.healthnotes.com

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Phenylalanine Source: Integrative Medicine Communications; www.drkoop.com Tyrosine Source: Integrative Medicine Communications; www.drkoop.com

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 MALIGNANT MELANOMA Overview In this chapter, we will give you a bibliography on recent dissertations relating to malignant melanoma. 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 “malignant melanoma” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on malignant melanoma, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Malignant Melanoma 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 malignant melanoma. 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: •

Physical and molecular characterization of human malignant melanoma antigens defined by a monkey antiserum and a mouse monoclonal antibody by Khosravi, Mohammad Javad, PhD from MCMASTER UNIVERSITY (CANADA), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK65445

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 MALIGNANT MELANOMA 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 “malignant melanoma” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on malignant melanoma, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Malignant Melanoma By performing a patent search focusing on malignant melanoma, 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 malignant melanoma: •

Combination therapy of IL-2 and DTIC for the treatment of melanoma Inventor(s): Bradley; Edward C. (Moraga, CA), Paradise; Carolyn M. (Emeryville, CA) Assignee(s): Cetus Corporation (Emeryville, CA) Patent Number: 4,999,339 Date filed: March 28, 1988 Abstract: Therapeutic treatment of malignant melanoma in humans is disclosed wherein a synergistically effective amount of DTIC in combination with IL-2 is administered to an individual having such cancer. Excerpt(s): This invention relates to the field of medical treatment. More particularly, this invention is directed to a method for treating malignant melanoma using a combination of IL-2 and DTIC (dimethyl-triazeno-imidazolecarboxmide). Melanoma in its advanced stages is an incurable disease. Seventy-five percent of skin cancer deaths in the United States are due to malignant melanoma (Cancer Manual, Sixth Edition, (1982), American Cancer Society, Boston, p. 104). Worldwide, the incidence has been rising sharply doubling, every decade over the past 30 years. Surgery is the only curative therapy for melanoma in its early stages, although this modality, if used aggressively for local recurrence or metastatic disease to regional nodes, is associated with only a 20%30% cure rate. The role of surgery in advanced diseases is palliative. Web site: http://www.delphion.com/details?pn=US04999339__

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Metastatic melanoma cell lines from monodelphis domestica for use in anti-cancer agent discovery Inventor(s): Dooley; Thomas P. (San Antonio, TX), Robinson; Edward S. (San Antonio, TX) Assignee(s): Southwest Foundation for Biomedical Research (San Antonio, TX) Patent Number: 5,869,332 Date filed: June 3, 1994 Abstract: A cell line of metastatic, pigmented, malignant melanoma cells made by exposing a litter of Monodelphis domestica suckling young to an accumulated dose of ultraviolet radiation and then continuing the ultraviolet exposure after the young are weaned to induce malignant melanoma tumors and culturing the tumor cells from lymph nodes. This cell line can be used to test anti-cancer agents in vitro. Further this cell line can be injected into Monodelphis domestica suckling young so that tumors develop in the animals, and the anti-cancer agents can be tested in vivo. Excerpt(s): The present invention relates to metastatic, pigmented, malignant melanoma cell lines from Monodelphis domestica for in vitro and in vivo experimental purposes and the methods and apparatus for producing such cell lines. The incidence of cutaneous malignant melanoma (CMM) is rapidly rising among Caucasians and is estimated to affect approximately one of every 100 Caucasian Americans within their lifetime. Melanoma results from the oncogenic transformation of the pigment-producing cells of the skin and hair, melanocytes. (Rhodes, et al., JAMA, 258:3146-3154 (1987);

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Jimbow, et al., Physiology, Biochemistry and Molecular Biology of the Skin, Vol. II, ed. Goldsmith, (N.Y.: Oxford Univ. Press, 1991); Elder and Clark, Pigment Cell, 8:51-80 (1987)). Although CMM is easily recognized clinically and treated surgically, this form of skin cancer causes about 6700 deaths each year in the USA, due to the propensity for melanoma to metastasize (NIH Consensus Development Panel on Early Melanoma, JAMA 268:1314-1319 (1992)), thus making it the most serious form of skin cancer. The risk factors for cutaneous melanoma include increased age, race, familial occurrence of this disease, ultraviolet radiation (UVR) exposure, dysplastic nevi, fair skin, among others. (Rhodes, et al. (1987); Jimbow, et al., (1991); Elder and Clark (1987); NIH, et al. (1992); Elwood and Lee., Sem. Oncol., 2:149-154 (1975)). Conventional chemotherapy strategies employing cytotoxic or anti-proliferative agents have not been highly successful for the treatment of metastatic melanoma to date. Therefore, oncologists are in need of more effective and safe therapies for the treatment of melanoma. Several laboratory animal models have been developed to study various aspects of melanoma tumorigenesis, genetics, immunology and therapy (Dooley, Oncol. Res., 6:1-9 (1994)). Although no single animal model perfectly matches the genetic, biochemical, and pathological characteristics of human melanoma, each of the common models has some value in specific research areas for comparative studies relative to human melanoma. The established mammalian models, i.e. rodents (primarily mouse) and pigs (Sinclair swine) have some value in specific areas for comparative studies of human melanoma, but they do not provide a satisfactory match for the genetic, biochemical and pathological characteristics of the human disease. Web site: http://www.delphion.com/details?pn=US05869332__ •

Monoclonal antibodies to cell surface antigens of human malignant melanoma Inventor(s): Dippold; Wolfgang G. (Mainz, DE), Ikeda; Hisami (Asahikawa, JP), Li; Lucy T. C. (New York, NY), Lloyd; Kenneth O. (Bronx, NY), Oettgen; Herbert F. (New Canaan, CT), Old; Lloyd J. (New York, NY) Assignee(s): Sloan-Kettering Institute for Cancer Research (New York, NY) Patent Number: 4,808,704 Date filed: May 22, 1986 Abstract: Monoclonal antibody recognizing human melanoma cells, method of production and use. Excerpt(s): The invention described herein was made in the course of work under a grant or award from the Department of Health, Education and Welfare. The present invention relates to the generation of monoclonal antibodies and their use in identifying or characterizing human malignant melanoma antigens. This is a useful diagnostic tool in the detection of human malignant melanoma as well as the study of the nature of human malignant melanoma. Immunofluorescent or enzymatic tagging agents can be bound to the highly specific antibodies provided by this invention, using normal procedures, as required for indexing methods. Cytotoxic agents can also be bound to the highly specific antibodies to produce so called "magic bullet" type therapeutic agents which selectively destroy the cells with which the specific antibody binds. Other investigators have studied melanoma including Koprowski, et. al. Proc. Natl. Acad. Sci. USA 75, 3405-3409 (1978); Yeh, et al. (proc. Natl. Acad. Sci. USA 76, 2927-2931 (1979) and Woodbury et al. Proc. Natl. Acad. Sci. USA 77, 2183-2187 (1980). (The work of the present invention has also been published and is available in the same Journal i.e. Dippold et al. Proc. Nat'l. Acad. Sci. (1980) 77: 6614-6118 and is hereby incorporated by

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reference. Of these, the p97 melanoma surface antigen described by Woodbury et al may be related to the gp 95 antigen identified by 6 of the monoclonal antibodies of the invention. Web site: http://www.delphion.com/details?pn=US04808704__ •

Thiourea derivatives, methods of their preparation and their use in neutron capture therapy of malignant melanoma Inventor(s): Gabel; Detlef (Bremen, DE) Assignee(s): The United States Department of Energy (Washington, DC) Patent Number: 5,021,572 Date filed: January 27, 1989 Abstract: The present invention pertains to boron containing thiouracil derivatives, their method of preparations, and their use in the therapy of malignant melanoma using boron neutron capture therapy. Excerpt(s): The present invention also relates to methods for the preparation of the compounds of formula I, and their application in neutron capture therapy of malignant melanoma. Thioureas are known as substances which accumulate in malignant melanoma due to its active melanin synthesis. Malignant melanoma is a tumor of melanocytes. Its incidence is especially high among the fair-skinned population. In most industrial nations its incidence is increasing. Web site: http://www.delphion.com/details?pn=US05021572__

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Treatment of melanomas with thalidomide alone or in combination with other antimelanoma agents Inventor(s): Andrulis, Jr.; Peter J. (Bethesda, MD), Drulak; Murray W. (Gaithersburg, MD) Assignee(s): Andrulis Pharmaceuticals Corp. (Bethesda, MD) Patent Number: 5,731,325 Date filed: June 6, 1995 Abstract: A method for treatment of malignant melanoma by administering an effective amount of thalidomide alone or in combination with other anti-melanoma drugs. Excerpt(s): The present invention is directed to compositions and methods for treating malignant melanoma. In one specific aspect, the present invention is directed to a method for treating melanomas with thalidomide. In another specific embodiment of the invention, melanoma is treated with thalidomide in combination with other antimelanoma drugs. The present invention also relates to methods of treating melanomas with cytokine/growth factor inhibitors such as those agents inhibitory to basic fibroblast growth factor (bFGF), TNF-alpha, IL-1 and/or melanoma growth stimulatory activity (MGSA) factor as well as pharmaceutical compositions containing relevant cytokine/growth factor inhibitors and/or other anti-melanoma drugs. Thalidomide was first synthesized and marketed in the 1950's as a sedative. The toxicity of the compound was so low that a dose killing 50% of animals (LD.sub.50) could not be established. Thalidomide was therefore thought to be a safer alternative to barbiturates. In 1961,

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thalidomide administered to pregnant women resulted in an epidemic of congenial malformations. The incidence of malformed babies paralleled the sales of thalidomide and quickly dropped off when thalidomide was removed from the market. Web site: http://www.delphion.com/details?pn=US05731325__ •

Use of vindesine in treating acute lymphatic leukemia and _other susceptible neoplasms Inventor(s): Cullinan; George J. (Trafalger, IN), Gerzon; Koert (Indianapolis, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 4,479,957 Date filed: April 2, 1981 Abstract: This invention relates to a method of treating neoplasms which comprises administering to a mammal suffering from a vindesinesusceptible neoplasm selected from the group consisting of acute lymphatic leukemia, acute granulocytic leukemia, chronic myeloid leukemia, non-small cell lung cancer, Hodgkin's disease, nonHodgkin's lymphoma, malignant melanoma carcinoma of the breast, esophageal carcinoma and testicular carcinoma an anti-neoplastically-effective amount of vindesine or a pharmaceutically-acceptable acid addition salt thereof. Excerpt(s): Several naturally-occurring alkaloids obtainable from Vinca rosea have been found active in the treatment of experimental malignancies in animals. Among these are leurosine (U.S. Pat. No. 3,370,057), vincaleukoblastine (vinblastine) to be referred to hereinafter as VLB (U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and leurocristine (VCR or vincrisitine) (both in U.S. Pat. No. 3,205,220), deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1958) desacetyl leurosine hydrazide is also disclosed therein); 4-desacetoxy vinblastine (U.S. Pat. No. 3,954,773; 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (U.S. Pat. No. 3,890,325) and vincadioline (U.S. Pat. No. 3,887,565). Two of these alkaloids, VLB and leurocristine, are now marketed as drugs for the treatment of neoplasms, VLB for the palliative treatment of lymphomas, generalized Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, mycosis fungoides, neuroblastoma, Letterer-Siwe disease, choriocarcinoma, carcinoma of the breast, and embryonal carcinoma of the testis. Vincristine is indicated in the treatment of acute leukemia, and in combination with other oncolytic agents, in Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, rhabdomyosarcoma, neuroblastoma and Wilm's Tumor. Chemical modification of the Vinca alkaloids has been rather limited. In the first place, the molecular structures involved are extremely complex and chemical reactions which affect a specific function of the molecule are difficult to develop. Secondly, alkaloids lacking desirable chemotherapeutic properties have been recovered from Vinca rosea fractions, and a determination of their structures has led to the conclusion that these compounds are closely related structurally to the antineoplastically-active alkaloids. Thus, antineoplastic activity seems to be limited to very specific structures, and the chances of obtaining more active drugs by modification of these structures would seem to be correspondingly slight. Among the successful modifications of physiologically-active alkaloids has been the preparation of dihydro VLB (U.S. Pat. No. 3,352,868) and the replacement of the acetyl group at C-4 (carbon no. 4 of the VLB ring system-see the numbered structure below) with higher alkanoyl group or with unrelated acyl groups. (See U.S. Pat. No. 3,392,173.) Several of these derivatives are capable of prolonging the life of mice inoculated with P1534 leukemia. One of the derivatives in which a chloracetyl group replaced the C-4 acetyl group of VLB was also

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a useful intermediate for the preparation of structurally modified VLB compounds in which an N,N-dialkylglycl group replaced the C-4 acetyl group of VLB (see U.S. Pat. No. 3,387,001). An intermediate compound, namely 4-desacetyl VLB, was produced during the chemical reactions leading to these latter derivatives. This intermediate, in which the C-4 acyl group was lacking, leaving an unesterified hydroxy group, has been reported to be a toxic material having little in vivo chemotherapeutic activity against the P1534 murine leukemia system by Hargrove, Lloydia, 27, 340 (1964). A more recent modification has been the replacement of the ester group at C-3 with a carboxamide group. These novel amides are fully described in the parent of this application and in its predecessors--see also Belgian Pat. No. 347,275 issued 10-2-74 and Barnett et al., J. Med. Chem., 21, 88 (1978). One of these amides, 4-desacetyl VLB C-3 carboxamide, generic name vindesine, proposed trademark ELDISINE.RTM., is undergoing an extensive clinical trial in humans for treatment of acute lymphatic leukemia, acute granulocytic leukemia, chronic myeloid leukemia, non-small cell lung cancer, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, carcinoma of the breast, esophageal carcinoma and testicular carcinoma. Web site: http://www.delphion.com/details?pn=US04479957__

Patent Applications on Malignant Melanoma 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 malignant melanoma: •

Classifying cancers Inventor(s): Ben-Dor, Amir; (Bellevue, WA), Bittner, Michael; (Rockville, MD), Chen, Yidong; (Rockville, MD), Dougherty, Edward; (College Station, TX), Jiang, Yuan; (Gaithersburg, MD), Meltzer, Paul; (Rockville, MD), Sampas, Nick; (San Jose, CA), Trent, Jeff; (Rockville, MD), Weeraratna, Ashani; (Owings Mil, MD), Yakhini, Zohar; (Zikhron Yaacov, IL) Correspondence: Agilent Technologies; Legal Department, 51upd; Intellectual Property Administration; P. O. Box 58043; Santa Clara; CA; 95052-8043; US Patent Application Number: 20030152923 Date filed: August 2, 2001 Abstract: The overexpression of certain marker genes including Wnt5a has been found useful in the identification of more aggressive forms of malignant melanoma. Therefore, the overexpression of these genes in tumor samples of malignant melanoma may be useful in the diagnosis, profiling, and treatment of patients suffering from this disease. Inhibitors of Wnt5a activity may be useful in the treatment of aggressive forms of malignant melanoma. Inhibition of Wnt5a activity may be effected by any method including anti-sense therapy, gene therapy, and pharmaceutical intervention. Excerpt(s): Cancer is the second leading cause of death in the United States after cardiovascular disease (Boring et al. Cancer J. Clin. 43:7, 1993; incorporated herein by reference). One in three Americans will develop cancer in his or her lifetime, and one of

9

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

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every four Americans will die of cancer. In order to better combat this deadly disease, efforts have recently focused on fine tuning the categorization of tumors; by categorizing cancers, physicians hope to better treat an individual's cancer by providing more effective treatments. Researchers and physicians have categorized cancers based on invasion, metastasis, gross pathology, microscopic pathology, imunohistochemical markers, and molecular markers. With the recent advances in gene chip technology, researchers are increasingly focusing on the categorization of tumors based on the expression of marker genes. The most common human cancers are malignant neoplasms of the skin (Hall et al. J. Am. Acad. Dermatol. 40:35-42, 1999; Weyers et al. Cancer 86:288299, 1999; each of which is incorporated herein by reference). The incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease (Byers et al. Hematol. Oncol. Clin. North Am. 12:717-735, 1998; McMasters et al Ann. Surg. Oncol. 6:467-475, 1999; each of which is incorporated herein by reference). Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular, or immunohistochemical marker defines subsets of this neoplasm (Weyers et al. Cancer 86:288-299, 1999; Byers et al. Hematol. Oncol. Clin. North Am. 12:717-735, 1998; each of which is incorporated herein by reference). Accordingly, though melanoma is thought to present with different "taxonomic" forms, these are considered part of a continuous spectrum rather than discrete entities (Weyers et al Cancer 86:288-299, 1999; incorporated herein by reference). Improved characterization and understanding of this potentially deadly disease would be valuable. The present invention provides a system for diagnosing aggressive forms of malignant melanoma based on the expression of certain marker genes within a tumor sample. In one embodiment, expression levels are determined for one or more of the following genes: Wnt5a (Seq. ID No.: 1, 2, & 3), MART-1 (Seq. ID No.: 4 & 5), pirin (Seq. ID No.: 6 & 7), HADHB (Seq. ID No.: 8 & 9), CD63 (Seq. ID No.: 10 & 11), EDNRB (Seq. ID No.: 12 & 13), PGAM1 (Seq. ID No.: 14 & 15), HXB (Seq. ID No.: 16 & 17), RXRA (Seq. ID No.: 18 & 19), integrin 1b (Seq. ID No.: 20 & 21), syndecan 4 (Seq. ID No.: 22 & 23), tropomyosin 1 (Seq. ID No.: 24 & 25), AXL (Seq. ID No.: 26 & 27), EphA2 (Seq. ID No.: 28 & 29), GAP43 (Seq. ID. No.: 30 & 31), PFKL (Seq. ID No.: 32 & 33), synuclein a (Seq. ID No.: 34 & 35), annexin A2 (Seq. ID No.: 36 & 37), CD20 (Seq. ID No.: 38 & 39), and RAB2 (Seq. ID No.: 40 & 41). In certain preferred embodiments, expression of a plurality of these genes is detected. In particularly preferred embodiments, Wnt5a is one of the genes whose expression is detected. According to the present invention, overexpression of Wnt5a in a tumor sample indicates a more aggressive form of the disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Curcumin and curcuminoid inhibition of angiogenesis Inventor(s): Arbiser, Jack L.; (Atlanta, GA) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20010025034 Date filed: January 18, 2001 Abstract: Methods for treating diseases or disorders of the skin which are characterized by angiogenesis have been developed using curcumin and curcumin analogs. Based on the results obtained with curcumin, it has been determined that other angiogenesis inhibitors can also be used to treat these skin disorders. It has further been discovered that curcumin acts to inhibit angiogenesis in part by inhibition of basic fibroblast growth

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factor (bFGF), and thereby provides a means for treating other disorders characterized by elevated levels of bFGF, such as bladder cancer, using curcumin and other analogues which also inhibit bFGF. Representative skin disorders to be treated include the malignant diseases angiosarcoma, hemangioendothelioma, basal cell carcinoma, squamous cell carcinoma, malignant melanoma and Karposi's sarcoma, and the nonmalignant diseases or conditions including psoriasis, lymphangiogenesis, hemangioma of childhood, Sturge-Weber syndrome, verruca vulgaris, neurofibromatosis, tuberous sclerosis, pyogenic granulomas, recessive dystrophic epidermolysis bullosa, venous ulcers, acne, rosacea, eczema, molluscum contagious, seborrheic keratosis, and actinic keratosis. Excerpt(s): The invention is generally in the field of methods of inhibiting angiogenesis, and more specifically is drawn to methods and compositions for inhibiting angiogenesis. Current treatments of cancer and related diseases have limited effectiveness and numerous serious unintended effects. Based primarily on chemical, radiation and surgical therapy, these treatments have progressed only incrementally during more than thirty years of intensive research to discover the origins and devise improved therapies of neoplastic diseases. Current research strategies emphasize the search for effective therapeutic modes with less risk, including the use of natural products and biological agents. This change in emphasis has been stimulated by the fact that many of the consequences, to patients and their offspring, of conventional cancer treatment, including new cancers, mutations and congenital defects, result from their actions on genetic material and mechanisms. Hong et al., J. Natl. Cancer Inst. Monogr. 17:49-53 (1995). Efforts continue to discover the origins of cancer at the genetic level, and correspondingly new treatments, but such interventions also may have serious unanticipated effects. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Detection of chromosome copy number changes to distinguish melanocytic nevi from malignant melanoma Inventor(s): Bastian, Boris; (San Francisco, CA), Pinkel, Daniel; (Walnut Creek, CA) Correspondence: Townsend And Townsend And Crew; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20010029021 Date filed: April 13, 2001 Abstract: The present invention provides for methods of distinguishing melanocytic nevi, such as Spitz nevi, from malignant melanoma. The methods comprise contacting a nucleic acid sample from a patient with a probe which binds selectively to a target polynucleotide sequence on a chromosomal region such as 11p, which is usually amplified in Spitz nevi. The nucleic acid sample is typically from skin tumor cells located within a tumor lesion on the skin of the patient. Using another probe which binds selectively to a chromosomal region such as 1q, 6p, 7p, 9p, or 10q, which usually show altered copy number in melanoma, the method can determine that those tumor cells with no changes in copy number of 1q, 6p, 7p, 9p, or 10q, are not melanoma cells but rather Spitz nevus cells. The finding of amplifications of chromosome 11p would be an additional indication of Spitz nevus. Excerpt(s): The melanocyte can give rise to a plethora of morphologically different tumors. Most of them are biologically benign and are referred to as melanocytic nevi.

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Examples of melanocytic nevi are congenital nevi, Spitz nevi, dysplastic or Clark's nevi, blue nevi, lentigo simplex, and deep penetrating nevus. Pigmented spindle cell nevus is regarded as a subset of Spitz nevi. Melanoma refers to malignant neoplasms of melanocytes. Its proper diagnosis and early treatment is of great importance because advanced melanoma has a poor prognosis, but most melanomas are curable if excised in their early stages. While clinicians make the initial diagnosis of pigmented lesions of the skin, pathologists make the final diagnosis. Although, in general the histopathological diagnosis of melanoma is straightforward, there is a subset of cases in that it is difficult to differentiate melanomas from benign neoplasm of melanocytes, which have many variants that share some features of melanomas (LeBoit, P. E. STIMULANTS OF MALIGNANT MELANOMA: A ROGUE'S GALLERY OF MELANOCYTIC AND NONMELANOCYTIC IMPOSTERS, In Malignant Melanoma and Melanocytic Neoplasms, P. E. Leboit, ed. (Philadelphia: Hanley & Belfus), pp. 195-258 (1994)). Even though the diagnostic criteria for separating the many simulators of melanoma are constantly refined, a subset of cases remains, where an unambiguous diagnosis cannot be reached (Farmer et al., DISCORDANCE IN THE HISTOPATHOLOGIC DIAGNOSIS OF MELANOMA AND MELANOCYTIC NEVI BETWEEN EXPERT PATHOLOGISTS, Human Pathol. 27: 528-31 (1996)). The most frequent and important diagnostic dilemma is the differential diagnosis between Spitz nevus, a neoplasm composed of large epithelioid or spindled melanocytes, and melanoma. Misdiagnosis of Spitz nevus as melanoma and vice versa has been repeatedly reported in the literature (Goldes et al., Pediatr. Dermatol., 1: 295-8 (1984); Okun, M. R. Arch. Dermatol. 115: 1416-1420 (1979); Peters et al., Histopathology, 10, 1289-1302 (1986)). A retrospective study of 102 melanomas of childhood found that only 60 cases were classified as melanoma by a panel of experts, the majority of the remainder being classified as Spitz nevi (Spatz, S., Int. J. Cancer 68, 317-24 (1996)). The hazard of mistaking a Spitz nevus for melanoma can be severe and traumatic: The patients may be subjected to needless surgery, unable to plan for the future, and psychologically traumatized. For obvious reasons, the misdiagnosis of a melanoma as a benign nevus can have even more dramatic consequences. The presence of this diagnostic gray zone has even led the authors of a review article in the "Continuing Medical Education" section of the Journal of the American Association of Dermatology to conclude that Spitz nevus and melanoma may "actually exist on a continuum of disease" (Casso et al., J. Am. Acad. Dermatol., 27, 90113 (1992)). The authors recommended that "treatment include complete excision of al Spitz nevi followed by reexcision of positive margins if present." The need for improved diagnostics for melanocytic neoplasms has led to numerous attempts to improve diagnostic accuracy by the use of markers that could be detected by immunohistochemistry. While there have been prior efforts aimed at resolving this problem, none have been satisfactory. For example, even though tests employing markers such as S100, HMB45 are useful in establishing that a poorly differentiated tumor is of melanocytic lineage, adjunctive techniques have been of little help in separating benign from malignant melanocytic lesions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Genetic changes in atypical nodular proliferations in congenital melanocytic nevi Inventor(s): Bastian, Boris C.; (San Francisco, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030143543 Date filed: January 4, 2002 Abstract: The invention provides methods of distinguishing benign growths arising from congenital melanocytic nevi from malignant melanoma. The methods comprise detecting a change in chromosome number that is specifically associated with benign growths. These changes include a gain of chromosome 10, a gain of chromosome 11, and a loss of chromosome 7. Excerpt(s): The melanocyte can give rise to a number of morphologically different tumors. Most of them are biologically benign and are referred to as melanocytic nevi. Examples of melanocytic nevi are congenital nevi, Spitz nevi (including pigmented spindle cell nevi, which are regarded as a subtype of Spitz nevi), dysplastic or Clark's nevi, blue nevi, lentigo simplex, and deep penetrating nevus. Patients with congenital melanocytic nevi (CMN) have an increased risk of developing melanoma. Whereas in small--(<1.5 cm) and intermediate-sized CMN (1.5-20 cm) the risk seems to be low (Rhodes, A. R., Med Clin North Am., 70:3-37 (1986); Sahin, S. et al., J Am Acad Dermatol., 39:428-33 (1998)), large CMN (>20 cm) carry a 5-15x times increased future risk to develop melanoma and rarely, other neural crest derived malignancies ((Swerdlow, A. J. et al., J Am Acad Dermatol., 32:595-9 (1995); Ruiz-Maldonado, R. et al., J Pediatr., 120:906-11 (1992); Quaba, A. A. and Wallace, A. F., Plast Reconstr Surg., 78:174-81 (1986); Gari, L. M. et al., Pediatr Dermatol., 5:151-8 (1988); Egan, C. L. et al., J Am Acad Dermatol., 39:923-32 (1998); Bittencourt, F. V. et al., Pediatrics, 106:736-41 (2000); DeDavid, M. et al., J Am Acad Dermatol., 36:409-16 (1997); Marghoob, A. A. et al., Arch Dermatol., 132:170-5 (1996)). Melanoma refers to malignant neoplasms of melanocytes. Its proper diagnosis and early treatment is of great importance because advanced melanoma has a poor prognosis, but most melanomas are curable if excised in their early stages. Although, in general the histopathological diagnosis of melanoma is straightforward, there is a subset of cases in that it is difficult to differentiate melanomas from benign neoplasms of melanocytes, which have many variants that share some features of melanomas (LeBoit, P. E. Stimulants of Malignant Melanoma: A Rogue's Gallery of Melanocytic and Non-Melanocytic Imposters, In Malignant Melanoma and Melanocytic Neoplasms, P. E. Leboit, ed. (Philadelphia: Hanley & Belfus), pp. 195-258 (1994)). Even though the diagnostic criteria for separating the many simulators of melanoma are constantly refined, a subset of cases remains, where an unambiguous diagnosis cannot be reached (Farmer et al., Discordance in the Histopathologic Diagnosis of Melanoma and Melanocytic Nevi Between Expert Pathologists, Human Pathol. 27: 528-31 (1996)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Human-derived bradeion proteins, DNA coding for the proteins, and uses thereof Inventor(s): Tanaka, Manami; (Ibaraki, JP), Tanaka, Tomoo; (Kanagawa, JP) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20030113753 Date filed: July 10, 2002 Abstract: This invention relates to a human-derived bradeion protein having the following properties:(i) it is a transmembranous protein;(ii) it has a transmembranous portion, an extracellular portion, and a cytoplasmic portion in its molecule as determined by a hydrophobicity analysis according to Kyte-Doolittle method;(iii) it is expressed in the human adult normal brain and heart, the expression level thereof in the heart being about 10% or lower of that in the brain, while it is not expressed in other adult normal organs of spleen, lung, liver, skeletal muscle, kidney and pancreas, and in fetal brain, lung, heart and kidney;(iv) it induces programmed cell death when overexpressed in a cultured human brain-derived undifferentiated nerve cell line;(v) it induces termination of cell division and aging when over-expressed in a cultured human brain-derived differentiated nerve cell;(vi) it is located in cytoplasm in the course of the induced cell death, and forms an intracellular aggregate when overexpressed; and(vii) it is expressed in a human colorectal cancer cell line or in a human malignant melanoma cell line, but not in leukemia, lymphoma and lung carcinoma,to a DNA encoding said bradeion protein, to a vector comprising said DNA, to a host cell comprising said vector, and to a method for detecting a cancer such as colorectal cancer or malignant melanoma. Excerpt(s): Japan Priority Application 325380/1998, filed Nov. 16, 1998, including the specification, drawings, claims and abstract, is incorporated herein by reference in its entirety. U.S. Priority application Ser. No. 09/440,936, filed Nov. 16, 1999, including the specification, drawings, claims and abstract, is incorporated herein by reference in its entirety. The present invention relates to a protein involved in long-term survival of cranial nerve cell, to DNA encoding the protein, and to uses thereof. More particularly, the present invention relates to human-derived bradeion protein or derivatives thereof, to DNA encoding the protein or the derivatives thereof, to a vector containing the DNA, to a host cell transformed or transfected with the vector, to an antibody immunologically reactive with the protein or the derivatives thereof, and to uses of the DNA or the antibody for detecting a cancer. Cranial nerve cells (neurons) are main elements for controlling survival of higher order animals. Once the neurons are produced, they do not divide at all and only gradually exfoliate or go through necrosis. Exfoliation of the neurons occurs in the normal state but is particularly accelerated by genetic diseases, brain ischemia, or status epilepticus, or under conditions of poor nutrition and low oxygen. Some disorders of cranial nerves associated with aging (e.g., dementia) result from deficiency of an absolute amount of functional neurons caused by accumulation of exfoliated neurons. Thus, the monitoring and control of the exfoliation, as well as regeneration of the functions of neurons, are the most demanding subject to be solved among the aging problems. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method and composition for selectively inhibiting melanoma Inventor(s): DasGupta, Tapas K.; (River Forest, IL), Kim, Darrick S.H.L.; (Chicago, IL), Pezzuto, John M.; (River Forest, IL) Correspondence: Marshall, Gerstein & Borun; 6300 Sears Tower; 233 South Wacker; Chicago; IL; 60606-6357; US Patent Application Number: 20030181429 Date filed: December 12, 2002 Abstract: A composition and method of preventing or inhibiting tumor growth, and of treating malignant melanoma, without toxic side effects are disclosed. Betulinic acid or a betulinic acid derivative is the active compound of the composition, which is topically applied to the situs of tumor. Excerpt(s): This is a continuation-in-part application of U.S. patent application Ser. No. 08/407,756, filed on Mar. 21, 1995, now U.S. Pat. No. ______. This invention relates to compositions and methods of selectively inhibiting tumors and, more particularly, to treating a malignant melanoma using plant-derived compounds and derivatives thereof. Over the past four decades the incidence of melanoma has been increasing at a higher rate than any other type of cancer. It is now theorized that one in 90 American Caucasians will develop malignant melanoma in their lifetime. While an increasing proportion of melanomas are diagnosed sufficiently early to respond to surgical treatment and achieve a greater than 90% ten-year survival rate, it is estimated that nearly 7,000 individuals suffering from metastatic melanoma will die in the United States this year. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method for detection of melanoma Inventor(s): Vogt, Thomas; (Pentling-Grossberg, DE) Correspondence: Gary Cary Ware & Friendenrich Llp; 4365 Executive Drive; Suite 1600; San Diego; CA; 92121-2189; US Patent Application Number: 20030108896 Date filed: June 27, 2002 Abstract: The present invention provides non-invasive methods for detecting, monitoring, staging, and diagnosing malignant melanoma in a skin sample of a subject. The methods include analyzing expression in skin sample of one or more melanoma skin markers. The melanoma skin markers include IL-1 RI, endothelin-2, ephrin-A5, IGF Binding Protein 7, HLA-A0202 heavy chain, Activin A (.beta.A subunit), TNF RII, SPC4, and CNTF R.alpha. The skin sample can include nucleic acids, and can be a human skin sample from a lesion suspected of being melanoma. Excerpt(s): This application claims priority under 35 U.S.C.sctn. 119(e) to Provisional Application Serial No. 60/302,348, filed Jun. 28, 2001, which is incorporated herein by reference in its entirety. This invention relates to methods related to melanoma patient for detecting expression of genes in a skin sample of the epidermis related to malignant melanoma. Malignant melanoma ranks second among adult cancers (behind adult leukemia) in potential years of life lost. Each year, over 47,000 new cases are diagnosed, and the incidence of cutaneous melanoma appears to be rising rapidly. Treatment of malignant melanoma involves surgical excision of the primary lesion, and vigilant

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monitoring to detect recurrence. Currently, there is no approved therapy for patients having intermediate risk of relapse. High-dose interferon, which can have serious side effects, is approved for treatment of patients having high-risk melanoma. There is no cure at this time for patients in whom metastasis to distant sites has occurred. 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 malignant melanoma, 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 “malignant melanoma” (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 malignant melanoma. You can also use this procedure to view pending patent applications concerning malignant melanoma. 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 MALIGNANT MELANOMA Overview This chapter provides bibliographic book references relating to malignant melanoma. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on malignant melanoma include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, 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. For the format option, select “Monograph/Book.” Now type “malignant melanoma” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on malignant melanoma: •

Palate Complaints Source: in Scully, C. Handbook of Oral Disease: Diagnosis and Management. New York, NY: Thieme New York. 2001. p.339-355. Contact: Available from Thieme New York. 333 Seventh Avenue, New York, NY 10001. (212) 760-0888, ext 110. PRICE: $35.00 plus shipping and handling. ISBN: 1841840874. Summary: This chapter on palate complaints is from a handbook of oral disease that is intended to be used by all members of the dental team who need a ready office reference. The handbook covers the more common and important soft tissue orofacial disorders and gives clinically relevant aspects of the etiology, diagnosis, treatment, and prevention. This chapter covers blisters, lumps, red lesions, ulceration, white lesions, adenomatoid hyperplasia, localized oral purpura (angina bullosa hemorrhagica), denture-induced stomatitis, Kaposi's sarcoma, malignant melanoma, papillary

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hyperplasia (overgrowth), stomatitis nicotina (smoker's palate), and torus palatinus. For each condition, the authors note etiology (cause), diagnosis, symptoms, epidemiology, risk factors, treatment, and prevention (where possible). Much of the information is provided in table or outline format for ease of reference. Full color photographs illustrate some conditions. 24 figures. 9 references.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “malignant melanoma” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “malignant melanoma” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “malignant melanoma” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Basic and Clinical Aspects of Malignant Melanoma (Cancer Treatment and Research) by Larry Nathanson; ISBN: 0898388562; http://www.amazon.com/exec/obidos/ASIN/0898388562/icongroupinterna

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Clinical Management of Malignant Melanoma (Cancer Treatment and Research, 21) by J.J. Costanzi; ISBN: 089838656X; http://www.amazon.com/exec/obidos/ASIN/089838656X/icongroupinterna

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Diagnosis and Management of Cutaneous Malignant Melanoma (Major Problems in Clinical Surgery) by Daniel Roses; ISBN: 0721677061; http://www.amazon.com/exec/obidos/ASIN/0721677061/icongroupinterna

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Epidemiological Aspects of Cutaneous Malignant Melanoma (Developments in Oncology, Vol 73) by Richard P. Gallagher, J. Mark Elwood; ISBN: 0792327403; http://www.amazon.com/exec/obidos/ASIN/0792327403/icongroupinterna

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Epidemiology of Malignant Melanoma (Recent Result in Cancer Research, Vol 102) by R.P. Gallagher; ISBN: 0387160205; http://www.amazon.com/exec/obidos/ASIN/0387160205/icongroupinterna

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Human malignant melanoma (Clinical oncology monographs); ISBN: 0808911104; http://www.amazon.com/exec/obidos/ASIN/0808911104/icongroupinterna

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Immunotherapy of Malignant Melanoma (Medical Intelligence Unit) by Stanley P. L. Leong; ISBN: 0412104911; http://www.amazon.com/exec/obidos/ASIN/0412104911/icongroupinterna

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Pathobiology and recognition of malignant melanoma (Monographs in pathology); ISBN: 0683060163; http://www.amazon.com/exec/obidos/ASIN/0683060163/icongroupinterna

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Pathobiology of Malignant Melanoma (Pigment Cell, Vol 8) by D.E. Elder; ISBN: 3805543484; http://www.amazon.com/exec/obidos/ASIN/3805543484/icongroupinterna

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Pathology of malignant melanoma (Masson monographs in dermatopathology); ISBN: 0893521329; http://www.amazon.com/exec/obidos/ASIN/0893521329/icongroupinterna

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Primary and Secondary Prevention of Malignant Melanoma (Pigment Cell, Vol 11) by Rona M. MacKie; ISBN: 380556273X; http://www.amazon.com/exec/obidos/ASIN/380556273X/icongroupinterna

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Stakeholder Opinions: Malignant Melanoma - High Hurdles, High Rewards, Are Vaccines Only Skin Deep? [DOWNLOAD: PDF] by Datamonitor; ISBN: B00029DSSK; http://www.amazon.com/exec/obidos/ASIN/B00029DSSK/icongroupinterna

Chapters on Malignant Melanoma In order to find chapters that specifically relate to malignant melanoma, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and malignant melanoma 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 “malignant melanoma” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on malignant melanoma: •

Benign, Premalignant, and Malignant Lesions Source: in Eisen, D. and Lynch, D.P. Mouth: Diagnosis and Treatment. St. Louis, MO: Mosby, Inc. 1998. p. 58-91. Contact: Available from Harcourt Health Sciences. Book Order Fulfillment Department, 11830 Westline Industrial Drive, St. Louis, MO 63146-9988. Website: www.mosby.com. PRICE: $79.95 plus shipping and handling. ISBN: 0815131054. Summary: The oral mucosal surfaces are subjected to daily irritation through normal masticatory (chewing) functions and hygiene measures. The oral mucosa can also be irritated by lack of oral health (which allows plaque and calculus to build up), and by various oral habits such as lip and cheek biting. The majority of masses noted in the oral cavity (mouth) actually represent reactions to these forms of trauma rather than true neoplastic (new tissue) lesions. This chapter on benign, premalignant, and malignant lesions is from a textbook on the mouth that offers information to primary care physicians and to many specialists in medicine and dentistry. The authors help readers undertake and interpret a careful history and physical examination to reveal the underlying source of the injury. Benign lesions covered include pyogenic granuloma, peripheral giant cell granuloma, keratoacanthoma, amputation neuroma, verruciform xanthoma, fibrous histiocytoma, lipoma, granular cell tumor, neurilemoma (schwannoma), neurofibroma, fibrous hyperplasia, pulp polyp, and melanotic neuroectodermal tumor of infancy. Premalignant lesions include leukoplakia, erythroplakia, smokeless tobacco lesions, oral submucous fibrosis, and actinic cheilitis. And the malignant neoplasms covered are squamous cell carcinoma, verrucous carcinoma, oral malignant melanoma, Hodgkin's disease (Hodgkin's lymphoma), nonHodgkin's lymphoma, cutaneous T cell lymphoma, Burkitt's lymphoma, Kaposi's sarcoma, and metastatic neoplasms. The chapter is illustrated with numerous full color photographs of the conditions under discussion. 32 figures. 1 table. 172 references.

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Intraoral Coloured or Pigmented Lesions Source: in Scully, C. and Cawson, R.A. Oral Disease: Colour Guide. 2nd ed. Edinburgh, Scotland: Churchill Livingstone. 1999. p. 73-88. Contact: Available from W.B. Saunders Company, A Harcourt Health Sciences Company. Book Order Fulfillment Department, 11830 Westline Industrial Drive, St Louis, MO 63146-9988. (800) 545-2522. Fax (800) 568-5136. E-mail: [email protected]. Website: www.wbsaunders.com. PRICE: $19.95 plus shipping and handling. ISBN: 044306170X. Summary: This chapter on intraoral colored or pigmented lesions is from a book that is intended as an aid to oral medicine and the diagnosis and treatment of oral disease. The chapter includes 16 full color photographs of intraoral colored or pigmented lesions, with textual information accompanying them. Conditions covered are: hereditary hemorrhagic telangiectasia (HHT), scleroderma (systemic sclerosis), hemangioma, Sturge-Weber syndrome, radiation induced lesions, denture induced stomatitis, erythematous candidosis, erythroplasia (erythroplakia), Kaposi's sarcoma, purpura, racial pigmentation, Peutz-Jeghers syndrome, drug induced hyperpigmentation, amalgam tattoo, pigmented nevi, and malignant melanoma. For each condition, the text briefly covers incidence and etiology, clinical features, diagnosis and diagnostic tests, and treatment options.

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Tumors and Tumor-like Lesions of the Colon, Rectum, Anus, and Perianal Region Source: in Stein, E. Anorectal and Colon Diseases: Textbook and Color Atlas of Proctology. New York, NY: Springer-Verlag. 2003. p. 223-294. Contact: Available from Springer-Verlag New York, Inc. 175 Fifth Avenue, New York, NY 10010. (800) SPRINGER or (212) 460-1500. Fax (800) 777-4643 or (201) 348-4505. Email: [email protected]. Website: www.springer-ny.com. PRICE: $199.00 plus shipping and handling. ISBN: 3540430393. Summary: This chapter on tumors and tumor-like lesions of the colon, rectum, anus, and perianal region is from a multidisciplinary reference book and atlas that covers all aspects of anorectal and colon disease (proctology). Topics in this chapter include epithelial tumors, colorectal polyps, carcinomas (cancer), colorectal carcinoma, anal carcinoma, neuroendocrine tumors, malignant melanoma, mesenchymal tumors and tumor-like lesions, tumors of fatty tissue, tumors of muscle, tumors of blood vessels, tumors of lymphatic vessels, lymphoma, malignant lymphoma, and pseudolymphoma. For each condition, the author discusses etiology, clinical features, diagnosis, and therapy. The chapter includes full-color and black-and-white illustrations and photographs, to support the heavily-visual aspects of proctology. Each section concludes with a list of references. 55 figures. 20 tables. 416 references.

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Diseases of the External Ear Source: in Ballenger, J.J.; Snow, J.B., Jr., eds. Otorhinolaryngology: Head and Neck Surgery. 15th ed. Baltimore, MD: Williams and Wilkins. 1996. p. 974-988. Contact: Available from Williams and Wilkins. P.O. Box 64686, Baltimore, MD 212644786. (800) 638-0672; Fax (800) 447-8438. PRICE: $179.00 plus shipping and handling. ISBN: 0683003151. Summary: This chapter, from a medical textbook on otorhinolaryngology, summarizes diseases of the external ear. Topics covered include problems of the auricle, including

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trauma, frostbite, and perichondritis; tumors of the external ear; benign tumors of the auricle, including angiomas, cysts, fibroma, papilloma, and Winkler's disease; the external auditory canal, including cerumen (earwax), foreign bodies, external otitis, malignant external otitis, chronic stenosing external otitis, and keratosis obliterans; benign tumors of the external auditory canal, including exostosis and adenoma; benign tumors of the middle ear, including glomus jugulare tumor; and malignant tumors of the ear, including carcinoma, ceruminoma, cystic adenoid carcinoma (Brooke's tumor), and malignant melanoma. 17 figures. 19 references.

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CHAPTER 7. PERIODICALS AND NEWS ON MALIGNANT MELANOMA Overview In this chapter, we suggest a number of news sources and present various periodicals that cover malignant melanoma.

News Services and Press Releases One of the simplest ways of tracking press releases on malignant melanoma 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 “malignant melanoma” (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 malignant melanoma. 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 “malignant melanoma” (or synonyms). The following was recently listed in this archive for malignant melanoma: •

Maxim seeks malignant melanoma treatment approval Source: Reuters Health eLine Date: July 19, 2000

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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. 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 “malignant melanoma” (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 “malignant melanoma” (or synonyms). If you know the name of a company that is relevant to malignant melanoma, 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 “malignant melanoma” (or synonyms).

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Academic Periodicals covering Malignant Melanoma Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to malignant melanoma. In addition to these sources, you can search for articles covering malignant melanoma 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 malignant melanoma. 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 malignant melanoma. 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 malignant melanoma: Bleomycin •

Systemic - U.S. Brands: Blenoxane http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202093.html

Carboplatin •

Systemic - U.S. Brands: Paraplatin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202115.html

Carmustine •

Systemic - U.S. Brands: BiCNU http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202117.html

Dacarbazine •

Systemic - U.S. Brands: DTIC-Dome http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202178.html

Interferons, Alpha •

Systemic - U.S. Brands: Alferon N; Intron A; Roferon-A http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202299.html

Melphalan •

Systemic - U.S. Brands: Alkeran http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202345.html

Tamoxifen •

Systemic - U.S. Brands: Nolvadex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202545.html

Vinblastine •

Systemic - U.S. Brands: Velban http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202593.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/.

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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 malignant melanoma 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 “malignant melanoma” (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 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 malignant melanoma: •

Interferon beta (recombinant) (trade name: R-IFN-beta) http://www.rarediseases.org/nord/search/nodd_full?code=101

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Histamine (trade name: Maxamine) http://www.rarediseases.org/nord/search/nodd_full?code=1022

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Deoxyribose, Phosphorothioate http://www.rarediseases.org/nord/search/nodd_full?code=1055

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Cisplatin/epinephrine (trade name: IntraDose) http://www.rarediseases.org/nord/search/nodd_full?code=1066

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Imexon (trade name: n/a) http://www.rarediseases.org/nord/search/nodd_full?code=1172

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Interleukin-2 (trade name: Teleleukin) http://www.rarediseases.org/nord/search/nodd_full?code=130

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DHA-pacitaxel (trade name: Taxoprexin) http://www.rarediseases.org/nord/search/nodd_full?code=1302

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Interleukin-2 (trade name: Teceleukin) http://www.rarediseases.org/nord/search/nodd_full?code=133

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Technetium Tc 99m anti-melanoma murine monoclonal (trade name: Oncotrac Melanoma Imaging Kit) http://www.rarediseases.org/nord/search/nodd_full?code=307

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Interferon alfa-2a (recombinant) (trade name: Roferon-A) http://www.rarediseases.org/nord/search/nodd_full?code=542

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Interferon alfa-2a (recombinant) (trade name: Roferon-A) http://www.rarediseases.org/nord/search/nodd_full?code=91

•

Pegylated arginine deiminase (trade name: Melanocid) http://www.rarediseases.org/nord/search/nodd_full?code=977

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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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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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/

•

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

•

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

•

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/

•

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

•

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

•

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

•

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 “malignant melanoma” (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 48289 400 662 22 119 49492

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 “malignant melanoma” (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 malignant melanoma can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based 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 malignant melanoma. 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 malignant melanoma. 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 “malignant melanoma”:

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Eye Cancer http://www.nlm.nih.gov/medlineplus/eyecancer.html Genetic Brain Disorders http://www.nlm.nih.gov/medlineplus/geneticbraindisorders.html Genetic Disorders http://www.nlm.nih.gov/medlineplus/geneticdisorders.html Macular Degeneration http://www.nlm.nih.gov/medlineplus/maculardegeneration.html Melanoma http://www.nlm.nih.gov/medlineplus/melanoma.html Skin Pigmentation Disorders http://www.nlm.nih.gov/medlineplus/skinpigmentationdisorders.html Sun Exposure http://www.nlm.nih.gov/medlineplus/sunexposure.html Vulvar Cancer http://www.nlm.nih.gov/medlineplus/vulvarcancer.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 malignant melanoma. 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/

Patient Resources

•

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 malignant melanoma. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with malignant melanoma. 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 malignant melanoma. 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 “malignant melanoma” (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 “malignant melanoma”. 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

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publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “malignant melanoma” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. 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 “malignant melanoma” (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

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

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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

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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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

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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). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on malignant melanoma: •

Basic Guidelines for Malignant Melanoma Malignant melanoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001442.htm Melanoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000850.htm Melanoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001442.htm Nevi Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000828.htm

•

Signs & Symptoms for Malignant Melanoma Itching Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003217.htm

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Macule Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003229.htm Papule Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003233.htm Skin lesion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm •

Diagnostics and Tests for Malignant Melanoma Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Skin biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003840.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm

•

Background Topics for Malignant Melanoma Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Cancer - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002166.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Macule Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003229.htm Melanin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002256.htm Metastasis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002260.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm

Online Glossaries 175

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

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Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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MALIGNANT MELANOMA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablation: The removal of an organ by surgery. [NIH] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] 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] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Actin: Essential component of the cell skeleton. [NIH] Actinic keratosis: A precancerous condition of thick, scaly patches of skin. Also called solar or senile keratosis. [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 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] Acyl: Chemical signal used by bacteria to communicate. [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] Adenoma: A benign epithelial tumor with a glandular organization. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections.

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Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adhesions: Pathological processes consisting of the union of the opposing surfaces of a wound. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [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 Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenaline: A hormone. Also called epinephrine. [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] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [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] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Age Distribution: The frequency of different ages or age groups in a given population. The distribution may refer to either how many or what proportion of the group. The population is usually patients with a specific disease but the concept is not restricted to humans and is not restricted to medicine. [NIH] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age-Adjusted: Summary measures of rates of morbidity or mortality in a population using statistical procedures to remove the effect of age differences in populations that are being

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compared. Age is probably the most important and the most common variable in determining the risk of morbidity and mortality. [NIH] Aggressiveness: The quality of being aggressive (= characterized by aggression; militant; enterprising; spreading with vigour; chemically active; variable and adaptable). [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] 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] 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]

Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [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] 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] 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: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [EU]

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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] Ampulla: A sac-like enlargement of a canal or duct. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [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] 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] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor. [NIH] Angiosarcoma: A type of cancer that begins in the lining of blood vessels. [NIH] 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] Anomalies: Birth defects; abnormalities. [NIH] Anorectal: Pertaining to the anus and rectum or to the junction region between the two. [EU] Antiangiogenic: Having to do with reducing the growth of new blood vessels. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU]

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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] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsants: Drugs used to prevent seizures or reduce their severity. [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] 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]

Antiproliferative: Counteracting a process of proliferation. [EU] Antiserum: The blood serum obtained from an animal after it has been immunized with a particular antigen. It will contain antibodies which are specific for that antigen as well as antibodies specific for any other antigen with which the animal has previously been immunized. [NIH] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Apheresis: Components plateletpheresis. [NIH]

being

separated

out,

as

leukapheresis,

plasmapheresis,

Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [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] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrestin: A 48-Kd protein of the outer segment of the retinal rods and a component of the phototransduction cascade. Arrestin quenches G-protein activation by binding to phosphorylated photolyzed rhodopsin. Arrestin causes experimental autoimmune uveitis when injected into laboratory animals. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Asparaginase: A hydrolase enzyme that converts L-asparagine and water to L-aspartate and NH3. EC 3.5.1.1. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspiration: The act of inhaling. [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] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autonomic: Self-controlling; functionally independent. [EU] 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

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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] Avian: A plasmodial infection in birds. [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] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] 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 cell carcinoma: A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] 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]

Benign tumor: A noncancerous growth that 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] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving

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chemical reactions in living organisms. [EU] 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 determine whether disease is present. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] 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] Blister: Visible accumulations of fluid within or beneath the epidermis. [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 vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [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 scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH]

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Boron Neutron Capture Therapy: A technique for the treatment of neoplasms, especially gliomas and melanomas in which boron-10, an isotope, is introduced into the target cells followed by irradiation with thermal neutrons. [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 neurotransmitter. [NIH] Brain Hypoxia: Lack of oxygen leading to unconsciousness. [NIH] Brain Infarction: The formation of an area of necrosis in the brain, including the cerebral hemispheres (cerebral infarction), thalami, basal ganglia, brain stem (brain stem infarctions), or cerebellum secondary to an insufficiency of arterial or venous blood flow. [NIH] Brain Ischemia: Localized reduction of blood flow to brain tissue due to arterial obtruction or systemic hypoperfusion. This frequently occurs in conjuction with brain hypoxia. Prolonged ischemia is associated with brain infarction. [NIH] Brain metastases: Cancer that has spread from the original (primary) tumor to the brain. [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] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] 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] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [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] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the

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interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] 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] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [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] Carcinogenicity: The ability to cause cancer. [NIH] Carcinoid: A type of tumor usually found in the gastrointestinal system (most often in the appendix), and sometimes in the lungs or other sites. Carcinoid tumors are usually benign. [NIH]

Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiogenic: Originating in the heart; caused by abnormal function of the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [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] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Castor Oil: Oil obtained from seeds of Ricinus communis that is used as a cathartic and as a plasticizer. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Causal: Pertaining to a cause; directed against a cause. [EU]

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Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cavernous Sinus: An irregularly shaped venous space in the dura mater at either side of the sphenoid bone. [NIH] CDC2: It is crucial for entry into mitosis of eukaryotic cells. [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 Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Adhesion Molecules: Surface ligands, usually glycoproteins, that mediate cell-to-cell adhesion. Their functions include the assembly and interconnection of various vertebrate systems, as well as maintenance of tissue integration, wound healing, morphogenic movements, cellular migrations, and metastasis. [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 Division: The fission of a cell. [NIH] Cell Fusion: Fusion of somatic cells in vitro or in vivo, which results in somatic cell hybridization. [NIH] Cell Lineage: The developmental history of cells as traced from the first division of the original cell or cells in the embryo. [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 motility: The ability of a cell to move. [NIH] Cell Movement: The movement of cells from one location to another. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [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] 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] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] 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] Cerumen: The yellow or brown waxy secretions produced by vestigial apocrine sweat

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glands in the external ear canal. [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] Cheilitis: Inflammation of the lips. It is of various etiologies and degrees of pathology. [NIH] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [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] Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]

Chemotherapy: Treatment with anticancer drugs. [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] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [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 originate in a teratoma of the testis, mediastinum, or pineal gland. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [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] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [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] Chromosome Abnormalities: Defects in the structure or number of chromosomes resulting in structural aberrations or manifesting as disease. [NIH]

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Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic leukemia: A slowly progressing cancer of the blood-forming tissues. [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] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [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] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [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] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Coliphages: Viruses whose host is Escherichia coli. [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] Colorectal: Having to do with the colon or the rectum. [NIH]

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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] Communis: Common tendon of the rectus group of muscles that surrounds the optic foramen and a portion of the superior orbital fissure, to the anterior margin of which it is attached at the spina recti lateralis. [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 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] 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] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray

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machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [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] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the 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] Consciousness: Sense of awareness of self and of the environment. [NIH] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or

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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] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coumarin: A fluorescent dye. [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] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cranial Nerves: Twelve pairs of nerves that carry general afferent, visceral afferent, special afferent, somatic efferent, and autonomic efferent fibers. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Crowns: A prosthetic restoration that reproduces the entire surface anatomy of the visible natural crown of a tooth. It may be partial (covering three or more surfaces of a tooth) or complete (covering all surfaces). It is made of gold or other metal, porcelain, or resin. [NIH] Cryostat: A batchwise operating apparatus in which a cryogenic liquid or solid is used to maintain by evaporation a cryotemperature which needs not be constant but may vary in a predetermined fashion. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or

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transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] 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] Cyclin: Molecule that regulates the cell cycle. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteinyldopa: Found in large amounts in the plasma and urine of patients with malignant melanoma. It is therefore used in the diagnosis of melanoma and for the detection of postoperative metastases. Cysteinyldopa is believed to be formed by the rapid enzymatic hydrolysis of 5-S-glutathionedopa found in melanin-producing cells. [NIH] 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] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [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] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decision Making: The process of making a selective intellectual judgment when presented with several complex alternatives consisting of several variables, and usually defining a course of action or an idea. [NIH]

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Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [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]

Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Abutments: Natural teeth or teeth roots used as anchorage for a fixed or removable denture or other prosthesis (such as an implant) serving the same purpose. [NIH] Dentures: An appliance used as an artificial or prosthetic replacement for missing teeth and adjacent tissues. It does not include crowns, dental abutments, nor artificial teeth. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatitis: Any inflammation of the skin. [NIH] Dermatologist: A doctor who specializes in the diagnosis and treatment of skin problems. [NIH]

Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Diagnostic procedure: A method used to identify a disease. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [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] Dimethyl: A volatile metabolite of the amino acid methionine. [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] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease. [NIH] Dissection: Cutting up of an organism for study. [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

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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 in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] 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] Dormancy: The period when an organism (i. e., a virus or a bacterium) is in the body but not producing any ill effects. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Dose-rate: The strength of a treatment given over a period of time. [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 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] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dysplastic nevi: Atypical moles; moles whose appearance is different from that of common moles. Dysplastic nevi are generally larger than ordinary moles and have irregular and indistinct borders. Their color frequently is not uniform and ranges from pink to dark brown; they usually are flat, but parts may be raised above the skin surface. [NIH] Dystrophic: Pertaining to toxic habitats low in nutrients. [NIH]

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Ectoderm: The outer of the three germ layers of the embryo. [NIH] Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed). [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [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] Effusion: The escape of fluid into a part or tissue, as an exudation or a transudation. [EU] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] 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] 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] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [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] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Emulsions: Colloids of two immiscible liquids where either phase may be either fatty or aqueous; lipid-in-water emulsions are usually liquid, like milk or lotion and water-in-lipid emulsions tend to be creams. [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 into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH]

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Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endostatin: A drug that is being studied for its ability to prevent the growth of new blood vessels into a solid tumor. Endostatin belongs to the family of drugs called angiogenesis inhibitors. [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] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [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] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [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] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [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] Epidermolysis Bullosa: Group of genetically determined disorders characterized by the

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blistering of skin and mucosae. There are four major forms: acquired, simple, junctional, and dystrophic. Each of the latter three has several varieties. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [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] Epistasis: The degree of dominance exerted by one gene on the expression of a non-allelic gene. [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] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]

Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Esophagectomy: An operation to remove a portion of the esophagus. [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] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [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] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excisional: The surgical procedure of removing a tumor by cutting it out. The biopsy is then examined under a microscope. [NIH] 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] Exfoliation: A falling off in scales or layers. [EU] Exocrine: Secreting outwardly, via a duct. [EU]

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Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exons: Coding regions of messenger RNA included in the genetic transcript which survive the processing of RNA in cell nuclei to become part of a spliced messenger of structural RNA in the cytoplasm. They include joining and diversity exons of immunoglobulin genes. [NIH]

Expert Systems: Computer programs based on knowledge developed from consultation with experts on a problem, and the processing and/or formalizing of this knowledge using these programs in such a manner that the problems may be solved. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

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] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Eye Color: Color of the iris. [NIH] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] 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] Fallopian tube: The oviduct, a muscular tube about 10 cm long, lying in the upper border of the broad ligament. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas

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fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibroma: A benign tumor of fibrous or fully developed connective tissue. [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] Flow Cytometry: Technique using an instrument system for making, processing, and 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] 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] Fold: A plication or doubling of various parts of the body. [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] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Frostbite: Damage to tissues as the result of low environmental temperatures. [NIH] Frozen Sections: Thinly cut sections of frozen tissue specimens prepared with a cryostat or freezing microtome. [NIH]

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Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Fuzzy Logic: Approximate, quantitative reasoning that is concerned with the linguistic ambiguity which exists in natural or synthetic language. At its core are variables such as good, bad, and young as well as modifiers such as more, less, and very. These ordinary terms represent fuzzy sets in a particular problem. Fuzzy logic plays a key role in many medical expert systems. [NIH] Galanin: A neurotransmitter. [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 between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] 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] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastric: Having to do with the stomach. [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] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gemfibrozil: A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established. [NIH]

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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 Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [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] 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] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [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] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [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 (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] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides

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in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [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] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [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] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [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] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Granular Cell Tumor: Unusual tumor affecting any site of the body, but most often encountered in the head and neck. Considerable debate has surrounded the histogenesis of this neoplasm; however, it is considered to be a myoblastoma of, usually, a benign nature. It affects women more often than men. When it develops beneath the epidermis or mucous membrane, it can lead to proliferation of the squamous cells and mimic squamous cell carcinoma. [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] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Groin: The external junctural region between the lower part of the abdomen and the thigh.

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[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] Hair Color: Color of hair or fur. [NIH] Hair follicles: Shafts or openings on the surface of the skin through which hair grows. [NIH] Hairy cell leukemia: A type of chronic leukemia in which the abnormal white blood cells appear to be covered with tiny hairs when viewed under a microscope. [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] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Helix-loop-helix: Regulatory protein of cell cycle. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hemiparesis: The weakness or paralysis affecting one side of the body. [NIH] Hemiplegia: Severe or complete loss of motor function on one side of the body. This condition is usually caused by BRAIN DISEASES that are localized to the cerebral hemisphere opposite to the side of weakness. Less frequently, BRAIN STEM lesions; cervical spinal cord diseases; peripheral nervous system diseases; and other conditions may manifest as hemiplegia. The term hemiparesis (see paresis) refers to mild to moderate weakness involving one side of the body. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Heparan Sulfate Proteoglycan: A substance released by astrocytes, which is critical in stopping nervous fibers in their tracks. [NIH] Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular

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weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [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] Heterodimers: Zippered pair of nonidentical proteins. [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]

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] Histamine dihydrochloride: A drug being studied for its ability to enhance the effectiveness of IL-2 in treating acute myeloid leukemia. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [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] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] 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] Hormonal: Pertaining to or of the nature of a hormone. [EU] 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] Host-cell: A cell whose metabolism is used for the growth and reproduction of a virus. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [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] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH]

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Hydatidiform Mole: A trophoblastic disease characterized by hydrops of the mesenchymal portion of the villus. Its karyotype is paternal and usually homozygotic. The tumor is indistinguishable from chorioadenoma destruens or invasive mole ( = hydatidiform mole, invasive) except by karyotype. There is no apparent relation by karyotype to choriocarcinoma. Hydatidiform refers to the presence of the hydropic state of some or all of the villi (Greek hydatis, a drop of water). [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] Hyperpigmentation: Excessive pigmentation of the skin, usually as a result of increased melanization of the epidermis rather than as a result of an increased number of melanocytes. Etiology is varied and the condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [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] Hyperthermic perfusion: A procedure in which a warmed solution containing anticancer drugs is used to bathe, or is passed through the blood vessels of, the tissue or organ containing the tumor. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [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] 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

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disposal of foreign ("non-self") material which enters the body. [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] Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction. [NIH]

Immunoelectrophoresis: A technique that combines protein electrophoresis and double immunodiffusion. In this procedure proteins are first separated by gel electrophoresis (usually agarose), then made visible by immunodiffusion of specific antibodies. A distinct elliptical precipitin arc results for each protein detectable by the antisera. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] 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] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [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] Immunotoxin: An antibody linked to a toxic substance. Some immmunotoxins can bind to cancer cells and kill them. [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] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In Situ Hybridization, Fluorescence: A type of in situ hybridization in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei. [NIH] 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]

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Incubated: Grown in the laboratory under controlled conditions. (For instance, white blood cells can be grown in special conditions so that they attack specific cancer cells when returned to the body.) [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] Infantile: Pertaining to an infant or to infancy. [EU] 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]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] 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] 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] Information Science: The field of knowledge, theory, and technology dealing with the collection of facts and figures, and the processes and methods involved in their manipulation, storage, dissemination, publication, and retrieval. It includes the fields of communication, publishing, library science and informatics. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Inguinal: Pertaining to the inguen, or groin. [EU] 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] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [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.

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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] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Integrins: A family of transmembrane glycoproteins consisting of noncovalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement, and other cells, while their intracellular domains interact with the cytoskeleton. The integrins consist of at least three identified families: the cytoadhesin receptors, the leukocyte adhesion receptors, and the very-late-antigen receptors. Each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and oncogenic transformation. [NIH] Intercellular Adhesion Molecule-1: A cell-surface ligand with a role in leukocyte adhesion and inflammation. Its production is induced by gamma-interferon and it is required for neutrophil migration into inflamed tissue. [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 Alfa-2b: A recombinant alfa interferon consisting of 165 amino acid residues with arginine in position 23 and histidine in position 34. It is used extensively as an antiviral and antineoplastic agent. [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] Interferon-beta: One of the type I interferons produced by fibroblasts in response to stimulation by live or inactivated virus or by double-stranded RNA. It is a cytokine with antiviral, antiproliferative, and immunomodulating activity. [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] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [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

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platelet factor 4. [NIH] Intermediate Filaments: Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. [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] 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] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intravascular: Within a vessel or vessels. [EU] 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]

Invertebrates: Animals that have no spinal column. [NIH] 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 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] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [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] Islet: Cell producing insulin in pancreas. [NIH]

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Isolated limb perfusion: A technique that may be used to deliver anticancer drugs directly to an arm or leg. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the cancer occurred. [NIH] 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] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [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] Keratosis: Any horny growth such as a wart or callus. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Lactate Dehydrogenase: A tetrameric enzyme that, along with the coenzyme NAD+, catalyzes the interconversion of lactate and pyruvate. In vertebrates, genes for three different subunits (LDH-A, LDH-B and LDH-C) exist. [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] Laser therapy: The use of an intensely powerful beam of light to kill cancer cells. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

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] Lentigo: Small circumscribed melanoses resembling, but differing histologically from, freckles. The concept includes senile lentigo ('liver spots') and nevoid lentigo (nevus spilus, lentigo simplex) and may also occur in association with multiple congenital defects or

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congenital syndromes (e.g., Peutz-Jeghers syndrome). [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [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] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukoplakia: A white patch that may develop on mucous membranes such as the cheek, gums, or tongue and may become cancerous. [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 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] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Limb perfusion: A technique that may be used to deliver anticancer drugs directly to an arm or leg. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the cancer occurred. [NIH] Linkage: 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] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lip: Either of the two fleshy, full-blooded margins of the mouth. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipoma: A benign tumor composed of fat cells. [NIH] Liposomes: Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins. [NIH] Liquor: 1. A liquid, especially an aqueous solution containing a medicinal substance. 2. A general term used in anatomical nomenclature for certain fluids of the body. [EU] Litter: Appliance consisting of an oblong frame over which is stretched a canvas or other material, used for carrying an injured or disabled person. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive

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substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [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] Locoregional: The characteristic of a disease-producing organism to transfer itself, but typically to the same region of the body (a leg, the lungs, .) [EU] 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] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lung metastases: Cancer that has spread from the original (primary) tumor to the lung. [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]

Lymph node mapping: The use of dyes and radioactive substances to identify lymph nodes that contain tumor cells. [NIH] Lymphadenectomy: A surgical procedure in which the lymph nodes are removed and examined to see whether they contain cancer. Also called lymph node dissection. [NIH] Lymphadenopathy: Disease or swelling of the lymph nodes. [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, 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]

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Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [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] Lymphosarcoma: An obsolete term for a malignant tumor of lymphatic tissue. [NIH] Lymphoscintigraphy: A method used to identify the sentinel node (the first draining lymph node near a tumor). A radioactive substance that can be taken up by lymph nodes is injected at the site of the tumor, and a doctor follows the movement of this substance on a computer screen. Once the lymph nodes that have taken up the substance are identified, they can be removed and examined to see if they contain tumor cells. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [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 tumor: A tumor capable of metastasizing. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mastication: The act and process of chewing and grinding food in the mouth. [NIH] Masticatory: 1. subserving or pertaining to mastication; affecting the muscles of mastication. 2. a remedy to be chewed but not swallowed. [EU] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [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] Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] 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

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with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Informatics: The field of information science concerned with the analysis and dissemination of medical data through the application of computers to various aspects of health care and medicine. [NIH] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] 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] Melanoma vaccine: A cancer vaccine prepared from human melanoma cancer cells. It can be used alone or with other therapy in treating melanoma. [NIH] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [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] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other

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career development situations. [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] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [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] Metastasize: To spread from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original (primary) tumor. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methoxsalen: A naturally occurring furocoumarin compound found in several species of plants, including Psoralea corylifolia. It is a photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [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] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH]

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Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mistletoe lectin: A substance that comes from the mistletoe plant, and that is being studied as a treatment for cancer. A lectin is 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] 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]

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] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] 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] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Morphological: Relating to the configuration or the structure of live organs. [NIH] 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]

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Mucosa: A mucous membrane, or tunica mucosa. [EU] 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] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Myalgia: Pain in a muscle or muscles. [EU] Mycoplasma: A genus of gram-negative, facultatively anaerobic bacteria bounded by a plasma membrane only. Its organisms are parasites and pathogens, found on the mucous membranes of humans, animals, and birds. [NIH] Mycosis: Any disease caused by a fungus. [EU] Mycosis Fungoides: A chronic malignant T-cell lymphoma of the skin. In the late stages the lymph nodes and viscera are affected. [NIH] Myelosuppression: A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Naevus: A circumscribed area of pigmentation or vascularization, usually in the form of a congenital benign neoplasm occurring in the skin or in various ocular tissues. [NIH] Nasal Mucosa: The mucous membrane lining the nasal cavity. [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] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH]

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Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [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] Neural Crest: A strip of specialized ectoderm flanking each side of the embryonal neural plate, which after the closure of the neural tube, forms a column of isolated cells along the dorsal aspect of the neural tube. Most of the cranial and all of the spinal sensory ganglion cells arise by differentiation of neural crest cells. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neuroectodermal tumor: A tumor of the central or peripheral nervous system. [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] Neuroendocrine tumor: A tumor derived from cells that release a hormone in response to a signal from the nervous system. Some examples of neuroendocrine tumors are carcinoid tumors, islet cell tumors, medullary thyroid carcinoma, and pheochromocytoma. These tumors secrete hormones in excess, causing a variety of symptoms. [NIH] Neurofibroma: A fibrous tumor, usually benign, arising from the nerve sheath or the endoneurium. [NIH] Neuroma: A tumor that arises in nerve cells. [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] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] 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] Neurotrophins: A nerve growth factor. [NIH] Neutron Capture Therapy: A technique for the treatment of neoplasms in which an isotope is introduced into target cells followed by irradiation with thermal neutrons. [NIH] 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]

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Neutrophil: A type of white blood cell. [NIH] Nevi and Melanomas: A collective term for the various types of nevi and melanomas. [NIH] Nevus: A benign growth on the skin, such as a mole. A mole is a cluster of melanocytes and surrounding supportive tissue that usually appears as a tan, brown, or flesh-colored spot on the skin. The plural of nevus is nevi (NEE-vye). [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [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] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] 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] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The

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prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] 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] 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] Oncology: The study of 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] Opacity: Degree of density (area most dense taken for reading). [NIH] Ophthalmic: Pertaining to the eye. [EU] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [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] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Ossification: The formation of bone or of a bony substance; the conversion of fibrous tissue or of cartilage into bone or a bony substance. [EU] Osteogenesis: The histogenesis of bone including ossification. It occurs continuously but particularly in the embryo and child and during fracture repair. [NIH] Otitis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, hearing loss, tinnitus, and vertigo. [EU] Otorhinolaryngology: That branch of medicine concerned with medical and surgical treatment of the head and neck, including the ears, nose and throat. [EU] 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] Overexpress: An excess of a particular protein on the surface of a cell. [NIH]

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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]

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] 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] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical antiinflammatory. It is also commonly used as an embedding material in histology. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresis: A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. "General paresis" and "general paralysis" may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. [NIH] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [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] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (=

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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] Pathologist: A doctor who identifies diseases by studying cells and tissues under a microscope. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Peer Review: An organized procedure carried out by a select committee of professionals in evaluating the performance of other professionals in meeting the standards of their specialty. Review by peers is used by editors in the evaluation of articles and other papers submitted for publication. Peer review is used also in the evaluation of grant applications. It is applied also in evaluating the quality of health care provided to patients. [NIH] Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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 vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perianal: Located around the anus. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Nervous System Diseases: Diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves. [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] 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] Pesticides: Chemicals used to destroy pests of any sort. The concept includes fungicides (industrial fungicides), insecticides, rodenticides, etc. [NIH]

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Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] 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] 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] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [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] Photochemotherapy: Therapy using oral or topical photosensitizing agents with subsequent exposure to light. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] Photosensitizing Agents: Drugs that are pharmacologically inactive but when exposed to ultraviolet radiation or sunlight are converted to their active metabolite to produce a beneficial reaction affecting the diseased tissue. These compounds can be administered topically or systemically and have been used therapeutically to treat psoriasis and various types of neoplasms. [NIH] Phototransduction: The transducing of light energy to afferent nerve impulses, such as takes place in the retinal rods and cones. After light photons are absorbed by the photopigments, the signal is transmitted to the outer segment membrane by the cyclic GMP second messenger system, where it closes the sodium channels. This channel gating ultimately generates an action potential in the inner retina. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [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] Phytotoxin: A substance which is toxic for plants. [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]

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Pilot study: The initial study examining a new method or treatment. [NIH] Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [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 and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [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] 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] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [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]

Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form.

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Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [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] 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] 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]

Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyp: A growth that protrudes from a mucous membrane. [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] Polyvalent: Having more than one valence. [EU] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postoperative: After surgery. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [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] 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]

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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] Predictive factor: A situation or condition that may increase a person's risk of developing a certain disease or disorder. [NIH] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [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] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] 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] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [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] Progeny: The offspring produced in any generation. [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]

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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] 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] Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all 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] 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] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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 Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [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] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues. [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] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

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

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cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They 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] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Pruritic: Pertaining to or characterized by pruritus. [EU] Psoralens: Substances found in many different plants, especially Psoralea corylifolia (Legume). They are used for skin diseases, especially vitiligo and as sunscreens. They interact with nucleic acids and are also used as research tools. Psoralens have a coumarin molecule with a furan ring. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [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 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] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [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]

Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU]

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Pyrimidine Dimers: Dimers found in DNA chains damaged by ultraviolet irradiation. They consist of two adjacent pyrimidine nucleotides, usually thymine nucleotides, in which the pyrimidine residues are covalently joined by a cyclobutane ring. These dimers stop DNA replication. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Health Care: The levels of excellence which characterize the health service or health care provided based on accepted standards of quality. [NIH] 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 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] 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] Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects. [NIH] Randomization: Also called random allocation. Is allocation of individuals to groups, e.g., for experimental and control regimens, by chance. Within the limits of chance variation, random allocation should make the control and experimental groups similar at the start of an investigation and ensure that personal judgment and prejudices of the investigator do not influence allocation. [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]

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Reactivation: The restoration of activity to something that has been inactivated. [EU] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] 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] 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] 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] 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] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regional lymph node: In oncology, a lymph node that drains lymph from the region around a tumor. [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] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [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] Reproduction Techniques: Methods pertaining to the generation of new individuals. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [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,

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4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [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] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ricin: A protein phytotoxin from the seeds of Ricinus communis, the castor oil plant. It agglutinates cells, is proteolytic, and causes lethal inflammation and hemorrhage if taken internally. [NIH] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]

Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rods: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide side vision and the ability to see objects in dim light (night vision). [NIH] Salivary: The duct that convey saliva to the mouth. [NIH]

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Salivary glands: Glands in the mouth that produce saliva. [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] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schwannoma: A tumor of the peripheral nervous system that begins in the nerve sheath (protective covering). It is almost always benign, but rare malignant schwannomas have been reported. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [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] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedatives, Barbiturate: Those derivatives of barbituric or thiobarbituric acid that are used as hypnotics or sedatives. The structural class of all such derivatives, regardless of use, is barbiturates. [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,

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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] Sella Turcica: A bony prominence situated on the upper surface of the body of the sphenoid bone. It houses the pituitary gland. [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] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sentinel lymph node: The first lymph node that cancer is likely to spread to from the primary tumor. Cancer cells may appear first in the sentinel node before spreading to other lymph nodes. [NIH] Sentinel lymph node mapping: The use of dyes and radioactive substances to identify the first lymph node to which cancer is likely to spread from the primary tumor. Cancer cells may appear first in the sentinel node before spreading to other lymph nodes and other places in the body. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] 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] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [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

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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] 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] Skin graft: Skin that is moved from one part of the body to another. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [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 Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [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] 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 cells: All the body cells except the reproductive (germ) cells. [NIH] 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] 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 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

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the extents of these reactions. [NIH] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [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] Sphenoid: An unpaired cranial bone with a body containing the sphenoid sinus and forming the posterior part of the medial walls of the orbits. [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] Spinal Cord Diseases: Pathologic conditions which feature spinal cord damage or dysfunction, including disorders involving the meninges and perimeningeal spaces surrounding the spinal cord. Traumatic injuries, vascular diseases, infections, and inflammatory/autoimmune processes may affect the spinal cord. [NIH] Spinal Nerves: The 31 paired peripheral nerves formed by the union of the dorsal and ventral spinal roots from each spinal cord segment. The spinal nerve plexuses and the spinal roots are also included. [NIH] Spinous: Like a spine or thorn in shape; having spines. [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] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [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] Stabilization: The creation of a stable state. [EU] 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]

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Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] 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] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

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] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]

Stool: The waste matter discharged in a bowel movement; feces. [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] Stress Fibers: Bundles of actin filaments (microfilaments) and myosin-II that span across the cell attaching to the cell membrane at focal adhesions and to the network of intermediate filaments that surrounds the nucleus. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Strontium: An element of the alkaline earth family of metals. It has the atomic symbol Sr, atomic number 38, and atomic weight 87.62. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] 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] Submucous: Occurring beneath the mucosa or a mucous membrane. [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

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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] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] 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] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [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] Syncytium: A living nucleated tissue without apparent cellular structure; a tissue composed of a mass of nucleated protoplasm without cell boundaries. [NIH] Synovial: Of pertaining to, or secreting synovia. [EU] Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH] Synovitis: Inflammation of a synovial membrane. It is usually painful, particularly on motion, and is characterized by a fluctuating swelling due to effusion within a synovial sac. Synovitis is qualified as fibrinous, gonorrhoeal, hyperplastic, lipomatous, metritic, puerperal, rheumatic, scarlatinal, syphilitic, tuberculous, urethral, etc. [EU] Systemic: Affecting the entire body. [NIH] Systemic therapy: Treatment that uses substances that travel through the bloodstream, reaching and affecting cells all over the body. [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]

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Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [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] 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] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [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] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used 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] Thiouracil: Occurs in seeds of Brassica and Crucifera species. Thiouracil has been used as antithyroid, coronary vasodilator, and in congestive heart failure although its use has been largely supplanted by other drugs. It is known to cause blood dyscrasias and suspected of terato- and carcinogenesis. [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] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [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]

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Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [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] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Tonsil: A round-to-oval mass of lymphoid tissue embedded in the lateral wall of the pharynx situated on each side of the fauces, between the anterior and posterior pillars of the soft palate. [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] Tourniquet: A device, band or elastic tube applied temporarily to press upon an artery to stop bleeding; a device to compress a blood vessel in order to stop bleeding. [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] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] 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]

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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] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transillumination: Passage of light through body tissues or cavities for examination of internal structures. [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] 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] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [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]

Tropomyosin: A protein found in the thin filaments of muscle fibers. It inhibits contraction of the muscle unless its position is modified by troponin. [NIH] Troponin: One of the minor protein components of skeletal muscle. Its function is to serve as the calcium-binding component in the troponin-tropomyosin B-actin-myosin complex by conferring calcium sensitivity to the cross-linked actin and myosin filaments. [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] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor Escape: The ability of tumors to evade destruction by the immune system. Theories concerning possible mechanisms by which this takes place involve both cellular and humoral immunity, and also costimulatory pathways related to CD28 antigens and CD80 antigens. [NIH] Tumor infiltrating lymphocytes: White blood cells that have left the bloodstream and

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migrated into a tumor. [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 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] Tumor-derived: Taken from an individual's own tumor tissue; may be used in the development of a vaccine that enhances the body's ability to build an immune response to the tumor. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [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; called also neoplasm. [EU] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [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] Urokinase: A drug that dissolves blood clots or prevents them from forming. [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]

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Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine adjuvant: A substance added to a vaccine to improve the immune response so that less vaccine is needed. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [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] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] 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] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens 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] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verruca: A circumscribed, cutaneous excrescence having a papilliferous surface; a small, circumscribed, epidermal tumor. [NIH] Vertigo: An illusion of movement; a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective vertigo). The term is sometimes erroneously used to mean any form of dizziness. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH]

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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] Vindesine: Vinblastine derivative with antineoplastic activity against acute leukemia, lung cancer, carcinoma of the breast, squamous cell carcinoma of the esophagus, head, and neck, and Hodgkin's and non-Hodgkin's lymphomas. Major side effects are myelosuppression and neurotoxicity. Vindesine is used extensively in chemotherapy protocols. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] 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] 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] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Vitiligo: A disorder consisting of areas of macular depigmentation, commonly on extensor aspects of extremities, on the face or neck, and in skin folds. Age of onset is often in young adulthood and the condition tends to progress gradually with lesions enlarging and extending until a quiescent state is reached. [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] Vulva: The external female genital organs, including the clitoris, vaginal lips, and the opening to the vagina. [NIH] Wart: A raised growth on the surface of the skin or other organ. [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]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH]

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Wound Healing: Restoration of integrity to traumatized tissue. [NIH] 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] Xeroderma Pigmentosum: A rare, pigmentary, and atrophic autosomal recessive disease affecting all races. It is manifested as an extreme photosensitivity to ultraviolet light as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. [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] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

247

INDEX A Abdominal, 90, 177, 222, 223 Aberrant, 34, 43, 63, 74, 177 Ablation, 22, 102, 177 Abortion, 177, 188, 227 Acceptor, 177, 212, 222, 241 Acetylcholine, 177, 219, 220 Acne, 134, 177 Actin, 46, 73, 86, 177, 216, 218, 237, 241 Actinic keratosis, 134, 177 Acute leukemia, 80, 131, 177, 244 Acute lymphoblastic leukemia, 177 Acute lymphocytic leukemia, 9, 177 Acute myeloid leukemia, 177, 205 Acyl, 131, 177 Adaptability, 177, 187 Adenocarcinoma, 177, 205, 220 Adenoma, 145, 177 Adenovirus, 62, 112, 177 Adhesions, 178, 237 Adjustment, 8, 178 Adjuvant, 5, 21, 47, 56, 64, 70, 75, 86, 92, 98, 116, 117, 178, 201 Adjuvant Therapy, 6, 56, 70, 98, 117, 178 Adolescence, 41, 178 Adrenal Medulla, 178, 198 Adrenaline, 89, 178 Adrenergic, 178, 195, 198, 238 Adverse Effect, 178, 235 Afferent, 178, 192, 199, 224 Affinity, 33, 178, 179, 182 Agar, 30, 178, 193, 207, 225 Age Distribution, 8, 178 Age Groups, 178 Age-Adjusted, 31, 178 Aggressiveness, 25, 179 Agonist, 179, 195, 238 Algorithms, 23, 179, 184 Alimentary, 179, 222 Alkaline, 179, 185, 237 Alkaloid, 179, 185, 220 Alkylating Agents, 95, 179, 193, 239 Alleles, 8, 41, 51, 179, 212 Allergen, 179, 194 Allogeneic, 14, 179, 203 Allograft, 77, 179 Alpha Particles, 179, 230 Alternative medicine, 148, 179

Amine, 179, 205 Amino Acid Sequence, 180, 181, 191, 202 Ampulla, 180, 197 Amputation, 143, 180 Anaerobic, 180, 218 Anaesthesia, 180, 208 Anal, 73, 144, 180, 197, 213, 218 Analog, 180, 200 Analogous, 180, 241 Anaphylatoxins, 180, 190 Anatomical, 180, 212, 233 Anesthesia, 77, 180 Anesthetics, 180, 183, 198 Angina, 141, 180 Angiogenesis, 15, 27, 36, 56, 88, 90, 97, 133, 134, 180, 197, 214 Angiogenesis inhibitor, 56, 133, 180, 197 Angiosarcoma, 134, 180 Animal model, 5, 6, 12, 36, 38, 39, 46, 129, 180 Anomalies, 180, 239 Anorectal, 64, 89, 94, 144, 180 Antiangiogenic, 56, 180 Antibacterial, 180, 236 Antibiotic, 181, 236, 239 Antibodies, 13, 18, 33, 43, 87, 104, 129, 181, 204, 205, 206, 207, 214, 217, 225, 230 Anticoagulant, 181, 228 Anticonvulsants, 181 Antigen-Antibody Complex, 181, 190 Antigen-presenting cell, 49, 181, 194 Anti-inflammatory, 39, 181, 202, 222, 227 Antimetabolite, 181, 200 Antineoplastic, 39, 131, 179, 181, 186, 200, 201, 209, 214, 215, 222, 226, 227, 244 Antineoplastic Agents, 179, 181, 244 Antiproliferative, 56, 181, 209 Antiserum, 125, 181 Antiviral, 56, 181, 201, 209 Anus, 144, 180, 181, 189, 223 Apheresis, 10, 181 Apolipoproteins, 181, 201 Apoptosis, 16, 27, 31, 35, 38, 43, 65, 68, 71, 77, 84, 87, 110, 112, 117, 118, 121, 181, 186 Aqueous, 182, 193, 196, 206, 212 Arginine, 9, 154, 180, 182, 209, 220 Arrestin, 45, 182

248

Malignant Melanoma

Arterial, 182, 185, 206, 228 Arteries, 182, 184, 192, 213, 216, 229 Arterioles, 182, 184, 185, 216, 243 Artery, 182, 184, 192, 222, 229, 240 Asparaginase, 9, 182 Aspartate, 182 Aspiration, 78, 182 Assay, 10, 17, 20, 23, 45, 47, 48, 182 Astrocytes, 182, 204 Astrocytoma, 21, 182 Attenuated, 182, 243 Atypical, 8, 56, 136, 182, 195 Auditory, 145, 182 Autoimmune disease, 22, 182 Autologous, 10, 58, 69, 81, 85, 88, 99, 182 Autonomic, 177, 182, 192, 223 Autonomic Nervous System, 182, 223 Avian, 48, 183 B Bacteria, 177, 180, 181, 183, 191, 199, 203, 216, 218, 232, 236, 240, 241, 243 Bacteriophage, 24, 183, 225, 241 Bacterium, 183, 191, 195 Barbiturate, 183, 239 Basal cell carcinoma, 59, 134, 183 Basal cells, 183 Basement Membrane, 183, 199 Basophils, 45, 183, 203, 212 Benign, 8, 26, 44, 53, 59, 66, 73, 134, 136, 143, 145, 177, 183, 186, 200, 201, 203, 204, 211, 212, 218, 219, 220, 222, 230, 233 Benign tumor, 145, 183, 200, 212 Beta-Thromboglobulin, 183, 209 Bilateral, 12, 64, 66, 183, 222 Bile, 183, 212, 237 Binding Sites, 59, 183 Bioassay, 38, 183 Biochemical, 22, 28, 39, 55, 129, 179, 181, 183, 200, 203, 211, 217, 234 Biological therapy, 184, 204 Biomarkers, 12, 20, 55, 73, 184 Biopsy, 40, 42, 52, 53, 63, 80, 103, 174, 184, 198 Biopsy specimen, 40, 184 Biosynthesis, 39, 184, 213, 234 Biotechnology, 60, 61, 148, 159, 184 Bladder, 12, 134, 184, 228, 242 Blister, 68, 184 Blood pressure, 184, 186, 206, 217, 229 Body Fluids, 184, 195, 242 Bolus, 67, 97, 184 Bolus infusion, 184

Bone Marrow, 11, 177, 184, 202, 204, 207, 213, 214, 215, 217, 218, 235, 237 Bone scan, 184, 233 Boron, 67, 110, 130, 184, 185, 193 Boron Neutron Capture Therapy, 110, 130, 184, 185 Bowel, 180, 185, 210, 211, 223, 237 Brachytherapy, 74, 120, 185, 210, 230, 245 Bradykinin, 185, 220 Brain Hypoxia, 185 Brain Infarction, 185 Brain Ischemia, 137, 185 Brain metastases, 36, 42, 67, 80, 102, 118, 185 Bronchi, 185, 198, 214, 240 Bronchial, 185, 205 Bronchiectasis, 46, 185 Bronchitis, 46, 185 Buccal, 185, 237 C Calcium, 185, 190, 214, 228, 241 Callus, 185, 196, 211 Camptothecin, 185, 210 Cancer vaccine, 185, 215 Candidosis, 144, 185 Capillary, 39, 185, 243 Carbohydrate, 186, 203, 226 Carbon Dioxide, 102, 186, 193, 201, 231 Carboplatin, 119, 152, 186 Carcinogen, 34, 186, 215, 218 Carcinogenesis, 12, 30, 44, 57, 186, 188, 239 Carcinogenic, 179, 186, 208, 221, 228, 237, 242 Carcinogenicity, 120, 186 Carcinoid, 186, 219 Cardiac, 186, 198, 218, 237 Cardiogenic, 39, 186 Cardiovascular, 39, 132, 186, 234 Cardiovascular disease, 132, 186 Case report, 64, 68, 78, 83, 84, 86, 102, 103, 186, 189 Case series, 20, 186, 189 Case-Control Studies, 105, 186, 197 Caspase, 51, 186 Castor Oil, 186, 232 Catabolism, 49, 186 Causal, 36, 41, 186, 197 Cause of Death, 3, 22, 132, 187 Cavernous Sinus, 94, 187 CDC2, 77, 187 Cell Adhesion, 18, 43, 49, 97, 187, 209

249

Cell Adhesion Molecules, 18, 187 Cell Cycle, 28, 37, 41, 112, 121, 187, 189, 193, 198, 204, 229 Cell Death, 9, 19, 51, 61, 137, 181, 187, 198, 202, 218 Cell Division, 137, 183, 187, 193, 198, 204, 210, 216, 217, 225, 233 Cell Fusion, 18, 187 Cell Lineage, 48, 187 Cell membrane, 187, 237 Cell motility, 30, 40, 49, 187 Cell Movement, 46, 187 Cell proliferation, 15, 187 Cell Size, 187, 200 Cell Survival, 49, 187, 204 Cell Transplantation, 85, 187 Central Nervous System, 6, 21, 177, 182, 187, 196, 201, 204, 234 Cerebral, 62, 106, 185, 187, 198, 204 Cerebrovascular, 186, 187 Cerebrum, 187, 225, 241 Cerumen, 145, 187 Cervical, 98, 107, 188, 204 Cervix, 177, 188, 231 Cheilitis, 143, 188 Chemokines, 45, 188 Chemoprevention, 31, 188 Chemopreventive, 11, 188 Chemotactic Factors, 188, 190 Chemotherapeutic agent, 19, 38, 118, 188 Chemotherapeutics, 24, 188 Chemotherapy, 9, 38, 42, 75, 85, 103, 111, 117, 118, 119, 120, 129, 178, 188, 244 Cholesterol, 183, 188, 192, 201, 213, 237, 238 Chondrocytes, 188, 200 Chondroitin sulfate, 30, 188 Choriocarcinoma, 131, 188, 206 Choroid, 74, 110, 188, 232 Chromatin, 182, 188, 197 Chromium, 47, 188 Chromosomal, 8, 21, 67, 134, 188 Chromosome, 23, 37, 51, 134, 136, 188, 191, 204, 212, 233 Chromosome Abnormalities, 51, 188 Chronic, 46, 131, 132, 145, 189, 204, 208, 218, 229, 233, 237, 244 Chronic leukemia, 189, 204 Cisplatin, 89, 113, 117, 118, 153, 189 Clinical Medicine, 189, 227 Clinical study, 189, 192

Clinical trial, 4, 16, 17, 19, 21, 31, 38, 43, 44, 47, 56, 92, 115, 132, 159, 189, 192, 228, 230 Clone, 30, 62, 189 Cloning, 184, 189, 208, 212 Cochlea, 189, 208 Coenzyme, 189, 211, 213 Cofactor, 189, 228, 239 Cohort Studies, 189, 197 Coliphages, 183, 189 Collagen, 90, 179, 183, 189, 199, 200, 201, 214, 225, 228 Colloidal, 101, 189 Colon, 25, 38, 42, 43, 98, 122, 144, 189, 190, 211 Colorectal, 12, 75, 111, 137, 144, 189, 190 Colorectal Cancer, 12, 137, 190 Communis, 186, 190, 232 Complement, 45, 180, 190, 209 Complementary and alternative medicine, 115, 123, 190 Complementary medicine, 115, 190 Computational Biology, 159, 190 Computed tomography, 190, 191, 233 Computerized axial tomography, 190, 233 Conception, 177, 188, 191, 227, 235, 237 Concomitant, 19, 191 Confounding, 54, 191 Congestive heart failure, 191, 239 Conjugated, 24, 58, 191 Conjugation, 59, 191 Conjunctiva, 78, 93, 191, 208 Connective Tissue, 184, 189, 191, 200, 201, 213, 216, 228, 232, 233 Consciousness, 191, 194, 195, 237 Consensus Sequence, 191 Conserved Sequence, 23, 191 Consultation, 39, 191, 199 Continuous infusion, 67, 191 Continuum, 135, 191 Contraindications, ii, 51, 191 Control group, 52, 192, 230 Controlled clinical trial, 31, 55, 192 Cooperative group, 16, 192 Coordination, 55, 192 Corneum, 192, 197 Coronary, 186, 192, 216, 239 Coronary heart disease, 186, 192 Coronary Thrombosis, 192, 216 Coumarin, 110, 111, 113, 192, 229 Cowpox, 192, 243 Cowpox Virus, 192, 243

250

Malignant Melanoma

Cranial, 137, 192, 199, 204, 219, 223, 236 Cranial Nerves, 137, 192 Cross-Sectional Studies, 192, 197 Crowns, 192, 194 Cryostat, 192, 200 Cues, 53, 192 Culture Media, 178, 192 Curative, 22, 47, 128, 193, 220, 239 Curcumin, 133, 193 Cyclic, 193, 204, 220, 224 Cyclin, 28, 112, 121, 193 Cysteine, 188, 193, 238 Cysteinyldopa, 88, 193 Cytogenetics, 12, 95, 193 Cytokine, 6, 16, 22, 26, 70, 97, 110, 130, 193, 200, 209, 239 Cytomegalovirus, 6, 193 Cytoplasm, 137, 182, 183, 187, 193, 197, 199, 217 Cytoskeleton, 46, 193, 209, 216 Cytostatic, 38, 193, 218 Cytotoxic, 8, 18, 38, 45, 47, 61, 71, 95, 112, 129, 193, 230 Cytotoxicity, 47, 189, 193 D Dacarbazine, 71, 79, 111, 113, 117, 119, 121, 152, 193 Data Collection, 12, 193 Decarboxylation, 193, 205 Decision Making, 29, 193 Deletion, 31, 51, 82, 182, 194 Dementia, 137, 194 Dendrites, 194, 219 Dendritic, 14, 19, 47, 49, 58, 69, 72, 82, 194, 215 Dendritic cell, 14, 19, 47, 49, 58, 69, 72, 82, 194 Density, 24, 41, 92, 194, 200, 221, 226 Dental Abutments, 194 Dentures, 4, 194 Deprivation, 28, 194 Dermal, 49, 56, 194 Dermatitis, 71, 194, 196 Dermatologist, 31, 194 Desensitization, 45, 194 Diagnostic procedure, 51, 127, 148, 194 Digestion, 179, 183, 185, 194, 210, 212, 237, 243 Digestive tract, 194, 235, 236 Dimethyl, 128, 194 Diploid, 194, 225, 226

Direct, iii, 17, 27, 29, 33, 35, 49, 51, 56, 151, 189, 194, 195, 231 Discrete, 53, 133, 194 Disease-Free Survival, 4, 194 Dissection, 69, 91, 92, 194, 213 Dissociation, 178, 194 Docetaxel, 117, 195 Dominance, 195, 198 Dopamine, 195, 219, 224 Dormancy, 15, 195 Dorsal, 195, 219, 226, 236 Dorsum, 100, 195, 201 Dose-rate, 120, 195 Drug Interactions, 152, 153, 195 Drug Resistance, 95, 195 Drug Tolerance, 195, 240 Duct, 37, 180, 195, 198, 232, 238 Duodenum, 183, 195, 197, 237 Dura mater, 187, 195 Dyes, 183, 195, 200, 213, 234 Dysplasia, 55, 195 Dysplastic nevi, 54, 129, 195 Dystrophic, 134, 195, 198 E Ectoderm, 196, 219 Eczema, 134, 196 Effector, 22, 34, 51, 87, 177, 190, 196 Efferent, 192, 196, 199 Efficacy, 19, 40, 42, 43, 44, 49, 53, 58, 65, 196, 241 Effusion, 196, 238 Elastic, 53, 196, 240 Elastin, 189, 196, 199 Elective, 101, 196 Electrons, 196, 210, 222, 230 Embryo, 55, 177, 187, 196, 208, 221, 227, 236 Embryo Transfer, 196, 227 Embryogenesis, 48, 196 Emphysema, 46, 196 Emulsions, 178, 196 Endemic, 196, 236 Endocrine System, 196, 219 Endocytosis, 50, 196 Endogenous, 6, 56, 195, 196, 240 Endometrium, 63, 196 Endoscope, 197 Endoscopic, 69, 103, 197 Endostatin, 56, 197 Endothelial cell, 41, 68, 197, 200, 209, 239 Endothelium, 197, 220, 225 Endothelium-derived, 197, 220

251

Endotoxins, 190, 197 Enhancer, 55, 197 Environmental Exposure, 12, 197, 221 Environmental Health, 158, 160, 197 Enzymatic, 33, 36, 129, 179, 185, 190, 193, 197, 205, 232 Enzyme Inhibitors, 36, 197 Eosinophils, 45, 197, 203, 212 Epidemic, 29, 131, 197, 236 Epidemiologic Studies, 13, 197 Epidemiological, 20, 82, 87, 142, 197 Epidermal, 5, 197, 211, 215, 243 Epidermis, 138, 183, 184, 192, 197, 203, 206, 211, 227, 229 Epidermoid carcinoma, 197, 236 Epidermolysis Bullosa, 134, 197 Epigastric, 198, 222 Epinephrine, 153, 178, 195, 198, 219, 242 Epistasis, 41, 198 Epithelial, 23, 144, 177, 198, 211, 222 Epithelial Cells, 23, 198 Epithelium, 8, 97, 183, 188, 197, 198, 210, 222 Epitope, 10, 83, 198 Erythrocytes, 184, 198 Escalation, 17, 198 Esophageal, 12, 131, 132, 198 Esophagectomy, 111, 119, 198 Esophagus, 13, 103, 111, 119, 120, 194, 198, 214, 224, 237, 244 Estrogen, 198, 234, 238 Ethnic Groups, 12, 198 Etoposide, 118, 198 Eukaryotic Cells, 187, 198, 207, 221, 242 Evoke, 198, 237 Excisional, 198, 245 Excitation, 198, 200, 219 Exfoliation, 137, 198 Exocrine, 198, 222 Exogenous, 196, 199, 202 Exons, 22, 199 Expert Systems, 199, 201 Extensor, 199, 229, 244 External-beam radiation, 199, 210, 230, 245 Extracellular, 28, 30, 36, 40, 137, 182, 191, 196, 199, 200, 209, 214 Extracellular Matrix, 28, 36, 40, 191, 199, 200, 209, 214 Extracellular Matrix Proteins, 199, 214 Extracellular Space, 199 Eye Color, 52, 54, 199

Eye Infections, 177, 199 F Facial, 199, 222 Facial Nerve, 199, 222 Fallopian tube, 199, 231 Family Planning, 159, 199 Fat, 184, 192, 199, 212, 232, 235 Fertilization in Vitro, 199, 227 Fibrinogen, 199, 225, 239 Fibroblast Growth Factor, 41, 94, 111, 130, 134, 200 Fibroblasts, 60, 200, 209 Fibroma, 145, 200 Fibrosis, 46, 143, 200, 233 Filgrastim, 119, 200 Flow Cytometry, 13, 38, 200 Fluorescence, 25, 84, 200, 207 Fluorescent Dyes, 200 Fluorouracil, 75, 200 Foam Cells, 107, 200, 245 Fold, 4, 56, 200 Free Radicals, 39, 194, 200 Friction, 68, 200 Frostbite, 145, 200 Frozen Sections, 18, 200 Fungi, 191, 199, 201, 216, 243, 245 Fungus, 201, 218 Fuzzy Logic, 24, 201 G Galanin, 46, 201 Gamma Rays, 201, 218, 230 Gamma-interferon, 201, 209 Ganglia, 177, 185, 201, 219, 223 Ganglion, 201, 219 Gas, 186, 201, 206, 214, 218, 220, 232 Gas exchange, 201, 232 Gastric, 201, 205 Gastrin, 201, 205 Gastrointestinal, 25, 52, 103, 185, 186, 198, 201, 214, 234, 238, 242 Gastrointestinal tract, 201, 234, 242 Gelatin, 193, 201, 203, 239 Gemfibrozil, 31, 201 Gene Expression, 12, 21, 29, 36, 37, 40, 55, 74, 76, 202 Gene Expression Profiling, 21, 202 Gene Targeting, 32, 56, 202 Gene Therapy, 18, 19, 56, 62, 65, 69, 81, 132, 178, 202 Genetic Code, 202, 220 Genetic Markers, 12, 51, 202

252

Malignant Melanoma

Genetics, 12, 21, 29, 31, 41, 84, 95, 129, 191, 193, 195, 202 Genital, 202, 244 Genotype, 12, 20, 23, 202, 224 Germ Cells, 202, 221, 235, 239 Giant Cells, 107, 202 Gland, 65, 78, 93, 178, 202, 213, 222, 225, 228, 233, 237, 238, 239 Glioma, 62, 202 Glucocorticoid, 6, 202, 227 Glucose, 26, 110, 111, 188, 202, 209, 233 Glucuronic Acid, 202, 204 Glycine, 179, 203, 219, 234 Glycoprotein, 50, 199, 202, 203, 239, 242 Glycosaminoglycan, 188, 203 Glycosylation, 33, 203 Gonad, 203 Gonadal, 29, 203, 237 Gonadotropin, 188, 203 Governing Board, 203, 226 Grade, 10, 21, 55, 58, 203 Graft, 203, 207 Graft Rejection, 203, 207 Gram-negative, 203, 218 Granular Cell Tumor, 143, 203 Granulocyte, 200, 203 Granulocyte Colony-Stimulating Factor, 200, 203 Granuloma, 143, 203 Groin, 203, 208 Growth factors, 17, 204 Guanine, 95, 204, 229 Guanylate Cyclase, 204, 220 H Hair Color, 54, 204 Hair follicles, 204, 244 Hairy cell leukemia, 12, 204 Half-Life, 9, 204 Haploid, 204, 225, 226 Haptens, 178, 204 Headache, 204, 208 Heart attack, 186, 204 Helix-loop-helix, 55, 204 Hematologic malignancies, 204, 213 Hemiparesis, 204 Hemiplegia, 4, 204 Hemoglobinopathies, 202, 204 Hemorrhage, 204, 229, 232, 237 Hemostasis, 204, 209, 234 Heparan Sulfate Proteoglycan, 28, 36, 204 Heparin, 92, 204, 225 Hepatocellular, 9, 205

Hepatocellular carcinoma, 9, 205 Hereditary, 12, 33, 60, 144, 205, 232 Heredity, 57, 202, 205 Heterodimers, 205, 209 Heterogeneity, 32, 84, 110, 178, 205 Histamine, 86, 153, 180, 205 Histamine dihydrochloride, 86, 205 Histidine, 205, 209 Histology, 44, 63, 205, 222 Homeostasis, 26, 205 Homogeneous, 191, 205 Homologous, 179, 202, 205, 233 Hormonal, 13, 205 Hormone, 22, 85, 178, 183, 198, 201, 205, 209, 215, 219, 227, 232, 239 Hormone therapy, 178, 205 Host-cell, 20, 205 Human papillomavirus, 107, 205 Humoral, 203, 205, 241 Hybrid, 51, 189, 205 Hybridomas, 205, 209 Hydatidiform Mole, 188, 206 Hydrogen, 177, 179, 186, 199, 206, 212, 217, 219, 222, 228 Hydrogen Peroxide, 206, 212 Hydrolysis, 9, 189, 193, 206, 226, 228 Hydroxylysine, 189, 206 Hydroxyproline, 179, 189, 206 Hyperpigmentation, 144, 206 Hyperplasia, 141, 143, 206 Hypersensitivity, 179, 194, 206, 232 Hypertension, 186, 204, 206, 240 Hyperthermic perfusion, 112, 206 Hypertrophy, 206 Hypnotic, 183, 206, 239 Hypoxia, 68, 206 Hypoxic, 34, 206 I Immune Sera, 206, 207 Immune system, 6, 10, 22, 37, 181, 184, 206, 207, 214, 241, 244 Immunization, 49, 69, 207, 227 Immunodeficiency, 50, 207 Immunodiffusion, 178, 207 Immunoelectrophoresis, 178, 207 Immunogenic, 9, 207 Immunoglobulin, 181, 199, 207, 217 Immunohistochemistry, 10, 11, 13, 39, 40, 103, 207 Immunologic, 6, 11, 47, 48, 56, 95, 188, 207, 230

253

Immunology, 5, 6, 25, 65, 66, 83, 112, 129, 178, 200, 207 Immunosuppressant, 179, 200, 207 Immunosuppressive, 202, 207 Immunosuppressive therapy, 207 Immunotherapy, 5, 10, 22, 45, 47, 49, 57, 62, 65, 66, 72, 83, 87, 97, 142, 184, 194, 207 Immunotoxin, 112, 207 Implant radiation, 207, 210, 230, 245 In situ, 13, 18, 21, 25, 40, 84, 207 In Situ Hybridization, 13, 21, 40, 84, 207 In Situ Hybridization, Fluorescence, 13, 207 Incision, 207, 210 Incubated, 47, 208 Induction, 6, 19, 49, 58, 61, 71, 208 Infancy, 143, 208 Infantile, 42, 208 Infarction, 183, 185, 192, 208, 216 Infertility, 29, 208 Influenza, 61, 208 Information Science, 208, 215 Infusion, 208 Inguinal, 69, 208 Inhalation, 84, 208 Initiation, 42, 208, 240 Inner ear, 55, 208 Inorganic, 189, 208 Insecticides, 208, 223 Insertional, 15, 208 Insight, 29, 30, 49, 209 Insulin, 25, 209, 210 Insulin-dependent diabetes mellitus, 209 Integrins, 18, 27, 49, 209 Intercellular Adhesion Molecule-1, 88, 209 Interferon Alfa-2b, 97, 209 Interferon-alpha, 41, 70, 86, 94, 118, 209 Interferon-beta, 83, 103, 209 Interleukin-2, 67, 84, 88, 97, 154, 209 Interleukin-6, 102, 209 Interleukin-8, 45, 76, 209 Intermediate Filaments, 210, 237 Internal radiation, 210, 230, 245 Interphase, 207, 210 Interstitial, 185, 199, 210, 245 Intestinal, 104, 210 Intestine, 185, 190, 210, 211 Intracellular, 13, 17, 30, 137, 208, 209, 210, 215, 220, 232 Intramuscular, 56, 210, 222 Intraocular, 99, 210

Intravascular, 80, 210 Intravenous, 56, 115, 117, 208, 210, 222 Intrinsic, 68, 178, 183, 210 Invasive, 18, 28, 32, 40, 44, 48, 49, 53, 138, 206, 210, 214 Invertebrates, 38, 210 Ionizing, 179, 197, 210, 230 Ions, 194, 206, 210, 217, 228 Irinotecan, 117, 210 Iris, 66, 199, 210 Irradiation, 62, 85, 185, 210, 216, 219, 230, 245 Ischemia, 185, 210 Islet, 210, 219 Isolated limb perfusion, 89, 111, 211 Isozymes, 45, 211 K Kb, 158, 211 Keratin, 211 Keratinocytes, 65, 209, 211 Keratoacanthoma, 143, 211 Keratosis, 134, 145, 177, 211 L Labile, 190, 211 Labyrinth, 189, 208, 211, 234, 243 Lactate Dehydrogenase, 33, 211 Large Intestine, 190, 194, 210, 211, 231, 235 Laser therapy, 93, 211 Latency, 32, 211 Latent, 211, 227 Laxative, 178, 211 Lectin, 90, 211, 215, 217 Lentigo, 33, 75, 87, 135, 136, 211 Lesion, 3, 4, 18, 23, 53, 59, 69, 102, 134, 138, 174, 203, 211, 212, 213, 242 Lethal, 34, 61, 212, 218, 232 Leukapheresis, 181, 212 Leukemia, 13, 19, 38, 45, 131, 137, 138, 177, 202, 204, 212 Leukocytes, 45, 183, 184, 188, 197, 209, 212, 217, 242 Leukoplakia, 143, 212 Levo, 212, 215 Ligament, 199, 212, 228 Ligands, 187, 209, 212 Ligase, 58, 212 Limb perfusion, 110, 212 Linkage, 13, 23, 41, 202, 212 Linkage Disequilibrium, 13, 23, 212 Lip, 69, 71, 143, 212 Lipid, 21, 31, 39, 181, 196, 200, 201, 209, 212, 245

254

Malignant Melanoma

Lipid Peroxidation, 39, 212 Lipoma, 143, 212 Liposomes, 65, 83, 212 Liquor, 212, 229 Litter, 128, 212 Liver, 16, 93, 137, 177, 183, 193, 203, 205, 211, 212, 213, 227, 233 Liver scan, 212, 233 Localization, 90, 207, 213 Localized, 21, 51, 111, 141, 185, 204, 208, 213, 225, 233, 242 Locoregional, 4, 77, 91, 213 Lomustine, 111, 213 Longitudinal study, 52, 213 Loop, 34, 213 Lovastatin, 31, 213 Low-density lipoprotein, 213 Lung metastases, 31, 84, 213 Lymph, 11, 49, 77, 89, 91, 92, 102, 128, 188, 197, 213, 214, 218, 231, 234 Lymph node, 11, 49, 89, 91, 92, 102, 128, 188, 213, 214, 218, 231, 234 Lymph node mapping, 213 Lymphadenectomy, 39, 100, 101, 213 Lymphadenopathy, 77, 213 Lymphatic, 88, 92, 100, 101, 131, 132, 144, 197, 208, 213, 214, 216, 235, 236, 239 Lymphatic system, 213, 235, 236, 239 Lymphoblasts, 177, 214 Lymphocyte, 8, 10, 62, 181, 214, 215 Lymphocytic, 214 Lymphoid, 13, 66, 181, 214, 240 Lymphoma, 13, 131, 132, 137, 143, 144, 204, 214, 218 Lymphosarcoma, 131, 214 Lymphoscintigraphy, 70, 74, 92, 214 Lysine, 59, 206, 214 M Magnetic Resonance Imaging, 68, 111, 214, 233 Malignancy, 3, 7, 21, 25, 49, 59, 61, 105, 214, 222 Malignant tumor, 5, 26, 145, 188, 214, 232 Mammary, 214, 238 Manifest, 204, 214 Mastication, 214 Masticatory, 143, 214 Matrix metalloproteinase, 40, 48, 214 Mechlorethamine, 214, 227 Mediastinum, 188, 214 Mediate, 10, 45, 83, 187, 195, 214 Mediator, 30, 32, 209, 214, 225, 234

Medical Informatics, 16, 215 Medical Records, 215, 232 MEDLINE, 159, 215 Medullary, 215, 219 Medulloblastoma, 21, 215 Melanin, 25, 30, 75, 130, 174, 193, 210, 215, 224, 242 Melanocytes, 8, 16, 22, 23, 26, 31, 34, 37, 40, 48, 55, 60, 111, 128, 130, 135, 136, 206, 215, 220 Melanoma vaccine, 30, 47, 215 Melanosis, 75, 81, 215 Melanosomes, 215 Melphalan, 89, 112, 152, 215 Membrane Proteins, 212, 215 Memory, 194, 215 Meninges, 187, 195, 215, 236 Menopause, 85, 215, 227 Mental, iv, 4, 158, 160, 194, 215, 227, 229, 234 Mental Disorders, 215, 227, 229 Mental Health, iv, 4, 158, 160, 215, 227, 229 Mentors, 25, 215 Mercury, 14, 200, 216 Mesenchymal, 144, 206, 216 Meta-Analysis, 35, 105, 216 Metabolite, 194, 213, 216, 224, 227 Metaphase, 207, 216 Metastasis, 4, 18, 21, 27, 28, 30, 36, 39, 40, 43, 45, 46, 49, 63, 65, 68, 76, 88, 90, 91, 97, 98, 106, 110, 118, 120, 133, 139, 174, 187, 214, 216 Metastasize, 21, 129, 216, 233 Methionine, 119, 194, 216, 238 Methoxsalen, 29, 216 MI, 73, 77, 175, 216 Microbe, 216, 240 Microbiology, 47, 182, 216 Microcirculation, 216, 225 Microfilaments, 210, 216, 237 Microorganism, 189, 216, 244 Microtubules, 210, 216, 222 Migration, 31, 48, 50, 209, 217 Mistletoe lectin, 117, 217 Mitochondrial Swelling, 217, 218 Mitosis, 182, 187, 217 Mitotic, 195, 198, 217, 244 Mitotic inhibitors, 195, 217 Modeling, 9, 59, 217 Modification, 25, 59, 131, 179, 217 Molecular Structure, 131, 217

255

Monitor, 105, 217, 220 Monoclonal, 36, 43, 50, 112, 125, 129, 154, 205, 210, 217, 230, 245 Monoclonal antibodies, 43, 50, 112, 129, 217 Monocytes, 45, 200, 209, 212, 217, 239 Mononuclear, 42, 203, 217, 242 Monotherapy, 118, 217 Morphological, 196, 201, 215, 217 Morphology, 5, 65, 217 Motility, 30, 46, 217, 234 Mucosa, 120, 143, 218, 237 Multivariate Analysis, 73, 218 Muscle Fibers, 218, 241 Mustard Gas, 218 Mutagen, 13, 218 Mutagenesis, 12, 15, 218 Mutagenic, 47, 60, 179, 218 Myalgia, 208, 218 Mycoplasma, 9, 218 Mycosis, 70, 131, 218 Mycosis Fungoides, 70, 131, 218 Myelosuppression, 218, 244 Myocardium, 216, 218 Myosin, 218, 237, 241 N Naevus, 66, 83, 93, 218 Nasal Mucosa, 208, 218 Necrosis, 137, 181, 185, 208, 216, 218 Neonatal, 5, 218 Neoplasia, 110, 118, 218 Neoplasm, 131, 133, 135, 203, 218, 222, 233, 242 Neoplastic, 134, 143, 205, 211, 214, 218, 221 Nerve Growth Factor, 219 Nervous System, 37, 48, 178, 182, 187, 214, 218, 219, 223, 238 Neural, 21, 48, 49, 55, 136, 178, 205, 219 Neural Crest, 48, 55, 136, 219 Neuroblastoma, 37, 131, 219 Neuroectodermal tumor, 49, 143, 219, 227 Neuroendocrine, 6, 144, 219 Neuroendocrine tumor, 144, 219 Neurofibroma, 143, 219 Neuroma, 143, 219 Neurons, 48, 137, 194, 201, 219 Neuropeptide, 46, 219 Neurotoxicity, 219, 244 Neurotransmitter, 177, 179, 185, 195, 201, 203, 205, 219, 237 Neurotrophins, 36, 219

Neutron Capture Therapy, 67, 112, 130, 219 Neutrons, 179, 185, 210, 219, 230 Neutrophil, 209, 220 Nevi and Melanomas, 35, 220 Nevus, 4, 8, 17, 33, 35, 41, 62, 66, 89, 97, 134, 135, 136, 211, 220 Niacin, 220, 241 Nitric Oxide, 39, 220 Nitrocamptothecin, 110, 117, 220 Nitrogen, 179, 199, 215, 220, 241 Non-small cell lung cancer, 131, 132, 220 Nuclear, 86, 88, 101, 185, 191, 196, 198, 201, 218, 220 Nuclei, 179, 191, 196, 199, 202, 207, 214, 217, 219, 220, 228 Nucleic acid, 134, 138, 202, 207, 220, 229, 230 Nucleus, 55, 182, 183, 188, 193, 197, 198, 201, 210, 217, 219, 220, 228, 237 O Observational study, 63, 96, 220 Occult, 39, 220 Ocular, 100, 218, 220 Odds Ratio, 220, 231 Ointments, 221, 222 Oncogene, 44, 59, 67, 68, 82, 95, 104, 111, 112, 221 Oncogenic, 22, 59, 62, 128, 209, 221, 228, 229 Oncolysis, 221 Oncolytic, 131, 221 Opacity, 194, 221 Ophthalmic, 96, 110, 221 Oral Health, 46, 143, 221 Orbit, 90, 221 Organ Culture, 221, 240 Organ Transplantation, 16, 221 Organelles, 193, 215, 217, 221 Orofacial, 141, 221 Ossification, 221 Osteogenesis, 69, 221 Otitis, 145, 221 Otorhinolaryngology, 144, 221 Ovaries, 221, 231, 234, 239 Ovary, 93, 203, 221 Overall survival, 5, 221 Overexpress, 14, 221 Oxidation, 177, 212, 222 P Paclitaxel, 119, 222 Palate, 3, 4, 141, 222, 237, 240

256

Malignant Melanoma

Palliative, 22, 128, 131, 222, 239 Pancreas, 46, 137, 177, 184, 209, 210, 222, 242 Pancreatic, 12, 43, 222 Pancreatic cancer, 12, 222 Papilla, 222 Papillary, 141, 222 Papilloma, 145, 222 Papillomavirus, 222 Paraffin, 13, 18, 222 Parenteral, 56, 222 Paresis, 204, 222 Parotid, 78, 93, 222 Partial response, 9, 222 Particle, 24, 222, 241 Patch, 212, 222 Pathogenesis, 5, 36, 49, 75, 222 Pathologic, 11, 49, 182, 184, 185, 192, 206, 222, 223, 229, 236, 243 Pathologic Processes, 182, 223 Pathologist, 7, 11, 223 Patient Education, 51, 168, 170, 175, 223 Peer Review, 11, 109, 223 Pelvic, 74, 223, 228 Pelvis, 221, 223, 242 Penis, 223, 231 Peptide, 10, 24, 26, 71, 179, 200, 211, 223, 226, 228 Perfusion, 10, 112, 206, 223 Perianal, 144, 223 Periodontal disease, 4, 223 Peripheral blood, 42, 209, 223 Peripheral Nervous System, 48, 204, 219, 223, 233, 238 Peripheral Nervous System Diseases, 204, 223 Peritoneal, 45, 90, 223 Peritoneum, 223 Pesticides, 13, 208, 223 Petroleum, 222, 224 Pharmacodynamic, 9, 224 Pharmacokinetic, 9, 224 Pharmacologic, 26, 180, 204, 224, 240 Pharynx, 208, 224, 240 Phenotype, 8, 12, 18, 20, 21, 27, 28, 33, 34, 40, 46, 49, 61, 76, 88, 105, 224 Phenylalanine, 28, 110, 123, 224, 242 Phosphorus, 185, 224 Phosphorylated, 58, 182, 189, 224 Phosphorylation, 28, 30, 43, 45, 58, 224 Photochemotherapy, 29, 224 Photosensitivity, 224, 245

Photosensitizing Agents, 224 Phototransduction, 182, 224 Physical Examination, 143, 224 Physiologic, 45, 179, 184, 204, 224, 231 Physiology, 25, 51, 129, 224 Phytotoxin, 224, 232 Pigment, 24, 48, 55, 97, 102, 118, 128, 142, 143, 215, 224 Pigmentation, 3, 41, 55, 59, 63, 99, 100, 144, 164, 206, 215, 218, 224 Pilot study, 13, 70, 107, 113, 225 Pineal gland, 188, 225 Pituitary Gland, 200, 225, 234 Plants, 179, 186, 202, 211, 216, 217, 224, 225, 229, 233, 240 Plaque, 15, 143, 225 Plasma, 9, 10, 26, 72, 99, 181, 183, 187, 193, 199, 201, 204, 212, 218, 225, 228, 234 Plasma cells, 181, 225 Plasmapheresis, 181, 225 Plasmin, 225 Plasminogen, 28, 105, 225 Plasminogen Activators, 28, 225 Platelet Activation, 50, 225 Platelet Aggregation, 180, 220, 225 Platelet Factor 4, 210, 225 Plateletpheresis, 181, 225 Platelets, 183, 218, 220, 225, 234 Platinum, 189, 213, 226 Ploidy, 69, 78, 226 Pneumonia, 192, 226 Podophyllotoxin, 198, 226 Polyethylene, 9, 226 Polymorphism, 33, 75, 80, 108, 226 Polyp, 143, 226 Polypeptide, 179, 180, 189, 191, 199, 225, 226, 245 Polyposis, 190, 226 Polysaccharide, 181, 203, 226, 228 Polyvalent, 5, 24, 226 Posterior, 180, 188, 195, 210, 222, 226, 233, 236, 240 Postoperative, 193, 226 Post-translational, 59, 226 Practicability, 226, 241 Practice Guidelines, 160, 226 Precancerous, 177, 188, 226, 227 Preclinical, 19, 37, 47, 226 Precursor, 32, 54, 56, 195, 196, 197, 203, 224, 225, 227, 228, 241, 242 Predictive factor, 102, 227 Predisposition, 8, 30, 35, 60, 93, 227

257

Prednisone, 227 Pregnancy Outcome, 29, 227 Premalignant, 15, 34, 143, 226, 227 Premenopausal, 12, 227 Prenatal, 196, 227 Prevalence, 23, 42, 54, 84, 221, 227 Prickle, 211, 227 Primary Prevention, 20, 30, 227 Primary tumor, 11, 15, 21, 39, 44, 227, 234 Primitive neuroectodermal tumors, 215, 227 Probe, 38, 80, 92, 134, 227 Procarbazine, 111, 227 Prodrug, 61, 75, 112, 227 Progeny, 191, 227 Progesterone, 227, 237 Prognostic factor, 21, 102, 227 Progressive, 44, 73, 194, 195, 198, 218, 225, 228, 242 Proline, 189, 206, 228 Promoter, 17, 43, 44, 55, 57, 228 Prone, 30, 32, 228 Prophylaxis, 228, 243 Prospective study, 63, 99, 100, 118, 213, 228 Prostate, 12, 22, 38, 42, 43, 79, 122, 184, 228, 231, 242 Protease, 27, 60, 228 Protein C, 45, 180, 181, 183, 211, 228, 241 Protein Kinases, 51, 77, 228 Protein S, 58, 108, 184, 191, 202, 228, 239 Proteoglycan, 30, 225, 228 Proteolytic, 190, 200, 225, 228, 232 Prothrombin, 228, 239 Protocol, 69, 112, 227, 228 Protons, 179, 206, 210, 228, 230 Proto-Oncogene Proteins, 222, 228, 229 Proto-Oncogene Proteins c-mos, 222, 229 Protozoa, 191, 216, 229, 243 Pruritic, 196, 229 Psoralens, 29, 229 Psoriasis, 134, 218, 224, 229 Psychiatric, 116, 119, 215, 229 Psychiatry, 6, 119, 229 Public Health, 8, 24, 25, 31, 53, 105, 160, 229 Public Policy, 159, 229 Publishing, 60, 208, 229 Pulmonary, 39, 49, 184, 229 Pulmonary Edema, 39, 229 Pulmonary hypertension, 39, 229 Pulse, 217, 229

Purines, 229, 234 Purpura, 141, 144, 229 Pyogenic, 134, 143, 229 Pyrimidine Dimers, 20, 230 Pyrimidines, 230, 234 Q Quality of Health Care, 223, 230, 241 R Race, 129, 215, 217, 230 Racemic, 215, 230 Radiation, 16, 17, 20, 24, 34, 37, 42, 54, 57, 64, 99, 134, 144, 178, 197, 199, 200, 201, 210, 230, 233, 242, 245 Radiation therapy, 24, 42, 64, 178, 199, 210, 230, 245 Radioactive, 43, 184, 204, 206, 207, 210, 212, 213, 214, 217, 220, 221, 230, 233, 234, 242, 245 Radioimmunotherapy, 230 Radiolabeled, 24, 43, 210, 230, 245 Radiotherapy, 94, 107, 185, 210, 230, 245 Random Allocation, 230 Randomization, 55, 230 Randomized, 5, 7, 31, 41, 45, 52, 53, 62, 64, 111, 121, 196, 230 Reactivation, 20, 231 Reagent, 43, 231 Recombinant, 17, 22, 26, 41, 69, 153, 154, 209, 231, 243 Recombination, 191, 202, 231 Rectum, 98, 144, 180, 181, 189, 190, 194, 201, 211, 228, 231 Recurrence, 44, 81, 90, 102, 111, 119, 128, 139, 188, 231 Reductase, 213, 231 Refer, 1, 178, 185, 190, 201, 213, 219, 230, 231, 240 Refraction, 231, 236 Refractory, 31, 39, 231 Regeneration, 137, 200, 231 Regimen, 196, 231 Regional lymph node, 4, 104, 231 Registries, 7, 231 Relapse, 10, 139, 231 Relative risk, 35, 231 Remission, 231 Reproduction Techniques, 227, 231 Reproductive system, 29, 231 Resected, 64, 231 Resection, 47, 77, 231 Respiration, 186, 217, 231 Respiratory failure, 39, 232

258

Malignant Melanoma

Response rate, 19, 42, 232 Retina, 94, 188, 224, 232, 243 Retinal, 182, 224, 232 Retinoblastoma, 34, 74, 232 Retrospective, 44, 63, 102, 120, 135, 232 Retrospective study, 102, 120, 135, 232 Retroviral vector, 202, 232 Rhabdomyosarcoma, 63, 90, 131, 232 Rheumatism, 232 Rheumatoid, 46, 232 Rheumatoid arthritis, 46, 232 Rhodopsin, 182, 232 Ricin, 112, 232 Rickettsiae, 232, 243 Risk factor, 8, 12, 18, 20, 23, 25, 32, 34, 41, 52, 54, 91, 99, 100, 107, 129, 142, 197, 228, 231, 232 Rods, 182, 224, 232 S Salivary, 193, 199, 222, 232, 233 Salivary glands, 193, 199, 233 Saponins, 233, 237 Sarcoma, 95, 131, 134, 141, 143, 144, 227, 233, 235 Scans, 74, 233 Scatter, 233, 242 Schwannoma, 143, 233 Sclera, 188, 191, 233, 243 Scleroderma, 144, 233 Sclerosis, 144, 233 Screening, 20, 23, 59, 101, 189, 233 Sebaceous, 233, 244 Secondary tumor, 216, 233 Secretion, 28, 29, 63, 188, 205, 209, 233, 234, 243 Sedative, 130, 183, 233 Sedatives, Barbiturate, 233 Segregation, 41, 48, 231, 233 Seizures, 181, 233, 237 Selective estrogen receptor modulator, 234, 238 Sella Turcica, 195, 225, 234 Semen, 228, 234 Semicircular canal, 208, 234 Semisynthetic, 185, 198, 234 Senescence, 10, 35, 234 Senile, 177, 211, 234 Sentinel lymph node, 69, 74, 80, 86, 92, 100, 101, 105, 234 Sentinel lymph node mapping, 92, 234 Septic, 39, 234 Sequencing, 33, 51, 234

Serine, 21, 229, 234 Serotonin, 219, 234, 241 Serum, 33, 42, 84, 88, 102, 105, 113, 121, 180, 181, 190, 201, 203, 206, 213, 234, 242 Sex Characteristics, 178, 234 Shock, 14, 19, 39, 234, 241 Side effect, 9, 29, 138, 139, 151, 153, 178, 184, 218, 234, 240, 244 Signs and Symptoms, 231, 235 Skeletal, 137, 235, 241 Skeleton, 177, 235 Skin graft, 26, 235 Skull, 221, 235 Small cell lung cancer, 64, 235 Small intestine, 195, 205, 210, 235 Smallpox, 235, 243 Smooth muscle, 86, 180, 200, 205, 235, 238 Social Support, 99, 235 Soft tissue, 89, 110, 141, 184, 235 Soft tissue sarcoma, 110, 235 Solid tumor, 11, 21, 24, 38, 42, 51, 180, 197, 213, 235 Soma, 235 Somatic, 8, 32, 178, 187, 192, 196, 205, 217, 223, 235, 239 Somatic cells, 187, 217, 235 Somatic mutations, 8, 33, 235 Specialist, 165, 235 Specificity, 24, 54, 178, 235 Spectrophotometry, 52, 236 Spectrum, 12, 25, 32, 54, 133, 193, 236 Sperm, 188, 235, 236 Sphenoid, 187, 234, 236 Spinal cord, 182, 187, 188, 195, 201, 204, 215, 219, 223, 236 Spinal Cord Diseases, 204, 236 Spinal Nerves, 223, 236 Spinous, 197, 211, 236 Spleen, 94, 137, 193, 213, 236 Spontaneous Abortion, 227, 236 Sporadic, 8, 12, 20, 23, 51, 56, 68, 232, 236 Squamous, 13, 43, 46, 134, 143, 197, 203, 211, 220, 236, 244 Squamous cell carcinoma, 13, 46, 134, 143, 197, 203, 211, 220, 236, 244 Squamous cells, 203, 236 Stabilization, 58, 236 Staging, 4, 46, 65, 93, 95, 103, 138, 233, 236 Standardize, 55, 236 Statistically significant, 31, 236 Status Epilepticus, 137, 237 Sterility, 208, 237

259

Steroid, 6, 233, 237 Stillbirth, 227, 237 Stimulant, 205, 237 Stimulus, 30, 198, 209, 211, 237 Stomach, 177, 194, 198, 201, 205, 224, 235, 236, 237 Stomatitis, 141, 144, 237 Stool, 189, 211, 237 Strand, 33, 237 Stress, 34, 46, 58, 97, 110, 174, 182, 227, 232, 237 Stress Fibers, 46, 237 Stroke, 4, 158, 186, 237 Stroma, 210, 237 Stromal, 56, 237 Strontium, 120, 237 Subacute, 208, 237 Subclinical, 6, 44, 208, 233, 237 Subcutaneous, 222, 237 Submucous, 143, 237 Subspecies, 235, 237, 243 Substance P, 216, 233, 237 Substrate, 27, 51, 197, 238 Substrate Specificity, 51, 238 Sulfur, 199, 216, 238 Superoxide, 39, 238 Supplementation, 119, 238 Support group, 174, 238 Suppression, 37, 238 Suppressive, 38, 238 Survival Rate, 138, 221, 238 Sweat, 187, 238 Sweat Glands, 188, 238 Sympathomimetic, 195, 198, 238 Symphysis, 228, 238 Syncytium, 202, 238 Synovial, 238 Synovial Membrane, 238 Synovitis, 77, 238 Systemic, 8, 17, 39, 56, 103, 104, 106, 111, 116, 119, 120, 144, 152, 184, 185, 198, 208, 210, 230, 233, 237, 238, 241, 243, 245 Systemic therapy, 116, 238 T Tamoxifen, 105, 112, 115, 121, 152, 234, 238 Telangiectasia, 144, 239 Telomerase, 72, 101, 239 Temozolomide, 42, 71, 95, 239 Teratogenic, 31, 179, 239 Teratoma, 188, 239 Testicular, 131, 132, 239

Testis, 131, 188, 239 Tetracycline, 17, 239 Thalidomide, 98, 130, 239 Therapeutics, 5, 14, 19, 22, 153, 239 Thermal, 112, 185, 194, 219, 239 Thiouracil, 130, 239 Threonine, 21, 229, 234, 239 Thrombin, 27, 199, 225, 228, 239 Thrombolytic, 225, 239 Thrombomodulin, 228, 239 Thrombosis, 92, 183, 209, 228, 237, 239 Thymus, 207, 213, 239 Thyroid, 72, 219, 239, 242 Thyroxine, 224, 239 Tinnitus, 221, 240 Tissue Culture, 29, 31, 240 Tolerance, 48, 177, 240 Tomography, 44, 68, 78, 110, 190, 191, 240 Tonsil, 65, 240 Topical, 54, 86, 105, 206, 222, 224, 240 Topoisomerase inhibitors, 210, 220, 240 Tourniquet, 211, 212, 240 Toxic, iv, 9, 132, 138, 179, 191, 193, 195, 197, 207, 215, 224, 226, 240 Toxicity, 6, 9, 11, 17, 29, 39, 55, 108, 130, 195, 216, 240 Toxicology, 160, 240 Toxin, 240 Trace element, 184, 188, 240 Trachea, 185, 214, 224, 239, 240 Transcriptase, 11, 101, 239, 240 Transcription Factors, 55, 240 Transduction, 15, 21, 30, 40, 50, 51, 241 Transfection, 9, 15, 65, 184, 202, 241 Transfer Factor, 207, 241 Transferases, 203, 241 Transillumination, 59, 241 Translation, 179, 241 Translational, 16, 23, 241 Transmitter, 177, 182, 195, 214, 241 Transplantation, 77, 196, 207, 241 Trauma, 143, 145, 204, 218, 240, 241 Treatment Failure, 10, 45, 241 Treatment Outcome, 10, 57, 241 Tropomyosin, 133, 241 Troponin, 241 Tryptophan, 49, 189, 234, 241 Tuberous Sclerosis, 134, 241 Tumor Escape, 22, 241 Tumor infiltrating lymphocytes, 10, 241 Tumor marker, 6, 184, 242 Tumor Necrosis Factor, 6, 239, 242

260

Malignant Melanoma

Tumor suppressor gene, 21, 32, 43, 57, 242 Tumor-derived, 49, 242 Tumorigenic, 15, 18, 242 Tumour, 66, 86, 88, 90, 99, 110, 119, 201, 221, 242, 245 Tunica, 218, 242 Tyrosine, 21, 28, 30, 31, 123, 195, 242 U Ubiquitin, 58, 242 Ulcer, 242 Ulceration, 21, 141, 242 Ultrasonography, 95, 242 Ultraviolet radiation, 104, 128, 129, 224, 242 Urethra, 91, 96, 223, 228, 242 Urine, 33, 184, 193, 242 Urokinase, 28, 105, 242 Uterus, 177, 188, 196, 221, 227, 231, 242, 243 Uveitis, 122, 182, 243 V Vaccination, 10, 14, 19, 49, 91, 105, 243 Vaccine adjuvant, 6, 243 Vaccines, 5, 10, 17, 22, 143, 243, 244 Vaccinia, 17, 69, 243 Vaccinia Virus, 17, 243 Vacuoles, 196, 221, 243 Vagina, 93, 95, 98, 188, 231, 243, 244 Vaginal, 68, 88, 243, 244 Variola, 243 Vascular, 13, 40, 41, 68, 87, 90, 106, 188, 197, 208, 216, 220, 225, 236, 243 Vascular endothelial growth factor, 41, 87, 90, 106, 243 Vascular Resistance, 40, 243 Vasoconstriction, 198, 243 Vasodilator, 185, 195, 205, 239, 243 Vector, 24, 69, 137, 208, 241, 243 Vein, 31, 210, 220, 222, 243 Venous, 134, 183, 185, 187, 228, 243 Venules, 184, 185, 216, 243 Verruca, 134, 243 Vertigo, 221, 243 Vestibule, 189, 208, 234, 243

Veterinary Medicine, 159, 243 Vinblastine, 131, 152, 244 Vinca Alkaloids, 112, 244 Vincristine, 111, 119, 131, 227, 244 Vindesine, 113, 117, 118, 120, 121, 131, 132, 244 Vinorelbine, 115, 116, 244 Viral, 6, 18, 56, 202, 208, 221, 241, 242, 244 Viral vector, 19, 244 Virulence, 182, 240, 244 Virus, 6, 17, 22, 50, 183, 192, 195, 197, 202, 205, 209, 225, 232, 235, 241, 243, 244 Viscera, 218, 235, 244 Visceral, 22, 183, 192, 223, 244 Vitiligo, 229, 244 Vitro, 10, 17, 19, 22, 26, 27, 28, 29, 30, 32, 36, 47, 48, 58, 61, 110, 112, 115, 117, 128, 187, 196, 202, 205, 207, 240, 244 Vivo, 5, 9, 10, 17, 19, 22, 24, 26, 27, 32, 34, 36, 38, 40, 43, 44, 47, 56, 58, 69, 72, 97, 110, 111, 112, 128, 132, 187, 202, 205, 207, 244 Vulgaris, 134, 244 Vulva, 65, 244 W Wart, 211, 244 White blood cell, 177, 181, 200, 203, 204, 208, 212, 213, 214, 218, 220, 225, 241, 244 Windpipe, 224, 239, 244 Womb, 231, 242, 244 Wound Healing, 187, 200, 209, 214, 245 X Xanthoma, 143, 245 Xenograft, 180, 245 Xeroderma Pigmentosum, 20, 245 X-ray, 174, 190, 200, 201, 210, 218, 220, 230, 233, 245 X-ray therapy, 210, 245 Y Yeasts, 185, 201, 224, 245 Z Zygote, 191, 245 Zymogen, 228, 245