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

GLIOBLASTOMA MULTIFORME 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., 1960Glioblastoma Multiforme: 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: 0-497-00481-X 1. Glioblastoma Multiforme-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 glioblastoma multiforme. 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 GLIOBLASTOMA MULTIFORME ................................................................. 3 Overview........................................................................................................................................ 3 Federally Funded Research on Glioblastoma Multiforme .............................................................. 3 E-Journals: PubMed Central ....................................................................................................... 51 The National Library of Medicine: PubMed ................................................................................ 51 CHAPTER 2. NUTRITION AND GLIOBLASTOMA MULTIFORME ....................................................... 97 Overview...................................................................................................................................... 97 Finding Nutrition Studies on Glioblastoma Multiforme............................................................. 97 Federal Resources on Nutrition ................................................................................................... 99 Additional Web Resources ......................................................................................................... 100 CHAPTER 3. ALTERNATIVE MEDICINE AND GLIOBLASTOMA MULTIFORME ............................... 101 Overview.................................................................................................................................... 101 National Center for Complementary and Alternative Medicine................................................ 101 Additional Web Resources ......................................................................................................... 108 General References ..................................................................................................................... 108 CHAPTER 4. DISSERTATIONS ON GLIOBLASTOMA MULTIFORME................................................. 109 Overview.................................................................................................................................... 109 Dissertations on Glioblastoma Multiforme................................................................................ 109 Keeping Current ........................................................................................................................ 110 CHAPTER 5. PATENTS ON GLIOBLASTOMA MULTIFORME ........................................................... 111 Overview.................................................................................................................................... 111 Patents on Glioblastoma Multiforme ......................................................................................... 111 Patent Applications on Glioblastoma Multiforme ..................................................................... 112 Keeping Current ........................................................................................................................ 115 CHAPTER 6. PERIODICALS AND NEWS ON GLIOBLASTOMA MULTIFORME ................................. 117 Overview.................................................................................................................................... 117 News Services and Press Releases.............................................................................................. 117 Academic Periodicals covering Glioblastoma Multiforme ......................................................... 119 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 121 Overview.................................................................................................................................... 121 U.S. Pharmacopeia..................................................................................................................... 121 Commercial Databases ............................................................................................................... 122 Researching Orphan Drugs ....................................................................................................... 122 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 127 Overview.................................................................................................................................... 127 NIH Guidelines.......................................................................................................................... 127 NIH Databases........................................................................................................................... 129 Other Commercial Databases..................................................................................................... 131 APPENDIX B. PATIENT RESOURCES ............................................................................................... 133 Overview.................................................................................................................................... 133 Patient Guideline Sources.......................................................................................................... 133 Finding Associations.................................................................................................................. 135 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 137 Overview.................................................................................................................................... 137 Preparation................................................................................................................................. 137 Finding a Local Medical Library................................................................................................ 137 Medical Libraries in the U.S. and Canada ................................................................................. 137 ONLINE GLOSSARIES................................................................................................................ 143 Online Dictionary Directories ................................................................................................... 143

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GLIOBLASTOMA MULTIFORME DICTIONARY................................................................ 145 INDEX .............................................................................................................................................. 203

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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 glioblastoma multiforme 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 glioblastoma multiforme, 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 glioblastoma multiforme, 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 glioblastoma multiforme. 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 glioblastoma multiforme, 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 glioblastoma multiforme. 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 GLIOBLASTOMA MULTIFORME Overview In this chapter, we will show you how to locate peer-reviewed references and studies on glioblastoma multiforme.

Federally Funded Research on Glioblastoma Multiforme The U.S. Government supports a variety of research studies relating to glioblastoma multiforme. 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 glioblastoma multiforme. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore glioblastoma multiforme. The following is typical of the type of information found when searching the CRISP database for glioblastoma multiforme: •

Project Title: 10Q TUMOR SUPPRESSOR GENE Principal Investigator & Institution: Yung, W K Alfred.; Professor; Neuro-Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-APR-1992; Project End 30-JUN-2003

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

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Summary: (Adapted from the investigator's abstract) The initiation and progression of the tumorigenic capabilities of neoplastic cells involves genetic alterations which lead to the activation of oncogenes and the loss of function of tumor suppressor genes. The objective of this project is to identify, confirm, and characterize a tumor-suppressor (TS) gene localized to the long arm of chromosome 10 (10q23-24) that is intimately involved in the progression of gliomas to high grade glioblastoma multiforme (GMB). A strong candidate suppressor gene has recently been identified in the critical region. Deletion of large segments, or an entire copy, of chromosome 10 represents a very frequent (-90 percent) molecular alteration in GBMs and several other cancers. The hypothesis of the study proposes the loss of function of a tumor suppressor gene on chromosome 10 directly contributes to the progression of these cancers. The candidate TS gene cloned at the critical region appears to encode for a novel protein tyrosine phosphatase (PTPase), implicating a potential role of the candidate TS gene in cell signaling. They have previously used a functional approach in microcell-mediated chromosomal transfer to demonstrate the presence and biological function of a TS gene on 10q involved in glioma oncogenesis. To further define the TS locus a series of three independent approaches were pursued to define a critical region, including the identification of homozygous deletions in gliomas cells. All three of the approaches and allelic deletion analysis of prostrate carcinomas directed the attention towards a single locus. A gene has now been cloned from this critical region and spans the homozygous deletions. Mutations to the gene in cultured glioma and prostrate cells along with alterations in several human tumor specimens have been observed. Motif analyses implicates the gene product as a novel PTPase. This proposal is directed at the characterization of the candidate TS gene. The tumor suppressive active of the candidate gene will be assessed by transfecting various constructs of the candidate gene into glioma cells. The mutation and as the possible presence and effect(s) of germline mutations. The proposed biochemical activity(s) of the candidate gene as a protein tyrosine phosphatase will be assessed. Furthermore, the effects of mutations on the proposed activity(s) and/or localization of the gene product will be addressed. Finally, the signaling pathway that the candidate TS gene may play a role in will be examined. This combination of functional and molecular approaches will demonstrate the functional activity of the candidate TS gene and initiate investigations into its mechanism(s) of action. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVE IMMUNOTHERAPY FOR GLIOBLASTOMA Principal Investigator & Institution: Yu, John S.; Co-Director; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the Applicant's Abstract): The purpose of this project is to advance promising cell based and gene based immunotherapy of malignant gliomas from preliminary animal studies to phase I/II clinical trials. We have shown that glioma tumor antigen presentation through subcutaneous vaccination with autologous dendritic cells primed against autologous major histocompatibility complex type I (MHC-I)-associated tumor peptides induces a potent anti-tumor immune response in a murine glioma model. We previously demonstrated that vaccination with tumor cells engineered to secrete granulocyte/macrophage-colony stimulating factor (GM-CSF) elicits a cytotoxic T-cell mediated immune response in murine intracranial glioma and metastasis models. We have implemented these preclinical studies into clinical protocols for patients with glioblastoma multiforme and anaplastic astrocytoma. We are completing a preliminary phase I trial based on a dendritic cell therapeutic strategy.

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Preliminary results demonstrate that this form of dendritic cell vaccination can induce a cytotoxic T-cell response which targets intracranial tumor cells. Three hypotheses are proposed for investigation: 1) Induction of peripheral antigen presentation will generate tumor specific T-cells. 2) Cytotoxic T-cells will migrate to and kill intracranial glioma cells. 3) Peripheral vaccination will induce clinical responses and extend survival in patients with glioblastoma and anaplastic astrocytoma. Based on our hypotheses, we will carry out two phase I studies of peripheral vaccination against glioma, the first using an alternative form of dendritic cell immunotherapy with an escalated dose of dendritic cells primed with tumor lysate derived peptides. Concurrently, we will initiate a phase I protocol using a vaccine consisting of allogeneic glioma cells mixed with fibroblasts engineered to secrete GM-CSF. In these studies, we propose the following specific aims: 1) to monitor patients for cellular immune responses and 2) to evaluate the safety and the efficacy of these immunologic strategies. A phase II trial will be initiated in year 3 of the training grant based on the phase I studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALLOGENEIC GLIOMA VACCINE USING TGF-BETA KNOCKOUTS Principal Investigator & Institution: Fakhrai, Habib A.; Novarx Corporation 8395 Camino Santa Fe, Ste a San Diego, Ca 921212635 Timing: Fiscal Year 2004; Project Start 16-APR-2004; Project End 31-OCT-2004 Summary: (provided by applicant): This application is phase I of a FAST TRACK SBIR grant proposal. The primary goal of this study is to generate a novel glioma cell vaccine comprised of six well-characterized allogeneic glioma cell lines in whichTGF-beta1 and TGF-beta2 secretion has been abrogated using gene knockout technology. The vaccine generated in this manner will be used to immunize patients with stage IV astrocytoma (glioblastoma multiforme and gliosarcoma) in a Phase II/III clinical trial with the goal of inducing antitumor immunity that leads to clinical responses, to be partially funded by the accompanying phase II grant proposal. By blocking secretion of the immunosuppressive TGF-beta molecules in this manner, we inhibit one of the major mechanisms by which tumor cells evade immune surveillance. Development of an effective therapy for this disease will benefit the approximately 20,000 new patients that develop glial tumors in the United States each year. The milestone for progressing to the phase II SBIR proposal will be successful generation and certification of master and working vaccine cell banks. The first aim of the study is to completely abrogate expression TGF-beta1 andTGF-beta2 by knocking out the paternal and maternal copies for TGF-beta1 and TGF-beta2 genes in six allogeneic glioma cell lines. Candidate cells chosen from eighteen malignant glioma cell lines carried in the cryopreservation inventory of NovaRx will be transfected with the constructed TGF-beta1 and TGF-beta2 knockout vectors. Following selection of cells in the presence of designated drugs, the surviving cell colonies will be expanded and characterized to ascertain the correct incorporation of the recombinant unit and expression of glioma-associated antigens. The lack of expression of TGF-beta1 and TGF-beta2 will be confirmed by Northern and Southern blot analyses, ELISA, and Western blot analyses. Additionally, we will characterize the gene-modified cells by HLA and glial cell marker phenotyping. We are expecting of a stable 100% down-regulation of TGF-beta1 and TGF-beta2 secretion. The second aim of the study is to generate master and working cell banks of the six allogeneic cell lines generated in Aim 1. The cell banks will be tested for the presence of bacteria, fungi, adventitious viruses, mycoplasma, and endotoxin in order to certify them for use in a Phase II/III clinical trial. Completion of Aims l and 2 serves as a milestone for initiation of the Phase II study. We anticipate that genetic modification of

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malignant glioma cells to block TGF-beta expression would result in the gene-modified cells becoming more immunogenic and suitable for active tumor immunotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASSESSMENT OF HYPOXIA IN MALIGNANT GLIOMAS USING EF5 Principal Investigator & Institution: Evans, Sydney M.; Associate Professor; Radiation Oncology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 04-JUN-2001; Project End 31-MAY-2004 Summary: (Provided by applicant) It has been known since the 1950s that hypoxic tumor cells require up to 3 times the radiation dose compared to aerobic cells for equal toxicity. Because the total radiation dose administered is limited by the tolerance of normal adjacent tissues, the search for approaches to overcome the "hypoxia problem" has dominated radiation biology research for the last half century. One of the major limitations to attacking this problem has been the inability to identify and quantitate the presence of hypoxic cells in individual patients. In the last decade, the availability of the Eppendorf needle electrode technology has allowed data to be obtained on tumor tissue oxygenation in patients. Such studies have demonstrated hypoxia to negatively influence outcome in cervix, sarcomas and head and neck cancers. There is also substantial evidence that hypoxia exists and is biologically relevant in malignant brain tumors. The overall goal of our clinical hypoxia program is to determine whether the presence, levels and patterns of EF5 binding are important in the prognosis and therapy response of cancer patients. Our interests include patients with sarcomas, head and neck squamous cancer, cervix cancer and now, patients with brain tumors. In the studies proposed herein, we will study EF5 binding in patients with de novo supratentorial malignant gliomas (SMG). Concurrent studies in the same patient group using the Eppendorf needle electrode will serve as a bridge to previously published work. We will determine the relationship between EF5 binding and clinical outcome in patients with glioblastoma multiforme (GBM) versus non-GBM histologies. To better understand the pathophysiology of MG, we will study the presence and levels of various additional biomarkers. These studies are the necessary preliminary studies towards non-invasive studies of hypoxia in brain tumors. These non-invasive studies will be based on Positron Emission Tomographic (PET) imaging of 18F-EF5 followed by hypoxia-specific treatment interventions. 18F-EF5 has been synthesized and studied in animal tumors by our group. The necessary additional pre-clinical studies and applications for permits for these PET studies are ongoing at the University of Pennsylvania (PENN). We project that we will be able to institute clinical EF5 PET studies at PENN in patients with brain tumors in approximately 2 years, corresponding to the time that much of the data from the studies proposed herein will mature. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOLOGICAL EVALUATION OF CCI-779 IN BRAIN TUMORS Principal Investigator & Institution: Hidalgo, Manuel; Associate Professor of Oncology; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 21-JUN-2002; Project End 31-MAY-2004 Summary: (provided by applicant): CCI-779 is a rapamycin analog cell cycle inhibitor currently in clinical development for cancer treatment. CCI-779 inhibits the mammalian target of rapamycin (mTOR) kinase which is a downstream mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway resulting in cell cycle arrest and induction of apoptosis. Previous data from our group suggest that CCI-779 is

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particularly effective in inhibiting the growth of cancer cells with hyperactivation in the PI3K/Akt signaling pathway as a result of deletions of the PTEN tumor suppressor gene. In addition, we have developed and optimized analytical methods to measure Akt activation in tumor tissues as well as the biological effects of CCI-779 in clinical specimens. Our long term goal is to optimally develop CCI-779 for the treatment of patients with cancer utilizing rationally-derived biological concepts. The objective of this research proposal is to determine the relationship between Akt hvperactivation in tumor tissues and the biological effects of CCI-779 on its target pathway with indices of outcome. The central hypothesis of the proposed research is that the therapeutic role of CCI-779 will be maximal in patients with Akt hyperactivated tumors in whom treatment with the agent inhibits mTOR signaling. We have elected to test this hypothesis in patients with recurrent glioblastoma multiforme due to the high frequency of PTEN mutations (30-40 percent) that result in Akt hyperactivation in this disease. In Specific Aim # 1, we will determine the relationship between Akt hyperactivation and outcome of patients with recurrent malignant glioblastoma who are treated with CCI-779. In Specific Aim # 2, we will relate the biological effects of CCI-779 on mTOR signaling in clinical specimens obtained from patients treated with the agent with parameters of outcome. Patients with recurrent malignant glioblastoma multiforme will be treated with CCI-779 under a National Cancer Institute (NCI) sponsored phase II study. Akt activation will be determined in tumor tissues using immunohistochemical methods previously developed by our group. The biological effects of CCI-779 will be measured in peripheral blood mononuclear cells (PBMC) using a kinase assay. The quantitative results of the biological tests will be related to indices of patient's outcome using uni and multivariate statistical methods. This proposal is innovative because it incorporates measurement of biological functions related to the molecular target of this novel agent to optimize its clinical development. The principal significance of these studies will be to provide hypothesis-generating data with regards to tailoring treatment with CCI-779 to patients most likely to benefit by this novel agent based on both molecular and pharmacodynamic factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOLOGICAL MAPPING OF BRAIN TUMORS USING MRI Principal Investigator & Institution: Mcmillan, Kathryn M.; Medical Physics; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2007 Summary: (provided by applicant): Integrating advanced magnetic resonance imaging (MRI) methods should better describe and delineate glioblastoma multiforme (GBM) brain tumors in preparation for radiation therapy treatment. We hypothesize that the use of these imaging modalities will result in more precise radiotherapy treatment planning. The proposed research is based upon extensive preliminary data indicating chemical shift imaging (CSI), perfusion and diffusion imaging and MR-based hypoxia mapping add additional information about tumor physiology that can be incorporated into a treatment pJan with the goal of decreasing the rate of tumor recurrence. Although regions of abnormality on T2 MRI are known to correlate with microscopic spread of tumor, some of this abnormality represents edema without malignant cells while other areas may contain a high concentration of malignant cells that should be incorporated into the treatment boost volume. While most malignant brain tumors recur within the radiation treatment fields, 20-25% of recurrences occur outside of these fields. Thus, the imaging techniques will be used to identify "high-risk subvolumes" within each tumor, which may be at high risk of recurrence. After completing radiotherapy, patients will be

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followed with serial advanced MRI scans; the study endpoint being the first recurrence. The location of the recurrence will test the prediction of the advanced imaging methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BORON NEUTRON CAPTURE THERAPY OF GLIOBLASTOMA MULTIFORME Principal Investigator & Institution: Diaz, Aidnag; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CATALASE MODULATION IN MALIGNANT AND NORMAL BRAIN CELLS Principal Investigator & Institution: Smith, Pameeka S.; Cancer Biology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2004; Project Start 17-JAN-2005 Summary: (provided by applicant): Glioblastoma Multiforme (GBM) is one of the most common brain lesions accounting for nearly half of all primary gliomas. Most gliomas are unresponsive to current cancer therapies due to the resistant nature of gliomas to radiation and chemotherapy. This resistance is hypothesized to be due in part to enhanced antioxidant enzyme activity. Catalase, an antioxidant enzyme that scavenges excess cellular hydrogen peroxides, is overexpressed in gliomas when compared to their normal cell counterpart, the astrocyte. Moreover, catalase expression has been found to correlate with increased resistance to oxidative stress. We hypothesize that inhibition of catalase using siRNA in gliomas will increase glioma sensitivity to radiation and anticancer agents. Radiation therapy, the major treatment modality for brain cancers, is limited by normal brain injury. We hypothesize that upregulation of catalase will protect normal brain cells from oxidative damage caused by radiation and chemotherapy agents. We will investigate the impact of catalase modulation in gliomas and normal brain cells to assess their impact on radiosensitization and radioprotection respectively. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL TRIALS IN USE OF PHOTODYNAMIC THERAPY FOR SUPRAFRONTAL BRAIN TUMORS Principal Investigator & Institution: Muller, Paul; Healthone Alliance 899 Logan St, Ste 203 Denver, Co 80203 Timing: Fiscal Year 2002 Summary: The overarching goal of project #2 is the assessment of the efficiency of porfimer sodium [Photofrin] in the photodynamic therapy of malignant brain tumors. Since brain tumors generally do not metastasize, improved local control should result in improved survival. We have shown Photofrin to have an effect on malignant glial tumors. Project #2 consists of two prospective clinical trials. The first [#1A] is a randomized controlled two arm clinical trail using Photofrin-PDT in newly diagnosed patients with malignant astrocytic tumors [malignant astrocytoma and glioblastoma multiforme] in order to determine whether the addition of Photofrin-PDT to standard surgical treatment[ surgical tumor resection, radiation therapy and chemotherapy] will

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result in a prolongation of the time to recurrence or progression and an increase in survival. Patients will be [after consent] stratified by treatment center and randomized to a no PDT control group or a high light dose [120 j/cm squared] PDT treatment group. The significance of differences in survival will be determined by the product limit estimate technique. The second is a randomized two arm clinical trial using PhotfrinPDT in recurrent malignant astrocytic tumors in order to ascertain the effect on survival of high light doses in comparison to low light doses. Patients will [after consent] be stratified by treatment center and randomized to a high light dose 120 j/cm squared or a low light dose [40 j/cm squared]. The significance of differences in survival will be determined by the product limit estimate technique. Also, we propose to carry out a number of ancillary measurements which will provide more fundamental information on the photosensitizer and light characteristics of human brain tumors. Photosensitizer measurement such as the uptake, photobleaching and distribution of Photofrin will be monitored, both by in vivo measurements at the time of surgery and PDT irradiation and by ex vivo analysis of tissue samples taken immediately before and after irradiation. Surgical specimens will be analyzed a) by extraction to measure the photosensitizer concentration and b) by confocal fluorescence microscopy, correlated with light microscopy, to assess the microdistribution of photosensitizer in the different tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPARATIVE DNA MICROARRAY ANALYSIS OF BRAIN TUMORS Principal Investigator & Institution: Brat, Daniel J.; Pathology and Lab Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 15-DEC-2001; Project End 30-NOV-2006 Summary: (provided by applicant): The following proposal is designed to provide the primary investigator, Daniel J. Brat, M.D., Ph.D., with necessary scientific experience and mentorship to allow a transition to an independent clinician scientist. Dr. Brat received his M.D. and Ph.D. degrees from Mayo Medical and Graduate Schools, and completed Anatomic Pathology and Neuropathology training at Johns Hopkins Hospital. His academic interests center on morphologic and molecular genetic investigations of primary brain tumors, both in terms of underlying mechanisms and classification. The goal of this proposal is to demonstrate a relationship between biologic behavior of brain tumors and their patterns of genetic alterations using comparative genomic hybridization in the format of DNA micro-arrays. Comprehensive tumor genotypes will be useful for determining pathways of genetic progression in distinct types of brain tumors, and for establishing patterns of genetic alterations that discriminate subsets of CNS neoplasms based on biologic behavior, response to therapy, and outcome. Genetic alterations that define certain gliomas are currently used to direct therapy: anaplastic oligodendrogliomas with 1p and 19q losses are sensitive to specific chemotherapy regimens. Distinct alterations among astrocytoma subtypes, including glioblastoma multiforme (GBM), have also been defined, but require further investigation in order to establish molecular subsets that may define behavior. Emerging micro-array technology offers the opportunity to define primary brain tumor genotypes comprehensively and precisely. Under the guidance of Erwin Van Meir, Ph.D., the first goal will be to demonstrate genetic alterations in the format of comparative genomic DNA arrays using a limited number of probes that are well characterized in adult GBMs. Once the experimental system has been validated, micro-arrays will be expanded to include a higher density of informational markers (200-300 loci). These will include gene families of significance in CNS tumorigenesis and markers from all chromosomes

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so that micro-arrays are useful for investigating patterns of genetic alterations in both glial and neuronal neoplasms, including those of childhood. Specialized DNA microarrays will be applied to biologically distinct brain tumors in order to define unique molecular genetic subgroups, and to gliomas from patients enrolled in clinical trials to determine if any patterns discriminate between tumors with regard to behavior, response to therapy, or clinical outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONSORTIUM THERAPEUTIC STUDIES OF CNS MALIGNANCIES Principal Investigator & Institution: Cloughesy, Timothy F.; Neurology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 14-MAY-2004; Project End 31-DEC-2008 Summary: (provided by applicant): UCLA Neuro-Oncology Program will participate in the clinical trials of the North American Brain Tumor Consortium (NABTC) as a "Member Institution". Member Institutions of the NABTC will also include, the University of Wisconsin, the University of Pittsburgh, Dana Farber Cancer Center, M D Anderson Cancer Center, the Neuro-Oncology Branch at the National Institutes of Health, the University of California, San Francisco, Memorial Sloan Kettering Cancer Center and the Pharmacokinetics Center at the University of Texas San Antonio. UCSF will be the Lead Institution and Dr. Prados the Group Leader for the NABTC. The focus of this grant will be to perform phase I and II clinical evaluations of promising new therapeutic agents or approaches for the treatment of primary CNS malignancies in adult patients, especially glioblastoma multiforme and other high grade gliomas. Additionally, we will perform ancillary laboratory studies of aspects of CNS tumor biology with potential clinical implications. UCLA will continue to extend it ongoing work with NABTC by interacting with other members of the consortium and with NCI in a concerted way to conceive, create and evaluate new approaches to the therapy of CNS tumors. This will be largely achieved through the existing environment and expertise that exist at UCLA including physician investigators, multidisciplinary approach, data management resources, patient population, expertise and advanced instrumentation for neuroimaging, surgery and radiation, and drug control procedures. UCLA will also provide an effective environment and expertise for multi-institutional protocol concept development and protocol conduct. Finally, significant infrastructure expertise exists at UCLA to aide the consortium with needs that are important for the acceleration of brain cancer translational research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONTRIBUTIONS OF AKT TO GLIOBLASTOMA FORMATION Principal Investigator & Institution: Pieper, Russ O.; Associate Professor; Neurological Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The long-term objective of this proposal is to improve the therapy of glioblastoma multiforme (GBM), the most common and fatal of human gliomas. GBM result from the step-wise accumulation of genetic alterations and often arise from low-grade gliomas and anaplastic astrocytomas (AA). We found that 4 alterations (telomerase and Ras activation and p53/pRb inactivation) in combination allowed normal human astrocytes to form AA. Additional Akt activation, however, allowed formation of 5-fold larger, necrotic GBM. These results suggest that Akt

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contributes to GBM formation, a finding consistent with Akt activation in greater than 80 percent of GBM. While Akt enhances growth and angiogenesis, these effects were not seen in vitro, nor were they noted in vivo until tumors reached a critical size, at which point the Akt-expressing cells rapidly expanded into modestly vascularized (yet still hypoxic) GBM while the non-Akt expressing cells slowly expanded into AA. The growth-enhancing properties of Akt therefore appear to be unmasked by an additional event which we believe to be hypoxia. We hypothesize that the stimulus for the formation of GBM is hypoxia, and that Akt activation uniquely allows cells to grow and survive under these conditions. We will test this hypothesis with the following specific Aims: 1) to determine if the point at which the growth of model AA and GBM diverge corresponds with the onset of hypoxia, 2) to determine if conditional activation of Akt drives proliferation/survival of hypoxic Ras tumors, and if conditional suppression of Akt inhibits proliferation/survival of hypoxic Ras+Akt tumors, 3) to determine if hypoxia selects for cells expressing high Akt levels in vivo, 4) to determine if hypoxic conditions alone allow differential proliferation/survival of Ras+ Akt versus Ras astrocytes, and 5) to determine at the molecular level if the effects of hypoxia on cell cycle regulation and survival are modulated by Akt. Defining Akt function may help identify targets useful in GBM therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--IMMUNOLOGICAL PRODUCT LAB

MONITORING

AND

CELLULAR

Principal Investigator & Institution: Whiteside, Theresa L.; Professor & Lab Director; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: THE IMMUNOLOGIC MONITORING AND CELLULAR PRODUCTS LABORATORY (IMCPL) will assume responsibility for providing immunologic laboratory support for the Programs in this Program Project. The specific objectives of this core will be to: 1) procure, process and bank human brain tumor or tissue specimens as well as body fluids for all projects; 2) establish human glioblastoma cell lines from tumor biopsies and maintain as well as expand these lines for pre-clinical studies; 3) measure or serially monitor cytokines and selected growth factors in the tumor microenvironment, body fluids or in cell supernatants; 4) develop, evaluate and perform monitoring assays to assess effects of immunotherapy or drug therapy on functions of immune cells, including apoptosis; 5) using ELISPOT assays for IFN-gamma production, to monitor changes in the frequency of anti-tumor CTL as a result of cytokine or cytokine+ vaccine administration to patients with brain tumors; 6) culture and evaluate characteristics of human dendritic cells (DC) for use in pre-clinical and clinical studies; 7) generate and provide quality cellular products, including fibroblasts, tumor cells or DC, transduced with the cytokine genes and secreting cytokines, specifically IL-4 for therapy of patients participating in clinical trials performed as a part of the Program; 8) perform safety testing on genetically-modified therapeutic products; 9) interact with investigators in projects 1 to 3 in the development of geneticallymodified human cellular products for in vivo and in vitro pre-clinical studies; 10) Perform evaluations of quality and sterility for all cultures and products designed for clinical use. To meet these diverse requirements, the Core will be organized into discrete units as follows: a) a cell product generation laboratory dedicated to culture, maintenance, genetic modification and selection of human cells for therapy; b) a tissue procurement and processing laboratory; c) a immunologic monitoring and cytokine unit; and d) a research laboratory for developmental preclinical studies. The IMCPL will

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operate according to the FDA guidelines for preparation of biologic products for therapy and will maintain good laboratory practice (GLP) standards. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--XENOGRAFT FACILITY Principal Investigator & Institution: Houghton, Peter J.; Member and Chairman; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 06-SEP-2002; Project End 30-JUN-2003 Summary: (provided by applicant): 1. The purpose of this core is to provide a facility for the propagation of xenografts of pediatric solo tumors, for use in all projects. The standard model will comprise tumor growing in the subcutaneous space of female severe combined immunodeficient (SCID) mice. 2. Coordinate tumor transplantation and make available tumor-bearing mice for biochemical and pharmacokinetic studies as required. 3. Undertake drug evaluation studies using standardized protocols. Data will be accessed directly into a microcomputer, and information distributed on a regular basis to individual project leaders, and to the Biostatistics Core for analysis. 4. Establish models of minimal residual disease for evaluating both cytotoxic and novel approaches to tumor eradication (e.g. gene therapy/antisense). 5. Develop models of disseminated disease as a secondary screen for drug evaluation. 6. Develop disseminated disease models with luciferase reporters for DNA damage, hypoxia, to monitor tumor growth, spread and drug-response using non-invasive techniques (Xenogen system). 7. Maintain and characterize human xenografts, and maintain frozen stocks. 8. Provide services (e.g. blood collection, 1 to 5 day infusions in mice). 9. To evaluate transgenic tumor models where requested. ) A program 'working committee' will serve to prioritize the order for evaluating new agents and strategies derived from individual projects, and for allocating resources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORRELATIVE GLIOBLASTOMAS

TRIAL

OF

FENRETINIDE

AGAINST

Principal Investigator & Institution: Puduvalli, Vinay K.; Neuro-Oncology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Malignant gliomas, the most common of which in adults is glioblastoma multiforme, carry a grave prognosis with high morbidity and mortality. Surgery, radiotherapy and chemotherapy are only of modest value in the management of these tumors. Among novel compounds being tested against gliomas, 13 cis-retinoic acid, as single agent or in combination, has shown activity against recurrent gliomas in clinical trials. Fenretinide, a related synthetic retinoid, induces apoptosis & decreases proliferation in a variety of malignancies in vitro and is well tolerated on oral administration in humans. Fenretinide inhibits proliferation of glioma cells by induction of apoptosis at 3 - 5 muM concentration (Puduvalli et al 1999). Data from Phase I trials indicate that fenretinide is well tolerated and concentrations of approximately10?M are achievable at a dose of 1200 mg/m2 twice daily. Based on these data, we hypothesize that fenretinide administered at this dose will result in glioma tissue concentrations sufficient to induce apoptosis and result in clinical efficacy in this tumor type. We also hypothesize that fenretinide can induce molecular & radiological changes that can serve as surrogate markers for the effect of this agent against gliomas. To test these hypotheses, we propose a Phase II trial (placebo-controlled) with clinical & correlative

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endpoints. Clinical Trial Design: 40 patients with recurrent glioblastoma due to undergo surgery will be randomized in a blinded manner to receive fenretinide or placebo orally (20 patients each group) for 7 days prior to surgery with serum samples being collected for pharmacokinetic studies. At surgery, resected tissue will be collected with concurrent serum samples for correlative studies. All 40 patients will then continue on open label fenrentinide therapy until tumor progression. Specific Aims: Aim 1) To determine the efficacy of fenretinide against recurrent glioblastomas as measured by 6month progression free survival (clinical endpoint) Aim 2) To determine the levels of fenretinide in glioma tissue and correlate it with serum concentrations. Aim 3) To determine whether fenretinide induces apoptosis in tumor tissue and correlate the degree of apoptosis with serum and tissue concentrations of 4-HPR and with clinical efficacy. Aim 4) To identify radiological and molecular surrogate markers of fenretinide effects on glioma tissue by utilizing - a) serum & tissue markers related to retinoid signaling such as retinol, retinol binding protein, retinoid receptors (RARgamma, RARbeta & RXR alpha) and IGF-1; b) Multivoxel MR Spectroscopy (MRS) of the tumor (before and after 7 day presurgery treatment with fenretinide) to detect changes indicative of apoptosis and correlate this with apoptosis seen in MRS-targeted tissue samples; c) Oligonucleotide microarrays to determine transcriptionally altered molecules relevant to gliomas including those that mediate invasion, angiogenesis and apoptosis. Data from this study about the tissue effects of fenretinide could hence provide new insights into the mechanism of action of fenretinide at the target tissue level. Such data could be relevant not only to future trials of retinoids in gliomas but also for ongoing trials of fenretinide in other malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE SIGNALING IN GLIOBLASTOMA CELLS Principal Investigator & Institution: Haque, Saikh J.; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 29-FEB-2004 Summary: (provided by applicant): The long-term objective of this proposal is to understand cytokine-mediated regulation of proliferation and apoptosis of malignant glioblastoma cells. Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumors, with an average survival of less than a year. GBM arises from a complex series of molecular events that include inactivation of tumor suppressor genes as well as overexpression and activation of proto-oncogenes. Consequently GBM cells become highly proliferative and resistant to apoptosis. The latent transcription factor Stat3, which is activated by IL-6-family of cytokines and other growth factors induces the expression of genes that are responsible for the suppression of apoptosis in a variety of human cancer cells. Although GBM cells secrete IL-6 and respond to it, little is known about the role of Stat3 activation in the regulation of apoptosis in GBM cells. We found that Stat3 is constitutively activated by an autocrine action of IL-6 in GBM tumor tissues and GBM cell lines. Inhibition of Stat3 activation by the Jak-specific tyrosine kinase inhibitor AG490 reduces steady state levels of anti-apoptotic proteins Bcl-2, BcIXL and Mcl-1, and induces apoptosis in GBM cells. In contrast, AG490 does not induce apoptosis in normal human astrocytes. Interestingly, Stat3 is activated by IL-4 in GBM cells that is in part, attributable to the expression of IL-13Ra2, a decoy receptor for IL-13. IL-4 normally activates Stat6 but not Stat3 by signaling through the classical Jak-Stat pathway, and produces growth arrest in normal human astrocytes and low-grade gliomas that do not express IL-13Ra2. In consideration of these observations, we hypothesize that (i) constitutive activation of Stat3 via an autocrine action of IL-6,

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provides survival signal in GBM cells by inducing the expression of anti-apoptotic genes, and (ii) IL-4 induces further activation of Stat3 in these cells via an IL-13Ra2dependent novel mechanism. To test these hypotheses we will pursue the following specific aims. 1. To define the role of activated Stat3 in the survival of GBM cells we will: (a) Express a dominant negative mutant Stat3 (DNStat3) and the suppressor of cytokine signaling (SOCS)-I in GBM cells via an ecdysone-inducible system, and determine their apoptotic response in vitro, and (b) Determine the effects of Stat3 inactivation by DNStat3, SOCS-1 and AG490 on the growth of intracranial and subcutaneous transplants of GBM cell lines in rodent brain tumor models. 2. To identify cellular and molecular mechanisms underlying the IL-4-mediated activation of Stat3 in IL-13Ra2expressing glioma cells we will: (a) Determine if IL-13Ra2 expression level parallels the malignancy grade of glioma and is associated with aberrant Stat activation by IL-4, and (b) Define the role of IL-13Ra2 in the regulation of IL-4-dependent signal transduction in GBM cells. This investigation will define cellular and molecular mechanisms underlying Stat3-mediated survival of GBM cells, and thus significantly advance our current understanding of the molecular pathobiology of GBM, and importantly will lead to the development of novel therapies for this deadly disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DAILY INTRAVENOUS DOSES OF RSR13 TO PATIENTS RECEIVING CRANIAL RADIATION Principal Investigator & Institution: Mahajan, Anita; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 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: DEVELOPMENT OF IMMUNODIAGNOSTICS FOR PANCREATIC CANCER Principal Investigator & Institution: Ghanbari, Hossein A.; Panacea Pharmaceuticals, Inc. 207 Perry Pky, Ste 2 Gaithersburg, Md 20877 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-AUG-2003 Summary: (provided by applicant): Current methods for the diagnosis and management of neoplastic disease rely heavily on imaging techniques, such as X-ray, CT scanning and MRI, tissue biopsy and histopathological findings. Much effort has been put forth to identify other less costly and less invasive means for the diagnosis and monitoring of cancers. In certain cases specific molecular tumor markers have been identified that show promise as potential diagnostic and prognostic indicators, but unfortunately, most of these markers lack the requisite specificity and sensitivity. The long-term objective of this research program is to develop immunodiagnostic assays for the detection of the tumor marker, human aspartyl (asparaginyl) beta-hydroxylase (HAAH). Recent work has demonstrated the over-expression of HAAH in a wide variety of malignant tumors, including pancreatic carcinoma, glioblastoma multiforme, hepatocellular carcinoma, and cholangiocarcinoma. Additionally, unlike other potential tumor markers, overexpression of HAAH displays high specificity for malignant cells. The dismal prognosis associated with cancer of the pancreas is because very few of these cancers are found prior to their spread to other organs. To date, no molecular markers for pancreatic cancer have been identified, validated and accepted for clinical use for early diagnosis. The Specific Aims of this proposal are to establish HAAH as a soluble marker for

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pancreatic cancer, to develop highly sensitive and specific immunoassays for the detection of HAAH in bodily fluids, and to correlate the levels of HAAH in the serum and/or pancreatic juice of individuals diagnosed with pancreatic carcinoma to disease diagnosis and patient outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG SENSITIVITY OF CALCIUM MODULATORS FROM BRAIN TUMOR Principal Investigator & Institution: Hait, William N.; Director; Medicine; 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-MAY-1987; Project End 31-DEC-2006 Summary: (provided by applicant): Glioblastoma multiforme (GBM) is one of the most devastating malignancies in children and adults. Despite aggressive treatment with surgery, radiation, and chemotherapy, the prognosis of patients with this disease has not improved substantially in the last two decades. Therefore, we have studied new approaches to treatment of GBM by investigating the calcium-calmodulin pathway of signal transduction that is used to transmit growth factor receptor activation to the nucleus for cell division and survival. We discovered that calmodulin-dependent kinase III, also termed elongation factor 2 kinase, was markedly overexpressed in GBM. We also found that this enzyme appeared to be mitogen activated. Furthermore, inhibitors of calmodulin signaling were potent cytotoxic agents against GBM cell lines. We recently cloned and sequenced elongation factor-2 kinase and described its unique characteristics. With little homology to any of the conventional protein kinases previously described, we established this kinase as a representative of a new superfamily of mitogen-activated protein kinases. In this proposal, we describe studies designed to validate the enzyme as a target for drug discovery for GBM, describe new and potentially promising inhibitors that target the unique features of the enzyme, and propose to move the most active agents through biochemical and cellular biology testing, through several increasingly rigorous animal models. Therefore, the overall goal of this proposal is to identify new drugs for the treatment of GBM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EGFR MEDIATED APOPTOSIS IN GLIOMAS Principal Investigator & Institution: Habib, Amyn A.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 22-JUN-1999; Project End 31-MAY-2004 Summary: Glioblastoma Multiforme is the most common malignant tumor of the central nervous system. It is resistant to current methods of treatment and is associated with a poor prognosis. The elucidation of novel strategies to kill glial tumor cells is thus an urgent need. The epidermal growth factor receptor (EGFR) gene is amplified and overexpressed in about half of these tumors. Epidermal growth factor acts as a mitogen and over-expression of its receptor may contribute to the excessive proliferation seen in cancer. However, ligand stimulation of cells over-expressing the EGFR also has been shown to induce apoptosis. Thus a key answered question in tumor biology is: what are the factors which determine whether excessive activation of growth factor receptors leads to mitogenesis versus apoptosis? An improved understanding of mechanisms involved in the preferential activation of apoptosis may lead to more effective treatment. Our first approach will e to use inducible transfection systems to determine the

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Glioblastoma Multiforme

threshold of receptor expression in glioma cells whereby a mitogenic signal changes to a death signal. Our preliminary data suggests that over-expression of the EGFR results in the aberrant activation of cell death pathways and leads to the recruitment of key proteins involved in apoptosis such as RIP and Caspase-8 to the EGFR mediated apoptosis in glioma cells in vitro as well as in animal models of glial tumors. The applicant is a board-certified neurologist who has taken care of patients with nervous system tumors and is committed to a career in academic neuro-oncology. The program outlined in this application provides a rigorous and intensive didactic and research experience, which will enable the applicant to pursue a career as an independent researcher. The mentor is the Director of Cancer Biology at Beth Israel Deaconess Medical Center (BIDMC), and has extensive experience in signal transduction mediated by receptor tyrosine kinases. The clinical mentor is a neuro-oncologist who is the CoDirector of the Brain Tumor Center at BIDMC. The academic environment at Harvard Medical School at BIDMC is well suited to pursue the goals outlined in this application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EGFR SIGNALING IN HUMAN NEURAL STEM CELL PHENOTYPE Principal Investigator & Institution: Boockvar, John A.; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 08-AUG-2002 Summary: (provided by applicant): Human neural stem cells have the potential to substitute for fetal tissue in central nervous system (CNS) transplantation strategies and to act as vehicles for the delivery of gene products to particular regions of the brain and spinal cord. Epidermal Growth Factor Receptor (EGFR) plays a role in determining properties of differentiated neural cells and we hypothesize that the EGFR plays an important role in determining the phenotype of human neural stem cells. Therefore, these studies will explore the growth, differentiation, survival, and motility properties of human neural stem cells in which EGFR signaling pathways are modified by genetic means. We will utilize erbB family receptor mutants that have been shown to activate or inhibit EGFR signals in order to test our model that EGFR signaling modulates the human neural stem cell phenotype. By modulating EGFR signaling, we propose to alter survival, proliferative, and motility phenotypes of neural stem cells in vitro and in vivo. We will assess the growth, survival and migration properties of these cells in the normal brain and the injured brain, using an experimental head injury model, with the rationale that normal and EGFR-modulated human neural stem cell clones will display distinct phenotypes in particular brain microenvironments. Finally, we will assess cognitive and motor improvements in brain-injured animals after neurotransplantation with the rationale that normal and EGFR-modulated human neural stem cell transplants modify functional outcome after closed head injury. The proposed studies have therapeutic implications for a wide array of neurological diseases, including traumatic CNS injury; neurodegenerative diseases including Parkinson?s and Alzheimer?s disease; single enzyme disorders; and glioblastoma multiforme. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENGINEERED HSV FOR TREATMENT OF MALIGNANT GLIOMAS Principal Investigator & Institution: Whitley, Richard J.; Professor of Pediatrics; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 15-AUG-1997; Project End 30-APR-2008

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Summary: (provided by applicant): This Program Project grant submission requests funds to support continued studies of genetically engineered HSV-1 (HSV) as a novel, yet practical approach to the treatment of human brain tumors. The interdisciplinary expertise of investigators at the University of Chicago (Drs. B. Roizman and R. Weichselbaum) and the University of Alabama at Birmingham (Drs. R. Whitley, J. Markert, Y. Gillespie and J. Parker) will continue to generate molecular biologic data on genetically engineered HSV and to translate their observations to Phase I clinical trials of human glioblastoma multiforme. This highly collegial and productive group of investigators began these studies four and a half years ago with three projects and two cores. We now propose four projects and three cores, as the clinical adaptation of our fundamental discoveries becomes more immediate. Roizman proposes to construct entirely novel therapeutic HSV that will specifically target cell surface receptors expressed specifically and at high abundance on glioma cells in situ. Already, they have preliminary constructs that selectively infect and, replicate only in, human glioma cells. Weichselbaum will focus on the synergistic anti-tumor interaction between HSV and radiation therapy. Based upon their fundamental observation that radiation enhances viral replication and spread within intracranial tumors, they propose to identify cellular and viral genes that are up/down regulated so that they can use these data to drive the design of new viruses that exhibit this synergistic effect. Whitley will focus on the generation of viruses with enhanced oncolytic potential for human gliomas. They will determine whether viruses selected with novel properties demonstrate enhanced neurovirulent properties. New viruses and treatment enhancing discoveries will be funneled into Markert, which will begin the process of translating genetically engineered viruses to clinical trials. A genetically engineered deltagamma1 34.5 HSV that expresses Interleukin-12 was constructed during the initial period of funding and will be the first candidate virus to be advanced into Phase I clinical trials. Each of these projects is supported by three cores: Whitley (including biostatistical support), Experimental Animal Glioma Model-Gillespie (testing safety and efficacy in relevant animal models) and Viral Production-Parker (production and characterization of highly purified, high-titered virus stocks). This team of investigators anticipates enhanced successes in the future period of funding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENHANCED DRUG DELIVERY TO METASTATIC BRAIN TUMORS Principal Investigator & Institution: Black, Keith L.; Director; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Brain capillary endothelium and its contiguous cells, pericytes and astrocytes, are the structural and functional components of the bloodbrain barrier (BBB). Microvessels supplying brain tumors retain characteristics of the BBB, forming a blood-tumor barrier (BTB). While adequate delivery of drugs occurs to systemic tumors, the BTB limits delivery of antineoplastic agents to metastatic brain tumors. Drugs such as Herceptin, which is effective in treating metastatic tumors outside the brain have a high failure rate within the brain due to inadequate delivery across the BTB. The incidence of metastatic brain tumors is ten-fold higher than primary brain tumors. We have demonstrated that calcium-sensitive potassium (KCa) channel agonists selectively increase drug delivery across the BTB, and have postulated the biochemical mechanisms of this selective BTB permeability increase. We also have preliminary data suggesting that ATP-sensitive potassium (KATP) channel agonists selectively increase BTB permeability independent of KCa channels. These novel

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Glioblastoma Multiforme

observations allow for a pharmacological mechanism for selectively increasing drug delivery across the BTB. This proposal will (a) further understand the mechanisms of KCa, and KATP channel activation in increasing BTB permeability and (b) optimize delivery of effective concentrations of drugs to metastatic breast and lung tumors in rats and humans via potassium channel-based mechanisms. We build on our data showing the ability of KCa channel agonists to selectively increase drug delivery across the BTB in rat glioma models and preliminary evidence suggesting that the BTB permeability increase may relate to over expression of KCa channels on glioma cells and tumor capillary endothelium. In this grant we will investigate 5 specific aims. Aim 1: To determine whether KCa and KATP channels are over expressed in metastatic brain tumor microvessels and tumor cells and whether increased expression correlates with increased permeability induced by KCa and KATP agonists. To test whether tumor cells can induce over expression of KCa or KATP channels on brain endothelial cells. Aim 2: To test by quantitative electron microscopy whether the mechanism of KATP channel agonist-induced BTB permeability increase is due to increased endothelial vesicular transport or opening of tight junctions. To test whether increased vesicle formation is correlated with changes in endothelial and tumor cell membrane potential. Aim 3: To investigate whether KCa and KATP channel agonists increase delivery of therapeutic monoclonal antibodies and chemotherapeutic drugs across the BTB into metastatic human breast and lung cancer in nude rats/mice. Aim 4: In nude rats/mice harboring metastatic breast and lung tumors we will investigate whether increased drug delivery across the BTB using KCa or KATP agonists results in inhibition of tumor growth, and whether survival is increased. Aim 5: The ability of a KATP channel agonist, minoxidil, to increase delivery of an anti-tumor drug to patients with brain tumors will be determined by LC-MS-MS in resected tumor tissues. This grant is responsive to the recent Brain Tumor PRG recommendation in 2001 to support studies to improve delivery of drugs across the BBB, particularly for metastatic brain tumors. Overall, these studies will further delineate the role of KCa and KATP channel activation as a mechanism for selective delivery of anti-cancer agents across the BTB and could potentially result in improved control of disease in patients with metastatic brain tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF ASTROCYTOMAS WITH HRMAS 1HMR SPECTROSCOPY Principal Investigator & Institution: Cheng, Leo L.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 15-FEB-1999; Project End 31-JAN-2004 Summary: Astrocytomas, the most common type of brain tumors, are primarily diagnosed by the histopathological evaluation of cellular morphological changes in biopsy samples. In addition to changes in cell morphology, tumors also display altered cellular biochemistry. Tumor metabolic alterations may provide valuable information for clinical grading, biology-based prognosis, and therapeutic monitoring of astrocytomas. Conventional ex vivo 1HMRS has been used to study tumor samples; however, it is hampered by the need for the often destructive chemical extraction of tissue. We propose to evaluate the diagnostic potential of the newly developed highresolution magic angle spinning (HRMAS) proton magnetic resonance spectroscopy (1HMRS) on intact specimens of human astrocytomas. We plan to quantify HRMAS metabolites and measure histopathological features on the same tumor specimens, to select tumor metabolic markers, and to establish biochemical databases for astrocytoma

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diagnosis and prognosis. Our specific aims are: 1) To quantify metabolic concentrations with HRMAS 1HMRS in different regions of normal human brain; 2) To quantify metabolic alterations in newly diagnosed, adult supratentorial, diffuse fibrillary astrocytomas, and to use these measures to identify and define HRMAS 1HMRS markers able to type and grade these tumors; 3) To evaluate the capability of HRMAS spectroscopic markers in predicting the histological grade of adult cerebral hemisphere astrocytomas; and 4) To evaluate the usefulness of HRMAS metabolic markers as independent indicators of tumor behavior and predictors of 2 year survival for patients with glioblastoma multiforme (GBM). If successful, our study will establish astrocytoma HRMAS metabolic databases and objective parameters to serve as an adjunct modality for predicting tumor development, progression and patient outcome. We expect that current diagnostic sensitivity and specificity will be improved by utilizing HRMAS 1HMRS tumor markers. The results from this study will also further current understanding of tumor neurobiology and provide new linkages among fields such as clinical pathology, clinical radiology, tumor biology and molecular genetics. Astrocytoma metabolic markers obtained from this study will have important implications on the future development of magnetic resonance spectroscopic imaging (MRSI) and localized in vivo MR spectroscopy for non-invasive diagnosis and therapeutic monitoring of these neoplasms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION BASED CLASSIFICATION OF GLIAL TUMORS Principal Investigator & Institution: Nelson, Stanley F.; Research Scientist; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JAN-2005 Summary: (Applicant's Description) Astrocytic brain tumors are among the most lethal and morbid tumors of adults, often occurring during the prime of life. The current system of diagnosis and classification of brain tumors is partially predictive of outcomes, and remains based primarily upon morphologic criteria. Although recent work has shown a number of genetic differences which are critical in the oncogenesis and progression of astrocytic tumors, there is insufficient data to develop a molecular classification system. The availability of cDNA clones, large amounts of sequence, data and the technology for cDNA arrays provides a platform for the large scale analysis of gene expression in astrocytoma. We propose to identify a set of genes that will allow the molecular characterization of brain tumors by using cDNA microarray technology. Using a flexible microarray format will enable us to easily alter the arrayed genes whose expression patterns are most informative allowing us to create cost-effective glial tumorrelated reagents. It is our central hypothesis that a much more detailed analysis of the genes that are expressed in astrocytomas will provide a more precise prognostic ability, subgroup patients for optimal treatment, and help identify appropriate therapeutic targets, subgroups patients for optimal treatment 1)To determine the optimal means of sampling low grade astrocytomas, anaplastic astrocytomas, and glioblastoma multiformes, to determine the degree of molecular heterogeneity within astrocytic tumors, to determine whether the heterogeneity is greater between tumors than within an individual tumor at each gene, and to determine the level of variance of each gene on the microarray. 2)To determine the gene expression profiles of 120 excisional glioma and meningioma brain tumor biopsies to develop a reclassification of the tumors based on gene expression profiles. 3)To develop a set of genes with prognostic importance in low

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grade astrocytomas. 4)To validate the importance of the genes from specific aims 2 and 3 in the prognosis of low grade astrocytomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR BRAIN TUMORS USING ANTISENSE CDNA TRANSCRIPTION GROW Principal Investigator & Institution: Ilan, Joseph; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002 Summary: This study represents a treatment approach based on an antisense gene therapy strategy for otherwise incurable malignant human brain tumors. The specific aims are (1) to demonstrate the safety of subcutaneous injection of autologous in-vitro cultured, transfected and irradiated glial tumor cells from patients with glioblastoma multiforme and (2) to demonstrate the efficacy of injection of autologous in-vitro cultured and transfected glial tumor cells in destruction of native tumor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY FOR GLIOMA Principal Investigator & Institution: Lowenstein, Pedro R.; Director and Professor; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Glioblastoma multiforme (GBM) is the most aggressive brain tumor and kills through intracranial growth and spread. We have previously shown (i) the efficiency of the herpes simplex virus type 1 thymidine kinase (HSV1-TK) and systemic ganciclovir (GCV) in eradicating an experimental syngeneic glioma model, (ii) 2-3 fold higher astrocyte- and glioma-specific high-level expression from the powerful 1.4kb major immediate early routine cytomegalovirus promoter (mCMV) compared to the human CMV equivalent, and (iii) unexpected long-term presence (12 months) of HSV1-TK in the brain. Although the efficiency of HSV 1-TK and GCV has been shown in a large variety of experimental models, the clinical results, while encouraging, remain inconclusive. The main reason thought to underlie this difference is the low levels of HSV1-TK expression from currently available vectors. Our experiments will address this issue by vastly increasing therapeutic transgene expression (through the use of a novel promoter) and reducing the viral vector toxicity (through the use of novel safer vectors of reduced toxicity). These findings will have important clinical implications and provide a blueprint for the implementation and design of Phase I clinical trials of gene therapy for GBM. We will validate the efficiency of a novel, safe, high capacity, helper dependent adenoviral vector (HC-Ad) expressing HSV1-TK under the control of the powerful mCMV promoter in a clinically relevant syngeneic experimental glioma model. HSV1-TK induces glioma cell death by phosphorylating the prodrug GCV, and killing both transduced and adjacent nontransduced, actively dividing cells. Killing of non-transduced cells, the 'bystander effect', amplifies this strategy's efficiency through cell-cell diffusion of cytotoxic intermediates (e.g. phosphorylated GCV), release of pro-apoptotic molecules, and immune stimulation. We hypothesize that our novel anti-tumor strategy will deliver high intraand peritumoral expression of the therapeutic transgene that, combined with systemic dosing of GCV, will lead to sustained and effective anti-tumor effect. Our long term aim is to translate this novel therapeutic approach into a Phase I clinical trial for GBM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE THERAPY MULTIFORME--PHASE I TRIAL

FOR

RECURRENT

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GLIOBLASTOMA

Principal Investigator & Institution: Lieberman, Frank; Mount Sinai School of Medicine of Cuny New York, Ny 10029 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY TARGETING HYPOXIC GLIOMA CELLS Principal Investigator & Institution: Deen, Dennis F.; Berthold and Belle N. Guggenhime Profess; Neurological Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: Radiation is a primary treatment modality for patients with malignant gliomas, and in most patients radiation therapy is clearly beneficial. However, the overall outcome of therapy for these patients is dismal, and most patients with glioblastoma multiforme (GBM) die within a year of diagnosis. The presence of hypoxic cells in brain tumors is a major obstacle for radiation therapy, because these cells are notoriously resistant to radiation-induced damage. Therefore, we propose to devise a gene therapy approach for killing hypoxic brain tumor cells during the course of radiation therapy. The DNA construct to be delivered to the tumor cells contains hypoxia-responsive elements (HREs) in the enhancer region of the promoter and a suicide gene. Under hypoxic conditions, the transcriptional complex hypoxia inducible factor-1 (HIF- 1) builds up in cells and binds to HREs. This, in turn, activates the adjacent promoter and causes expression of the downstream suicide gene that kills the cell. This project has 2 goals. The first is to investigate how several cellular or intratumoral characteristics impact on this gene therapy strategy. The second is to investigate whether the gene therapy enhances the radiation response of the tumor cells. We propose 4 specific aims to accomplish these goals. 1) investigate the relationship between HIF-1 and oxygenation status in brain tumor and normal brain; 2) evaluate suicide genes under low pH and in noncycling brain tumor cells; 3) reveal and investigate any bystander effect (BE) produced by specific suicide genes under hypoxic conditions; 4) determine whether expression of suicide genes in hypoxic and oxic cells enhances their response to radiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC PATHWAYS TOWARD GLIOMAGENESIS Principal Investigator & Institution: Maher, Elizabeth A.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 06-JUL-1999; Project End 30-JUN-2004 Summary: (Applicant's Description): Patients with de novo glioblastoma multiforme have a median survival of nine months when treated with currently available therapy. Although the prognosis for low-grade astrocytomas is significantly better, in at least 50 percent of cases, these tumors will progress to intermediate-grade (anaplastic) astrocytomas and finally to glioblastoma multiforme. Progress in the understanding of the pathogenesis of these deadly brain tumors has been hampered by the lack of a bonafide animal model that recapitulates the genetics and biology of this disease. Cytogenetic analysis of clinical glioma specimens has identified multiple genetic lesions

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Glioblastoma Multiforme

known to be involved in oncogenic/tumor suppressor pathways. The working hypothesis of the applicant is that distinct genetic pathways govern the development of the two clinical subtypes of glioblastoma. Those that develop from low- or intermediategrade astrocytomas accumulate mutations over time in key pathways involved in growth, differentiation, apoptosis and angiogenesis, producing progressively more aggressive phenotypes. In contrast, de novo glioblastomas arise as a consequence of a critical combination of mutations in which the initial phenotype is the highest grade tumor. The DePinho laboratory has engineered and extensively characterized strains of mice with deletions of several of the genes which likely participate in the pathogenesis of these distinct disease entities. The availability of these mice coupled with the laboratory's expertise in transgenic and knockout technology, provides the applicant with a unique opportunity to probe the genetic mechanisms of gliomagenesis, develop a spontaneous mouse model of glioblastoma, and gain conceptual and technical experience in these areas. Aim 1: To generate a transgenic mouse that expresses fluorescently-labeled intermediate filaments, GFAP and nestin, to be used as specific markers of astrocytes and stem cells, respectively, in all experiments. Aim 2: To assess the role of overexpression of the oncogene, EGFR, in the pathogenesis of glioblastoma. Aim 3: To study the biological effects of known mutations in key tumor suppressor pathways governing growth, differentiation and survival of glial cells and how such mutations functionally interact with activated EGFR. Aim 4: To identify genes that cooperate with known oncogenes and tumor suppressors in the development and/or progression of malignant gliomas using a well-established retroviral insertional approach. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENOMIC & GENETIC CHARACTERIZATION OF AMPLICONS IN GBMS Principal Investigator & Institution: Chin, Lynda; Assistant Professor of Adult Oncology; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 24-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Alterations in EGFR, PDGF, INK4a, p53 and/or PTEN are among the most common lesions encountered in malignant gliomas. Notably, a significant proportion of malignant gliomas do not harbor these signature genetic lesions, implying that many other glioma relevant mutations remain unidentified. Recent advances in functional genomics have provided new capabilities for the rapid identification and characterization of candidate glioma-relevant genes and their pathways. Taking advantage of the presence of recurrent chromosomal alterations associated with amplification or deletion of specific genes in malignant gliomas, arraybased CGH technique has identified five high-frequency regions of gains. Employing the newly optimized array-based CGH on cDNA microarray platform, we will finely map and characterize these five loci of chromosomal aberrations to identify all candidate genes within the minimal regions of involvement. Complemented with various expression - based analyses, we will identify the most likely targets of CNAs for in vitro and in vivo functional validation. The highest potential candidate glioma oncogene will be further validated by rigorous in vivo transgenesis study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLIOMA THROUGH GENOMICS AND TRANSGENIC MOUSE MODEL Principal Investigator & Institution: Zhang, Wei; Director, Cancer Genomics Core Lab.; Pathology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2008 Summary: (provided by applicant): Glioma represents the single most frequent primary brain malignancy. The most advanced form of glioma, also the most invasive, is glioblastoma or GBM that comprises 50-60% of all gliomas. The median survival for GBM patients is less than a year. Only about 20% of patients respond to therapy and live for more than 1.5 years following initial diagnosis. Intensive research during the last two decades has demonstrated that cancer progresses with an accumulation of genetic and molecular alterations that enables cells to acquire at least six capabilities (Hanahan and Weinberg, Cell 100:57-70, 2000). Evidence from in vitro and in vivo model systems has been accumulated that identifies some of those events at gene expression level. Animal models including transgenic and knockout models have been used to test the importance of some of the identified molecular events in in vivo setting (van Dyke and Jacks, 2002). For example, expression of EGFR (Holland et al., 1998), PDGF (Dai et al., 2002), K-ras in combination with akt (Holland et al., 2000), have been shown to induce gliomas in transgenic models, which has been highly valuable to sort out what the key events are in tumor formation and tumor phenotypes. Some models, such as the glialspecific mouse model (the RCAS/tv-a system) developed by Holland and Varmus (Holland et al., 1998) permit transgenic expression of multiple genes in one experimental setting thus the effect of gene combination can be evaluated. Using genomics and informatics approaches, we have profiled gene expression in different grades of gliomas and identified genes, such as insulin-like growth factor binding protein 2 (IGFBP2), that are uniquely overexpressed in GBM (Fuller et al., 1999). Our in intro experiments showed that IGFBP2 overexpressing cells was more invasive. IGFBP2 was also associated with shortened survival in GBMs (Sallinen et al., 2000, and our unpublished data). These studies led us to hypothesize that IGFBP2 is a key molecule that contributes to invasion of GBM cells and short survival of GMB patients. We also hypothesize that IGFBP2 overexpression plays a positive role in glioma progression to GBMs. In this project, we propose to test the hypotheses using the RCAS/tv-a mouse model. We further hypothesize that GBMs developed in mice are homologous to human GBMs and this can be evaluated by comparative gene expression profiling as well as focused set of genes. The three specific aims are: (1) To test whether IGFBP2 enhances GBM development shortens survival of GBM mice, and increases GBM cell invasion in vivo. (2) To examine whether IGFBP2 plays an important role in progression from low-grade glioma to GBM. (3) To characterize mouse gliomas using gene expression profiling. Through this program, we want to enrich our knowledge of IGFBP2 pathways that are likely important for glioma development and progression; we also want to use genomics approach to evaluate whether mouse gliomas faithfully represent human gliomas at gene expression levels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RESISTANCE

GSH

TRANSFERASE

PI

POLYMORPHISM

AND

DRUG

Principal Investigator & Institution: Ali-Osman, Francis; Professor & Head; Experimental Pediatrics; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-JAN-2004

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Glioblastoma Multiforme

Summary: (Applicant's Abstract) Malignant brain tumors continue to increase in incidence in the US, and currently are the most common solid tumors of childhood and adolescence. Unfortunately, however, brain tumors remain among the most therapeutically intractable of human tumors, and long term survivors are rare among patients with highly anaplastic astrocytomas or glioblastoma multiforme. A major cause of failure of brain tumor therapy, as in most other human cancers, is drug resistance, and much effort has been devoted towards understanding the cellular and molecular mechanisms that underly it. These studies have shown that drug resistance mechanisms often involve the dysregulation of genes, many of which are involved in normal cellular processes, such as metabolism, transport, DNA repair and cell cycle progression. One of the best characterized of these mechanisms is that of GST-pi overexpression. This application is founded on two significant recent findings from the applicant's laboratory related to the GST-pi gene. The first is that in gliomas, GST-pi over-expression is associated with drug resistance, malignant progression and poor patient survival. Secondly, he has made the potentially very important discovery that the human GST-pi gene locus is polymorphic and contains, at least, three allelic GST-pi gene variants. One of these variants, hGSTP1*C, is more frequently present in gliomas than in normal cells/tissues. The applicant has cloned the variant cDNAs and shown the encoded proteins to be structurally and functionally different. These findings are having a significant impact in the field of GST research. The primary goal of this application is to examine the influence of this newly discovered GST-pi genetic polymorphism on drug resistance in human gliomas and to determine whether specific GST-pi genotype/phenotypes are associated with differential therapeutic outcome and in patient survival. The Specific aims are: 1) To determine by molecular dynamic modeling, the differential binding affinities of anticancer agents to the active sites of proteins encoded by GST-pi allelic gene variants and correlate these with the differential abilities of the GST-pi proteins to inactivate anticancer agents; 2) To determine whether different GST-pi gene variants confer different levels of drug resistance to malignant glioma cells; 3) To determine whether GST-pi allelotype is related to the level of in vitro drug resistance of gliomas, and with in vivo response to therapy and survival of glioma patients following chemotherapy; and, 4) To determine whether down-regulation of GST-pi gene expression in gliomas that express different GST-pi gene variants will differentially affect drug resistance. The applicant believes that this application is wellfocused and has a significant degree of novelty, with respect to the hypothesis, preliminary data and experimental techniques to be used. He believes the results are likely to make important and critical contributions to understanding the cellular, molecular and genetic mechanisms involved in GST-pi mediated drug resistance in human gliomas that will be applicable to many other human tumor types for which GST-pi over-expression has been shown to be an important determinant of drug resistance and failure of patients to respond to therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH-RESOLUTION CGH CHARACTERIZATION OF BRAIN TUMORS Principal Investigator & Institution: Gregory, Simon G.; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-JAN-2006 Summary: (provided by applicant): It has been known for many years that malignant tumors have chromosome losses that contribute to their malignancy. In recent years, considerable research effort has been directed at identifying the one common region of

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deletion that occurs within specific tumor types in order to identify the actual gene(s) involved in the transformations. Traditionally, loss of heterozygosity mapping, using polymorphic markers and genotype information, and comparative genomic hybridization (CGH), utilizing normal metaphase chromosomes as the template upon which differentially labeled test and control samples are hybridized, have been used to identify chromosomal rearrangements. However, these approaches have proven to be relatively time consuming and have low resolution when identifying aberrant chromosomal regions. The project outlined here describes the development of highresolution, chromosome specific, CGH arrays for the detection of chromosomal deletions and amplifications in neurological neoplasia. High-resolution array CGH will allow for very rapid and accurate (100 -200 kilobase) characterization of chromosomal rearrangements within a large number of tumors. High-resolution genome-wide coverage, on a per-chromosome basis, will be achieved by utilizing complete, overlapping, minimum-tile path clones that were generated by the Human Genome Project in its production of highly accurate genomic sequence. The research project contains four basic aims; aim 1, the generation of genome-wide 1Mb, chromosome and region specific high-resolution CGH arrays, including the purification of minimum-tile path DNA and production of amino linked DOP-PCR products; aim 2, the characterization of the arrays by testing with differentially labeled normal DNA's as well as known deletions and amplifications; aim 3, the characterization of clinically defined brain tumor types (glioblastoma multiforme, oligoastrocytoma and oligodendroglioma) by high-resolution CGH hybridization to determine exact regions of chromosomal rearrangement and therefore the putative disease causing genes within them; aim 4, investigate the use of high-resolution CGH arrays as a diagnostic tool for predicting the responsiveness of oligodendrogliomas to chemotherapeutic treatment that are associated with known chromosome deletions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMAGING SIGNALING CHANGES IN CANCER AND TREATMENT Principal Investigator & Institution: Blasberg, Ronald G.; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 30-APR-2009 Summary: (provided by applicant): The most common brain tumors are gliomas, and the most common malignant variant is glioblastoma multiforme (GBM). The absence of effective therapy for this tumor requires a better understanding of the biology of glioma formation and progression. Recent studies have identified abnormal signaling pathways in gliomas and transgenic animal models have shown that some of these signaling abnormalities are causally related to glioma formation and progression. The overall aim of the proposed research is to build on these recent findings and to develop noninvasive in vivo reporter imaging systems that can be used in the study malignant transformation (oncogenesis) of gliomas and other tumors, and for the assessment of targeted drug therapy. We plan to develop and validate methods for non-invasive optical and radionuclide imaging of PDGF and EGFR signaling through the Ras/Raf/MEK/Erk- and PKB/Akt/mTOR-mediated pathways in transduced cell lines and tumor-bearing animals. This proposal combines established transgenic animal models of gliomas that exist at our institution (Dr. E. Holland) with the molecular imaging experience of the applicant's laboratory. Specifically, we plan to develop multimodal reporter systems for both optical- and radionuclide based imaging that will be validated by a series of in vitro and in vivo experiments and molecular assays. We plan to develop and study transgenic animals expressing these reporter systems, and then

26

Glioblastoma Multiforme

develop double-transgenic reporter animals in order to: 1) image aberrant signaling and pathway activity during oncogenesis, and 2) image and monitor signal pathway activity during targeted drug therapy. The potential benefits of developing transgenic animals bearing signal transduction reporter systems are substantial. Once developed, these reporter systems and the transgenic animals bearing the reporter systems can be used to study oncognesis in different organ systems and could be useful in the study of other disease processes as well. The ability to image and monitor signal transduction pathway activity during targeted drug therapy offers a new approach to the assessment of drug efficacy in animal models. This can be performed in vivo and noninvasively, and may be particularly useful in the assessment of cytostatic drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERFERON-MEDIATED SUPPRESSION OF MMP-9 GENE EXPRESSION AND FUNCTION IN GLIOMAS Principal Investigator & Institution: Benveniste, Etty N.; Professor and Chair; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-MAY-2007 Summary: Glioblastoma multiforme (GBM) is the most malignant and common brain tumor. The diffusively infiltrative nature of GBMs is one of the major causes of mortality in patients afflicted with this form of cancer. Studies to assess the invasiveness of glioma cells in vitro have demonstrated a strong correlation between glioma invasion and high levels of matrix metalloproteinase-9 (MMP-9) expression; in this regard, selective inhibition of MMP-9 represents an important therapeutic target for treatment of GBMs. Interferons (IFNs) are multi-functional cytokines that have anti-viral, anti-proliferative, anti-angiogenic and immunomodulatory effects. We have made the novel observation that IFN-gamma and IFN-beta potently inhibit MMP-9 gene expression in human glioma cells. We hypothesize that IFNs will have an inhibitory influence on glioma cells, leading to the arrest of tumor cell invasion and angiogenesis via the suppression of MMP-9 expression. We will identify, for the first time, the molecular mechanisms underlying the in vitro inhibitory effects of IFN-gamma and IFN-beta, and investigate the involvement of two transcription factors, STAT-1alpha and CIITA, in this response (Specific Aims #1 and #2). These data will further our understanding of the regulatory mechanisms of MMP-9 gene transcription and identify important therapeutic targets to abrogate MMP-9 expression. In vivo studies will follow to validate the effectiveness of IFN suppression of MMP-9. The efficacy of IFN-gamma and IFN-beta gene therapy on the growth, invasion and angiogenic properties of human glioma cells transplanted into the brains of immunocompromised mice will be examined (Specific Aim #3). Lastly, we have the unique opportunity to evaluate the effectiveness of IFN-beta gene transfer in patients with GBMs (Specific Aim #4). The combination of in vitro basic science experiments and translational in vivo studies will lead to a comprehensive understanding of the role of MMP-9 in glioma cell biology, and the potential of IFNs to ameliorate the detrimental effects of MMPs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LARGE SCALE GENE EXPRESSION ANALYSIS TO IDENTIFY MALIGNANT GLIOMAS Principal Investigator & Institution: Riggins, Gregory J.; Assistant Professor; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004

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Summary: (provided by applicant): The goal of this project will be to identify genes with brain cancer or pathway specific expression that can be used as potential targets. This will include immunebased targeting by Projects 1 and 3 on this SPORE, as we1l as screens of small molecule inhibitors for this project. Using Serial Analysis of Gene Expression (SAGE) and real-time PCR, we will analyze the genes expressed specifically in the membrane bound polysomal mRNP fraction (destined for the cell surface) of glioblastomas to derive tumor-specific antigens for Project 1. We will use bioinformatics, real-time PCR and immunohistochemistry to locate and evaluate tumor markers specific astrocytic and oligodendro glioma tumors for a 'tumor vaccine' by Project 3. For this project we will evaluate the genes transcriptionally activated by EGFRvIII mutations in glioma cells, found in our laboratory using SAGE. These genes will provide biomarkers for inhibition of mutation specific activation. We have also recently identified carbonic anhydrase 9 (CA9) as a hypoxia activated gene in GBM [Lal, 2001 494]. We will evaluate existing therapeutics for CA9 and known carbonic anhydrase inhibitors. Finally, using a l0,000-plus small-molecule inhibitor library we will screen for inhibitors of genes and pathways that are involved in growth and invasion of gliomas to identify novel lead compounds. Specifically, we will search for those compound: that inhibit the transcription of genes normally activated by EGFRvIII and for inhibitors of the transcriptional activation of CA9. By combining SAGE with small-molecule screens we hope to locate inhibitors that target transcriptional activation specific to glioblastomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MARIMASTAT IN PATIENTS W/ GLIOBLASTOMA MULTIFORME OF GLIOSARCOMA Principal Investigator & Institution: Greenberg, Harry S.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 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: MARIMASTAT IN PATIENTS W/ GLIOBLASTOMA MULTIFORME OR GLIOSARCOMA Principal Investigator & Institution: Pruitt, Amy; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 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: MECHANISMS OF CELLULAR RADIOSENSITIVITY Principal Investigator & Institution: Williams, Jerry R.; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: This project will determine whether novel patterns of dose and dose-rate can improve radiation therapy of human cancer when based on mechanisms that determine radiosensitivity in human tumor cells. We have made three novel observations in a system of genetically-defined human colorectal tumor cells: 1) two distinctly different patterns of response to acute and protracted irradiation (radioresponse phenotypes) are observed and p53 predicts the pattern of response observed in a specific cell line; 2)

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Glioblastoma Multiforme

protracted irradiation alters the radiosensitivity in tumor cells through two distinct mechanisms, with some cells becoming more resistant and some more sensitive depending on the specific cell type; 3) p21- modulated apoptosis has no effect on in vitro radio-sensitivity but modifies tumor response. Importantly, other radio-resistant tumor cells such as glioblastomas can be dramatically sensitized by protracted irradiation and if this sensitizing process can be translated into the clinic it might have significant impact. These data taken together suggest that radiotherapy of tumors, to be optimally effective, should exploit the particular radio-response phenotype of the constituent tumor cells. We have used these several observations to construct a new model that we term the alpha-omega model. This model presents a new analytical structure for planning radiation therapy protocols that use combinations of dose and dose-rate to achieve optimal effects. We now propose to use the alpha omega model to suggest patterns of acute and protracted irradiation hypothesized to produce maximum cell kill in vitro and test these predictions experimentally. Project 2 will provide data that describe the effects of tumor microenvironment on mechanisms of radiosensitivity including radio-sensitization by protracted irradiation. These data when combined with results from this project will be used to propose radiotherapy protocols that will maximize response in experimental tumors. The several cores and projects will together test these hypotheses and if successful, translate these into the clinic. This project will test the hypothesis: Radiotherapy protocols of combined acute and protracted irradiation will improve response in cells and tumors in such protocols are based on the radio- response phenotype of the constituent cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF HERBAL RADIOSENSITIZATION OF GLIOMA CELLS Principal Investigator & Institution: Yount, Garret L.; Scientist; California Pacific Med Ctr-Pacific Camp 2200 Webster Street, Suite 514 San Francisco, Ca 94115 Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 30-JUN-2003 Summary: Gliomas are the most common central nervous system tumors. Glioblastoma multiforme (GM), the highest-grade malignant, grows very rapidly-sometimes doubling in size every 10 days- and is nearly uniformly fatal. GM tumors are generally treated by surgery followed by radiation. Although radiation therapy is the most effective postoperative adjuvant for GM, however, it has not substantially altered longterm disease control. The median survival of patients with GM has remained approximately 1 year, regardless of therapeutic approach. The poor clinical outcome of patients with GM is associated with a characteristic in vivo and in vitro radioresistance of these brain tumors compared to other human neoplasms. Furthermore, although conventional synthetic radiosensitizing drugs can potentiate tumor-cell killing by radiation, undesirable normal tissue morbidity prevents repeated administration of the sensitizer and is thus a major obstacle to its use. Approaches that can enhance the radiosensitivity of such resistant tumor cells are much needed to reduce mortality in cancer patients. We discovered that berberine, a relatively non-toxic compound isolated from Chinese medicinal herbs, could enhance the radiation response of radioresistant human glioma cells in vitro. In addition, we showed that berberine could trigger an endogenous cell-suicide mechanisms, apoptosis, in GM tumor cells that express mutant p53, a genetic defect endogenous cell-suicide mechanism, apoptosis, in GM tumor cells that express mutant p53, a genetic defect thought to contribute to radioresistance in many cell types. We propose to extend these findings by comparing the efficacy of berberine with conventional radiosensitizers in cultures of GM tumor cells and normal

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human brain cells. In traditional Chinese Medical practice, herbs are nearly always prescribed in combination, with the intention of regulating the biological action of each individual herb. Thus, our second aim is to determine whether the effect of berberine, as a radiosensitizer, can be enhanced by combining it with other herbal compounds. Our third aim is to determine the mechanisms of radiosensitization by berberine and by any optimal combination treatments discovered. Cellular and molecular pathways mediating radiosensitization will be evaluated by time-lapse video microscopy and nucleic acid array-based gene expression analysis. These studies represent an initial step toward the clinical goal of providing improved multi-modality radiotherapy for patients with gliomas. In addition, because more than half of adult malignancies and high-grade pediatric brain tumors harbor p53 mutations, important clinical applications may emerge from the elucidation of p53-independent mechanisms of apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF PDT INDUCED AND INHERENT RESISTANCE Principal Investigator & Institution: Singh, Gurmit; Director of Research; Healthone Alliance 899 Logan St, Ste 203 Denver, Co 80203 Timing: Fiscal Year 2002 Summary: The overall objectives of this study are: (a) to elucidate the mechanism(s) of photodynamic therapy induced resistance by various photosensitizers and; (b) to investigate factors responsible for the varying degree of inherent sensitivity to photodynamic therapy in various human tumors. The research focus is based on the following primary hypotheses: (1) That the induction of resistance to PDT in tumor cells is dependent on the ability of cells to alter the stress signals. (2) The inherent modulate the oxidative stress mediated by PDT. (3) That the combination of photosensitizers with unique intracellular distribution may synergize the PDT induced phototoxicity. It would also ensure the responsiveness of heterogenous tumors to multiple intracellular targets. The project comprises several groups of experiments: (i) characterization of photosensitizer cellular/intracellular localization in parent and PDT- induced resistant variants in vitro; (ii) assessment of subcellular targets of PDT induced photocytotoxicity in parent and resistant variants in vitro; (iii) examination of pathways involved in PDT mediated responsiveness of cells, in particular the pathways for recovery of PDT induced damage including DNA repair pathways; (iv) investigation of the role of PDT induced cell examination of the role of chaperones on PDT - induced oxidative stress in human tumor cells; and (vii) examination of the importance of mitochondrial-bound hexokinases. The selection of in vitro PDT - induced resistant variants is expected to amplify the biochemical or other intracellular changes associated with resistance. This, and the degree of cross-resistance between the photosensitizers are expected to provide clues as to the mechanisms of action of photosensitizers in vitro. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METABOLIC POLYMORPHISMS AND SURVIVAL FROM BRAIN TUMORS Principal Investigator & Institution: Bondy, Melissa L.; Professor of Epidemiology; Epidemiology; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The outcome for patients with primary malignant brain tumors is poor. Radiotherapy and chemotherapy have improved the outcome,

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Glioblastoma Multiforme

especially in the chemotherapy-sensitive group of tumors such as anaplastic astrocytoma and anaplastic oligodendroglioma. Yet it is not possible to identify the patients who will benefit from such treatments in advance. Inherited variability in metabolism of therapeutic agents is suggested to be responsible, in part for individual differences in response to cancer treatment. Overall purpose of the proposed study is to investigate the role of genetic polymorphisms in the glutathione s-transferase (GST) enzyme family in predicting survival in 305 patients with anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma, treated at the University of Texas MD Anderson Cancer Center between 1994 and 2004. We hypothesize that patients with inherent low GST activity have reduced clearance of reactive agents of chemo- and radiotherapy and are more likely to have a better treatment effect at the tumor site. Further, we predict that individuals with low activity GST genotypes will have increased survival time when compared to those with inherently high GST activity. We will determine the frequencies of GSTM1, GSTT1, and GSTP1 polymorphisms in 350 cases by polymerase chain reaction and restriction fragment length polymorphisms. We will review medical records of the 350 patients and abstract information on outcome, treatment and clinically significant adverse events related to radiotherapy and, chemotherapy that required delaying or cessation of treatment. To assess if GST polymorphisms are associated with outcome in patients with primary malignant brain tumor we will perform Kaplan-Meier and Cox proportional hazard analyses. To explore whether metabolic polymorphisms of the GST enzyme family are correlated with occurrence of adverse effects secondary to chemotherapy we will use logistic regression, Kaplan-Meier and Cox proportional hazard analyses. Based on the results of the proposed study, in the future chemotherapy regimens can be tailored according to individual patient's metabolic enzyme profile. Thus, patients who can tolerate higher doses of chemotherapy can be treated more efficiently, suffering from less side effects and potentially may have a better outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROPET AND NIR FLUORESCENCE IMAGING TUMOR ANGIOGENESIS Principal Investigator & Institution: Chen, Xiaoyuan; Radiology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Our long-term objective is to develop and validate new imaging markers and techniques that identify the angiogenic properties of precancerous or cancerous cells that will predict clinical course and response to intervention. It has been recently established that tumor growth is angiogenesis dependent, and there is a specific correlation between blood vessel density in cancers and their metastatic potential. Anti-angiogenic therapy aimed at blocking new blood vessel growth in tumors is of great interest, since they may provide a practical means for long-term control of cancer. Imaging can play a major role in the pre-clinical development and clinical application of anti-angiogenic therapy. Integrin alphavbeta3, which is not readily detectable in quiescent vessels but becomes highly expressed in angiogenic vessels and various malignant human tumors, is an important adhesion receptor affecting tumor growth, local invasiveness, and metastatic potential. Tumor angiogenesis can be blocked in vivo by antagonizing the alphavbeta3 integrin with small peptides containing the Arg-Gly-Asp (RGD) amino acid sequence. Because of its highly restricted expression and its vital role in angiogenesis, the alphavbeta3 integrin is an attractive candidate in anticancer therapy. The ability to quantify the alphavbeta3

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expression level in tumors and other angiogenesis related diseases is of vital importance for therapeutic planning of alphavbeta3 targeted therapy. Systemic optimization of molecular probes for evaluation of tumor targeting efficacy as well as in vivo pharmacokinetics and pharmacodynamics will also enable rapid drug screening and new drug discovery. In this project we propose to develop a series of new cyclic RGD peptide based probes for microPET and optical imaging of tumor angiogenesis in different solid tumor models. Aim 1: label cyclic RGD peptides for microPET imaging and near-infrared fluorescence (NIRF) imaging of glioblastoma model. Aim 2: Apply the radiotracers and NIRF probes with optimal tumor targeting efficacy and in vivo pharmacokinetics to image different solid tumor models. We anticipate that noninvasive serial studies of alphavbeta3 expression and functional activity using microPET and NIRF imaging will become important tools complementary each other to evaluate the role of alphavbeta3 integrin during tumor progression and metastasis. All the results obtained here will be used for future application of a R01 type grant. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODIFICATION OF EFFERENT IMMUNOLOGICAL RESPONSES Principal Investigator & Institution: Glorioso, Joseph C.; Professor and Chairman; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: Survival of patients with malignant glioma remains poor despite the availability of surgical debulking, radiation therapy, and chemotherapeutic regimens. Progress in applying gene therapy to the treatment of cancer provides an additional strategy which may prove effective in combination with more standard therapies. NUREL-C2 is a completely inactivated herpes simplex virus (HSV)- based gene transfer vehicle that expresses the four novel therapeutic proteins ICP0, thymidine kinase, connexin-43 and TNFalpha which work in concert to kill tumor cells when used in combination with intravenous administration of the anti-cancer drug ganciclovir (GCV) and radiosurgery. Animal experiments using this combination of gene and conventional therapies to treat intracerebral implants of radiosensitive human glioblastoma cells have resulted in excellent tumor control and improved survival. To establish the maximum the maximum potential of this approach, additional preclinical studies are proposed to optimize the contributions of each component to the combined treatment and to evaluate efficacy in models of radioresistant human glioblastoma (Aim 1). The vector and combined therapy will be systematically tested for safety and dose-limiting toxicity in normal mice and rhesus monkeys to expand our current results (Aim 2). A Phase I clinical trial is proposed with two consecutive components involving a) pre- and postsurgical intracranial NUREL-C2 inoculation followed by GCT treatment, and b) stereotactic NUREL-C2 delivery into the tumor with maintenance on GCV and gamma knife radiosurgery two days later. Using a battery of molecular, serological, imaging and clinical tests, patients will be evaluated for adverse effects of viral vector implantation, vector toxicity prior to, during, and after GCV treatment, short-term vector distribution and transgene expression in the tumor, metabolic activity of the tumor, and imaging responses to therapy. Safe vector dose will be determined in the first aim of the trial by dose escalation between consecutive groups of 3 patients. In the second arm, potential changes in toxicity profile and safe dose due to the combination with radiosurgery will be identified. Concurrent manifestations of efficacy will be recorded (Aim 3). In the final Aim, the therapeutic potential of HSV vectors expressing radiosensitizing genes or novel genes from Projects 1 and 2 will be tested for effectiveness in glioma models. Effective genes will be incorporated into NUREL-C2 and

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Glioblastoma Multiforme

the new derivatives tested for improved cytocidal qualities in vitro and efficacy in vivo to arrive at an optimally effective gene transfer agent for the treatment of malignant glioma (Aim 4). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GLIOMA THERAPIES AND DIAGNOSTICS Principal Investigator & Institution: Mikkelsen, Tom; Co-Director; Neurological Surgery; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2005 Summary: (provided by applicant): Malignant gliomas remain among the most refractory malignancies, causing significant functional deficits and high mortality in patients. Median survival is still measured in weeks, and fewer than 5% of patients diagnosed with the most common subtype, glioblastoma multiforme, are alive at five years. Notwithstanding the fact that this is an orphan indication with only 20,000-25,000 new cases annually, the impact belies the numbers. Furthermore, despite 20 years of active clinical trials, these median survival numbers have barely changed. The gap, it appears, is in the lack of novel therapeutics for early-phase clinical testing. Recently, the NCI supported two brain tumor Specialized Programs in Research Excellence (SPOREs), each affiliated with one of two brain tumor consortia, University of Alabama Birmingham (UAB) with New Advances in Brain Tumor Therapy (NABTT), and University of California San Francisco (UCSF) with the North American Brain Tumor Consortium (NABTC). Even these SPORE programs are limited in their ability to provide the critical product development and for-profit support to move novel strategies directly into the clinic and beyond. This AP4 application seeks to directly address translational, commercializable research with a specific focus on late-stage preclinical therapeutics and direct translation into IND agents for pilot clinical studies. We will take advantage of a number of novel approaches from our center researchers including a highly novel cellular therapy platform (Chopp), promising agents from the UAB SPORE program (Rosenfeld), and generate new contacts for future "drugable" targets towards glioma invasion and angiogenesis, areas in which our two academic groups have distinguished themselves. We will have available the resources from the NCI/NINDS Neuro-oncology Branch, with whom we have an ongoing collaboration for expression profiling and target assessment in clinical material (NCI/NINDS Fine) and the computation and screening capabilities from TGen, the Translational Genomics Institute (Berens). These discoveries will be assessed and developed for commercialization though partnership with corporate entities experienced in drug development and financing strategies, including Toucan Capital Corn. (Ms. Powers) and two of its portfolio companies: Oncocidex (Dr. Herring) and Cognate Therapeutics (Dr. Gordon). This Center will capture the entrepreneurial spirit from these diverse but complementary players, all highly motivated in the core mission, expanding the pipeline of novel therapeutics and diagnostics for malignant glioma patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROONCOLOGY Principal Investigator & Institution: Buckner, Jan C.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002

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Summary: The NCCTG Neuro-Oncology Program consists of three components: Cancer Treatment Trials, Neurobehavioral Studies, and Laboratory Correlates. These complementary components contribute to improving duration and quality of life in patients with primary central nervous system malignancies and to enhancing our understanding of the underlying disease process. During the previous grant cycle, in low-grade glioma patients, we observed that 65 cGy radiation is not better than 50 cGy; pro-carbazine, CCNU, grade glioma patients, we observed that 65 cGy radiation is not better than 50 cGy; procarbazine, CCNU, and vincristine (PCV) is an active regimen as initial therapy; and deletions in chromosomes 1p and 19q are associated with the diagnosis of low-grade oligodendrogliona, but not with low-grade oligoastrocytoma. In patients with high-grade glioma (glioblastoma multiforme, anaplastic oligoastrocytoma), we demonstrated that recombinant alpha interferon does not improve survival when added to radiation and BCNU, but is considerably more toxic; than grading (grade 3 versus grade 4) has significant prognostic value in patients with anaplastic oligoastrocytoma; and that, grade for grade, patients with anaplastic oligoastrocytoma have a statistically significant improved survival compared to those with pure astrocytoma. Moreover, tumoral EGFR amplification, absence of p53 mutations, and PTEN deletions are associated with poor survival in anaplastic astrocytoma patients. Glioblastoma and gliosarcoma patients have essentially identical clinical courses and genetic abnormalities. In recurrent glioma patients, we identified two active regimens: MOP (nitrogen mustard, vincristine, and procarbazine) and irinotecan. Ph. Pharmacokinetic studies demonstrated increase in CPT-11 clearance and variable metabolism in patients receiving irinotecal and anti-convulsants concurrently. Non-glioblastoma patients were more likely to respond to treatment than those with recurrent glioblastoma. Neurobehavioral studies indicated that good baseline Folstein and Folstein mini-mental status examination (MMSE) score is associated with better survival on multi-variate analyses. Few patients with high-grade glioma had diminished mini-mental examination scores at one year and 18 months in the absence of tumor progression. Conversely, reduction in mini-mental status examination scores correlated strongly with both at diagnosis, and were more likely to have cognitive decline to have cognitive decline as a consequence of treatment compared with younger patients. In patients with primary CNS lymphoma, we found a high response rate with CHOP (cyclophosphamide, doxorubicin, vincristine, and dexamethasone), but the duration of benefit was very short. As in patients with high-grade glioma, MMSE scores declined in close association with tumor progression. Future plans include continued evaluation of agents with radiosensitizing properties including cisplatin and irinotecan. We will continue to evaluate the efficacy of new regimens in recurrent glioma patients, including pyrazoloacridine plus carboplatin and the rapamycin analog, CCI 779. NCCTG has recruited investigators demonstrating experience with inhibitors of tumor invasion, as well as gene therapy. There are two main gene therapy approaches current in preclinical investigation: fusogenic membrane glycoproteins such as the measles virus F and H proteins and the truncated Gibbon Ape Leukemia virus surface protein (GALV). Neurobehavioral studies, including evaluation and treatment of impaired cognitive status, depression, fatigue, and excessive daytime somnolence, are in process. Pharmacokinetic studies to investigate interactions among chemotherapeutic agents and anti-convulsants will continue. Studies of genetic alterations in glioma, especially anaplastic astrocytoma and low- grade glioma, will be expanded through collaborations with Drs. Robert Jenkins (Mayo) David James (Mayo), and Bert Feuerstein (UCSF). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW CONSORTIUM

APPROACHES

TO

BRAIN

TUMOR

THERAPY

CNS

Principal Investigator & Institution: Grossman, Stuart A.; Professor of Oncology, Medicine and Neur; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 21-MAR-1994; Project End 31-DEC-2002 Summary: The primary long-term objective of this proposal is to improve the therapeutic outcome for adults with primary brain tumors. This will be accomplished by fostering Phase I and II clinical evaluations of promising new agents, biologic approaches, routes of administration, and trial design in the treatment of primary malignancies of the central nervous system through the continued efforts the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium." This consortium is specifically designed to combine and focus the experience, resources, and capabilities of thirteen outstanding medical institutions (Brown University, Columbia University, Emory University, Henry Ford Hospital, Johns Hopkins University, Massachusetts General Hospital, Moffitt Cancer Center, Northwestern University [Chicago], the University of Alabama, the University of Texas at San Antonio, the University of Pennsylvania, Wake Forest University, and Washington University) to bear on primary brain tumors. The participating institutions have (1) a large number of adult patients with primary brain tumors, (2) expert multidisciplinary clinical teams caring for these patients, (3) extensive clinical and laboratory resources, (4) a striking number of ongoing high quality, clinically relevant, peer-reviewed and NIH funded clinical and laboratory brain tumor research projects, (5) nationally recognized expertise in oncology, pharmacology, new drug development, Phase I and II clinical trials, neurosurgery, and neuropathology, (6) extensive expertise in biostatistics, data management, and the coordination of multi-institutional studies, and (7) exceptional reputations for excellence in clinical care and research. The consortium adds to these strengths with a well-defined and smoothly functioning structure, an emphasis on clinical trial design, protocol development, quality control, study monitoring, and data management and analysis. The secondary long-term objective of this proposal is to utilize this consortium to share human brain tumor specimens as well as other clinical and laboratory data to conduct additional research pertaining to (1) the basic biology of primary brain tumors, (2) the neuro-pharmacology of new therapies for primary brain tumors, and (3) improving the care and quality of life of adults with primary brain tumors. This objective will be reached using the strengths of the participating institutions and the NABTT Correlative Biology Research Center, The NABTT Pharmacology Center, and The NABTT Working and Scientific Committees. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW APPROACHES TO BRAIN TUMOR THERAPY--A CNS CONSORTIUM Principal Investigator & Institution: Hochberg, Fred H.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 18-MAR-1994; Project End 31-DEC-2002 Summary: The Massachusetts General Hospital is a co-founding institution of and major contributor to the consortium New Approaches to Brain Tumor Therapy (NABTT). The MGH role has been highly productive with patient accrual second only to the NABTT center. In this application we provide for quality control of these clinical trials as well as internal audits through our protocol office. The MGH investigators perform Chair

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functions on three NABTT committees (Gene Therapy, Morbidity and Corporate), have sponsored two active protocols (9-AC Recurrent and High Dose MTX Therapy of Brain Lymphoma with Deferred Radiotherapy), co- authored the seminal NABTT data relating drug levels to CYP-450 induction, and established the Corporate-NABTT interaction. The MGH funded PO-1 (Gene Therapy of Brain Tumors) reflects translational clinical studies which flourished from NABTT interactions with Drs. Grossman and Colvin. The molecular classification system of Dr. D. Louis (MGH), which will serve to provide new stratifications for NABTT studies, reflects the utility of the NABTT Brain Tumor Bank. The MGH provides three resources to NABTT: (1) Genetic therapies (Drs. Breakefield and Chiocca), (2) Phase I agents (Dr. Chabner) their analysis and modeling (Dr. Supko), and (3) Assessment of morbidity and quality of life (Drs. Batchelor and Barker). (1) Dr. Hochberg heads the NABTT gene therapy committee which will provide the NABTT protocols for p53 transfection (Onyx, Introgen, Schering) to commence in 1997-8. We will make available to collaborators our herpes, adeno and amplicon vectors expressing CYP450 for the activation of prodrugs within gliomas. Most important for these NABTT studies is our template for rodent testing, primatesafety and IND application. We serve as a resource to NABTT for assessment of neuropathologic endpoints, evaluation of transgene expression and efficacy testing. (2) Dr. Chabner heads the phase I drug committee for NABTT and will make available a variety of agents including sarCNU, spicamycin and angiogenesis inhibitors. These latter compounds include TNP-470, penicillamine and VEGF MAB. TNP-470 is under evaluation at the MGH using of fMRI and fCT as surrogate markers of glioma angiogenesis. These techniques can be co-registered over FDG-PET images to provide vascular-metabolic maps of tumor, area- around-tumor and normal brain tissue. These maps will be correlated with in vitro analysis of vascular markers performed by our collaborator Dr. S. Brem. (3) Dr. Hochberg brings to NABTT the pilot study of an industry-sponsored assessment of quality of life of American patients with malignant glioma. This study will provide for validation of both physician and patient instruments for assessing outcome. The instruments are viewed as potential replacement for the KPS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL STRATEGIES FOR BRAIN TUMOR THERAPY Principal Investigator & Institution: Pollack, Ian F.; Walter Dandy Professor of Neurosurgery; Neurological Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: The prognosis for children and adults with malignant brain tumors has improved minimally during the last two decades; median survival remains less than one year for patients with malignant glioma, the most common intrinsic brain tumor. These statistics provide a strong rationale for coordinate efforts to identify innovative approaches for the treatment of these tumors. The unifying hypothesis of this program project grant is that novel therapeutic strategies that take into account the unique features of central nervous system tumors will induce tumor regression, and will potential the efficacy of conventional therapies. Each project is translationally oriented, with a common goal of addressing fundamental biological issues relevant to the tumor growth process and evaluating innovative treatment approaches using a series of preclinical glioma models, as a basis for identifying promising strategies that can be advanced into clinical therapeutics. Project 1 is based on the hypothesis that inhibition of the aberrantly activated signal transduction pathways of malignant gliomas, or direct activation of apoptosis signaling pathways, will induce glioma cell killing, potentially in

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Glioblastoma Multiforme

a genotype-specific fashion, and that this approach will have independent therapeutic activity in preclinical glioma models, and potentiate the effects of other approaches. Project 2 postulates that apoptotic or necrotic glioma cells, such as those produced by promising agents from Project 1, will constitute an optimal mechanism for antigen delivery to antigen presenting cells, and that the conditions for active immunization with such cells can be optimized to promote an effective anti-0tumor immune response. Project 3 postulates that gene delivery, using replication-defective Herpes virus vectors incorporating novel multi-gene constructs engineered to facilitate transcellular transfer of therapeutically relevant gene products, can achieve tumor cell killing and enhance the effects of other treatment strategies. This project will also generate many of the vector constructs that will be used in Projects 1 and 2. The Administrative/Biostatistics/Clinical Support Core (A) provides essential infrastructure support for the basic and clinical research activities of the component projects and other cores. The Cellular and Tissue Imaging Core (B) provides a panopoly of advanced microscopic imaging capabilities used in each of the component projects. The Immunological Monitoring and Cellular Products Laboratory Core (C) provides banking of tissue and serum samples for each of the projects, maintenance of native and transduced cell lines, preparation of biological products, and comprehensive therapeutic monitoring that are essential for the innovative pilot clinical protocols incorporated within this program. Taken together, the multi-disciplinary interactions that have evolved within the context of this program of this program optimize our changes to identify and refine promising therapeutic approaches that can be applied clinically to improve the otherwise discouraging prognosis of patients with malignant gliomas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXYGEN SENSING IN HUMAN GLIOMA CELLS Principal Investigator & Institution: Verma, Ajay; Associate Professor; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, Md 20852 Timing: Fiscal Year 2002; Project Start 25-JUL-1998; Project End 30-JUN-2006 Summary: (provided by applicant): Despite major advances in diagnosis and therapy there have been no improvements in the survival of patients with primary malignant brain tumors. Gliomas are the most common primary brain tumors in humans and glioblastoma multiforme (GBM) is the most aggressive of these tumors. GBMs are highly resistant to radiation and chemotherapy and nearly all patients with GBM die of their disease with a median survival of one year. In addition to genetic alterations, tumor hypoxia may play a role in the malignant progression of gliomas. This may be because tumor hypoxia induces the expression of angiogenic and cell survivalpromoting cytokines and enhances the glycolytic capability of cancer cells. Hypoxia activates gene expression via the transcription factor HIF-1 which can also be turned on by certain growth factors. We have identified a novel biochemical pathway by which glycolytic metabolites such as lactate and pyruvate stabilize HIF-1alpha protein levels independently of hypoxia. Since the majority of hypoxia-independent activators of HIF1 also enhance glycolysis, this pathway may provide a mechanism accounting for their actions. Our recent discovery of autocrine erythropoietin signaling in human cancer also points to a major role for hypoxia in enhancing the survival of cancer cells via mechanisms not previously appreciated. The research proposed here will explore the relationship between hypoxia, altered gene expression, cell metabolism and cell survival. Our hypothesis is that hypoxia-induced changes in the ,qlycolytic metabolism of cancer cells results in the self-sustaining activation of HIF-1alpha regulated genes, even in the absence of persisting hypoxia. We will test our hypothesis by pursuing four

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aims: Specific Aim #1: Determine the mechanism by which glycolytic metabolites regulate HIF-1alpha protein stability. Specific Aim #2: Test the hypothesis that hypoxiaindependent activators of HIF-1alpha act via regulation of glycolysis. Specific Aim #3: Determine whether hypoxic selection of treatment-resistant glioma cells results from the self-sustaining activation of HIF-1alpha regulated genes. Specific Aim #4: Test the hypothesis that erythropoietin signaling plays a prominent role in the hypoxia-induced selection of glioma cells with diminished apoptotic potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE I / II TRIAL FOR NEUTRON CAPTURE THERAPY Principal Investigator & Institution: Palmer, Matthew R.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 21-SEP-2001; Project End 31-AUG-2004 Summary: Neutron capture therapy (NCT) is a unique form of radiation due to the combination of high linear energy transfer (LET) properties and biological targeting. Extensive preclinical work and early clinical experiences have shown NCT to be active against melanoma, and glioblastoma, diseases poorly controlled by conventional radiation. This phase I/II trial is designed to determine the maximum tolerated dose (MTD) for cranial NCT irradiation, an important parameter for future clinical trials. Sixteen patients with either metastatic melanoma or biopsy proven glioblastoma multiforme will be entered. A standard dose escalation scheme will be employed, 3 patients per dose cohort, 10 percent increase in normal tissue dose per cohort. The starting point will be a volume average brain dose of 7.0 RBE-Gy given in two fractions. Boron-delivery will be through the use of l-p-boronophenylalanine-fructose (BPA-f), 14 grams/meter-squared IV, over 90 minutes. Neutron irradiation will take place at the newly constructed fission converter beam (FCB) medical facility at the MIT Nuclear Reactor Laboratory. The FCB produces a high intensity epithermal neutron fluence with a low level of contamination that approaches theoretical limits. The clinical impact is in a greatly increased therapeutic gain. The following are the specific research objectives for the two-year period: (1.) To categorize the time course, uniformity and severity of acute and chronic normal tissue reactions following cranial NCT using the newly constructed fission converter beam (FCB) facility. (2.) To determine a maximum tolerated dose (MTD) for cranial NCT. (3.) To examine, through serial objective measurements, the clinical response of metastatic melanoma nodules and glioblastoma multiforme following NCT. (4.) To further the level of understanding of the pharmacokinetics of 1 -boronophenylalanine-fructose (BPA-f) through the measurement of blood and plasma concentrations of 10B and the refinement of the predictive accuracy of a two-compartment pharmacokinetic model developed by this research group. The long-term objective is to integrate NCT into the established therapeutic mainstream for melanoma, primary brain tumors, and other malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHASE I STUDY OF DENDRITIC CELL IMMUNOTHERAPY Principal Investigator & Institution: Liau, Linda M.; Surgery; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: (provided by applicant): Malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) are the most frequent primary brain tumors in adults and account for about 2 percent of all cancers. It is currently incurable, inevitably fatal, and

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Glioblastoma Multiforme

inflicts an enormous social and economic impact, often striking patients during the prime of their lives. This sobering fact underscores the need to rethink standard approaches to treating brain cancer and to base therapeutic strategies on advances in our understanding of basic cancer biology and tumor immunology. Although a recent renaissance in cancer vaccine research has produced a plethora of approaches designed to elicit immune responses against extra-cranial tumors, there is a paucity of rigorous clinical evaluations of immunotherapeutic treatments for intra-cranial brain tumors. This is due primarily to gaps in our existing knowledge of the unique immunological milieu of the central nervous system (CNS), which have limited conclusive hypotheses about whether brain tumor immunotherapy is actually feasible, safe, or clinically relevant. Therefore, the broad, long-term objectives of this research are: i) to develop and optimize immunotherapy approaches for the clinical treatment of intracranial brain tumors; and ii) to gain a better understanding of the anti-tumor immune responses generated within the traditionally "immune privileged" CNS. In order to achieve these objectives, this project initiates a Phase I study of dendritic cell (DC) immunotherapy for patients with malignant gliomas. Dendritic cells, antigen-presenting cells specialized to elicit cellular immunity, have been used in pilot clinical trials for patients with non-CNS cancers. The specific aims of our project are: 1) to determine the feasibility, safety and toxicity of intradermal injections of autologous peptide-pulsed dendritic cells in patients with CNS gliomas; 2) to monitor tumor progression and cellular/humoral immune responses in brain tumor patients injected with antigen-pulsed dendritic cells and compare them with those of historical controls; and 3) to evaluate the nature of immune infiltrates and cytokine profiles in brain tumor specimens prior to treatment (at initial surgical resection) and following DC vaccination (at subsequent surgical resection for recurrence or autopsy). Correlation of the clinical and immunological response data in these patients will hopefully validate mechanistic hypotheses that systemic immune responses can translate to relevant immune responses within the CNS, which in turn may result in clinical benefit for brain tumor patients. The results of this research will help to determine the pertinent clinical and immunological endpoint measures that can meaningfully guide further clinical development of brain tumor immunotherapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE II REPETITIVE IV DOSES OF RSR13 TO PT RECEIVING CRANIAL RADIATI Principal Investigator & Institution: Lesser, Glenn J.; Wake Forest University 1834 Wake Forest Road Winston-Salem, Nc 27106 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PHASE II STUDY OF 44GY FROM 131I-81C6 FOR CNS TUMORS Principal Investigator & Institution: Reardon, David; Surgery; Duke University Durham, Nc 27710 Timing: Fiscal Year 2003; Project Start 29-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The outcome for patients with glioblastoma multiforme, the most common primary malignant brain tumor, remains dismal. Median survival with current therapy including surgery, radiotherapy and chemotherapy remains 40-50 weeks from diagnosis while available salvage therapies are ineffective following recurrence. Most cases progress at the primary site indicating that local

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control is the critical first step to improve outcome. In response to the dire need for effective, innovative therapies for patients with malignant brain tumors, our center has developed radiolabeled monoclonal antibodies (mAB) that specifically target tumor antigens. 81C6, a murine IgG2b mAB reacts with an isoform of the extracellular matrix protein tenascin which is highly upregulated and expressed by malignant glioma. Previously completed phase I and II studies in which a fixed dose of 131I-labeled 81C6 was administered directly into the surgical created resection cavity (SCRC), confirmed that this approach improves survival for patients with malignant glioma with acceptable toxicity. A key observation from dosimetry studies accompanying these trials is the demonstration that outcome correlated most closely with delivered dose to the SCRC perimeter. Specifically, patients who received less than 44 Gy to the SCRC perimeter had minimal toxicity from radionecrosis but had a higher rate of tumor recurrence. Conversely those patients who received more than 44 Gy had a lower rate of tumor recurrence but a higher rate of symptomatic radionecrosis. Our HYPOTHESIS is that our phase II study with 131I -81C6 administered to deliver 44 Gy to the 2 cm SCRC perimeter will improve survival of patients with newly diagnosed malignant glioma while minimizing radiation injury to normal CNS tissue. The SPECIFIC AIMS of this proposal are: Specific Aim 1. To define the efficacy of 131I -labeled anti-tenascin monoclonal antibody 81C6 administered at a dose to deliver 44 Gy to the 2 cm perimeter of resection cavity of patients with newly diagnosed malignant glioma; Specific Aim 2. To further define the toxicity of this approach and Specific Aim 3.To determine the impact of this therapy on quality of life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE II STUDY TO EVALUATE RSR13 THERAPY WITH RADIATION FOR GLIOBLASTOMA Principal Investigator & Institution: Rozental, Jack; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHI-381: A NOVEL ANTI-LEUKEMIC AGENT Principal Investigator & Institution: Cetkovic-Cvrlje, Pharmaceuticals, Llc 2685 Patton Rd St. Paul, Mn 55113

Marina;

Paradigm

Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 30-SEP-2004 Summary: (provided by applicant): Microtubules, which are formed by the selfassociation of the alpha/beta-tubulin heterodimers, provide structural support for a cell and play key roles in cell motility, mitosis, and meiosis. They are also the targets of several anticancer agents, indicating their importance in maintaining cell viability. Currently available tubulin binding anticancer drugs, including new taxol derivatives and epothilones, interact with beta-tubulin subunit of the alpha/beta-tubulin heterodimers and have no effect on microtubule minus ends. Furthermore, cancer cells with an altered beta-tubulin expression profile may be resistant to these agents. We used a three-dimensional computer model of tubulin constructed based upon its recently resolved electron crystallographic structure for rational design of a novel monotetrahydrofuran (THF)-containing synthetic anticancer drug targeting a unique narrow binding cavity on the surface of alpha-tubulin. We discovered a previously unidentified region with a remarkable abundance of leucine residues, which is located between the

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Glioblastoma Multiforme

GDP/GTP binding site and the taxol binding site. This unique region contains a narrow cavity with elongated dimensions, which could accommodate a fully stretched aliphatic chain with a length of up to twelve carbon atoms. Using this model, a comprehensive structure search of the organic compound files in the Parker Hughes Institute Drug Discovery Program led to the identification of the recently reported chiral THF-epoxides as potential molecular templates for the rational synthesis of novel anti-cancer drugs containing structural elements capable of hydrophobic binding interactions with this leucine-rich binding cavity of tubulin. Our lead compound designated as COBRA-1, inhibited GTP-induced tubulin polymerization in cell free turbidity assays. Treatment of human breast cancer and brain tumor (glioblastoma) cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Like other microtubuleinterfering agents, COBRA-1 activated the pro-apoptotic c-Jun N-terminal kinase (JNK) signal transduction pathway, as evidenced by rapid induction of c-jun expression. The further development of COBRA-1 as an anticancer agent will depend on in vivo efficacy, and toxicity studies in relevant animal models. We are now proposing to use the severe combined immunodeficiency (SCID) mouse model for detailed in vivo anticancer activity in SCID mice challenged with human breast cancer or glioblastoma cells. Our specific aims are: (i) To study the in vivo toxicity profile of COBRA-1 in BALB/c mice and (ii) To study the in vivo anti-cancer activity of COBRA-1 in a SCID mouse model of metastatic human breast cancer and glioblastoma. The knowledge gained from these studies described under Specific Aims 1-2 is expected to facilitate the design of innovative treatment regimens employing COBRA-1 for the treatment of metastatic solid tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRECLINICAL MODELS FOR HUMAN ASTROCYTOMAS Principal Investigator & Institution: Gutmann, David H.; Associate Professor; Neurology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 30-JUN-2005 Summary: The prognosis for malignant brain tumors (astrocytomas) remains essentially unchanged despite significant advancements in neuro-oncology and radiation therapy. Our ability to design targeted therapies for astrocytomas (gliomas) is heavily dependent upon a more complete understanding of the molecular pathogenesis of these tumors and the availability of appropriate preclinical models to test potential biological therapies. Genetic alterations in human astrocytomas differ between astrocytoma grades and involve gene products important for regulating (1) growth factor signaling pathways and (2) cell cycle progression. Studies from our laboratory have demonstrated that activation of p21-ras is a common feature of low and high- grade astrocytomas and that approximately 60 percent of GBMs harbor alterations in the rap1 signaling pathway. In addition, high-grade gliomas exhibit loss of PTEN/MMAC1 expression or epidermal growth factor receptor (EGF-R) amplification/activation, suggesting a role for these proteins in astrocytoma progression. Over the past year, we have developed transgenic mice with astrocyte-specific expression of EGF-R, EGF- RvIII and p21-ras (G12V). The B8 p2l-ras (G12V) transgenic mouse strain develops astrocytomas with a latency of 3-4 months that are histologically and biologically similar to human astrocytomas. In this proposal, we propose to employ transgenic mouse models to critically evaluate the hypothesis that abnormalities in growth factor signaling and cell cycle control genetically cooperate in the molecular pathogenesis of astrocytomas. Specifically, we wish to determine whether (1) abnormal ras and rap1 signaling in astrocytes is necessary or sufficient for astrocytoma development, (2) loss of

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PTEN/MMAC1 signaling or EGF-R alterations are associated with astrocytoma progression, and (3) abnormal rap1 and ras signaling in astrocytes combined with defective cell cycle control is associated with astrocytoma progression. The development and characterization of mouse models mimicking the histology and molecular pathogenesis of human astrocytomas would greatly advance our ability to treat human astrocytomas by serving as informative preclinical models to test novel therapeutic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRE-CLINICAL TRIALS OF GEM MODELS FOR GLIOMAS Principal Investigator & Institution: Holland, Eric C.; Associate Attending; SloanKettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The overall objective of this proposal is to use magnetic resonance imaging (MRI) to evaluate the efficacy of novel experimental therapeutics against genetically engineered mouse (GEM) models of gliomas. Two different models will be evaluated which include the PDGF-driven oligodendroglioma and the Ras+ Akt-driven glioblastoma multiforme models. Alterations in different signaling pathways produce these two distinct tumor types, thus we hypothesize that these different tumors will elicit a different therapeutic response to the specific combinations of small molecules to be evaluated in this proposal Induction of tumors will be accomplished using our GEM models followed by MRI-selection of tumors for inclusion in the therapeutic trials. Quantitative assessment of therapeutic outcomes will be accomplished using both TI-, T2-, and diffusion-weighted multislice MRI. Each animal will serve as its own control which will offer the distinct advantage of noninvasively determining both cell kill values and changes in tumor water diffusion coefficient (ADC) values as quantitative endpoints of therapeutic efficacy. Histological evaluation of therapeutic effects will also be accomplished on harvested tumor tissue. This proposal will be accomplished by a close collaboration between Memorial SloanKettering Cancer Center (MSKCC) and Molecular Therapeutics (MRx), a company proficient in pre-clinical noninvasive imaging of mouse cancer models MSKCC will provide the producer cell lines, will assist with establishing the necessary protocols for MRx scientists to initiate the tumor models, and will design the pre-clinical trials including procurement of the therapeutic agents to be evaluated MRx will house the GEM models for pre-clinical iherapeutic studies. Tumors will be induced using MSKCCprovided producer cell lines and animals will be imaged over time to identify animals with tumors for inclusion into the therapeutic trial. All of the digital MRI data will undergo digital image post-processing to generate quantitative 3-dimensional tumor volumes and ADC maps over time. These will be used to calculate pre- and post-tumor growth kinetics and log (cell kill) values MSKCC will also be responsible for the processing and pathological interpretation of the brain tissues as well as well as their correlation to the processed digital MRI data forwarded from MRx. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PRODUCTION OF ALTERNATIVE FGF RECEPTOR FORMS IN TUMORS Principal Investigator & Institution: Cote, Gilbert J.; Associate Professor; Internal Medicine; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JUL-1995; Project End 30-APR-2005

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Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PTEN SIGNALING AND GROWTH CONTROL IN THE NERVOUS SYSTEM Principal Investigator & Institution: Baker, Suzanne J.; Associate Member; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: PTEN is a tumor suppressor that negatively regulates the phosphoinositide 3-kinase (PI3K) signaling pathway, a central mediator of signal transduction for growth, proliferation and cell survival. PTEN is inactivated by somatic mutation in diverse human tumors including glioblastoma, endometrial carcinoma, and prostate carcinoma. Germline mutations in PTEN result in a number of phenotypic abnormalities with variable penetrance including macrocephaly, hamartomas in multiple tissues, cancer predisposition, and neurological abnormalities. Thus PTEN inactivation has consequences in multiple organ systems, and causes tumorigenesis and developmental abnormalities in the nervous system. We plan to determine Pten function in the regulation of normal and neoplastic growth in the brain. Towards this goal, we used crelox technology to selectively inactivate Pten in granule neurons of the cerebellum and dentate gyrus in mouse. Our preliminary data showed that Pten deficiency results in a dramatic loss of neuronal size regulation and abnormalities in cell migration. Unexpectedly, we did not observe differences in neuronal proliferation and survival despite the reported role of the PI3K pathway in these processes in granule cells. We hypothesize that Pten is critical for the appropriate control of downstream effectors required for both cell growth control and tumor suppression. We propose studies to determine the contribution of the downstream effectors Akt, mTor and S6k to the Ptenmediated regulation of neuronal size. We will also identify other gone targets that are involved in growth regulation. Finally, we will determine the effects of Pten deficiency on cell growth, proliferation, survival, and tumorigenic potential in astrocytes, the cell background that gives rise to PTEN-deficient glioblastomas. We will determine if the same signaling pathways that contribute to aberrant regulation of cell size in postmitotic neurons are critical to Pten function in normal and neoplastic growth in astrocytes. Novel animal models with selective and inducible expression of cre recombinase will also be developed to allow analysis of Pten function at different stages of development. Our results will be integrated with results from the other projects in this program to determine which aspects of growth regulation in granule cells contribute to tumorigenesis in this cell type to give rise to medulloblastoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RADIATION ENHANCEMENT OF HSV ANTI-TUMOR EFFECTS Principal Investigator & Institution: Weichselbaum, Ralph R.; Professor and Chairman; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2008 Summary: Glioblastoma multiforme (GBM), or grade IV malignant glioma is an almost uniformly fatal brain tumor despite aggressive combination approaches using surgery, radiotherapy and chemotherapy. While radiation therapy has proven to be the most effective adjunctive modality, modifications, including altered fractionation, dose escalation with radiosurgery, conformal radiotherapy and brachytherapy, have not significantly improved the natural history of progression of these tumors. The thrust of

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this Program Project continues to focus on development of genetically engineered herpes simplex viruses (HSV) for improved therapy of these tumors. In the first 4 1/2 years of funding, we made the seminal observation that radiation synergistically improved regressions and cure-rates of heterotopic and orthotopic human GBM xenografts treated with genetically engineered HSV-1. We showed that modest doses of radiation enhanced proliferation and spread of genetically altered HSV-1 throughout the tumor bed in flank and intracranial GBM xenografts. Thus, we hypothesize that the biology of HSV-1 and the molecular response of GBM to ionizing radiation can be integrated to provide a basis for the translation of HSV-1 and therapeutic radiation to the clinical setting. Therefore, we propose to (i) identify doses and timing of radiation to maximize HSV-1 replication in GBM, (ii) identify genes that mediate radioresistancc in GBM and test whether these genes mediate HSV-1 proliferation and spread following ionizing radiation, (iii) validate genes in Aim 2 or identify other cellular genes that mediate HSV-1 proliferation and spread following radiotherapy, and (iv) select viruses that have an increased ability to replicate in radioresistant cells or under conditions of radiation. Our studies will rationally develop new strategies and reagents to significantly improve treatment of GBM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF ATM IN RADIOSENSITIVITY OF GLIOMAS Principal Investigator & Institution: Guha, Chandan; Associate Professor; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2002; Project Start 10-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Glioblastoma multiforme (GBM) is one of the most lethal cancers. Radiotherapy prolongs survival only modestly, because the dose is limited by the tolerance of the normal brain tissues. In order to improve the results of radiotherapy we propose to increase the intrinsic radiosensitivity of GBM by selectively targeting ATM (Ataxia-Telangiectasia mutated), which is a key mediator of the DNA damage surveillance pathway in an irradiated cell. As proof of principle, we downregulated ATM expression in GBM cells and enhanced their radiosensitivity. Invitro, the surviving fraction after 2 Gy (SF2) decreased, from >0.5 without antisense to 0.28-0.35 with antisense. It is notable that the average SF2 of cells isolated from GBMs, which are incurable by radiotherapy, is 0.5 whereas the average SF2 of cells isolated from anaplastic astrocytomas, which are curable by radiotherapy, is 0.34. In-vivo about half the tumors were cured, with a dose of irradiation that, without the antisense, cured a few. In order to increase the transduction efficiency of our genetic antisense vectors in GBM cells, we constructed an E1B-deleted replicating adenoviral vector (Adeno-E1BE alphaATM) and successfully attenuated ATM protein expression in U-87 (p53 w.t.) and U-138 (p53 mut) GBM cells resulting in enhanced radiosensitivity in vitro. Interestingly, BIBA-Adeno-aATM enhanced the tumoricidal effects of the parent Adeno-E1B virus, even without irradiation. We further demonstrated the safety of Adeno-E1B -alphaATM in human umbilical vein endothelial cells and mouse astrocytes in vitro, and the mouse brain in vivo. Finally, we demonstrated that the human hexokinase II (hHKII) promoter is induced 15-fold in GBM cells when compared to expression in cultured normal neurons and astrocytes. Hypoxia and irradiation further induced the hHKII promoter. We now propose: (I) To investigate the role of ATM and its downstream targets in determining the radiosensitivity of GBM cells. The adenoviral vectors will be used as tools to down regulate ATM in molecularly well-chracterized GBM cells. (II) To further enhance the therapeutic benefit of Adeno-E1B cLATM virus by regulating the expression of the antisense ATM RNA under the control of a tumor-specific, hypoxia-

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sensitive, radio-inducible hHKII promoter. The infectivity/tropism of Adeno-EIBAaATM virus to GBM cells will be increased by constructing vectors with adenoviral fiber mutation, F/K20. (III) To construct conditionally replicating antisense-ATM herpes simplex virus (HSV) vectors, expressing antisense-ATM under the control of the HKII promoter. We will also examine whether neural progenitor cells can be used to deliver the HSV antisense-ATM vector to tumor cells in the brain. (IV) To investigate the combined toxicity of the virus vectors, ATM attenuation and radiation therapy in cultured endothelial cells, astrocytes, oligodendrocytes, neurons and brain tissues in mice models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF STAT3ALPHA IN MUTANT EGFR SIGNALING IN GLIOMA Principal Investigator & Institution: Schaefer, Timothy S.; Igen, Inc. 16020 Industrial Dr Gaithersburg, Md 20877 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant) Glioblastoma multiforme (GBM) are highly vascularized tumors of the brain. One of the most frequently observed genetic alterations in GBM is the rearrangement of the epidermal growth factor receptor (EGFR). This mutation EGFRvIII, the result of exons 2-8, results in a receptor that no longer binds ligand and is constitutively activated. The expression of this receptor results in the activation of a number of signaling pathways and confers an increase in the proliferative capacity and tumorigenicity of cells expressing the receptor. Signal transducers and activators of transcription (Stat) proteins are a family of latent transcription factors normally activated by numerous cytokines and growth factors. One member of the family, Stat3, has been implicated in aberrant cell proliferation and constitutively activated Stat3cx has been seen in several types of neoplastic cells and solid tumors. In experiments designed to explore Stat3 signaling in human brain tumors, we have found that Stat3a is constitutively activated in low- and high-grade glioma (compared to normal brain tissue). In other preliminary experiments, we have demonstrated a direct interaction between Stat3a and EGFRvIII in extracts from cells that express both proteins. The expression of EGFRvIII leads to the activation of Stat3a with a concomitant increase in Stat3a-mediated transcription and this activation required serine phosphorylation on serine residue 727 indicating a convergence of more than one signaling event in Stat3a activation by EG FRvIII. In experiments described here, we propose to determine the role of Stat3a in the growth properties imparted by EGFRvIII expression both in vitro and in vivo using EGFRvIII derived mutants that cannot activate Stat3a and by the use of dominant-negative Stat3a molecules to directly block Stat3cx mediated signaling. The in vitro studies will be performed using cultured glioma cells that express EGFRvIII while the In vivo experiments will be performed using a novel intracranial induction system developed in our laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF UPA AND UPAR IN HUMAN GLIOMA INVASIVENESS Principal Investigator & Institution: Rao, Jasti S.; Professor and Head; Biomedical & Therapeutic Sci; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 05-MAY-1998; Project End 30-APR-2005 Summary: (Adapted from the investigator's abstract) Despite many therapeutic strategies for glioblastoma multiforme, the survival rate in patients with this aggressive

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cerebral malignancy remains poor. These gliomas are highly resistant even to combinations of different therapies such as surgery, radiotherapy, and chemotherapy. Recent compelling evidence from cellular and molecular studies of the mechanisms underlying the invasiveness of human gliomas has implicated serine proteases and their receptors in the invasion process. We propose here to identify the mechanisms that lead to the inhibition of one of these molecules by using an adenoviral construct carrying antisense messages for uPA and its receptor, uPAR, and by using specific inhibitors of signaling pathway molecules. Our specific aims are to: (1) Construct adenovirus carrying a truncated 1020 bp uPA gene and a truncated 300 bp uPAR gene that express antisense messages that downregulate a key step in the proteolytic cascade on glioma cell growth, adhesion, migration, invasion and tumor formation in both in vivo and in vitro models. (la) Construct a bicistronic adenovirus vector (Ad-uPAR-uPA) that is driven by the independent promoter elements CMV, bovine growth hormone, and SV40 polyadenylation signals and investigate the effect of this bicistronic construct on the invasion, adhesion and migration of human glioma cells. (ib) Determine the efficiency of the bicistronic construct in inhibiting the invasion and growth of human glioma cells in vivo in nude mice; and evaluate the toxicity of the intracerebrally injected constructs in Fischer/Wistar rats. (ic) Determine the effect of the bicistronic construct on the levels of integrins, MMP-2, and other signaling pathway molecules in glioma cell cultures. (2) Determine how the c-raf ERK, MEKK-JNK, and FAK-MAPK signaling pathways participate in regulating uPA and uPAR in human glioma cell lines. (2a) Determine whether uPA and uPAR gene expression is downregulated in glioblastoma cells transfected with expression vectors encoding dominant-negative ERK- 1 and EKR-2 or kinase-deficient c-raf constructs, (2b) Assess the ability of a kinase-inactive JNK and a kinase-inactive MEKK to downregulate uPA and uPAR expression. (2c) Assess the ability of focal adhesion kinase (FAK) to downregulate uPA and uPAR expression. (2d) Identify inhibitors of the signaling pathway(s) that reduce the expression of uPA and uPAR and the invasiveness of glioblastoma cell lines in vitro. We believe that identifying the molecular mechanisms that regulate the overexpression of uPA or uPAR could lead to the development of novel anti-invasive therapeutic agents whose mode of action depends on the antagonism of uPA or uPAR overexpression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RSR13 ADMINISTERED TO PATIENTS RECEIVING CRANIAL RADIATION THERAPY Principal Investigator & Institution: Ruffer, James; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 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: RSR13 IN GLIOBLASTOMA MULTIFORME RADIATION THERAPY PTS Principal Investigator & Institution: Powers, Stephen K.; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2002 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SCH52365: PHASE I STUDY OF CYCLIC ORAL ADMINISTRATION Principal Investigator & Institution: Rowinsky, Eric K.; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002 Summary: SCH 52365 (Temodal) is an oral alkylating agent of the imidazotetrazine derivative group which exhibits broad spectrum antitumor activity and better toxicity profile than similar compounds. It has been demonstrated in murine tumors that Temodal's activity is schedule dependent with higher activity demonstrated using a daily schedule for 5 consecutive days. On this schedule the compound produced significant increases in survival time of leukemia or lymphoma bearing mice. Temodal has also undergone previous Phase I studies in adult and pediatric patients and phase II studies in patients with gioblastoma multiforme. This study is open label, rising multiple-dose Phase I and is designed to characterize the safety profile and to determine the MTD and DLT of SCH 52365 when administered orally to cancer patients using a modified dosing regimen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SU101 VERSUS PROCARBAZINE FOR FIRST RELAPSE PATIENTS W/ GLIOBLASTOMA Principal Investigator & Institution: Junck, Larry R.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 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: SU101 VS PROCARBAZINE FOR GLIOBLASTOMA MULTIFORME IN FIRST RELAPSE Principal Investigator & Institution: Dropcho, Edward J.; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 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: TARGETED DELIVERY OF R-ADV FOR TREATMENT OF GLIOBLASTOMA Principal Investigator & Institution: Li, Yibing; Genepharm, Inc. 136 S Wolfe Rd Sunnyvale, Ca 94086 Timing: Fiscal Year 2002; Project Start 26-SEP-2002; Project End 31-DEC-2003 Summary: (provided by applicant): Adenoviruses are efficient vectors for the in vivo gene delivery in gene therapy. Adenoviruses efficiently infect many cell/tissue types and express therapeutic genes. However, viral infection of healthy tissues can cause toxicity and adverse effects. A therapeutic approach that targets the virus to diseased tissue while preventing infection of surrounding healthy tissue would be optimal. Our proposal attempts to address both of these issues by blocking native adenoviral infection, and specifically redirecting virus to disease tissues using a fusion protein with an antibody Fc binding domain. This protein adaptor has a unique strength: it can be flexibly adapted to target any marker for which there is a specific antibody. Our studies

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have demonstrated in endothelial culture that adenovirus, fusion protein and antibody complex could target the ICAM-l receptor while blocking native infection pathway. We propose to test our strategy in vivo targeting glioblastoma, a fatal disease for which no effective therapy present. The interleukin-13 receptor was found overexpressed on many glioblastomas and thus can be used as a specific marker for targeting. The goal is to demonstrate the feasibility of our strategy to mediate specific adenoviral infection in a murine xenografted glioblastoma model. This technology may ultimately improve gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETED EGFR ANTISENSE GENE THERAPY OF BRAIN CANCER Principal Investigator & Institution: Boado, Ruben J.; Armagen Technologies, Inc. 914 Colorado Blvd Santa Monica, Ca 90401 Timing: Fiscal Year 2004; Project Start 23-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant): The incidence of brain cancer in the U.S. is surprisingly high, and includes 15,000 new cases per year of the highly malignant primary brain cancer, glioblastoma multiforme (GBM), and about 150,000 cases per year of metastatic cancer to brain. The epidermal growth factor receptor (EGFR) plays an oncogenic role in over 100,000 cases of brain cancer per year, and is the number 1 target of new cancer therapeutics in development. Up to 50% of patients with brain cancer express mutant forms of the EGFR, which are generally resistant to drugs that block the wild type EGFR. Moreover, the success of anti-EGFR cancer therapeutics for the brain is limited by the presence of the blood-brain barrier (BBB), which is intact in the early phase of brain cancer, when treatment is still possible. None of the large molecule drugs (monoclonal antibodies, cancer vaccines, gene therapies) cross the BBB, and >98% of small molecule cancer therapeutics do not cross the BBB. Therefore, the development of BBB drug/gene targeting technologies is a crucial step in the war against cancer of the brain. The present work will exploit a new form of non-viral, noninvasive gene therapy of the brain for the treatment of EGFR-dependent GBM or metastatic cancer. The new gene delivery technology employs pegylated immunoliposomes (PILs) and is non-invasive, requiring only weekly intravenous injections. The PIL gene transfer technology will be combined with the power of antisense mechanisms to develop new gene therapies of brain cancer that are capable of >90% knockdown of either the wild type or mutant EGFR. Since RNA-based forms of antisense drugs are unstable in vivo, the present work will develop new plasmid based gene medicines that produce antisense RNA within the target cancer cell that specifically attack either the wild type or mutant EGFR mRNA. The EGFR antisense encoding gene medicine will be delivered to brain cancer with a genetically engineered recombinant protein that acts as a molecular Trojan horse (MTH). This MTH ferries the PIL carrying the gene medicine across the membrane barriers in the body that separate the blood from the nucleus of the brain cancer cell. The MTH triggers the sequential receptor-mediated transcytosis of the PIL across the BBB, and the receptor-mediated endocytosis of the PIL into the brain cancer cell. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TEMODAR + O6-BENZYLGUANINE THERAPY IN MALIGNANT GLIOMA Principal Investigator & Institution: Quinn, Jennifer A.; Medicine; Duke University Durham, Nc 27710

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Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): The prognosis of patients with malignant glioma remains dismal, with conventional treatment with surgery, radiotherapy and alkylnitrosourea-based chemotherapy failing to cure all patients with glioblastoma multiforme and the majority of patients with anaplastic astrocytoma. This failure is due almost exclusively to de novo or acquired resistance to chemotherapy resulting in subsequent tumor growth and patient death. Temodar is a methylating agent recently shown to be active in the treatment of malignant glioma. The FDA approved Temodar in 1999 for the treatment of patients with recurrent anaplastic astrocytoma. Temodar is now being used as a standard of care for many, albeit not all, patients with glioblastoma multiforme and anaplastic astrocytoma. Unfortunately, the majority of patients with malignant glioma treated with Temodar demonstrate de novo or acquired resistance with subsequent tumor progression. A series of studies conducted predominantly, but not exclusively, for non-CNS tumors has demonstrated that two mechanisms of resistance appear to be operational in mediating resistance to Temodar. The first of these mechanisms which involves removal of the methyl adduct on the O6-position of guanine via O6-alkylguanine-DNA alkyltransferase (AGT) has been shown in both cell culture and xenografts studies to produce resistance to Temodar. AGT depletion by the substrate analog O6-benzylguanine (BG) have been found to increase the cytotoxicity of Temodar in vitro and in vivo. Similarly, a deficiency to DNA mismatch repair has recently been shown to confer resistance to Temodar in vitro and in vivo. The Brain Tumor Center at Duke has conducted four clinical trials using BG alone (1 trial), BG plus BCNU (2 trials), or BG plus Temodar (1 trial) for adults with recurrent malignant glioma (presented in more detail in Section 3: Preliminary Data). These results demonstrate that BG: 1) is non-toxic; 2) can be administered safely with appropriate dose modifications of BCNU or Temodar; and 3) in preliminary phase 1 results can restore sensitivity to Temodar in Temodar-resistant malignant glioma. The hypotheses of this proposal are that: 1) AGT is the major mechanism of resistance to Temodar in malignant glioma; 2) BG-mediated depletion of AGT can restore sensitivity to Temodar in patients with Temodar -resistant malignant glioma. The specific aims of this proposal are: 1) To define the role of BG in restoring Temodar sensitivity in patients with Temodar-resistant malignant glioma; 2) To further define the toxicity of combination therapy using Temodar plus BG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF JNK IN GLIAL TUMOR PATHOGENESIS Principal Investigator & Institution: Wong, Albert J.; Professor; Microbiology and Immunology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Our long term goals are to understand the molecular mechanisms underlying glioblastoma multiforme, the most common and deadly among human brain tumors. The EGF receptor has been strongly implicated and much research on its downstream signaling has focused on the ERK signaling module. Unexpectedly, our work has instead led us to study a pathway not commonly considered downstream of the EGF receptor or in tumorigenesis, the JNK pathway. We have found that 86 percent of primary glioblastoma tumors show activation of a 54 kDa JNK isoform. EGF induces strong JNK activation in 69 percent of cell lines derived from glioblastoma tumors but only weak activation was observed in 6 normal cell lines. Further work in two tumor cell lines has indicated that JNK is important for anchorage

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independent growth and the prevention of apoptosis. We hypothesize that an important difference between glioblastoma tumors and normal tissues is that EGF receptor signals are also directed towards the JNK pathway. The goals of this application are to further study the mechanisms by which JNK becomes activated and how it contributes to multiple phenotypes. In Specific Aim #1, we will examine the mechanisms underlying the enhanced EGF induced activation of JNK seen in glioblastoma cell lines. Several points at which signals can be directed towards the JNK signaling module will be examined: 1) the small GTPases, Rac and Cdc42; 2) PI 3-kinase; and 3) Gab1. These molecules will be tested for increased activity/binding following EGF addition in glioblastoma cell lines as compared to normal astrocyte cell lines. Dominant negative versions of these molecules will be used to confirm their roles in JNK activation. In Specific Aim #2, we will determine which JNK isoform the 54 kDa form corresponds to using RNase protection. Next, we will identify the mechanisms by which it became preferentially phosphorylated. Most importantly, we will determine what properties this isoform has that might contribute to tumorigenesis. The localization of the 54 kDa isoform will be studied in tumor sections and the transcription factors that bind to this isoform in tumors will also be studied. In Specific Aim #3, we will evaluate the relative contribution of JNK and ERK to glial tumorigenesis. The notion that JNK contributes to tumorigenesis is relatively new and not well studied, especially in animal models, but there is a much more extensive literature on the contribution of ERK to tumorigenesis. Thus, we will attempt to clarify the relative contribution of these two signaling modules to these critical phenotypes in vivo: 1) tumor formation in athymic mice, 2) angiogenesis, 3) cell proliferation, and 4) prevention of apoptosis. This work will further enhance our knowledge of this novel signaling pathway in this human cancer and provide new avenues for diagnostics and therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPY OF GLIOBLASTOMA WITH NOVEL APOPTOTIC PEPTIDE Principal Investigator & Institution: Pollock, Allan S.; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2005 Summary: (provided by applicant): This application describes the use of the N-terminal propiece of the lnterleukin-1 alpha precursor molecule for the specific induction of tumor cell apoptosis. No function has ever been attributed to this pro-piece fragment. We describe the mechanisms of cellular entry, nuclear targeting, inter-action with pre mRNA splicing factors, and modulation of alternative splicing of an apoptotic protein by the IL-1 alpha propiece. In addition, we demonstrate propiece interaction with important families of proteins modulating mitochondrial function. The result is tumor cell apoptosis. Importantly, normal diploid primary human cells do not undergo IL-1 alpha propiece-induced apoptosis. The IL-1 alpha propiece maybe delivered to cells either via an expression vector or as a peptide. In the latter case the propiece enters cells by a unique and non-saturable mechanism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TNT-1B IN ANAPLASTIC ASTROCYTOMA & GLIOBLASTOMA MULTIFORME Principal Investigator & Institution: Haines, Stephen J.; Professor & Chairman; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425

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Glioblastoma Multiforme

Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: UPCC7399: PYRAZOLACRIDINE DIAGNOSED GLIOBLASTOMA MULTIFORME

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Principal Investigator & Institution: Alavi, Jane B.; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ZD1839 THERAPY OF GLIOBLASTOMA MULTIFORME Principal Investigator & Institution: Friedman, Henry S.; Professor; Surgery; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2003 Summary: (Provided by applicant): Despite decades of intensive nervous system (CNS) neoplasms remains very poor. Median survival for adults with the most common form of CNS tumor, the cerebral glioblastoma, is 8-12 months after diagnosis. Occasional responses to single or multiple agent chemotherapy are seen in the setting of recurrent tumor, but these responses are generally of short duration, and cures are rare. Identification of agents active against glial malignancies is challenging, with no drug tested to date reliably producing responses in a majority of treated patients. Gene amplification, related to increasing grade of glioma malignancy, has been found to occur in approximately 50 percent of all glioblastoma multiforme (GBM) cases. Although amplification of N-myc and gli (2-4 percent overall) has been reported by different groups, amplification of these genes and c-myc or K-ras are considered sporadic as compared to the amplification of c-erb 1, or the epidermal growth factor (EGFR) gene. The EGFR gene, 110 kb in size, 26 exons in organization, is localized to chromosome arm 7pll-13. Beginning with the initial description of EGFR gene amplification by Libermann et al (1985), subsequent studies have confirmed that approximately 37-58 percent of GBMs, but only isolated anaplastic astrocytomas, amplify the EGFR gene. ZD 1839 is a potent inhibitor in vitro of EGFR tyrosine kinase, competitive with ATP, and noncompetitive with peptide substrate. ZD 1839 inhibits the proliferation of EGFstimulated KB oral squamous carcinoma cells. This effect is readily reversible on removal of the compound. Enzyme inhibition appears to be selective, with little activity against other kinases tested. Growth inhibition in vivo of a wide variety of human tumour xenograft models in nude mice was demonstrated at a range of once daily, oral doses between 12.5 and 200 mg/kg per day for up to 4 months. In some already established tumours treatment with ZD 1839 produced significant regressions. From the xenograft studies, it is not yet clear if there is a correlation between the level of EGFR expression and antitumor response. The specific aims of this proposal are: 1) To identify the activity and toxicity of ZD 1839 in the treatment of adults with glioblastoma multiforme in first relapse; 2) to determine if qualitative and quantitative levels of genotypic and phenotypic EGFR expression predict response of GBM to ZD 1839. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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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 “glioblastoma multiforme” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for glioblastoma multiforme in the PubMed Central database: •

Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. by Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY.; 1993 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=300905

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 glioblastoma multiforme, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “glioblastoma multiforme” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for glioblastoma multiforme (hyperlinks lead to article summaries): •

3 4

A case of spinal glioblastoma multiforme: immunohistochemical study and review of the literature. Author(s): Strik HM, Effenberger O, Schafer O, Risch U, Wickboldt J, Meyermann R. Source: Journal of Neuro-Oncology. 2000 December; 50(3): 239-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11263503

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. 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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A genome-wide allelotype study of primary and corresponding recurrent glioblastoma multiforme in one patient. Author(s): Hu J, Jiang CC, Ng HK, Pang JC, Tong CY, Chen SQ. Source: Chinese Medical Journal. 2004 March; 117(3): 456-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15043792

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A phase II study of preradiation chemotherapy followed by external beam radiotherapy for the treatment of patients with newly diagnosed glioblastoma multiforme: an Eastern Cooperative Oncology Group study (E2393). Author(s): Gilbert M, O'Neill A, Grossman S, Grunnet M, Mehta M, Jubelirer S, Hellman R. Source: Journal of Neuro-Oncology. 2000 April; 47(2): 145-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10982156

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A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Author(s): Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. Source: British Journal of Cancer. 2000 September; 83(5): 588-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10944597

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A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Author(s): Rainov NG. Source: Human Gene Therapy. 2000 November 20; 11(17): 2389-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11096443

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A retrospective analysis of postradiation chemotherapy in 133 patients with glioblastoma multiforme. Author(s): Reni M, Cozzarini C, Ferreri AJ, Ceresoli GL, Galli L, Bianchi A, Villa E. Source: Cancer Investigation. 2000; 18(6): 510-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10923098

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Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. Author(s): Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, Fisher B, Fulton D, Gulavita S, Hao C, Husain S, Murtha A, Petruk K, Stewart D, Tai P, Urtasun R, Cairncross JG, Forsyth P. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 May 1; 22(9): 1583-8. Epub 2004 March 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051755

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Aberrant p21 regulation in radioresistant primary glioblastoma multiforme cells bearing wild-type p53. Author(s): Kraus A, Gross MW, Knuechel R, Munkel K, Neff F, Schlegel J. Source: Journal of Neurosurgery. 2000 November; 93(5): 863-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11059670

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Abscess within a glioblastoma multiforme--case report. Author(s): Ichikawa M, Shimizu Y, Sato M, Imataka K, Masuda A, Hara Y, Kitano H, Suzuki F. Source: Neurol Med Chir (Tokyo). 1992 October; 32(11): 829-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1280341

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Accelerated fractionation radiotherapy for hospitalized glioblastoma multiforme patients with poor prognostic factors. Author(s): Hernandez JC, Maruyama Y, Yaes R, Chin HW. Source: Journal of Neuro-Oncology. 1990 August; 9(1): 41-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2170591

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Acidic and basic fibroblast growth factors are present in glioblastoma multiforme and normal brain. Author(s): Stefanik DF, Rizkalla LR, Soi A, Goldblatt SA, Rizkalla WM. Source: Annals of the New York Academy of Sciences. 1991; 638: 477-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1723863

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Acidic and basic fibroblast growth factors are present in glioblastoma multiforme. Author(s): Stefanik DF, Rizkalla LR, Soi A, Goldblatt SA, Rizkalla WM. Source: Cancer Research. 1991 October 15; 51(20): 5760-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1717153

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Acute changes in glucose uptake after treatment: the effects of carmustine (BCNU) on human glioblastoma multiforme. Author(s): Rozental JM, Cohen JD, Mehta MP, Levine RL, Hanson JM, Nickles RJ. Source: Journal of Neuro-Oncology. 1993 January; 15(1): 57-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8384254

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Adoptive immunotherapy with adherent lymphokine-activated killer (A-LAK) cells in glioblastoma multiforme. Author(s): Munari L, Silvani A, Passerini CG, Radrizzani M, Parmiani G, Boiardi A. Source: Journal of Neurosurgical Sciences. 1990 July-December; 34(3-4): 283-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1965907

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Alpha-1-antichymotrypsin in human glioblastoma multiforme cells and its relation to GFAP immunostaining. Author(s): Kroh H, Cervos-Navarro J. Source: Clin Neuropathol. 1991 July-August; 10(4): 181-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1653125

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Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human T98G glioblastoma multiforme xenografts. Author(s): Teicher BA, Menon K, Alvarez E, Galbreath E, Shih C, Faul M. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2001 March; 7(3): 634-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11297259

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Antiproliferative effect of lonidamine on a human glioblastoma multiforme cell line. Author(s): Iacopino F, Sica G, Macri P, Paggi MG, Scerrati M, Roselli R, Marchetti P, Della Cuna GR, Marini L. Source: Journal of Neurosurgical Sciences. 1990 July-December; 34(3-4): 193-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1965900

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Application of bacterial artificial chromosome array-based comparative genomic hybridization and spectral karyotyping to the analysis of glioblastoma multiforme. Author(s): Cowell JK, Matsui S, Wang YD, LaDuca J, Conroy J, McQuaid D, Nowak NJ. Source: Cancer Genetics and Cytogenetics. 2004 May; 151(1): 36-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15120909

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Association of epidermal growth factor receptor gene amplification with loss of chromosome 10 in human glioblastoma multiforme. Author(s): von Deimling A, Louis DN, von Ammon K, Petersen I, Hoell T, Chung RY, Martuza RL, Schoenfeld DA, Yasargil MG, Wiestler OD, et al. Source: Journal of Neurosurgery. 1992 August; 77(2): 295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1320666

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Autocrine pathways of the vascular endothelial growth factor (VEGF) in glioblastoma multiforme: clinical relevance of radiation-induced increase of VEGF levels. Author(s): Steiner HH, Karcher S, Mueller MM, Nalbantis E, Kunze S, Herold-Mende C. Source: Journal of Neuro-Oncology. 2004 January; 66(1-2): 129-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015778

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Bilateral osteonecrosis of the tarsus coincident with glioblastoma multiforme. Author(s): Heliotis M, Tsiridis E, Donell ST, Marshall TJ, Scott DG. Source: Journal of the Royal Society of Medicine. 2001 December; 94(12): 635-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11733591

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Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity. Author(s): Coderre JA, Chanana AD, Joel DD, Elowitz EH, Micca PL, Nawrocky MM, Chadha M, Gebbers JO, Shady M, Peress NS, Slatkin DN. Source: Radiation Research. 1998 February; 149(2): 163-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9457896

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Biodistribution of p-boronophenylalanine in patients with glioblastoma multiforme for use in boron neutron capture therapy. Author(s): Elowitz EH, Bergland RM, Coderre JA, Joel DD, Chadha M, Chanana AD. Source: Neurosurgery. 1998 March; 42(3): 463-8; Discussion 468-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9526978

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Biological and molecular analysis of a low-grade recurrence of a glioblastoma multiforme. Author(s): Scheck AC, Shapiro JR, Coons SW, Norman SA, Johnson PC. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1996 January; 2(1): 187-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9816106

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Biology and morphology of glioblastoma multiforme. Author(s): Zulch KJ. Source: Acta Radiol Ther Phys Biol. 1969 February-April; 8(1): 65-77. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4308247

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Bone marrow metastasis from glioblastoma multiforme. Author(s): Mousavi M. Source: J Med Soc N J. 1980 December; 77(13): 904-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6259365

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Bone metastases from secondary glioblastoma multiforme: a case report. Author(s): Cervio A, Piedimonte F, Salaberry J, Alcorta SC, Salvat J, Diez B, Sevlever G. Source: Journal of Neuro-Oncology. 2001 April; 52(2): 141-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11508813

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Bone metastasis of glioblastoma multiforme confirmed by fine needle biopsy. Author(s): Frappaz D, Mornex F, Saint-Pierre G, Ranchere-Vince D, Jouvet A, Chassagne-Clement C, Thiesse P, Mere P, Deruty R. Source: Acta Neurochirurgica. 1999; 141(5): 551-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10392217

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Boron neutron capture therapy for glioblastoma multiforme using pboronophenylalanine and epithermal neutrons: trial design and early clinical results. Author(s): Coderre JA, Elowitz EH, Chadha M, Bergland R, Capala J, Joel DD, Liu HB, Slatkin DN, Chanana AD. Source: Journal of Neuro-Oncology. 1997 May; 33(1-2): 141-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9151231

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Boron neutron capture therapy for glioblastoma multiforme: clinical studies in Sweden. Author(s): Capala J, Stenstam BH, Skold K, af Rosenschold PM, Giusti V, Persson C, Wallin E, Brun A, Franzen L, Carlsson J, Salford L, Ceberg C, Persson B, Pellettieri L, Henriksson R. Source: Journal of Neuro-Oncology. 2003 March-April; 62(1-2): 135-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12749709

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Boron neutron-capture therapy (BNCT) for glioblastoma multiforme (GBM) using the epithermal neutron beam at the Brookhaven National Laboratory. Author(s): Chadha M, Capala J, Coderre JA, Elowitz EH, Iwai J, Joel DD, Liu HB, Wielopolski L, Chanana AD. Source: International Journal of Radiation Oncology, Biology, Physics. 1998 March 1; 40(4): 829-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9531367

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Brachytherapy. Results of two different therapy strategies for patients with primary glioblastoma multiforme. Author(s): Vordermark D. Source: Cancer. 2001 March 15; 91(6): 1185-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11267965

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Brachytherapy: Results of two different therapy strategies for patients with primary glioblastoma multiforme. Author(s): Koot RW, Maarouf M, Hulshof MC, Voges J, Treuer H, Koedooder C, Sturm V, Bosch DA. Source: Cancer. 2000 June 15; 88(12): 2796-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10870063

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Brain stem and spinal metastases of supratentorial glioblastoma multiforme: a clinical series. Author(s): Vertosick FT Jr, Selker RG. Source: Neurosurgery. 1990 October; 27(4): 516-21; Discussion 521-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2172859

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Bromodeoxyuridine labeling index in glioblastoma multiforme: relation to radiation response, age, and survival. Author(s): Barker FG, Prados MD, Chang SM, Davis RL, Gutin PH, Lamborn KR, Larson DA, McDermott MW, Sneed PK, Wilson CB. Source: International Journal of Radiation Oncology, Biology, Physics. 1996 March 1; 34(4): 803-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8598356

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Case-control study of use of nonsteroidal antiinflammatory drugs and glioblastoma multiforme. Author(s): Sivak-Sears NR, Schwartzbaum JA, Miike R, Moghadassi M, Wrensch M. Source: American Journal of Epidemiology. 2004 June 15; 159(12): 1131-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15191930

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Cell type selective accumulation of mercaptoundecahydro- closo-dodecaborate (BSH) in glioblastoma multiforme. Author(s): Neumann M, Bergmann M, Gabel D. Source: Acta Neurochirurgica. 2003 November; 145(11): 971-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14628202

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Central neurogenic hyperventilation in a conscious child associated with glioblastoma multiforme. Author(s): Shahar E, Postovsky S, Bennett O. Source: Pediatric Neurology. 2004 April; 30(4): 287-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15087110

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Cerebral granular cell tumor occurring with glioblastoma multiforme: case report. Author(s): Harris CP, Townsend JJ, Brockmeyer DL, Heilbrun MP. Source: Surgical Neurology. 1991 September; 36(3): 202-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1652163

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Cervical metastatic glioblastoma multiforme. Author(s): Zappia JJ, Wolf GT. Source: Archives of Otolaryngology--Head & Neck Surgery. 1992 July; 118(7): 755-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1320896

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Changes in glial fibrillary acidic protein and karyotype during culturing of two cell lines established from human glioblastoma multiforme. Author(s): Bocchini V, Casalone R, Collini P, Rebel G, Lo Curto F. Source: Cell and Tissue Research. 1991 July; 265(1): 73-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1655272

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Characterization of chromosomal aberrations in a case of glioblastoma multiforme combining cytogenetic and molecular cytogenetic techniques. Author(s): Zuber MA, Krupp W, Holland H, Froster UG. Source: Cancer Genetics and Cytogenetics. 2002 October 15; 138(2): 111-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505254

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Characterization of interleukin-2-initiated versus OKT3-initiated human tumorinfiltrating lymphocytes from glioblastoma multiforme: growth characteristics, cytolytic activity, and cell phenotype. Author(s): Grimm EA, Bruner JM, Carinhas J, Koppen JA, Loudon WG, Owen-Schaub L, Steck PA, Moser RP. Source: Cancer Immunology, Immunotherapy : Cii. 1991; 32(6): 391-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1848799

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Chemotherapy for glioblastoma multiforme. Author(s): Lord J, Coleman EA. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1991 February; 23(1): 68-70. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1826720

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Classification of glioblastoma multiforme in adults by molecular genetics. Author(s): Benjamin R, Capparella J, Brown A. Source: Cancer Journal (Sudbury, Mass.). 2003 March-April; 9(2): 82-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784873

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Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Author(s): Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H. Source: Acta Neuropathologica. 2000 September; 100(3): 323-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10965803

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Clonal composition of glioblastoma multiforme. Author(s): Berkman RA, Clark WC, Saxena A, Robertson JT, Oldfield EH, Ali IU. Source: Journal of Neurosurgery. 1992 September; 77(3): 432-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1324297

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Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI774. Author(s): Efferth T, Ramirez T, Gebhart E, Halatsch ME. Source: Biochemical Pharmacology. 2004 May 1; 67(9): 1689-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15081868

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Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme. Author(s): Baumann F, Bjeljac M, Kollias SS, Baumert BG, Brandner S, Rousson V, Yonekawa Y, Bernays RL. Source: Journal of Neuro-Oncology. 2004 March-April; 67(1-2): 191-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15072467

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Comparative genetic patterns of glioblastoma multiforme: potential diagnostic tool for tumor classification. Author(s): Wiltshire RN, Rasheed BK, Friedman HS, Friedman AH, Bigner SH. Source: Neuro-Oncology. 2000 July; 2(3): 164-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11302337

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Comparative treatment planning: proton vs. x-ray beams against glioblastoma multiforme. Author(s): Tatsuzaki H, Urie MM, Linggood R. Source: International Journal of Radiation Oncology, Biology, Physics. 1992; 22(2): 26573. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1310962

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Comparison of intensity-modulated radiotherapy with three-dimensional conformal radiation therapy planning for glioblastoma multiforme. Author(s): Chan MF, Schupak K, Burman C, Chui CS, Ling CC. Source: Medical Dosimetry : Official Journal of the American Association of Medical Dosimetrists. 2003 Winter; 28(4): 261-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684191

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Comparison of proliferation indices in glioblastoma multiforme by whole tissue section vs tissue microarray. Author(s): Chiesa-Vottero AG, Rybicki LA, Prayson RA. Source: American Journal of Clinical Pathology. 2003 December; 120(6): 902-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671979

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Congenital glioblastoma multiforme--report of an autopsy case. Author(s): Jung WH, Choi S, Oh KK, Chi JG. Source: Journal of Korean Medical Science. 1990 December; 5(4): 225-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1966036

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Cystic glioblastoma multiforme: survival outcomes in 22 cases. Author(s): Maldaun MV, Suki D, Lang FF, Prabhu S, Shi W, Fuller GN, Wildrick DM, Sawaya R. Source: Journal of Neurosurgery. 2004 January; 100(1): 61-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743913

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DAB389EGF fusion protein therapy of refractory glioblastoma multiforme. Author(s): Cohen KA, Liu T, Bissonette R, Puri RK, Frankel AE. Source: Current Pharmaceutical Biotechnology. 2003 February; 4(1): 39-49. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12570681

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Decreased BOLD functional MR activation of the motor and sensory cortices adjacent to a glioblastoma multiforme: implications for image-guided neurosurgery. Author(s): Holodny AI, Schulder M, Liu WC, Maldjian JA, Kalnin AJ. Source: Ajnr. American Journal of Neuroradiology. 1999 April; 20(4): 609-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10319970

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Deficiency of CD4+CD45RA+ lymphocytes in patients with glioblastoma multiforme. Author(s): Menage P, Thibault G, Lebranchu Y, Jan M, Bardos P. Source: Eur J Med. 1992 October; 1(6): 362-4. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1285221

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Demonstration of a brachytherapy boost dose-response relationship in glioblastoma multiforme: headed in the right direction. Author(s): Schultz CJ. Source: International Journal of Radiation Oncology, Biology, Physics. 1996 April 1; 35(1): 187-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8641918

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Demonstration of brachytherapy boost dose-response relationships in glioblastoma multiforme. Author(s): Sneed PK, Lamborn KR, Larson DA, Prados MD, Malec MK, McDermott MW, Weaver KA, Phillips TL, Wara WM, Gutin PH. Source: International Journal of Radiation Oncology, Biology, Physics. 1996 April 1; 35(1): 37-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8641924

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Detection of multiple gene amplifications in glioblastoma multiforme using arraybased comparative genomic hybridization. Author(s): Hui AB, Lo KW, Yin XL, Poon WS, Ng HK. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2001 May; 81(5): 717-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11351043

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Determination of the subcellular distribution of mercaptoundecahydro-closododecaborate (BSH) in human glioblastoma multiforme by electron microscopy. Author(s): Neumann M, Kunz U, Lehmann H, Gabel D. Source: Journal of Neuro-Oncology. 2002 April; 57(2): 97-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12125978

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Development of glioblastoma multiforme following traumatic cerebral contusion: case report and review of literature. Author(s): Moorthy RK, Rajshekhar V. Source: Surgical Neurology. 2004 February; 61(2): 180-4; Discussion 184. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751638

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Differential expression in glioblastoma multiforme and cerebral hemangioblastoma of cytoplasmic proteins that bind two different domains within the 3'-untranslated region of the human glucose transporter 1 (GLUT1) messenger RNA. Author(s): Tsukamoto H, Boado RJ, Pardridge WM. Source: The Journal of Clinical Investigation. 1996 June 15; 97(12): 2823-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8675694

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Differential expression of beta-catenin in human glioblastoma multiforme and normal brain tissue. Author(s): Yano H, Hara A, Takenaka K, Nakatani K, Shinoda J, Shimokawa K, Yoshimi N, Mori H, Sakai N. Source: Neurological Research. 2000 October; 22(7): 650-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11091968

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Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Author(s): Sano T, Lin H, Chen X, Langford LA, Koul D, Bondy ML, Hess KR, Myers JN, Hong YK, Yung WK, Steck PA. Source: Cancer Research. 1999 April 15; 59(8): 1820-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10213484

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Differentiation of glioblastoma multiforme from astrocytomas by in vitro 1H MRS analysis of human brain tumors. Author(s): Carpinelli G, Carapella CM, Palombi L, Raus L, Caroli F, Podo F. Source: Anticancer Res. 1996 May-June; 16(3B): 1559-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8694526

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Diffuse bony metastases at presentation in a child with glioblastoma multiforme. A case report. Author(s): Gamis AS, Egelhoff J, Roloson G, Young J, Woods GM, Newman R, Freeman AI. Source: Cancer. 1990 July 1; 66(1): 180-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2162242

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Diffuse vertebral body metastasis from a glioblastoma multiforme: a technetium-99m Sestamibi single-photon emission computerized tomography study. Author(s): Beauchesne P, Soler C, Mosnier JF. Source: Journal of Neurosurgery. 2000 November; 93(5): 887-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11059674

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Diphtheria toxin-epidermal growth factor fusion protein and Pseudomonas exotoxininterleukin 13 fusion protein exert synergistic toxicity against human glioblastoma multiforme cells. Author(s): Liu TF, Willingham MC, Tatter SB, Cohen KA, Lowe AC, Thorburn A, Frankel AE. Source: Bioconjugate Chemistry. 2003 November-December; 14(6): 1107-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624623

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Distant angiogenesis in a patient with glioblastoma multiforme. Author(s): Romberger CF, Wollman RL, Wainer BH. Source: Clin Neuropathol. 1990 March-April; 9(2): 97-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1692777

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Distinct radiochemotherapy protocols differentially influence cellular proliferation and expression of p53 and Bcl-2 in glioblastoma multiforme relapses in vivo. Author(s): Deininger MH, Grote E, Wickboldt J, Meyermann R. Source: Journal of Neuro-Oncology. 2000 June; 48(2): 121-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11083075

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Distribution of epidermal growth factor receptor protein correlates with gain in chromosome 7 revealed by comparative genomic hybridization after microdissection in glioblastoma multiforme. Author(s): Romeike BF, Jung V, Feiden W, Moringlane JR, Zang KD, Urbschat SM. Source: Pathology, Research and Practice. 2001; 197(6): 427-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11432670

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Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastoma multiforme. Author(s): Marutani M, Tonoki H, Tada M, Takahashi M, Kashiwazaki H, Hida Y, Hamada J, Asaka M, Moriuchi T. Source: Cancer Research. 1999 October 1; 59(19): 4765-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10519380

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Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy. Author(s): Schwartz RB, Holman BL, Polak JF, Garada BM, Schwartz MS, Folkerth R, Carvalho PA, Loeffler JS, Shrieve DC, Black PM, Alexander E 3rd. Source: Journal of Neurosurgery. 1998 July; 89(1): 60-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9647173

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Effect of recombinant fibroblast interferon and recombinant immune interferon on growth and the antigenic phenotype of multidrug-resistant human glioblastoma multiforme cells. Author(s): Reddy PG, Graham GM, Datta S, Guarini L, Moulton TA, Jiang HP, Gottesman MM, Ferrone S, Fisher PB. Source: Journal of the National Cancer Institute. 1991 September 18; 83(18): 1307-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1653364

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EGFR but not PDGFR-beta expression correlates to the antiproliferative effect of growth factor withdrawal in glioblastoma multiforme cell lines. Author(s): Halatsch ME, Gehrke E, Borhani FA, Efferth T, Werner C, Nomikos P, Schmidt U, Buchfelder M. Source: Anticancer Res. 2003 May-June; 23(3B): 2315-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894509

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EGFR overexpression and radiation response in glioblastoma multiforme. Author(s): Barker FG 2nd, Simmons ML, Chang SM, Prados MD, Larson DA, Sneed PK, Wara WM, Berger MS, Chen P, Israel MA, Aldape KD. Source: International Journal of Radiation Oncology, Biology, Physics. 2001 October 1; 51(2): 410-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11567815

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Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. Author(s): Friedman HS, Dolan ME, Moschel RC, Pegg AE, Felker GM, Rich J, Bigner DD, Schold SC Jr. Source: Journal of the National Cancer Institute. 1992 December 16; 84(24): 1926-31. Erratum In: J Natl Cancer Inst 1994 July 6; 86(13): 1027. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1334154

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Epidermal growth factor receptor gene amplification as a prognostic marker in glioblastoma multiforme: results of a meta-analysis. Author(s): Huncharek M, Kupelnick B. Source: Oncology Research. 2000; 12(2): 107-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11132923

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Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Author(s): Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY. Source: Molecular Biology of the Cell. 1993 January; 4(1): 121-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7680247

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Establishment and characterization of a human cell line from paediatric cerebellar glioblastoma multiforme. Author(s): Di Tomaso E, Pang JC, Lam HK, Tian XX, Suen KW, Hui AB, Hjelm NM. Source: Neuropathology and Applied Neurobiology. 2000 February; 26(1): 22-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10736064

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Establishment and characterization of two cell lines derived from human glioblastoma multiforme. Author(s): Bacciocchi G, Gibelli N, Zibera C, Pedrazzoli P, Bergamaschi G, De Piceis Polver P, Danova M, Mazzini G, Palomba L, Tupler R, et al. Source: Anticancer Res. 1992 May-June; 12(3): 853-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1320358

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European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme. Author(s): van den Bent MJ, Grisold W, Frappaz D, Stupp R, Desir JP, Lesimple T, Dittrich C, de Jonge MJ, Brandes A, Frenay M, Carpentier AF, Chollet P, Oliveira J, Baron B, Lacombe D, Schuessler M, Fumoleau P; European Organization for Research and Treatment of Cancer New Drug Development Group; European Organization for Research and Treatment of Cancer Brain Tumor Group. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2003 December; 14(12): 1732-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14630677

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Evaluation of MRI score in the differentiation between glioblastoma multiforme and metastatic adenocarcinoma of the brain. Author(s): Asari S, Makabe T, Katayama S, Itoh T, Tsuchida S, Kunishio K, Ohmoto T. Source: Acta Neurochirurgica. 1993; 122(1-2): 54-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8392778

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Evaluation of pre-radiotherapy cyclophosphamide in patients with newly diagnosed glioblastoma multiforme. Writing Committee for The Brain Tumor Center at Duke. Author(s): Bottom KS, Ashley DM, Friedman HS, Longee DC. Source: Journal of Neuro-Oncology. 2000; 46(2): 151-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10894368

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Evaluation of software for registration of contrast-enhanced brain MR images in patients with glioblastoma multiforme. Author(s): Barboriak DP, Provenzale JM. Source: Ajr. American Journal of Roentgenology. 2002 July; 179(1): 245-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12076945

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Experiences with reoperation on recurrent glioblastoma multiforme. Author(s): Pinsker M, Lumenta C. Source: Zentralblatt Fur Neurochirurgie. 2001; 62(2): 43-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11786935

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Expression and functional activity of heat shock proteins in human glioblastoma multiforme. Author(s): Hermisson M, Strik H, Rieger J, Dichgans J, Meyermann R, Weller M. Source: Neurology. 2000 March 28; 54(6): 1357-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10746610

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Expression of JC virus T-antigen in a patient with MS and glioblastoma multiforme. Author(s): Del Valle L, Delbue S, Gordon J, Enam S, Croul S, Ferrante P, Khalili K. Source: Neurology. 2002 March 26; 58(6): 895-900. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11914404

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Expression of p19INK4d, CDK4, CDK6 in glioblastoma multiforme. Author(s): Lam PY, Di Tomaso E, Ng HK, Pang JC, Roussel MF, Hjelm NM. Source: British Journal of Neurosurgery. 2000 February; 14(1): 28-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10884881

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Expression of the epidermal growth factor receptor in astrocytic tumours is specifically associated with glioblastoma multiforme. Author(s): Agosti RM, Leuthold M, Gullick WJ, Yasargil MG, Wiestler OD. Source: Virchows Arch a Pathol Anat Histopathol. 1992; 420(4): 321-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1314448

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Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Author(s): Rascher G, Fischmann A, Kroger S, Duffner F, Grote EH, Wolburg H. Source: Acta Neuropathologica. 2002 July; 104(1): 85-91. Epub 2002 March 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12070669

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Extraneural metastases of infratentorial glioblastoma multiforme to the peritoneal cavity. Author(s): Newton HB, Rosenblum MK, Walker RW. Source: Cancer. 1992 April 15; 69(8): 2149-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1311985

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Familial glioblastoma multiforme without neurofibromatosis. Author(s): Chemke J, Katznelson D, Zucker G. Source: American Journal of Medical Genetics. 1985 August; 21(4): 731-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2992272

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Fast neutron beam radiotherapy of glioblastoma multiforme. Author(s): Parker RG, Berry HC, Gerdes AJ, Soronen MD, Shaw CM. Source: Am J Roentgenol. 1976 August; 127(2): 331-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=182016

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Fast neutron radiation therapy for glioblastoma multiforme. Results of an RTOG study. Author(s): Griffin TW, Davis R, Laramore G, Hendrickson F, Rodrigues-Antunez A, Hussey D, Nelson J. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 1983 December; 6(6): 661-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6314799

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Fast-neutron irradiation of glioblastoma multiforme. Neuropathological analysis. Author(s): Shaw CM, Sumi SM, Alvord EC Jr, Gerdes AJ, Spence A, Parker RG. Source: Journal of Neurosurgery. 1978 July; 49(1): 1-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=207833

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Feasibility and toxicity of CCNU therapy in elderly patients with glioblastoma multiforme. Author(s): Piribauer M, Fazeny-Dorner B, Rossler K, Ungersbock K, Czech T, Killer M, Dieckmann K, Birner P, Prayer D, Hainfellner J, Muhm M, Marosi C. Source: Anti-Cancer Drugs. 2003 February; 14(2): 137-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12569300

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Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme. Author(s): Morrison RS, Yamaguchi F, Bruner JM, Tang M, McKeehan W, Berger MS. Source: Cancer Research. 1994 May 15; 54(10): 2794-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8168112

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Fibroblast growth factor receptor-1 alpha-exon exclusion and polypyrimidine tractbinding protein in glioblastoma multiforme tumors. Author(s): Jin W, McCutcheon IE, Fuller GN, Huang ES, Cote GJ. Source: Cancer Research. 2000 March 1; 60(5): 1221-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10728679

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Fine-needle aspiration in metastatic glioblastoma multiforme. Author(s): Gonzalez-Campora R, Otal Salaverri C, Vazquez-Ramirez F, Salguero Villadiego M, Galera-Davidson H. Source: Diagnostic Cytopathology. 1997 December; 17(6): 487. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9407215

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First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia. Author(s): Brandes AA, Basso U, Reni M, Vastola F, Tosoni A, Cavallo G, Scopece L, Ferreri AJ, Panucci MG, Monfardini S, Ermani M; Gruppo Italiano Cooperativo di Neuro-Oncologia. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 May 1; 22(9): 1598-604. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15117981

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Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. Author(s): Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Source: Journal of Neurosurgery. 2000 December; 93(6): 1003-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11117842

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Fluorescence-guided resection of glioblastoma multiforme by using high-dose fluorescein sodium. Technical note. Author(s): Shinoda J, Yano H, Yoshimura S, Okumura A, Kaku Y, Iwama T, Sakai N. Source: Journal of Neurosurgery. 2003 September; 99(3): 597-603. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12959452

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Fractionation study in the treatment of glioblastoma multiforme. Author(s): Simpson WJ, Platts ME. Source: International Journal of Radiation Oncology, Biology, Physics. 1976 July-August; 1(7-8): 639-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=185170

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Gain of chromosome 7 detected by comparative genomic hybridization accumulates with age in patients with glioblastoma multiforme. Author(s): Zuber MA, Koschny R, Koschny T, Froster UG. Source: Cancer Genetics and Cytogenetics. 2002 July 1; 136(1): 92-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12165461

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Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Author(s): Nwokedi EC, DiBiase SJ, Jabbour S, Herman J, Amin P, Chin LS. Source: Neurosurgery. 2002 January; 50(1): 41-6; Discussion 46-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11844233

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Gene amplification and splice variants of 25-hydroxyvitamin D3 1,alpha-hydroxylase (CYP27B1) in glioblastoma multiforme--a possible role in tumor progression? Author(s): Diesel B, Fischer U, Meese E. Source: Recent Results Cancer Res. 2003; 164: 151-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899520

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Genetic analysis of a multifocal glioblastoma multiforme: a suitable tool to gain new aspects in glioma development. Author(s): Krex D, Mohr B, Appelt H, Schackert HK, Schackert G. Source: Neurosurgery. 2003 December; 53(6): 1377-84; Discussion 1384. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633303

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Genome-wide allelotype study of primary glioblastoma multiforme. Author(s): Hu J, Jiang C, Ng HK, Pang JC, Tong CY, Chen S. Source: Chinese Medical Journal. 2003 April; 116(4): 577-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875726

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Glioblastoma multiforme and ascending weakness. Author(s): Cooke LJ, Morrish W, Becker WJ. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2002 November; 29(4): 372-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12463493

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Glioblastoma multiforme in a case of acquired immunodeficiency syndrome: investigation a possible oncogenic influence of human immunodeficiency virus on glial cells. Case report and review of the literature. Author(s): Vannemreddy PS, Fowler M, Polin RS, Todd JR, Nanda A. Source: Journal of Neurosurgery. 2000 January; 92(1): 161-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10616096

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Glioblastoma multiforme in adults: results of treatment. Author(s): Jose B, Duncan A, Paris K, Lindberg RD, Spanos WJ Jr. Source: J Ky Med Assoc. 1990 December; 88(12): 650-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2177493

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Glioblastoma multiforme in an Asian population: evidence for a distinct genetic pathway. Author(s): Das A, Tan WL, Teo J, Smith DR. Source: Journal of Neuro-Oncology. 2002 November; 60(2): 117-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12635658

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Glioblastoma multiforme occurring in a patient following exposure to polychlorinated biphenyls. Author(s): Petruska DA, Engelhard HH. Source: J Ky Med Assoc. 1991 October; 89(10): 496-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1660512

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Glioblastoma multiforme occurring in a patient treated with gamma knife surgery. Case report and review of the literature. Author(s): Shamisa A, Bance M, Nag S, Tator C, Wong S, Noren G, Guha A. Source: Journal of Neurosurgery. 2001 May; 94(5): 816-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11354416

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Glioblastoma multiforme of the brain stem in a patient with acquired immunodeficiency syndrome. Author(s): Wolff R, Zimmermann M, Marquardt G, Lanfermann H, Nafe R, Seifert V. Source: Acta Neurochirurgica. 2002 September; 144(9): 941-4; Discussion 944-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12376778

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Glioblastoma multiforme of the conus medullaris. Author(s): Scarrow AM, Rajendran P, Welch WC. Source: Clinical Neurology and Neurosurgery. 2000 September; 102(3): 166-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10996716

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Glioblastoma multiforme of the hippocampus in advanced Alzheimer's disease. Author(s): Poole EC, Kepes JJ. Source: Neuropathology and Applied Neurobiology. 1991 December; 17(6): 509-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1666175

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Glioblastoma multiforme of the pineal region: case report. Author(s): Gasparetto EL, Warszawiak D, Adam GP, Bleggi-Torres LF, de Carvalho Neto A. Source: Arquivos De Neuro-Psiquiatria. 2003 June; 61(2B): 468-72. Epub 2003 July 28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894287

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Glioblastoma multiforme presenting as osteoblastic metastatic disease: case report and review of the literature. Author(s): Myers T, Egelhoff J, Myers M. Source: Ajnr. American Journal of Neuroradiology. 1990 July-August; 11(4): 802-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2164320

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Glioblastoma multiforme: introduction. Author(s): Markert J. Source: Cancer Journal (Sudbury, Mass.). 2003 May-June; 9(3): 148. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952299

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Glioblastoma multiforme: introduction. Author(s): Markert J. Source: Cancer Journal (Sudbury, Mass.). 2003 March-April; 9(2): 71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784871

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Glioblastoma multiforme: the terminator. Author(s): Holland EC. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 June 6; 97(12): 6242-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10841526

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Halogenated pyrimidines as radiosensitizers in the treatment of glioblastoma multiforme. Author(s): Jackson D, Kinsella T, Rowland J, Wright D, Katz D, Main D, Collins J, Kornblith P, Glatstein E. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 1987 October; 10(5): 437-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2821790

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Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme. Author(s): Osoba D, Brada M, Yung WK, Prados M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2000 April; 18(7): 1481-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10735896

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Heterogeneity, polyploidy, aneusomy, and 9p deletion in human glioblastoma multiforme. Author(s): Park SH, Maeda T, Mohapatra G, Waldman FM, Davis RL, Feuerstein BG. Source: Cancer Genetics and Cytogenetics. 1995 September; 83(2): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7553582

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Heterotransplantation of human glioblastoma multiforme and meningioma to nude mice. Author(s): Rana MW, Pinkerton H, Thornton H, Nagy D. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). 1977 May; 155(1): 85-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=193127

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High concentration of locally administered human fibroblast interferon in a glioblastoma multiforme. Discrepancy between clinical response and sensitivity of the tumor cells to the interferon in vitro. Author(s): Fukui M, Sawa H, Takeshita I, Kitamura K, Satoh Y, Kasama K. Source: Fukuoka Igaku Zasshi. 1986 February; 77(2): 135-43. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3011624

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High dose BCNU followed by autologous bone marrow infusion in glioblastoma multiforme. Author(s): Carella AM, Giordano D, Santini G, Frassoni F, Podesta M, Van Lint MT, Bacigalupo A, Nati S, Vimercati R, Occhini D, Bistolfi F, Lucarelli G, Lercari G, Marmont AM. Source: Tumori. 1981 October 31; 67(5): 473-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6275588

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High dose tamoxifen and radiotherapy in patients with glioblastoma multiforme: a phase IB study. Author(s): Muanza T, Shenouda G, Souhami L, Leblanc R, Mohr G, Corns R, Langleben A. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2000 November; 27(4): 302-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11097520

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High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples. Author(s): Kirches E, Krause G, Warich-Kirches M, Weis S, Schneider T, Meyer-Puttlitz B, Mawrin C, Dietzmann K. Source: International Journal of Cancer. Journal International Du Cancer. 2001 August 15; 93(4): 534-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11477557

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High-dose BCNU with ABMT followed by radiation therapy in the treatment of supratentorial glioblastoma multiforme. Author(s): Linassier C, Benboubker L, Velut S, Calais G, Saudeau D, Jan M, Autret A, Berger C, Biron P, Colombat P. Source: Bone Marrow Transplantation. 1996 September; 18 Suppl 1: S69-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8899180

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High-dose BCNU with autologous bone marrow rescue for recurrent glioblastoma multiforme. Author(s): Hochberg FH, Parker LM, Takvorian T, Canellos GP, Zervas NT. Source: Journal of Neurosurgery. 1981 April; 54(4): 455-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6259300

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High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Author(s): Nakagawa K, Aoki Y, Fujimaki T, Tago M, Terahara A, Karasawa K, Sakata K, Sasaki Y, Matsutani M, Akanuma A. Source: International Journal of Radiation Oncology, Biology, Physics. 1998 March 15; 40(5): 1141-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9539570

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High-dose interstitial brachytherapy for glioblastoma multiforme. Author(s): Micheletti E, Baroncelli G, La Face B, Feroldi P, Galelli M, Giunta F. Source: Tumori. 1994 February 28; 80(1): 44-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8191598

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Histologic factors of prognostic significance in the glioblastoma multiforme. Author(s): Burger PC, Vollmer RT. Source: Cancer. 1980 September 1; 46(5): 1179-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6260329

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Hormonal effects on glioblastoma multiforme in the nude rat model. Author(s): Plunkett RJ, Lis A, Barone TA, Fronckowiak MD, Greenberg SJ. Source: Journal of Neurosurgery. 1999 June; 90(6): 1072-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10350254

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Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes. Author(s): Yoshida J, Mizuno M, Fujii M, Kajita Y, Nakahara N, Hatano M, Saito R, Nobayashi M, Wakabayashi T. Source: Human Gene Therapy. 2004 January; 15(1): 77-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14965379

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Hydroxyurea accelerates the loss of epidermal growth factor receptor genes amplified as double-minute chromosomes in human glioblastoma multiforme. Author(s): Canute GW, Longo SL, Longo JA, Winfield JA, Nevaldine BH, Hahn PJ. Source: Neurosurgery. 1996 November; 39(5): 976-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8905754

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Hyperfractionated and accelerated-hyperfractionated radiotherapy for glioblastoma multiforme. Author(s): Nieder C, Nestle U, Ketter R, Kolles H, Gentner SJ, Steudel WI, Schnabel K. Source: Radiation Oncology Investigations. 1999; 7(1): 36-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10030622

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Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme. Author(s): Floyd NS, Woo SY, Teh BS, Prado C, Mai WY, Trask T, Gildenberg PL, Holoye P, Augspurger ME, Carpenter LS, Lu HH, Chiu JK, Grant WH 3rd, Butler EB. Source: International Journal of Radiation Oncology, Biology, Physics. 2004 March 1; 58(3): 721-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14967426

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Hypofractionated radiation therapy in patients with glioblastoma multiforme: results of treatment and impact of prognostic factors. Author(s): Slotman BJ, Kralendonk JH, van Alphen HA, Kamphorst W, Karim AB. Source: International Journal of Radiation Oncology, Biology, Physics. 1996 March 1; 34(4): 895-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8598367

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Hypofractionation in glioblastoma multiforme. Author(s): Hulshof MC, Schimmel EC, Andries Bosch D, Gonzalez Gonzalez D. Source: Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2000 February; 54(2): 143-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10699477

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Identification of HLA a*0201 glioblastoma multiforme cell lines for immunotherapy by PCR-SSP and DNA sequencing. Author(s): Wu AH, Hall WA, Low WC. Source: Journal of Neuro-Oncology. 2004 January; 66(1-2): 1-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015764

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Images in neuro-oncology. Glioblastoma multiforme. Author(s): Baehring JM. Source: Journal of Neuro-Oncology. 2004 March-April; 67(1-2): 75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15072450

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Immune response induced by retrovirus-mediated HSV-tk/GCV pharmacogene therapy in patients with glioblastoma multiforme. Author(s): Rainov NG, Kramm CM, Banning U, Riemann D, Holzhausen HJ, Heidecke V, Burger KJ, Burkert W, Korholz D. Source: Gene Therapy. 2000 November; 7(21): 1853-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11110418

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Immunohistochemical tenascin-C expression in paediatric supratentorial glioblastoma multiforme. Author(s): Germano A, Galatioto S, Caffo M, Caruso G, La Torre D, Cardia E, Tomasello F. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 2000 June; 16(6): 357-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10933231

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Immunotoxin treatment targeted to the high-molecular-weight melanoma-associated antigen prolonging the survival of immunodeficient rats with invasive intracranial human glioblastoma multiforme. Author(s): Hjortland GO, Garman-Vik SS, Juell S, Olsen OE, Hirschberg H, Fodstad O, Engebraaten O. Source: Journal of Neurosurgery. 2004 February; 100(2): 320-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15086240

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In situ detection of telomerase catalytic subunit mRNA in glioblastoma multiforme. Author(s): Falchetti ML, Pallini R, D'Ambrosio E, Pierconti F, Martini M, Cimino-Reale G, Verna R, Maira G, Larocca LM. Source: International Journal of Cancer. Journal International Du Cancer. 2000 December 15; 88(6): 895-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11093811

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In situ detection of telomeres by fluorescence in situ hybridization and telomerase activity in glioblastoma multiforme: correlation with p53 status, EGFR, c-myc, MIB1, and Topoisomerase IIalpha protein expression. Author(s): Miracco C, De Santi MM, Luzi P, Lalinga AV, Laurini L, De Nisi MC, Angeloni G, Brogi M, Cardone C, Carducci A, Arcuri F, Tosi P, Rubino G, Pirtoli L. Source: International Journal of Oncology. 2003 December; 23(6): 1529-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14612923

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In vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme. Author(s): Hall WA, Godal A, Juell S, Fodstad O. Source: Journal of Neurosurgery. 1992 May; 76(5): 838-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1314294

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In vitro intrinsic radiation sensitivity of glioblastoma multiforme. Author(s): Taghian A, Suit H, Pardo F, Gioioso D, Tomkinson K, DuBois W, Gerweck L. Source: International Journal of Radiation Oncology, Biology, Physics. 1992; 23(1): 55-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1315313

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Increased hMSH2 protein expression in glioblastoma multiforme. Author(s): Srivastava T, Chattopadhyay P, Mahapatra AK, Sarkar C, Sinha S. Source: Journal of Neuro-Oncology. 2004 January; 66(1-2): 51-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015769

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Induction of growth suppression and modification of gene expression in multi-drugresistant human glioblastoma multiforme cells by recombinant human fibroblast and immune interferon. Author(s): Moulton TA, Jiang H, Guarini L, Fetell MR, Fisher PB. Source: International Journal of Cancer. Journal International Du Cancer. 1992 May 28; 51(3): 373-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1317362

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Influence of type and extent of surgery on early results and survival time in glioblastoma multiforme. Author(s): Hollerhage HG, Zumkeller M, Becker M, Dietz H. Source: Acta Neurochirurgica. 1991; 113(1-2): 31-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1665950

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Infratemporal and intraorbital metastasis of the glioblastoma multiforme. A case report. Author(s): Erdem A, Tun K, Ugur HC, Erekul S. Source: Neuro-Chirurgie. 2004 June; 50(2-3 Pt 1): 101-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15213638

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Integrin beta3 overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of beta3 overexpression in glioblastoma multiforme. Author(s): Kanamori M, Vanden Berg SR, Bergers G, Berger MS, Pieper RO. Source: Cancer Research. 2004 April 15; 64(8): 2751-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15087390

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Interleukin-1 beta decreases HLA class II expression on a glioblastoma multiforme cell line. Author(s): Cowan EP, Pierce ML, Dhib-Jalbut S. Source: Journal of Neuroimmunology. 1991 July; 33(1): 17-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1711536

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Intracerebral neurocysticercosis mimicking glioblastoma multiforme: a rare differential diagnosis in Central Europe. Author(s): Sabel M, Neuen-Jacob E, Vogt C, Weber F. Source: Neuroradiology. 2001 March; 43(3): 227-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11305755

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Intracranial fibrosarcoma arising 5 years after chemotherapy alone for glioblastoma multiforme in a child. Author(s): Kaminski JM, Yang CC, Yagmai F, Movsas B, Lee M, Barrett JT. Source: Pediatric Neurosurgery. 2000 November; 33(5): 257-260. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11155063

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Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines. Author(s): Halatsch ME, Gehrke EE, Vougioukas VI, Botefur IC, A-Borhani F, Efferth T, Gebhart E, Domhof S, Schmidt U, Buchfelder M. Source: Journal of Neurosurgery. 2004 March; 100(3): 523-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15035290

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Irradiation fields and doses in glioblastoma multiforme: are current standards adequate? Author(s): Reni M, Cozzarini C, Panucci MG, Ceresoli GL, Ferreri AJ, Fiorino C, Truci G, Falini A, Tartara F, Terreni MR, Verusio C, Villa E. Source: Tumori. 2001 March-April; 87(2): 85-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11401212

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Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Author(s): McLendon RE, Halperin EC. Source: Cancer. 2003 October 15; 98(8): 1745-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534892

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Letter: Glioblastoma multiforme. Author(s): Walker MD. Source: Journal of Neurosurgery. 1974 September; 41(3): 405. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4370150

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Levamisole in the treatment of glioblastoma multiforme. Author(s): Fischer SP, Lindermuth J, Hash C, Shenkin HA. Source: Journal of Surgical Oncology. 1985 March; 28(3): 214-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2983151

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Liver graft-transmitted glioblastoma multiforme. A case report and experience with 13 multiorgan donors suffering from primary cerebral neoplasia. Author(s): Jonas S, Bechstein WO, Lemmens HP, Neuhaus R, Thalmann U, Neuhaus P. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1996; 9(4): 426-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8819282

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Local chemotherapy with cisplatin-depot for glioblastoma multiforme. Author(s): Sheleg SV, Korotkevich EA, Zhavrid EA, Muravskaya GV, Smeyanovich AF, Shanko YG, Yurkshtovich TL, Bychkovsky PB, Belyaev SA. Source: Journal of Neuro-Oncology. 2002 October; 60(1): 53-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416546

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Local immunotherapy of recurrent glioblastoma multiforme by intracerebral perfusion of interleukin-2 and LAK cells. Author(s): Blancher A, Roubinet F, Grancher AS, Tremoulet M, Bonate A, Delisle MB, Calot JP, Pourreau C, Franks C, Ducos J, et al. Source: European Cytokine Network. 1993 September-October; 4(5): 331-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8117934

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Local interstitial chemotherapy with sustained release bucladesine in de novo glioblastoma multiforme: a preliminary study. Author(s): Dalbasti T, Oktar N, Cagli S, Ozdamar N. Source: Journal of Neuro-Oncology. 2002 January; 56(2): 167-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11995818

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Local invasivity of glioblastoma multiforme with destruction of skull bone. Case report and review of the literature. Author(s): Rainov NG, Holzhausen HJ, Meyer H, Burkert W. Source: Neurosurgical Review. 1996; 19(3): 183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8875508

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Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Author(s): Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, Risau W, Engelhardt B. Source: Acta Neuropathologica. 2003 June; 105(6): 586-92. Epub 2003 February 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12734665

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Localized shaped field radiotherapy of malignant glioblastoma multiforme. Author(s): Schryver AD, Greitz T, Forsby N, Brun A. Source: International Journal of Radiation Oncology, Biology, Physics. 1976 July-August; 1(7-8): 713-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=185173

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Long-term follow-up on National Cancer Institute Phase I/II study of glioblastoma multiforme treated with iododeoxyuridine and hyperfractionated irradiation. Author(s): Goffman TE, Dachowski LJ, Bobo H, Oldfield EH, Steinberg SM, Cook J, Mitchell JB, Katz D, Smith R, Glatstein E. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1992 February; 10(2): 264-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1310102

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Long-term glioblastoma multiforme survivors: a population-based study. Author(s): Scott JN, Rewcastle NB, Brasher PM, Fulton D, Hagen NA, MacKinnon JA, Sutherland G, Cairncross JG, Forsyth P. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 1998 August; 25(3): 197-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9706720

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Long-term survival in patients with glioblastoma multiforme. Author(s): Chandler KL, Prados MD, Malec M, Wilson CB. Source: Neurosurgery. 1993 May; 32(5): 716-20; Discussion 720. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8388081

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Long-term survival of glioblastoma multiforme: importance of histopathological reevaluation. Author(s): Kraus JA, Wenghoefer M, Schmidt MC, von Deimling A, Berweiler U, Roggendorf W, Diete S, Dietzmann K, Muller B, Heuser K, Reifenberger G, Schlegel U. Source: Journal of Neurology. 2000 June; 247(6): 455-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10929275

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Long-term survivors of glioblastoma multiforme: clinical and molecular characteristics. Author(s): Morita M, Rosenblum MK, Bilsky MH, Fraser RA, Rosenfeld MR. Source: Journal of Neuro-Oncology. 1996 March; 27(3): 259-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8847560

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Loss of heterozygosity on chromosome 10 in human glioblastoma multiforme. Author(s): Fujimoto M, Fults DW, Thomas GA, Nakamura Y, Heilbrun MP, White R, Story JL, Naylor SL, Kagan-Hallet KS, Sheridan PJ. Source: Genomics. 1989 February; 4(2): 210-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2544511

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Lymph node metastases from glioblastoma multiforme. Author(s): Wallace CJ, Forsyth PA, Edwards DR. Source: Ajnr. American Journal of Neuroradiology. 1996 November-December; 17(10): 1929-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8933881

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Macrophage/microglial cell subpopulations in glioblastoma multiforme relapses are differentially altered by radiochemotherapy. Author(s): Deininger MH, Pater S, Strik H, Meyermann R. Source: Journal of Neuro-Oncology. 2001 December; 55(3): 141-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11859968

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Magnetic resonance image-guided proteomics of human glioblastoma multiforme. Author(s): Hobbs SK, Shi G, Homer R, Harsh G, Atlas SW, Bednarski MD. Source: Journal of Magnetic Resonance Imaging : Jmri. 2003 November; 18(5): 530-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579395

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Metastases from glioblastoma multiforme (GBM) are a rare but important event. Author(s): Waite K, Old S, Burnet N. Source: Clin Oncol (R Coll Radiol). 2002 April; 14(2): 181. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12069130

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Metastasis along the stereotactic biopsy trajectory in glioblastoma multiforme. Author(s): Pierallini A, Caramia F, Piattella MC, Pantano P, Santoro A, Di Stefano D, Bozzao L. Source: Acta Neurochirurgica. 1999; 141(9): 1011-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10526085

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Metastatic epithelioid sarcoma to the brain: palisaded necrosis mimicking glioblastoma multiforme. Author(s): Prayson RA, Chahlavi A. Source: Annals of Diagnostic Pathology. 2002 October; 6(5): 302-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12376923

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Metastatic seeding of the stereotactic biopsy tract in glioblastoma multiforme: case report and review of the literature. Author(s): Steinmetz MP, Barnett GH, Kim BS, Chidel MA, Suh JH. Source: Journal of Neuro-Oncology. 2001 December; 55(3): 167-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11859971

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Mitogenesis in glioblastoma multiforme cell lines: a role for NGF and its TrkA receptors. Author(s): Singer HS, Hansen B, Martinie D, Karp CL. Source: Journal of Neuro-Oncology. 1999; 45(1): 1-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10728904

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Mixed glioblastoma multiforme and sarcoma. A clinicopathologic study of 26 radiation therapy oncology group cases. Author(s): Meis JM, Martz KL, Nelson JS. Source: Cancer. 1991 May 1; 67(9): 2342-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1849447

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Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferonalpha and interferon-gamma treatment of human glioblastoma multiforme. Author(s): Yang I, Kremen TJ, Giovannone AJ, Paik E, Odesa SK, Prins RM, Liau LM. Source: Journal of Neurosurgery. 2004 February; 100(2): 310-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15086239

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Molecular analysis of the PTEN, TP53 and CDKN2A tumor suppressor genes in longterm survivors of glioblastoma multiforme. Author(s): Kraus JA, Glesmann N, Beck M, Krex D, Klockgether T, Schackert G, Schlegel U. Source: Journal of Neuro-Oncology. 2000 June; 48(2): 89-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11083071

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Molecular and cytogenetic analysis of glioblastoma multiforme. Author(s): Mao X, Hamoudi RA. Source: Cancer Genetics and Cytogenetics. 2000 October 15; 122(2): 87-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11106817

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Molecular evidence of apoptotic death in malignant brain tumors including glioblastoma multiforme: upregulation of calpain and caspase-3. Author(s): Ray SK, Patel SJ, Welsh CT, Wilford GG, Hogan EL, Banik NL. Source: Journal of Neuroscience Research. 2002 July 15; 69(2): 197-206. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12111801

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Molecular genetics of radiographically defined de novo glioblastoma multiforme. Author(s): Tortosa A, Ino Y, Odell N, Swilley S, Sasaki H, Louis DN, Henson JW. Source: Neuropathology and Applied Neurobiology. 2000 December; 26(6): 544-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11123721

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Molecular response of human glioblastoma multiforme cells to ionizing radiation: cell cycle arrest, modulation of the expression of cyclin-dependent kinase inhibitors, and autophagy. Author(s): Yao KC, Komata T, Kondo Y, Kanzawa T, Kondo S, Germano IM. Source: Journal of Neurosurgery. 2003 February; 98(2): 378-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12593626

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Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Author(s): Brada M, Hoang-Xuan K, Rampling R, Dietrich PY, Dirix LY, Macdonald D, Heimans JJ, Zonnenberg BA, Bravo-Marques JM, Henriksson R, Stupp R, Yue N, Bruner J, Dugan M, Rao S, Zaknoen S. Source: Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo. 2001 February; 12(2): 259-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11300335

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Multicentric glioblastoma multiforme determined by positron emission tomography: a case report. Author(s): Jawahar A, Weilbaecher C, Shorter C, Stout N, Nanda A. Source: Clinical Neurology and Neurosurgery. 2003 December; 106(1): 38-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14643915

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Multiple colorectal carcinomas, polyposis coli, and neurofibromatosis, followed by multiple glioblastoma multiforme. Author(s): Pratt CB, Jane JA. Source: Journal of the National Cancer Institute. 1991 June 19; 83(12): 880-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1648143

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Multivariate analysis of clinical prognostic factors in patients with glioblastoma multiforme treated with a combined modality approach. Author(s): Jeremic B, Milicic B, Grujicic D, Dagovic A, Aleksandrovic J. Source: Journal of Cancer Research and Clinical Oncology. 2003 August; 129(8): 477-84. Epub 2003 July 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12884028

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Necrosis as a prognostic factor in glioblastoma multiforme. Author(s): Barker FG 2nd, Davis RL, Chang SM, Prados MD. Source: Cancer. 1996 March 15; 77(6): 1161-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8635139

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N-myc oncogene amplification in a pediatric case of glioblastoma multiforme. Author(s): Stenger AM, Garre ML, Cama A, Andreussi L, Brisigotti M, Tonini GP, Cornaglia-Ferraris P. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 1991 November; 7(7): 410-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1665398

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Northern California Oncology Group protocol 6G91: response to treatment with radiation therapy and seven-drug chemotherapy in patients with glioblastoma multiforme. Author(s): Levin VA, Wara WM, Davis RL, Silver P, Resser KJ, Yatsko K, Nutik S, Gutin PH, Wilson CB. Source: Cancer Treat Rep. 1986 June; 70(6): 739-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3015402

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Nothing ventured, nothing gained: Treatment of glioblastoma multiforme in the elderly. Author(s): Shaw EG. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 May 1; 22(9): 1540-1. Epub 2004 March 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15051758

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Novel protein inhibitor of calmodulin-dependent cyclic nucleotide phosphodiesterase from glioblastoma multiforme. Author(s): Lal S, Raju RV, Sharma RK. Source: Neurochemical Research. 1998 April; 23(4): 533-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9566588

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Nucleolar organizer regions and post-operative survival in glioblastoma multiforme. Author(s): Nicoll JA, Candy E. Source: Neuropathology and Applied Neurobiology. 1991 February; 17(1): 17-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1647498

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O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. Author(s): Balana C, Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, Sarries C, Mendez P, Sanchez JJ, Rosell R. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 April; 9(4): 1461-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684420

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Observations on patients with cerebral astrocytoma (glioblastoma multiforme) treated by irradiation under whole-body hypothermia. Author(s): Bloch M, Bloom HJ, Penman J, Walsh L. Source: British Journal of Cancer. 1966 December; 20(4): 722-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4290202

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Occurrence of glioblastoma multiforme in three closely related patients. Author(s): Siqueira EB, Kranzler LI, Schaffer L. Source: Surgical Neurology. 1985 October; 24(4): 387-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2994246

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Occurrence of glioblastoma multiforme in three generations of a cancer family. Author(s): Salcman M, Solomon L. Source: Neurosurgery. 1984 May; 14(5): 557-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6328353

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Oral prodromal signs of a central nervous system malignant neoplasm--glioblastoma multiforme: report of case. Author(s): Cohen S, Baumgartner JC, Carpenter WM, Parisi JE, Knuut AL. Source: The Journal of the American Dental Association. 1986 May; 112(5): 643-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3011871

84

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Outcome in elderly patients undergoing definitive surgery and radiation therapy for supratentorial glioblastoma multiforme at a tertiary care institution. Author(s): Mohan DS, Suh JH, Phan JL, Kupelian PA, Cohen BH, Barnett GH. Source: International Journal of Radiation Oncology, Biology, Physics. 1998 December 1; 42(5): 981-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9869219

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Overexpression of vascular endothelial growth factor isoforms drives oxygenation and growth but not progression to glioblastoma multiforme in a human model of gliomagenesis. Author(s): Sonoda Y, Kanamori M, Deen DF, Cheng SY, Berger MS, Pieper RO. Source: Cancer Research. 2003 April 15; 63(8): 1962-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702589

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Over-representation of PPARgamma sequence variants in sporadic cases of glioblastoma multiforme: preliminary evidence for common low penetrance modifiers for brain tumour risk in the general population. Author(s): Zhou XP, Smith WM, Gimm O, Mueller E, Gao X, Sarraf P, Prior TW, Plass C, von Deimling A, Black PM, Yates AJ, Eng C. Source: Journal of Medical Genetics. 2000 June; 37(6): 410-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10851250

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Oxidant stress and glioblastoma multiforme risk: serum antioxidants, gammaglutamyl transpeptidase, and ferritin. Author(s): Schwartzbaum JA, Cornwell DG. Source: Nutrition and Cancer. 2000; 38(1): 40-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11341043

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Patients presenting with CNS lesions. Case 3. Sequential myeloproliferative disease and glioblastoma multiforme in a renal transplant recipient. Author(s): Au WY, Hung KN, Loong F, Ma SK. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 November 1; 21(21): 4062-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581430

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Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme. Author(s): Larson DA, Suplica JM, Chang SM, Lamborn KR, McDermott MW, Sneed PK, Prados MD, Wara WM, Nicholas MK, Berger MS. Source: Neuro-Oncology. 2004 April; 6(2): 119-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15134626

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Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American Brain Tumor Consortium study. Author(s): Prados MD, Yung WK, Fine HA, Greenberg HS, Junck L, Chang SM, Nicholas MK, Robins HI, Mehta MP, Fink KL, Jaeckle KA, Kuhn J, Hess KR, Schold SC Jr; North American Brain Tumor Consortium study. Source: Neuro-Oncology. 2004 January; 6(1): 33-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769138

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Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme. Author(s): Chua SL, Rosenthal MA, Wong SS, Ashley DM, Woods AM, Dowling A, Cher LM. Source: Neuro-Oncology. 2004 January; 6(1): 38-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769139

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Phase I study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group Trial 9507. Author(s): Fisher BJ, Scott C, Macdonald DR, Coughlin C, Curran WJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 February 15; 19(4): 1111-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11181676

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Phase I/II trial of superselective arterial 5-FU infusion with concomitant external beam radiation for patients with either anaplastic astrocytoma or glioblastoma multiforme. Author(s): Larner JM, Kersh CR, Constable WC, Kline P, Ferguson R, Short R, Jane JA. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 1991 December; 14(6): 514-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1659783

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Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations. Author(s): Chinot OL, Barrie M, Frauger E, Dufour H, Figarella-Branger D, Palmari J, Braguer D, Hoang-Xuan K, Moktari K, Peragut JC, Martin PM, Grisoli F. Source: Cancer. 2004 May 15; 100(10): 2208-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15139066

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Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or < or = 20 cm(2), respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients. Author(s): Coughlin C, Scott C, Langer C, Coia L, Curran W, Rubin P. Source: International Journal of Radiation Oncology, Biology, Physics. 2000 December 1; 48(5): 1351-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11121633

86

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Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme. Author(s): Prados MD, Wara WM, Sneed PK, McDermott M, Chang SM, Rabbitt J, Page M, Malec M, Davis RL, Gutin PH, Lamborn K, Wilson CB, Phillips TL, Larson DA. Source: International Journal of Radiation Oncology, Biology, Physics. 2001 January 1; 49(1): 71-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11163499

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Postoperative epilepsy in patients undergoing craniotomy for glioblastoma multiforme. Author(s): Telfeian AE, Philips MF, Crino PB, Judy KD. Source: J Exp Clin Cancer Res. 2001 March; 20(1): 5-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11370829

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Postoperative radiotherapy for glioblastoma multiforme. Author(s): Lin JC, Jan JS. Source: Zhonghua Yi Xue Za Zhi (Taipei). 1992 December; 50(6): 454-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1338021

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Prevalence of glioblastoma multiforme in subjects with prior therapeutic radiation. Author(s): Hodges LC, Smith JL, Garrett A, Tate S. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1992 April; 24(2): 79-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1318344

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Prevalence of glioblastoma multiforme subjects with prior herbicide exposure. Author(s): Smith-Rooker JL, Garrett A, Hodges LC, Shue V. Source: The Journal of Neuroscience Nursing : Journal of the American Association of Neuroscience Nurses. 1992 October; 24(5): 260-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1328422

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Prognostic relevance of MAPK expression in glioblastoma multiforme. Author(s): Mawrin C, Diete S, Treuheit T, Kropf S, Vorwerk CK, Boltze C, Kirches E, Firsching R, Dietzmann K. Source: International Journal of Oncology. 2003 September; 23(3): 641-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888899

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Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Author(s): Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, Makino K, Saya H, Hirano H, Kuratsu J, Oka K, Ishimaru Y, Ushio Y. Source: Cancer Research. 2003 October 15; 63(20): 6962-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583498

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Promising survival for patients with glioblastoma multiforme treated with individualised chemotherapy based on in vitro drug sensitivity testing. Author(s): Iwadate Y, Fujimoto S, Namba H, Yamaura A. Source: British Journal of Cancer. 2003 November 17; 89(10): 1896-900. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14612899

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Quality and duration of survival in glioblastoma multiforme. Combined surgical, radiation, and lomustine therapy. Author(s): Hochberg FH, Linggood R, Wolfson L, Baker WH, Kornblith P. Source: Jama : the Journal of the American Medical Association. 1979 March 9; 241(10): 1016-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=216819

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Quality of life after brachytherapy in patients with glioblastoma multiforme. Author(s): Koot RW, de Heer K, Oort FJ, Hulshof MC, Bosch DA, de Haes JC. Source: European Journal of Cancer (Oxford, England : 1990). 2004 May; 40(7): 1013-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15093576

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Quality of life in patients with glioblastoma multiforme participating in a randomized study of brachytherapy as a boost treatment. Author(s): Bampoe J, Laperriere N, Pintilie M, Glen J, Micallef J, Bernstein M. Source: Journal of Neurosurgery. 2000 December; 93(6): 917-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11117863

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Quality-adjusted survival after tumor resection and/or radiation therapy for elderly patients with glioblastoma multiforme. Author(s): Muacevic A, Kreth FW. Source: Journal of Neurology. 2003 May; 250(5): 561-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736735

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Quantification of microheterogeneity in glioblastoma multiforme with ex vivo highresolution magic-angle spinning (HRMAS) proton magnetic resonance spectroscopy. Author(s): Cheng LL, Anthony DC, Comite AR, Black PM, Tzika AA, Gonzalez RG. Source: Neuro-Oncology. 2000 April; 2(2): 87-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11303625

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Quantitative immunohistological analysis of the microvasculature in untreated human glioblastoma multiforme. Computer-assisted image analysis of whole-tumor sections. Author(s): Wesseling P, van der Laak JA, de Leeuw H, Ruiter DJ, Burger PC. Source: Journal of Neurosurgery. 1994 December; 81(6): 902-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7525899

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Quantitative morphology of human glioblastoma multiforme microvessels: structural basis of blood-brain barrier defect. Author(s): Coomber BL, Stewart PA, Hayakawa K, Farrell CL, Del Maestro RF. Source: Journal of Neuro-Oncology. 1987; 5(4): 299-307. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2831312

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Radiation response and survival time in patients with glioblastoma multiforme. Author(s): Barker FG 2nd, Prados MD, Chang SM, Gutin PH, Lamborn KR, Larson DA, Malec MK, McDermott MW, Sneed PK, Wara WM, Wilson CB. Source: Journal of Neurosurgery. 1996 March; 84(3): 442-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8609556

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Radiation response of xenografts of a human squamous cell carcinoma and a glioblastoma multiforme: a progress report. Author(s): Suit HD, Zietman A, Tomkinson K, Ramsay J, Gerweck L, Sedlacek R. Source: International Journal of Radiation Oncology, Biology, Physics. 1990 February; 18(2): 365-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2154419

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Radiation therapy treatment planning in supratentorial glioblastoma multiforme: an analysis based on post mortem topographic anatomy with CT correlations. Author(s): Halperin EC, Bentel G, Heinz ER, Burger PC. Source: International Journal of Radiation Oncology, Biology, Physics. 1989 December; 17(6): 1347-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2557310

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Radiation-induced cerebellar glioblastoma multiforme subsequent to treatment of an astrocytoma of the cervical spinal cord. Author(s): Rappaport ZH, Loven D, Ben-Aharon U. Source: Neurosurgery. 1991 October; 29(4): 606-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1658678

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Radiologically confirmed de novo glioblastoma multiforme and hippocampal sclerosis associated with the first onset of nonconvulsive simple partial status epilepticus. Author(s): Chang JW, Chang JH, Park SC, Kim TS, Park YG, Chung SS. Source: Acta Neurochirurgica. 2001; 143(3): 297-300; Discussion 300-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11460918

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Radiotherapy and chemotherapy with or without carbogen and nicotinamide in inoperable biopsy-proven glioblastoma multiforme. Author(s): Simon JM, Noel G, Chiras J, Hoang-Xuan K, Delattre JY, Baillet F, Mazeron JJ. Source: Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2003 April; 67(1): 45-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12758239

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Radiotherapy of glioblastoma multiforme. Feasibility of increased fraction size and shortened overall treatment. Author(s): Lang O, Liebermeister E, Liesegang J, Sautter-Bihl ML. Source: Strahlentherapie Und Onkologie : Organ Der Deutschen Rontgengesellschaft. [et Al]. 1998 December; 174(12): 629-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9879350

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Reactivation of human neurotropic JC virus expressing oncogenic protein in a recurrent glioblastoma multiforme. Author(s): Del Valle L, Azizi SA, Krynska B, Enam S, Croul SE, Khalili K. Source: Annals of Neurology. 2000 December; 48(6): 932-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11117551

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Reactivation of insulin-like growth factor binding protein 2 expression in glioblastoma multiforme: a revelation by parallel gene expression profiling. Author(s): Fuller GN, Rhee CH, Hess KR, Caskey LS, Wang R, Bruner JM, Yung WK, Zhang W. Source: Cancer Research. 1999 September 1; 59(17): 4228-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10485462

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Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. Author(s): Debinski W, Gibo DM, Slagle B, Powers SK, Gillespie GY. Source: International Journal of Oncology. 1999 September; 15(3): 481-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10427128

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Recurrent multicentric glioblastoma multiforme responds to thalidomide and chemotherapy. Author(s): Phuphanich S. Source: Oncology (Huntingt). 2002 March; 16(3): 276, 278. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046387

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Role of CD44 in the invasiveness of glioblastoma multiforme and the noninvasiveness of meningioma: an immunohistochemistry study. Author(s): Ariza A, Lopez D, Mate JL, Isamat M, Musulen E, Pujol M, Ley A, NavasPalacios JJ. Source: Human Pathology. 1995 October; 26(10): 1144-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7557949

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Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme. Author(s): Koka V, Potti A, Forseen SE, Pervez H, Fraiman GN, Koch M, Levitt R. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2003 August; 26(4): 332-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902879

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Role of radiation therapy and radiosurgery in glioblastoma multiforme. Author(s): Fiveash JB, Spencer SA. Source: Cancer Journal (Sudbury, Mass.). 2003 May-June; 9(3): 222-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952307

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

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Scanning electron microscopic study of three glioblastoma multiforme (GBM) cell lines of the Chinese brain in vitro and in vivo. Author(s): Lee WH, Tu YC. Source: Zhonghua Yi Xue Za Zhi (Taipei). 1991 September; 48(3): 177-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1657334

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Secretion of alpha 2-macroglobulin, alpha 2-antiplasmin, and plasminogen activator inhibitor-1 by glioblastoma multiforme in primary organ culture. Author(s): Keohane ME, Hall SW, VandenBerg SR, Gonias SL. Source: Journal of Neurosurgery. 1990 August; 73(2): 234-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1694891

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Sphingosine-1-phosphate stimulates motility and invasiveness of human glioblastoma multiforme cells. Author(s): Van Brocklyn JR, Young N, Roof R. Source: Cancer Letters. 2003 September 10; 199(1): 53-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12963123

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Spinal cord glioblastoma multiforme with intracranial dissemination--case report. Author(s): Asano N, Kitamura K, Seo Y, Mukai K, Soga T, Hondo H, Matsumoto K. Source: Neurol Med Chir (Tokyo). 1990 July; 30(7): 489-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1701860

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Statistical modelling in analysis of prognosis in glioblastoma multiforme: a study of clinical variables and Ki-67 index. Author(s): Pigott TJ, Lowe JS, Palmer J. Source: British Journal of Neurosurgery. 1991; 5(1): 61-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1850599

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Stereotactic radiosurgery versus fractionated stereotactic radiotherapy boost for patients with glioblastoma multiforme. Author(s): Cho KH, Hall WA, Lo SS, Dusenbery KE. Source: Technology in Cancer Research & Treatment. 2004 February; 3(1): 41-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14750892

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Subsets of glioblastoma multiforme defined by molecular genetic analysis. Author(s): von Deimling A, von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN. Source: Brain Pathology (Zurich, Switzerland). 1993 January; 3(1): 19-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8269081

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Survival analysis in patients with glioblastoma multiforme: predictive value of choline-to-N-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume. Author(s): Oh J, Henry RG, Pirzkall A, Lu Y, Li X, Catalaa I, Chang S, Dillon WP, Nelson SJ. Source: Journal of Magnetic Resonance Imaging : Jmri. 2004 May; 19(5): 546-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15112303

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Survival improvement in patients with glioblastoma multiforme during the last 20 years in a single tertiary-care center. Author(s): Fazeny-Dorner B, Gyries A, Rossler K, Ungersbock K, Czech T, Budinsky A, Killer M, Dieckmann K, Piribauer M, Baumgartner G, Prayer D, Veitl M, Muhm M, Marosi C. Source: Wiener Klinische Wochenschrift. 2003 June 24; 115(11): 389-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12879737

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Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Author(s): Lanzetta G, Campanella C, Rozzi A, Nappa M, Costa A, Fedele F, Innocenzi G, Gagliardi FM, Salvati M, Minniti G, Frati A, Frati L, Vecchione A. Source: Anticancer Res. 2003 November-December; 23(6D): 5159-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981983

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The Akt/protein kinase B-dependent anti-apoptotic pathway and the mitogenactivated protein kinase cascade are alternatively activated in human glioblastoma multiforme. Author(s): Schlegel J, Piontek G, Budde B, Neff F, Kraus A. Source: Cancer Letters. 2000 September 29; 158(1): 103-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10940516

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The effects of irradiation on cell migration from glioblastoma multiforme biopsy spheroids. Author(s): Kleynen CE, Stoter TR, Tadema TM, Stalpers LJ, Dirven CM, Leenstra S, Van Der Valk P, Slotman BJ, Sminia P. Source: Anticancer Res. 2003 November-December; 23(6C): 4907-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981944

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The prognostic significance of midline shift at presentation on survival in patients with glioblastoma multiforme. Author(s): Gamburg ES, Regine WF, Patchell RA, Strottmann JM, Mohiuddin M, Young AB. Source: International Journal of Radiation Oncology, Biology, Physics. 2000 December 1; 48(5): 1359-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11121634

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The use of hypofractionated intensity-modulated irradiation in the treatment of glioblastoma multiforme: preliminary results of a prospective trial. Author(s): Sultanem K, Patrocinio H, Lambert C, Corns R, Leblanc R, Parker W, Shenouda G, Souhami L. Source: International Journal of Radiation Oncology, Biology, Physics. 2004 January 1; 58(1): 247-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14697445

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Topotecan selectively enhances the radioresponse of human small-cell lung carcinoma and glioblastoma multiforme xenografts in nude mice. Author(s): Chastagner P, Kozin SV, Taghian A. Source: International Journal of Radiation Oncology, Biology, Physics. 2001 July 1; 50(3): 777-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11395247

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Transferrin receptor on glioblastoma multiforme. Author(s): Hall WA. Source: Journal of Neurosurgery. 1991 February; 74(2): 313-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1846410

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Treatment costs for glioblastoma multiforme in Nova Scotia. Author(s): Mendez I, Jacobs P, MacDougall A, Schultz M. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2001 February; 28(1): 61-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11252298

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Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial. Author(s): Prados MD, McDermott M, Chang SM, Wilson CB, Fick J, Culver KW, Van Gilder J, Keles GE, Spence A, Berger M. Source: Journal of Neuro-Oncology. 2003 December; 65(3): 269-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14682377

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Triphasic waves in a patient with glioblastoma multiforme. Author(s): Ghanem Q. Source: Clin Electroencephalogr. 1992 April; 23(2): 95-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1316246

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Ultrastructural features of pleomorphic xanthoastrocytoma: a comparative study with glioblastoma multiforme. Author(s): Hirose T, Giannini C, Scheithauer BW. Source: Ultrastructural Pathology. 2001 November-December; 25(6): 469-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11783911

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Uncommon metastasis of a glioblastoma multiforme in liver and spleen. Author(s): Widjaja A, Mix H, Golkel C, Flemming P, Egensperger R, Holstein A, Rademaker J, Becker H, Hundt M, Wagner S, Manns MP. Source: Digestion. 2000; 61(3): 219-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10773729

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Unusual nasal and orbital involvement of glioblastoma multiforme: a case report and review of the literature. Author(s): Brandes A, Carollo C, Gardiman M, Scelzi E, Bottin R, Zampieri P, Rigon A, Fiorentino MV. Source: Journal of Neuro-Oncology. 1998 January; 36(2): 179-83. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9525817

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Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. Author(s): Bacher M, Schrader J, Thompson N, Kuschela K, Gemsa D, Waeber G, Schlegel J. Source: American Journal of Pathology. 2003 January; 162(1): 11-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12507885

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Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Author(s): Phuong LK, Allen C, Peng KW, Giannini C, Greiner S, TenEyck CJ, Mishra PK, Macura SI, Russell SJ, Galanis EC. Source: Cancer Research. 2003 May 15; 63(10): 2462-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12750267

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Value of sequential computed tomography in the multimodality treatment of glioblastoma multiforme. Author(s): Salcman M, Levine H, Rao K. Source: Neurosurgery. 1981 January; 8(1): 15-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6259550

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Variation in response to CCNU of glioblastoma multiforme in brain and cervical lymph node. Case report. Author(s): Steinbok P, Dolman CL, Goldie JH. Source: Journal of Neurosurgery. 1985 June; 62(6): 918-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2987441

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Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme. Author(s): Haddad SF, Moore SA, Schelper RL, Goeken JA. Source: Journal of Neuropathology and Experimental Neurology. 1992 September; 51(5): 488-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1381413

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VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme. Author(s): Debinski W, Slagle-Webb B, Achen MG, Stacker SA, Tulchinsky E, Gillespie GY, Gibo DM. Source: Molecular Medicine (Cambridge, Mass.). 2001 September; 7(9): 598-608. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11778649

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Vertebral body metastasis of glioblastoma multiforme with epidural mass formation. Contrast-enhanced MRI study. Author(s): Mihara F, Ikeda M, Rothman MI, Numaguchi Y, Kristt D. Source: Clinical Imaging. 1994 October-December; 18(4): 386-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8000959

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Visualization of microvascularity in glioblastoma multiforme with 8-T high-spatialresolution MR imaging. Author(s): Christoforidis GA, Grecula JC, Newton HB, Kangarlu A, Abduljalil AM, Schmalbrock P, Chakeres DW. Source: Ajnr. American Journal of Neuroradiology. 2002 October; 23(9): 1553-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12372746

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Volumetric analysis of 18F-FDG PET in glioblastoma multiforme: prognostic information and possible role in definition of target volumes in radiation dose escalation. Author(s): Tralins KS, Douglas JG, Stelzer KJ, Mankoff DA, Silbergeld DL, Rostomily RC, Hummel S, Scharnhorst J, Krohn KA, Spence AM, Rostomilly R. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2002 December; 43(12): 1667-73. Erratum In: J Nucl Med. 2003 October; 44(10): 1603. Rostomilly Robert [corrected to Rostomily Robert C]. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12468518

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Which glioblastoma multiforme patient will become a long-term survivor? A population-based study. Author(s): Scott JN, Rewcastle NB, Brasher PM, Fulton D, MacKinnon JA, Hamilton M, Cairncross JG, Forsyth P. Source: Annals of Neurology. 1999 August; 46(2): 183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10443883

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Widespread extracranial metastases of glioblastoma multiforme. Report of case and clinicopathological review of cases in literature. Author(s): Komatsu K, Hiratsuka H, Takahashi S, Kamisasa A, Inaba Y. Source: Bull Tokyo Med Dent Univ. 1972 March; 19(1): 29-49. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4338365

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CHAPTER 2. NUTRITION AND GLIOBLASTOMA MULTIFORME Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and glioblastoma multiforme.

Finding Nutrition Studies on Glioblastoma Multiforme 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 “glioblastoma multiforme” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

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

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

A beta-adrenergic agonist modulates DR alpha gene transcription via enhanced cAMP levels in a glioblastoma multiforme line. Author(s): Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599-7295. Source: Basta, P V Moore, T L Yokota, S Ting, J P J-Immunol. 1989 April 15; 142(8): 2895901 0022-1767

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Antiproliferative and apoptotic effect of ascorbyl stearate in human glioblastoma multiforme cells: modulation of insulin-like growth factor-I receptor (IGF-IR) expression. Author(s): Department of Neurology, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, Tampa, USA. [email protected] Source: Naidu, K A Tang, J L Naidu, K A Prockop, L D Nicosia, S V Coppola, D JNeurooncol. 2001 August; 54(1): 15-22 0167-594X

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Growth inhibition and modulation of antigenic phenotype in human melanoma and glioblastoma multiforme cells by caffeic acid phenethyl ester (CAPE) Author(s): Division of Pediatric Hematology/Oncology, Columbia University, College of Physicians and Surgeons, New York, New York 10032. Source: Guarini, L Su, Z Z Zucker, S Lin, J Grunberger, D Fisher, P B Cell-Mol-Biol. 1992 August; 38(5): 513-27 0145-5680

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Influence of extent of surgery and tumor location on treatment outcome of patients with glioblastoma multiforme treated with combined modality approach. Author(s): Department of Oncology, University Hospital, Kragujevac, Yugoslavia. Source: Jeremic, B Grujicic, D Antunovic, V Djuric, L Stojanovic, M Shibamoto, Y JNeurooncol. 1994; 21(2): 177-85 0167-594X

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Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma. NABTT CNS Consortium. Author(s): Massachusetts General Hospital, Boston 02114, USA. Source: Hochberg, F Grossman, S A Mikkelsen, T Glantz, M Fisher, J D Piantadosi, S Neuro-oncol. 2000 January; 2(1): 29-33 1522-8517

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Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines. Author(s): INSERM U26, Hopital F. Widal, Paris, France. [email protected] Source: Decleves, Xavier Fajac, Anne Lehmann Che, Jacqueline Tardy, Marcienne Mercier, Claire Hurbain, Ilse Laplanche, Jean Louis Bernaudin, Jean Francois Scherrmann, Jean Michel Int-J-Cancer. 2002 Mar 10; 98(2): 173-80 0020-7136

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Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost. Author(s): Department of Radiation Oncology, University of California, San Francisco 94143. Source: Sneed, P K Gutin, P H Larson, D A Malec, M K Phillips, T L Prados, M D Scharfen, C O Weaver, K A Wara, W M Int-J-Radiat-Oncol-Biol-Phys. 1994 July 1; 29(4): 719-27 0360-3016

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Structure of the human allelic glutathione S-transferase-pi gene variant, hGSTP1 C, cloned from a glioblastoma multiforme cell line. Author(s): Department of Experimental Pediatrics, University of Texas-MD Anderson Cancer Center, Houston 77030, USA. Source: Lo, H W Ali Osman, F Chem-Biol-Interact. 1998 April 24; 111-11291-102 00092797

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Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study. Author(s): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-2410, USA. [email protected] Source: Kleinberg, L Grossman, S A Carson, K Lesser, G O'Neill, A Pearlman, J Phillips, P Herman, T Gerber, M J-Clin-Oncol. 2002 July 15; 20(14): 3149-55 0732-183X

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Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. Author(s): Institute of Molecular Pathology, University of Copenhagen, Denmark. Source: Lund, E L Bastholm, L Kristjansen, P E Clin-Cancer-Res. 2000 March; 6(3): 971-8 1078-0432

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Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study. Author(s): Department of Neuroradiology, National University Hospital, Rigshospitalet, Copenhagen, Denmark. [email protected] Source: Lassen, U Kristjansen, P E Wagner, A Kostel janetz, M Poulsen, H S JNeurooncol. 1999 June; 43(2): 161-6 0167-594X

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Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Author(s): Department of Radiation Oncology, Staten Island University Hospital, New York 10305, USA. Source: Lederman, G Wronski, M Arbit, E Odaimi, M Wertheim, S Lombardi, E Wrzolek, M Am-J-Clin-Oncol. 2000 April; 23(2): 155-9 0277-3732

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(68Ga)-EDTA positron emission tomography in the diagnosis of brain tumors. Author(s): Ilsen HW, Sato M, Pawlik G, Herholz K, Wienhard K, Heiss WD. Source: Neuroradiology. 1984; 26(5): 393-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6100508

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A multidrug combination designed for reversing resistance to BCNU in glioblastoma multiforme. Author(s): Brandes AA, Turazzi S, Basso U, Pasetto LM, Guglielmi B, Volpin L, Iuzzolino P, Amista P, Pinna G, Scienza R, Ermani M. Source: Neurology. 2002 June 25; 58(12): 1759-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12084873

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A phase II trial of high-dose bromodeoxyuridine with accelerated fractionation radiotherapy followed by procarbazine, lomustine, and vincristine for glioblastoma multiforme. Author(s): Groves MD, Maor MH, Meyers C, Kyritsis AP, Jaeckle KA, Yung WK, Sawaya RE, Hess K, Bruner JM, Peterson P, Levin VA. Source: International Journal of Radiation Oncology, Biology, Physics. 1999 August 1; 45(1): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10477016

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A study of concurrent radiochemotherapy with paclitaxel in glioblastoma multiforme. Author(s): Julka PK, Awasthy BS, Rath GK, Agarwal S, Varna T, Mahapatra AK, Singh R. Source: Australasian Radiology. 2000 February; 44(1): 84-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10761264

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Acute toxicity from BOPP (BCNU, vincristine, procarbazine, cisplatinum) chemotherapy for glioblastoma multiforme. Author(s): Jeremic B, Barjaktarevic Z, Mijatovic L, Djuric L. Source: J Chemother. 1990 February; 2(1): 67-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2159057

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Antisense anti-MDM2 oligonucleotides as a novel approach to the treatment of glioblastoma multiforme. Author(s): Prasad G, Wang H, Agrawal S, Zhang R. Source: Anticancer Res. 2002 January-February; 22(1A): 107-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12017271

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Brain cancer: a case of glioblastoma multiforme. Author(s): Chang R, Finlay J, Badmaev V, Singh RH, Chapman J. Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 2002 October; 8(5): 551-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12470435

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Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: a new modality treatment. Author(s): Fatigante L, Ducci F, Cartei F, Colosimo S, Marini C, Prediletto R, Danesi R, Laddaga M, Del Tacca M, Caciagli P. Source: International Journal of Radiation Oncology, Biology, Physics. 1997 February 1; 37(3): 499-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9112444

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Carboplatin and teniposide concurrent with radiotherapy in patients with glioblastoma multiforme: a phase II study.

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Author(s): Brandes AA, Rigon A, Zampieri P, Ermani M, Carollo C, Altavilla G, Turazzi S, Chierichetti F, Florentino MV. Source: Cancer. 1998 January 15; 82(2): 355-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9445194 •

Complete remission of recurrent glioblastoma multiforme following local infusions of lymphokine activated killer cells. Case report. Author(s): Naganuma H, Kimurat R, Sasaki A, Fukamachi A, Nukui H, Tasaka K. Source: Acta Neurochirurgica. 1989; 99(3-4): 157-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2549767

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Evaluation of bromodeoxyuridine in glioblastoma multiforme: a Northern California Cancer Center Phase II study. Author(s): Phillips TL, Levin VA, Ahn DK, Gutin PH, Davis RL, Wilson CB, Prados MD, Wara WM, Flam MS. Source: International Journal of Radiation Oncology, Biology, Physics. 1991 August; 21(3): 709-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1651306

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Fractionated stereotactic radiosurgery and concurrent taxol in recurrent glioblastoma multiforme: a preliminary report. Author(s): Lederman G, Arbit E, Odaimi M, Lombardi E, Wrzolek M, Wronski M. Source: International Journal of Radiation Oncology, Biology, Physics. 1998 February 1; 40(3): 661-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9486617

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Glioblastoma multiforme. Author(s): Weiss HD. Source: Archives of Neurology. 1977 February; 34(2): 131-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=189738

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Growth inhibition and modulation of antigenic phenotype in human melanoma and glioblastoma multiforme cells by caffeic acid phenethyl ester (CAPE) Author(s): Guarini L, Su ZZ, Zucker S, Lin J, Grunberger D, Fisher PB. Source: Cell Mol Biol. 1992 August; 38(5): 513-27. Erratum In: Cell Mol Biol 1992 September; 38(6): 615. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1281753

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Influence of extent of surgery and tumor location on treatment outcome of patients with glioblastoma multiforme treated with combined modality approach. Author(s): Jeremic B, Grujicic D, Antunovic V, Djuric L, Stojanovic M, Shibamoto Y.

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Source: Journal of Neuro-Oncology. 1994; 21(2): 177-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7861194 •

Integrative tumor board: glioblastoma multiforme: case presentation. Author(s): Dixit S, Pueschel JK, Wallace JM, Bolletino RC, Block KI. Source: Integrative Cancer Therapies. 2004 June; 3(2): 149-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165500

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Integrative tumor board: glioblastoma multiforme: integrative physician's perspective. Author(s): Block KI. Source: Integrative Cancer Therapies. 2004 June; 3(2): 170-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165504

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Integrative tumor board: glioblastoma multiforme: neurooncology. Author(s): Pueschel JK. Source: Integrative Cancer Therapies. 2004 June; 3(2): 151-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165501

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Integrative tumor board: glioblastoma multiforme: nutritional and botanical approach. Author(s): Wallace JM. Source: Integrative Cancer Therapies. 2004 June; 3(2): 152-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165502

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Integrative tumor board: glioblastoma multiforme: the patient as a person. Author(s): Bolletino RC. Source: Integrative Cancer Therapies. 2004 June; 3(2): 163-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165503

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Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma. NABTT CNS Consortium. Author(s): Hochberg F, Grossman SA, Mikkelsen T, Glantz M, Fisher JD, Piantadosi S. Source: Neuro-Oncology. 2000 January; 2(1): 29-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11302251

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Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines. Author(s): Decleves X, Fajac A, Lehmann-Che J, Tardy M, Mercier C, Hurbain I, Laplanche JL, Bernaudin JF, Scherrmann JM.

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Source: International Journal of Cancer. Journal International Du Cancer. 2002 March 10; 98(2): 173-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11857404 •

Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme. Author(s): Raymond E, Campone M, Stupp R, Menten J, Chollet P, Lesimple T, FetyDeporte R, Lacombe D, Paoletti X, Fumoleau P; EORTC Early Clinical Studies Group (ECSG); Brain Tumor Studies Group (BTSG); New Drug Development Program (NDDP). Source: European Journal of Cancer (Oxford, England : 1990). 2002 July; 38(10): 1348-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091065

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Novel chemotherapeutic agents for the treatment of glioblastoma multiforme. Author(s): Jendrossek V, Belka C, Bamberg M. Source: Expert Opinion on Investigational Drugs. 2003 December; 12(12): 1899-924. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14640936

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Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme. Author(s): Wolff JE, Molenkamp G, Westphal S, Pietsch T, Gnekow A, Kortmann RD, Kuehl J. Source: Cancer. 2000 November 15; 89(10): 2131-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11066055

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PCV chemotherapy for recurrent glioblastoma multiforme. Author(s): Boiardi A. Source: Neurology. 2001 June 26; 56(12): 1782. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11425963

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PCV chemotherapy for recurrent glioblastoma multiforme. Author(s): Kappelle AC, Postma TJ, Taphoorn MJ, Groeneveld GJ, van den Bent MJ, van Groeningen CJ, Zonnenberg BA, Sneeuw KC, Heimans JJ. Source: Neurology. 2001 January 9; 56(1): 118-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11148250

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Phase II radiation therapy oncology group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme. Author(s): Langer CJ, Ruffer J, Rhodes H, Paulus R, Murray K, Movsas B, Curran W. Source: International Journal of Radiation Oncology, Biology, Physics. 2001 September 1; 51(1): 113-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11516860

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Phase II study of accelerated fractionation radiation therapy with carboplatin followed by vincristine chemotherapy for the treatment of glioblastoma multiforme. Author(s): Levin VA, Maor MH, Thall PF, Yung WK, Bruner J, Sawaya R, Kyritsis AP, Leeds N, Woo S, Rodriguez L, et al. Source: International Journal of Radiation Oncology, Biology, Physics. 1995 September 30; 33(2): 357-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7673023

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Phase II study of combination taxol and estramustine phosphate in the treatment of recurrent glioblastoma multiforme. Author(s): Rosenthal MA, Gruber ML, Glass J, Nirenberg A, Finlay J, Hochster H, Muggia FM. Source: Journal of Neuro-Oncology. 2000 March; 47(1): 59-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10930101

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Phase III randomized study of postradiotherapy chemotherapy with alphadifluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. Author(s): Levin VA, Uhm JH, Jaeckle KA, Choucair A, Flynn PJ, Yung WKA, Prados MD, Bruner JM, Chang SM, Kyritsis AP, Gleason MJ, Hess KR. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 October; 6(10): 3878-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11051233

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Preirradiation ifosfamide, carboplatin, and etoposide for the treatment of anaplastic astrocytomas and glioblastoma multiforme: a phase II study. Author(s): Lopez-Aguilar E, Sepulveda-Vildosola AC, Rivera-Marquez H, CerecedoDiaz F, Hernandez-Contreras I, Ramon-Garcia G, Diegoperez-Ramirez J, SantacruzCastillo E. Source: Archives of Medical Research. 2000 March-April; 31(2): 186-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10880725

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Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New Approaches to Brain Tumor Therapy Central Nervous System Consortium. Author(s): Fetell MR, Grossman SA, Fisher JD, Erlanger B, Rowinsky E, Stockel J, Piantadosi S. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1997 September; 15(9): 3121-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9294475

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Radiation and concomitant weekly administration of paclitaxel in patients with glioblastoma multiforme. A phase II study. Author(s): Fountzilas G, Karavelis A, Capizzello A, Kalogera-Fountzila A, Karkavelas G, Zamboglou N, Selviaridis P, Foroglou G, Tourkantonis A.

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Source: Journal of Neuro-Oncology. 1999; 45(2): 159-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10778731 •

Recurrent glioblastoma multiforme: potential benefits using fractionated stereotactic radiotherapy and concurrent taxol. Author(s): Lederman G, Arbit E, Odaimi M, Wertheim S, Lombardi E. Source: Stereotactic and Functional Neurosurgery. 1997; 69(1-4 Pt 2): 162-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9711751

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Regimen-related toxicity of myeloablative chemotherapy with BCNU, thiotepa, and etoposide followed by autologous stem cell rescue for children with newly diagnosed glioblastoma multiforme: report from the Children's Cancer Group. Author(s): Grovas AC, Boyett JM, Lindsley K, Rosenblum M, Yates AJ, Finlay JL. Source: Medical and Pediatric Oncology. 1999 August; 33(2): 83-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10398181

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Salvage chemotherapy with CPT-11 for recurrent glioblastoma multiforme. Author(s): Chamberlain MC. Source: Journal of Neuro-Oncology. 2002 January; 56(2): 183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11995820

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The effects of anticancer drugs in combination with nimodipine and verapamil on cultured cells of glioblastoma multiforme. Author(s): Durmaz R, Deliorman S, Uyar R, Isiksoy S, Erol K, Tel E. Source: Clinical Neurology and Neurosurgery. 1999 December; 101(4): 238-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10622452

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Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study. Author(s): Lassen U, Kristjansen PE, Wagner A, Kosteljanetz M, Poulsen HS. Source: Journal of Neuro-Oncology. 1999 June; 43(2): 161-6. Erratum In: J Neurooncol. 2003 May; 62(3): 361. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10533728

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Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Author(s): Lederman G, Wronski M, Arbit E, Odaimi M, Wertheim S, Lombardi E, Wrzolek M. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2000 April; 23(2): 155-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10776976

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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/

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

Dissertations on Glioblastoma Multiforme 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 glioblastoma multiforme. 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: •

Isoflavones and their novel analogues: Effects on EGFR and PTEN/AKT-mediated signaling pathways in glioblastoma multiforme cells by Lynch, Launa M. J., PhD from Idaho State University, 2003, 159 pages http://wwwlib.umi.com/dissertations/fullcit/3083903

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The growth characteristics of glioblastoma multiforme in the anterior chamber of the guinea pig eye by Garretson, Henry D; ADVDEG from McGill University (Canada), 1968 http://wwwlib.umi.com/dissertations/fullcit/NK02677

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

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CHAPTER 5. PATENTS ON GLIOBLASTOMA MULTIFORME 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 “glioblastoma multiforme” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on glioblastoma multiforme, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Glioblastoma Multiforme By performing a patent search focusing on glioblastoma multiforme, 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 glioblastoma multiforme: •

Method of diagnosing and treating gliomas Inventor(s): Sontheimer; Harald W. (Birmingham, AL), Ullrich; Nicole (Fairfield, CT) Assignee(s): UAB Research Foundation (Birmingham, AL) Patent Number: 5,905,027 Date filed: December 26, 1996 Abstract: The present invention provides a recombinant toxin and monoclonal antibody which specifically binds to glial-derived or meningioma-derived tumor cells. Also provided are various methods of screening for malignant gliomas and meningiomas. Further provided are methods of treating malignant gliomas, including glioblastoma multiforme and astrocytomas. Excerpt(s): The present invention relates generally to the fields of cell physiology, neurology and neuro-oncology. More specifically, the present invention relates to a novel method of diagnosing and treating gliomas and meningiomas. Glial cells comprise a large proportion of the total cell population in the CNS. Unlike neurons, glial cells retain the ability to proliferate postnatally, and some glial cells still proliferate in the adult or aged brain. Uncontrolled glial proliferation can lead to aggressive primary intracranial tumors, the vast majority of which are astrocytomas, and therefore, of glial origin. Tumors of astrocytic origin vary widely in morphology and behavior, and, according to the 1993 WHO classification schema, can be separated into three subsets. Astrocytomas, the lowest grade tumors, are generally well-differentiated and tend to grow slowly. Anaplastic astrocytomas are characterized by increased cellularity, nuclear pleomorphism, and increased mitotic activity. They are intermediate grade tumors and show a tendency to progress to a more aggressive grade. Glioblastomas are considered the most aggressive, with poorly differentiated cells, vascular proliferation, and necrosis. Due to the common morphological heterogeneity of cells within a single tumor, such classification is not clear-cut and is somewhat unsatisfactory. The term "astrocyte-derived tumors" as used herein refers to astrocytomas. Meningiomas are tumor originating in the meninges. Significant progress has been made in identifying physiologically important growth factors, receptors, and signal transduction pathways that control normal and malignant cell proliferation. It is now commonly accepted that growth factor binding leads to activation of oncogenes such as the ras/raf pathway, and ras in turn regulates gene expression through at least two mitogen-activated protein kinases. Interestingly, the ras/raf pathway is in crosstalk with the cAMP signaling cascade which is activated by numerous hormones and neurotransmitters. Web site: http://www.delphion.com/details?pn=US05905027__

Patent Applications on Glioblastoma Multiforme 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

9

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

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several years.) The following patent applications have been filed since December 2000 relating to glioblastoma multiforme: •

EST-defined probe for cancer progression Inventor(s): McKinnon, Randy D.; (Piscataway, NJ) Correspondence: Perkins Coie Llp; Post Office Box 1208; Seattle; WA; 98111-1208; US Patent Application Number: 20030044811 Date filed: October 20, 2001 Abstract: Nucleic acid sequences that identify a gene product associated with Glioblastoma Multiforme are disclosed. Nucleic acid probes for mRNA transcripts whose expression is associated with glioblast transformation and methods for using these probes in identifying patients at risk for progression into a malignant phenotype are also disclosed. Excerpt(s): The present utility patent application claims priority to provisional patent application U.S. Ser. No. 60/242,160 (McKinnon, R. D.), filed Oct. 20, 2000, the disclosure of which is incorporated by reference in its entirety herein. The present invention relates to the field of brain cancer therapy, treatment and diagnosis. Glioblastoma multiforme (GBM), the single most fatal form of cancer known to man, has been termed "The Terminator" (Proc. Natl. Acad. Sci 97:6242-44). It is 95% fatal within 10 months of diagnosis, independent of intervention approaches, and there is a disturbing recent increase in incidence especially in the elderly. The disease amounts a terrible toll on patients, families, and clinicians charged with their care. In spite of immense scrutiny, essentially nothing is known of the etiology, cell physiology and molecular genetics of the disease. In addition, attempts at treating the disease have been unsuccessful due to the complex character of the tumor. Thus, novel therapies and treatments for this disease are important and urgently desired. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Novel method of diagnosing and treating gliomas Inventor(s): Sontheimer, Harald W.; (Birmingham, AL), Ullrich, Nicole; (Fairfield, CT) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20020065216 Date filed: October 4, 2001 Abstract: The present invention provides a recombinant toxin and monoclonal antibody which specifically binds to glial-derived or meningioma-derived tumor cells. Also provided are various methods of screening for malignant gliomas and meningiomas. Further provided are methods of treating malignant gliomas, including glioblastoma multiforme and astrocytomas. Excerpt(s): The present invention relates generally to the fields of cell physiology, neurology and neuro-oncology. More specifically, the present invention relates to a novel method of diagnosing and treating gliomas and meningiomas. Glial cells comprise a large proportion of the total cell population in the CNS. Unlike neurons, glial cells retain the ability to proliferate postnatally, and some glial cells still proliferate in the adult or aged brain. Uncontrolled glial proliferation can lead to aggressive primary

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intracranial tumors, the vast majority of which are astrocytomas, and therefore, of glial origin. Tumors of astrocytic origin vary widely in morphology and behavior, and, according to the 1993 WHO classification schema, can be separated into three subsets. Astrocytomas, the lowest grade tumors, are generally well-differentiated and tend to grow slowly. Anaplastic astrocytomas are characterized by increased cellularity, nuclear pleomorphism, and increased mitotic activity. They are intermediate grade tumors and show a tendency to progress to a more aggressive grade. Glioblastomas are considered the most aggressive, with poorly differentiated cells, vascular proliferation, and necrosis. Due to the common morphological heterogeneity of cells within a single tumor, such classification is not clear-cut and is somewhat unsatisfactory. The term "astrocyte-derived tumors" as used herein refers to astrocytomas. Meningiomas are tumor originating in the meninges. Significant progress has been made in identifying physiologically important growth factors, receptors, and signal transduction pathways that control normal and malignant cell proliferation. It is now commonly accepted that growth factor binding leads to activation of oncogenes such as the ras/raf pathway, and ras in turn regulates gene expression through at least two mitogen-activated. protein kinases. Interestingly, the ras/raf pathway is in crosstalk with the cAMP signaling cascade which is activated by numerous hormones and neurotransmitters. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Strong gene sets for glioma classification Inventor(s): Dougherty, Ed; (College Station, TX), Fuller, Greg; (Houston, TX), Hess, Kenneth; (Houston, TX), Zhang, Wei; (Houston, TX) Correspondence: Fulbright & Jaworski L.L.P.; 600 Congress AVE.; Suite 2400; Austin; TX; 78701; US Patent Application Number: 20040053277 Date filed: March 17, 2003 Abstract: The present invention provides a number of gene markers whose expression is altered in various gliomas. In particular, by examining the expression these markers, one can accurately classify a glioma as glioblastoma multiforme (GM), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO) or oligodendroglioma (OL). The diagnosis may be performed on nucleic acids, for example, using a DNA microarray, or on protein, for example, using immunologic means. Also disclosed are methods of therapy. Excerpt(s): The present application claims priority to co-pending U.S. Provisional Patent Application Serial No. 60/364,608 filed on Mar. 15, 2002. The entire text of the abovereferenced disclosure is specifically incorporated herein by reference without disclaimer. The present invention relates generally to the fields of molecular biology and oncology. More particularly, it concerns the classification of gliomas based on the expression of various proteins identified as relevant to various glioma states. Gliomas are complex cancers with different growth characteristics and involves different types of cells. Because the original clone of tumor cells may exist at any stage during the cell differentiation, the boundaries between cell lineages can be blurred. The current morphologically-based tumor classifications often mix cell lineage features with tumor growth characteristics. The results are subjective and there can be disagreements among physicians as to what kind of tumor cell is involved. To date, a successful application of gene-based classification has not been applied to gliomas.

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

VEGF-D expression in brain cancer Inventor(s): Debinski, Waldemar; (Hershey, PA), Gibo, Denise M.; (Hershey, PA) Correspondence: Stanley A. Kim, PH.D., ESQ.; Akerman, Senterfitt & Eidson, P.A.; 222 Lakeview Avenue, Suite 400,; P.O. Box 3188; West Palm Beach; FL; 33402-3188; US Patent Application Number: 20020164624 Date filed: February 12, 2002 Abstract: VEGF-D serves as a target for diagnosing and treating glioblastoma multiforme and related brain cancers. Cancer in a brain tissue sample is detected by analyzing expression of VEGF-D in the sample. Brain cancer is treated by modulating VEGF-D gene expression in cells of the cancer, and by inhibiting angiogenesis associated with the cancer by interfering with VEGF-D binding to a VEGF-D receptor. Excerpt(s): The present application claims the priority of U.S. provisional patent application Ser. number 60/268,089 filed Feb. 12, 2001. The invention relates to the fields of medicine, angiogenesis and neuro-oncology. More particularly, the invention relates to compositions and methods for detecting and treating malignant tumors. Cancer is presently the second leading cause of death in developed nations. Wingo et al., J. Reg. Management, 25:43-51 (1998). Despite recent research that has revealed many of the molecular mechanisms of tumorigenesis, few new treatments have achieved widespread clinical success in treating solid tumors. Current treatments for most malignancies thus remain gross resection, chemotherapy, and radiotherapy. While increasingly successful, each of these treatments still causes numerous undesired side effects. The primary cause of these side effects is that none of these conventional methods specifically targets only diseased cells. For example, surgery results in pain, traumatic injury to healthy tissue, and scarring. Radiotherapy and chemotherapy cause nausea, immune suppression, gastric ulceration and secondary tumorigenesis. 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 glioblastoma multiforme, 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 “glioblastoma multiforme” (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 glioblastoma multiforme. You can also use this procedure to view pending patent applications concerning glioblastoma multiforme. 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. PERIODICALS AND NEWS ON GLIOBLASTOMA MULTIFORME Overview In this chapter, we suggest a number of news sources and present various periodicals that cover glioblastoma multiforme.

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

Combination gene therapy reduces glioblastoma multiforme tumors Source: Reuters Medical News Date: June 02, 1998

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

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Academic Periodicals covering Glioblastoma Multiforme Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to glioblastoma multiforme. In addition to these sources, you can search for articles covering glioblastoma multiforme 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 7. 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 glioblastoma multiforme. 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).

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

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/.

PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee.

Researching Orphan Drugs Although the list of orphan drugs is revised on a daily basis, you can quickly research orphan drugs that might be applicable to glioblastoma multiforme 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 “glioblastoma multiforme” (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

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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 glioblastoma multiforme: •

Hypericin http://www.rarediseases.org/nord/search/nodd_full?code=1058

•

Hypericin http://www.rarediseases.org/nord/search/nodd_full?code=1063

•

Sodium Monomercaptoundecahydro-closo-dodecaborate (trade name: Borocell) http://www.rarediseases.org/nord/search/nodd_full?code=48

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

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APPENDICES

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

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

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

•

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 “glioblastoma multiforme” (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 8266 21 301 5 31 8624

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 “glioblastoma multiforme” (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 glioblastoma multiforme 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 glioblastoma multiforme. 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 glioblastoma multiforme. 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 “glioblastoma multiforme”:

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Bleeding Disorders http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html Brain Cancer http://www.nlm.nih.gov/medlineplus/braincancer.html Cancer http://www.nlm.nih.gov/medlineplus/cancer.html Neurologic Diseases http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html Ovarian Cancer http://www.nlm.nih.gov/medlineplus/ovariancancer.html Spinal Cord Diseases http://www.nlm.nih.gov/medlineplus/spinalcorddiseases.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 glioblastoma multiforme. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

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

•

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

•

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

•

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

•

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

•

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

Patient Resources

•

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

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to glioblastoma multiforme. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with glioblastoma multiforme. 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 glioblastoma multiforme. 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 “glioblastoma multiforme” (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 “glioblastoma multiforme”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “glioblastoma multiforme” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.

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

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

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

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

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

21

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

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

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

•

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

•

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

•

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

•

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

•

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

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

22

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

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•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

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

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

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

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

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

•

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

•

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

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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

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

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

•

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

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GLIOBLASTOMA MULTIFORME DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-phosphate: A drug that halts cell suicide in human white blood cells. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and

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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] 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] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Agrin: A protein component of the synaptic basal lamina. It has been shown to induce clustering of acetylcholine receptors on the surface of muscle fibers and other synaptic molecules in both synapse regeneration and development. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] 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] Allografts: A graft of tissue obtained from the body of another animal of the same species

Dictionary 147

but with genotype differing from that of the recipient; tissue graft from a donor of one genotype to a host of another genotype with host and donor being members of the same species. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alternative Splicing: A process whereby multiple protein isoforms are generated from a single gene. Alternative splicing involves the splicing together of nonconsecutive exons during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form messenger RNA. The alternative forms produce proteins in which one part is common while the other part is different. [NIH] 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] 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] Aminocamptothecin: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. [NIH] Aminolevulinic Acid: A compound produced from succinyl-CoA and glycine as an intermediate in heme synthesis. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [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] 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]

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Anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] 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] 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] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antibody-Dependent Cell Cytotoxicity: The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface IgG whose Fc portion is intact. The effector cell is a "killer" cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [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-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]

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Anti-infective: An agent that so acts. [EU] 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]

Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiplasmin: A member of the serpin superfamily found in human plasma that inhibits the lysis of fibrin clots which are induced by plasminogen activator. It is a glycoprotein, molecular weight approximately 70,000 that migrates in the alpha 2 region in immunoelectrophoresis. It is the principal plasmin inactivator in blood, rapidly forming a very stable complex with plasmin. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] 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 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] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [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] Articulation: The relationship of two bodies by means of a moveable joint. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] 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)

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is not well understood. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autopsy: Postmortem examination of the body. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [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] Bacterial Physiology: Physiological processes and activities of bacteria. [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] 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 Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [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]

Berberine: An alkaloid from Hydrastis canadensis L., Berberidaceae. It is also found in many other plants. It is relatively toxic parenterally, but has been used orally for various parasitic and fungal infections and as antidiarrheal. [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] Biochemical: Relating to biochemistry; characterized by, produced by, or involving 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]

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Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [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] 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] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Fluids: Liquid components of living organisms. [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] 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] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Bromodeoxyuridine: A nucleoside that substitutes for thymidine in DNA and thus acts as an antimetabolite. It causes breaks in chromosomes and has been proposed as an antiviral and antineoplastic agent. It has been given orphan drug status for use in the treatment of primary brain tumors. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [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] 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 interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Carbogen: An inhalant of oxygen and carbon dioxide that increases the sensitivity of tumor cells to the effects of radiation therapy. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] 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] Carbonate Dehydratase: A zinc-containing enzyme of erythrocytes with molecular weight

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of 30 kD. It is among the most active of known enzymes and catalyzes the reversible hydration of carbon dioxide, which is significant in the transport of CO2 from the tissues to the lungs. The enzyme is inhibited by acetazolamide. EC 4.2.1.1. [NIH] Carbonic Anhydrase Inhibitors: A class of compounds that reduces the secretion of H+ ions by the proximal kidney tubule through inhibition of carbonic anhydrase (carbonate dehydratase). [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinoembryonic Antigen: A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the respone to colon cancer treatment. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] 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] Carmustine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]

Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [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 Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH]

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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 Physiology: Characteristics and physiological processes of cells from cell division to cell death. [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] Cellular Structures: Components of a cell. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental

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protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [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] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Chondrocytes: Polymorphic cells that form cartilage. [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] 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 Deletion: Actual loss of a portion of the chromosome. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical series: A case series in which the patients receive treatment in a clinic or other medical facility. [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]

Clonic: Pertaining to or of the nature of clonus. [EU] 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] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been

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used also in the therapy of familial Mediterranean fever (periodic disease). [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] 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] 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]

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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 machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized 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 machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [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] 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] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Contralateral: Having to do with the opposite side of the body. [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] Contusion: A bruise; an injury of a part without a break in the skin. [EU] Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsants: Substances that act in the brain stem or spinal cord to produce tonic or clonic convulsions, often by removing normal inhibitory tone. They were formerly used to stimulate respiration or as antidotes to barbiturate overdose. They are now most commonly used as experimental tools. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [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] 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

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pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Cortices: The outer layer of an organ; used especially of the cerebrum and cerebellum. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cryofixation: Fixation of a tissue by localized cooling at very low temperature. [NIH] Cryopreservation: Preservation of cells, tissues, organs, or embryos by freezing. In histological preparations, cryopreservation or cryofixation is used to maintain the existing form, structure, and chemical composition of all the constituent elements of the specimens. [NIH]

Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] 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] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [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] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. [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] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

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

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special organs. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]

De novo: In cancer, the first occurrence of cancer in the body. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] 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] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [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] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Difluoromethylornithine: DFMO. An anticancer drug that has been shown to reduce the risk of cancer in animals. [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] 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

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blended; not running together; separate. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [NIH] Dose-rate: The strength of a treatment given over a period of time. [NIH] Dosimetry: All the methods either of measuring directly, or of measuring indirectly and computing, absorbed dose, absorbed dose rate, exposure, exposure rate, dose equivalent, and the science associated with these methods. [NIH] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals. [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] Duodenum: The first part of the small intestine. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the

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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] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [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] 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] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometrium: The layer of tissue that lines the uterus. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [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.

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[NIH]

Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH]

for

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [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] Ependymal: It lines the cavities of the brain's ventricles and the spinal cord and slowly divides to create a stem cell. [NIH] Ependymal tumors: A type of brain tumor that usually begins in the central canal of the spinal cord. Ependymomas may also develop in the cells lining the ventricles of the brain, which produce and store the special fluid (cerebrospinal fluid) that protects the brain and spinal cord. Also called ependymomas. [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] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] 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] Epidural: The space between the wall of the spinal canal and the covering of the spinal cord. An epidural injection is given into this space. [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] 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] Erythrocyte Volume: Volume of circulating erythrocytes. It is usually measured by radioisotope dilution technique. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH]

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Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estramustine: A nitrogen mustard linked to estradiol, usually as phosphate; used to treat prostatic neoplasms; also has radiation protective properties. [NIH] Estrogen: One of the two female sex hormones. [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] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Exotoxin: Toxic substance excreted by living bacterial cells. [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] Extraction: The process or act of pulling or drawing out. [EU]

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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] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fast Neutrons: Neutrons, the energy of which exceeds some arbitrary level, usually around one million electron volts. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fenretinide: A synthetic retinoid that is used orally as a chemopreventive against prostate cancer and in women at risk of developing contralateral breast cancer. It is also effective as an antineoplastic agent. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [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 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] Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a

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fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] 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] Fold: A plication or doubling of various parts of the body. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [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] 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] Gamma knife: Radiation therapy in which high-energy rays are aimed at a tumor from many angles in a single treatment session. [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] Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] 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] 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 Amplification: A selective increase in the number of copies of a gene coding for a specific protein without a proportional increase in other genes. It occurs naturally via the

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excision of a copy of the repeating sequence from the chromosome and its extrachromosomal replication in a plasmid, or via the production of an RNA transcript of the entire repeating sequence of ribosomal RNA followed by the reverse transcription of the molecule to produce an additional copy of the original DNA sequence. Laboratory techniques have been introduced for inducing disproportional replication by unequal crossing over, uptake of DNA from lysed cells, or generation of extrachromosomal sequences from rolling circle replication. [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] Gene-modified: Cells that have been altered to contain different genetic material than they originally contained. [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 testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [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] Glial Fibrillary Acidic Protein: An intermediate filament protein found only in glial cells or cells of glial origin. MW 51,000. [NIH] Glial tumors: A general term for many types of tumors of the central nervous system, including astrocytomas, ependymal tumors, glioblastoma multiforme, and primitive neuroectodermal tumors. [NIH] Glioblastoma: A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in

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any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Gliosarcoma: A type of glioma. [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] Glucokinase: A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. They are found in invertebrates and microorganisms and are highly specific for glucose. (Enzyme Nomenclature, 1992) EC 2.7.1.2. [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] Glufosfamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [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] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [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] Grading: A system for classifying cancer cells in terms of how abnormal they appear when examined under a microscope. The objective of a grading system is to provide information about the probable growth rate of the tumor and its tendency to spread. The systems used to grade tumors vary with each type of cancer. Grading plays a role in treatment decisions. [NIH]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] 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

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carcinoma. [NIH] Granule: A small pill made from sucrose. [EU] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [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] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Health Physics: The science concerned with problems of radiation protection relevant to reducing or preventing radiation exposure, and the effects of ionizing radiation on humans and their environment. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha and two beta chains. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [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]

Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Herbicide: A chemical that kills plants. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterodimers: Zippered pair of nonidentical proteins. [NIH]

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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]

Heterogenic: Derived from a different source or species. Also called heterogenous. [NIH] Heterogenous: Derived from a different source or species. Also called heterogenic. [NIH] Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Hexokinase: An enzyme that catalyzes the conversion of ATP and a D-hexose to ADP and a D-hexose 6-phosphate. D-Glucose, D-mannose, D-fructose, sorbitol, and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. (From Enzyme Nomenclature, 1992) EC 2.7.1.1. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] 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] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] 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] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperfractionation: A way of giving radiation therapy in smaller-than-usual doses two or three times a day instead of once a day. [NIH]

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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] 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] Hyperventilation: A pulmonary ventilation rate faster than is metabolically necessary for the exchange of gases. It is the result of an increased frequency of breathing, an increased tidal volume, or a combination of both. It causes an excess intake of oxygen and the blowing off of carbon dioxide. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]

Hypothermia: Lower than normal body temperature, especially in warm-blooded animals; in man usually accidental or unintentional. [NIH] 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] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] 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] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [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

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amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] 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] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] 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 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] 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] 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]

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] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inoperable: Not suitable to be operated upon. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which

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occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] 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] Insulin-like: Muscular growth factor. [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] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-13: T-lymphocyte-derived cytokine that produces proliferation, immunoglobulin isotype switching, and immunoglobulin production by immature Blymphocytes. It appears to play a role in regulating inflammatory and immune responses. [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] 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] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU]

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Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial tumors: Tumors that occur in the brain. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [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] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]

Kilobase: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH]

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Kinetic: Pertaining to or producing motion. [EU] 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] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [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] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [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] Linear Energy Transfer: Rate of energy dissipation along the path of charged particles. In radiobiology and health physics, exposure is measured in kiloelectron volts per micrometer of tissue (keV/micrometer T). [NIH] Linkages: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] 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] 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 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] Lomustine: An alkylating agent of value against both hematologic malignancies and solid tumors. [NIH] Loss of Heterozygosity: The loss of one allele at a specific locus, caused by a deletion mutation; or loss of a chromosome from a chromosome pair. It is detected when heterozygous markers for a locus appear monomorphic because one of the alleles was deleted. When this occurs at a tumor suppressor gene locus where one of the alleles is

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already abnormal, it can result in neoplastic transformation. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, 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] 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] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] 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] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [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]

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Malignant tumor: A tumor capable of metastasizing. [NIH] Mammary: Pertaining to the mamma, or breast. [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] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Measles Virus: The type species of morbillivirus and the cause of the highly infectious human disease measles, which affects mostly children. [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] 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 with antibody or by the action of antigen with a sensitized lymphocyte. [EU] 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] 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] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [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] 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] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningioma: A type of tumor that occurs in the meninges, the membranes that cover and protect the brain and spinal cord. Meningiomas usually grow slowly. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU]

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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] Metastatic cancer: Cancer that has spread from the place in which it started to other parts of the body. [NIH] Methyltransferase: A drug-metabolizing enzyme. [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] Microfilaments: The smallest of the cytoskeletal filaments. They are composed chiefly of actin. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [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] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [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

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altered permeability of the membranes of respiring mitochondria. [NIH] Mitogen-Activated Protein Kinase Kinases: A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate mitogen-activated protein kinases and are themselves phosphorylated by MAP kinase kinase kinases. JNK kinases (also known as SAPK kinases) are a subfamily. EC 2.7.10.- [NIH] Mitogen-Activated Protein Kinases: A superfamily of protein-serine-threonine kinases that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by mitogen-activated protein kinase kinases which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP kinase kinase kinases). Families of these mitogen-activated protein kinases (MAPKs) include extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs) (also known as c-jun terminal kinases (JNKs)), and p38-mitogen-activated protein kinases. EC 2,7,1.- [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] 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 Probes: A group of atoms or molecules attached to other molecules or cellular structures and used in studying the properties of these molecules and structures. Radioactive DNA or RNA sequences are used in molecular genetics to detect the presence of a complementary sequence by molecular hybridization. [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] Morbillivirus: A genus of the family Paramyxoviridae (subfamily Paramyxovirinae) where all the virions have hemagglutinin but not neuraminidase activity. All members produce

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both cytoplasmic and intranuclear inclusion bodies. MEASLES VIRUS is the type species. [NIH]

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] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multimodality treatment: Therapy that combines more than one method of treatment. [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] 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] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myoglobin: A conjugated protein which is the oxygen-transporting pigment of muscle. It is made up of one globin polypeptide chain and one heme group. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Needle biopsy: The removal of tissue or fluid with a needle for examination under a microscope. Also called fine-needle aspiration. [NIH] 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] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and

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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] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurologist: A doctor who specializes in the diagnosis and treatment of disorders of the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] 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] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] 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] 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] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [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] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] 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

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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] Oligodendroglial: A cell that lays down myelin. [NIH] Oligodendroglioma: A rare, slow-growing tumor that begins in brain cells called oligodendrocytes, which provide support and nourishment for cells that transmit nerve impulses. Also called oligodendroglial tumor. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncogenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [NIH] Oncology: The study of cancer. [NIH] 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] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [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] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] 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] Osteonecrosis: Death of a bone or part of a bone, either atraumatic or posttraumatic. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 -

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oxygenation the process of supplying, treating, or mixing with oxygen. [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] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] 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] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [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 (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillamine: 3-Mercapto-D-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in Wilson's disease. [NIH] Penicillin: An antibiotic drug used to treat infection. [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] Pericytes: Smooth muscle cell that wraps around normal blood vessels. [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

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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] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] 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] 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] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylating: Attached to a phosphate group. [NIH]

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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] Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [NIH] Photosensitizer: A drug used in photodynamic therapy. When absorbed by cancer cells and exposed to light, the drug becomes active and kills the cancer cells. [NIH] 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] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] 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] 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 Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [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] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic

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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]

Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [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] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polychlorinated Biphenyls: Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] 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] Polyploidy: The chromosomal constitution of a cell containing multiples of the normal number of chromosomes; includes triploidy (symbol: 3N), tetraploidy (symbol: 4N), etc. [NIH]

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] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Porfimer sodium: An anticancer drug that is also used in cancer prevention. It belongs to the family of drugs called photosensitizing agents. [NIH]

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Porphyrins: A group of compounds containing the porphin structure, four pyrrole rings connected by methine bridges in a cyclic configuration to which a variety of side chains are attached. The nature of the side chain is indicated by a prefix, as uroporphyrin, hematoporphyrin, etc. The porphyrins, in combination with iron, form the heme component in biologically significant compounds such as hemoglobin and myoglobin. [NIH] 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] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [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] 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] 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] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [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]

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Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Promoter: A chemical substance that increases the activity of a carcinogenic process. [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] Prostatic Neoplasms: Tumors or cancer of the prostate. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Isoforms: Different forms of a protein that may be produced from different genes, or from the same gene by alternative splicing. [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [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] Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. EC 2.7.10. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or

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vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They 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] Proto-Oncogenes: Normal cellular genes homologous to viral oncogenes. The products of proto-oncogenes are important regulators of biological processes and appear to be involved in the events that serve to maintain the ordered procession through the cell cycle. Protooncogenes have names of the form c-onc. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] 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 Ventilation: The total volume of gas per minute inspired or expired measured in liters per minute. [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] Pyramidal Cells: Projection neurons in the cerebral cortex and the hippocampus. Pyramidal cells have a pyramid-shaped soma with the apex and an apical dendrite pointed toward the pial surface and other dendrites and an axon emerging from the base. The axons may have local collaterals but also project outside their cortical region. [NIH] Pyrazoloacridine: An anticancer drug that belongs to the family of drugs called acridines. [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 Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quiescent: Marked by a state of inactivity or repose. [EU]

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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] 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 oncologist: A doctor who specializes in using radiation to treat cancer. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiobiology: That part of biology which deals with the effects of radiation on living organisms. [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] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radionuclide Imaging: Process whereby a radionuclide is injected or measured (through tissue) from an external source, and a display is obtained from any one of several rectilinear scanner or gamma camera systems. The image obtained from a moving detector is called a scan, while the image obtained from a stationary camera device is called a scintiphotograph. [NIH]

Radiosensitization: The use of a drug that makes tumor cells more sensitive to radiation therapy. [NIH] Radiosensitizers: Drugs that make tumor cells more sensitive to radiation. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively.

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At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] 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] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [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] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Reoperation: A repeat operation for the same condition in the same patient. It includes reoperation for reexamination, reoperation for disease progression or recurrence, or reoperation following operative failure. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Residual disease: Cancer cells that remain after attempts have been made to remove the cancer. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] 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]

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Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [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] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] 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] 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] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol

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triphosphate system, and the cyclic GMP system. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] 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] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU]

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Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [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] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] 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] Somnolence: Sleepiness; also unnatural drowsiness. [EU] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH]

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Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cells: Flat cells that look like fish scales under a microscope. These cells cover internal and external surfaces of the body. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

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] Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Steady state: Dynamic equilibrium. [EU] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Stereotactic biopsy: A biopsy procedure that uses a computer and a three-dimensional scanning device to find a tumor site and guide the removal of tissue for examination under a microscope. [NIH] Stereotactic radiosurgery: A radiation therapy technique involving a rigid head frame that is attached to the skull; high-dose radiation is administered through openings in the head frame to the tumor while decreasing the amount of radiation given to normal brain tissue. This procedure does not involve surgery. Also called stereotaxic radiosurgery and stereotactic radiation therapy. [NIH]

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Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] 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] 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] 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] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] 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] Supratentorial: Located in the upper part of the brain. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between

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neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synthetic retinoid: A substance related to vitamin A that is produced in a laboratory. [NIH] Systemic: Affecting the entire 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] Tarsus: The region of the articulation between the foot and the leg. [NIH] Technetium: The first artificially produced element and a radioactive fission product of uranium. The stablest isotope has a mass number 99 and is used diagnostically as a radioactive imaging agent. Technetium has the atomic symbol Tc, atomic number 43, and atomic weight 98.91. [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] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teniposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Teniposide 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 cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the G2 and S phases of the cycle. [NIH] Thalidomide: A pharmaceutical agent originally introduced as a non-barbiturate hypnotic, but withdrawn from the market because of its known tetratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor alpha from monocytes, and modulates other cytokine action. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thiotepa: A very toxic alkylating antineoplastic agent also used as an insect sterilant. It causes skin, gastrointestinal, CNS, and bone marrow damage. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), thiotepa may reasonably be anticipated to be a carcinogen (Merck Index, 11th ed). [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH]

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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] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [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] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [NIH] Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerase. [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

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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] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Translating: Conversion from one language to another language. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] 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 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]

Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] 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

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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] 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] 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] 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] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uranium: A radioactive element of the actinide series of metals. It has an atomic symbol U, atomic number 92, and atomic weight 238.03. U-235 is used as the fissionable fuel in nuclear weapons and as fuel in nuclear power reactors. [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] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] 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]

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] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [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] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary

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Glioblastoma Multiforme

artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vertebral: Of or pertaining to a vertebra. [EU] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] 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] 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] 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] War: Hostile conflict between organized groups of people. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH]

Dictionary 201

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] 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]

203

INDEX 1 1-phosphate, 91, 145, 183 A Abdomen, 145, 162, 174, 182, 183, 194, 195, 200 Abdominal, 145, 182, 183 Aberrant, 14, 16, 25, 26, 42, 44, 53, 145 Acatalasia, 145, 153 Acceptor, 145, 174, 181, 197 Acetylcholine, 145, 146, 155, 180 Acidity, 145, 183 Acquired Immunodeficiency Syndrome, 69, 145 Adaptability, 145, 153, 154 Adaptation, 17, 145 Adduct, 48, 145 Adenocarcinoma, 64, 145, 168 Adenovirus, 45, 47, 145 Adjustment, 145 Adjuvant, 28, 52, 146 Adolescence, 24, 146 Adrenergic, 98, 146, 162 Adverse Effect, 30, 31, 46, 146, 192 Aerobic, 6, 146 Affinity, 146, 149, 174, 193 Agonist, 18, 98, 146, 196 Agrin, 66, 146 Algorithms, 146, 151 Alkaline, 146, 152 Alkaloid, 146, 150, 152, 155 Alkylating Agents, 146, 153, 167, 196, 199 Alleles, 146, 174 Allergen, 146, 192 Allogeneic, 5, 146, 167 Allografts, 146, 169 Alopecia, 147, 158 Alpha Particles, 147, 189 Alternative medicine, 118, 147 Alternative Splicing, 49, 147, 187 Amino acid, 30, 147, 148, 163, 166, 167, 174, 182, 183, 185, 187, 191, 192, 195, 196, 198, 199 Amino Acid Sequence, 30, 147, 148, 163, 166 Aminocamptothecin, 98, 104, 147 Aminolevulinic Acid, 67, 147 Amplification, 22, 33, 40, 50, 68, 82, 147 Amyloid, 147

Anaerobic, 147, 179 Anaesthesia, 147, 171 Analog, 6, 33, 48, 147, 165 Analogous, 147, 198 Anaplastic, 4, 9, 10, 19, 21, 24, 30, 33, 37, 43, 48, 50, 73, 85, 106, 112, 114, 148 Anatomical, 148, 154, 177, 191 Angiogenesis, 11, 13, 22, 26, 30, 32, 35, 49, 62, 94, 99, 115, 148, 176 Angiogenesis inhibitor, 35, 148 Animal model, 15, 16, 17, 21, 23, 25, 40, 42, 49, 148 Annealing, 148, 185 Antagonism, 45, 148 Antibacterial, 148, 194 Antibiotic, 148, 159, 160, 182, 194 Antibodies, 148, 170, 175, 178, 189 Antibody, 39, 46, 112, 113, 146, 148, 156, 169, 170, 171, 173, 176, 178, 189, 192, 193, 201 Antibody-Dependent Cell Cytotoxicity, 148, 173 Anticoagulant, 148, 187 Antigen, 4, 36, 38, 65, 74, 146, 148, 156, 159, 169, 170, 171, 172, 176, 177, 192 Antigen-presenting cell, 38, 148, 159 Anti-infective, 149, 169, 173 Anti-inflammatory, 149, 159, 167, 186 Antimetabolite, 149, 152 Antineoplastic, 17, 146, 149, 152, 153, 158, 160, 164, 176, 182, 185, 186, 196, 197, 200 Antineoplastic Agents, 17, 146, 149, 200 Antioxidant, 8, 149, 181 Antiplasmin, 90, 149 Antiproliferative, 54, 63, 98, 149 Antiviral, 149, 152, 172 Apoptosis, 6, 11, 12, 13, 15, 22, 28, 35, 40, 49, 149, 153 Aqueous, 149, 158, 169 Arrhythmia, 149, 200 Arterial, 85, 149, 187 Arteries, 149, 151, 157, 177 Arterioles, 149, 151, 152 Artery, 149, 151, 158, 188, 200 Articulation, 149, 196 Aseptic, 149, 181, 195 Aspiration, 149 Assay, 7, 149

204

Glioblastoma Multiforme

Astrocytes, 10, 13, 17, 22, 40, 42, 43, 149, 150, 177 Astrocytoma, 4, 5, 8, 9, 18, 19, 30, 33, 37, 40, 48, 73, 83, 85, 88, 98, 104, 114, 150, 166 Atrophy, 150, 180 Attenuated, 43, 150, 199 Attenuation, 44, 150 Autologous, 4, 20, 38, 71, 72, 107, 150 Autopsy, 38, 59, 150 Axons, 150, 159, 188 B Bacteria, 5, 148, 150, 164, 167, 175, 177, 179, 184, 194, 198, 199 Bacterial Physiology, 145, 150 Bacteriophage, 150, 198 Barbiturate, 150, 157, 196 Basal Ganglia, 150, 167 Basement Membrane, 150, 163 Basophils, 150, 168, 174 Benign, 150, 167, 179, 189 Berberine, 28, 150 Bile, 150, 169, 174 Biochemical, 4, 12, 15, 17, 18, 29, 36, 58, 146, 149, 150, 151 Biological therapy, 150, 168 Biological Transport, 151, 159 Biomarkers, 6, 27, 151 Biopsy, 14, 18, 37, 89, 92, 151, 163, 194 Biosynthesis, 151, 192 Biotechnology, 51, 60, 118, 129, 151 Bladder, 151, 187, 199 Blood Coagulation, 151, 152, 197 Blood Glucose, 151, 168, 170, 172 Blood pressure, 151, 178, 180, 193 Blood vessel, 30, 58, 148, 151, 152, 154, 155, 161, 174, 175, 177, 182, 193, 197, 199 Blood Volume, 91, 151 Blood-Brain Barrier, 17, 47, 66, 78, 88, 151 Blot, 5, 151 Body Fluids, 11, 151, 193, 198 Bone Marrow, 71, 72, 151, 163, 166, 168, 170, 175, 176, 178, 193, 196 Bone scan, 151, 191 Boron, 37, 55, 56, 151, 152 Boron Neutron Capture Therapy, 55, 151, 152 Brachytherapy, 42, 56, 60, 72, 84, 87, 152, 172, 173, 189, 201 Brain Stem, 69, 152, 154, 157 Bromodeoxyuridine, 57, 102, 103, 152

C Calcium, 15, 17, 152, 156, 176, 180, 187, 200 Calcium channel blocker, 152, 200 Calmodulin, 15, 83, 152 Calpain, 81, 152 Camptothecin, 105, 152, 173 Cancer vaccine, 38, 47, 152 Capillary, 17, 152, 200 Carbogen, 89, 102, 152 Carbohydrate, 152, 185 Carbon Dioxide, 152, 153, 165, 170, 190 Carbonate Dehydratase, 152, 153 Carbonic Anhydrase Inhibitors, 27, 153 Carboplatin, 33, 102, 106, 153 Carcinoembryonic Antigen, 94, 153 Carcinogen, 145, 153, 196 Carcinogenic, 146, 153, 171, 181, 187, 199 Carcinoma, 14, 42, 50, 93, 153 Cardiac, 152, 153, 160, 162, 179 Carmustine, 53, 99, 107, 153 Case report, 53, 55, 57, 61, 62, 69, 70, 75, 77, 78, 80, 81, 91, 94, 103, 153 Case series, 153, 155 Caspase, 16, 81, 153 Catalase, 8, 145, 153 Cause of Death, 115, 153 Cell Adhesion, 153, 172 Cell Count, 8, 153 Cell Cycle, 6, 11, 24, 40, 81, 153, 155, 158, 163, 188, 196 Cell Death, 16, 20, 149, 153, 154, 163, 179, 196 Cell Differentiation, 114, 153 Cell Division, 15, 150, 153, 154, 163, 168, 176, 177, 178, 184, 192 Cell Lineage, 114, 154 Cell membrane, 18, 151, 154, 183 Cell motility, 39, 154 Cell Physiology, 112, 113, 154 Cell proliferation, 44, 49, 112, 114, 154 Cell Size, 42, 154 Cell Survival, 36, 42, 154, 168 Cellular Structures, 154, 178 Central Nervous System, 15, 16, 28, 33, 34, 35, 38, 83, 106, 145, 154, 165, 166, 167, 177, 185 Cerebellar, 64, 88, 154 Cerebellum, 42, 154, 158, 185 Cerebral, 19, 45, 50, 57, 61, 77, 83, 91, 150, 151, 152, 154, 157, 162, 163, 164, 167, 188 Cerebral hemispheres, 150, 152, 154, 167

205

Cerebrovascular, 154, 180 Cerebrum, 154, 158 Cervical, 57, 88, 94, 154 Cervix, 6, 154 Character, 113, 154, 159 Chemopreventive, 154, 164 Chemotherapeutic agent, 33, 105, 154 Chin, 22, 53, 68, 154, 176 Cholesterol, 150, 155, 196 Choline, 91, 155 Chondrocytes, 155, 164 Choroid, 155, 157, 190 Chromatin, 149, 155, 162 Chromosomal, 4, 22, 25, 58, 147, 155, 184, 185, 191 Chromosome, 4, 24, 50, 54, 62, 68, 79, 155, 166, 173, 174, 192 Chromosome Deletion, 25, 155 Chronic, 37, 155, 171, 195 CIS, 12, 155 Cisplatin, 33, 67, 77, 83, 99, 107, 155 Clinical Medicine, 155, 186 Clinical Protocols, 4, 36, 155 Clinical series, 56, 155 Clinical trial, 3, 4, 5, 8, 10, 11, 12, 17, 20, 31, 32, 34, 37, 38, 41, 48, 92, 129, 155, 157, 187, 189 Clone, 114, 155 Clonic, 155, 157 Cloning, 151, 155, 172 Cofactor, 155, 187, 197 Colchicine, 155, 198 Collagen, 147, 150, 156, 163, 164, 176 Colon, 153, 156 Colorectal, 27, 82, 156 Complement, 148, 156, 172, 173, 175, 192 Complementary and alternative medicine, 101, 108, 156 Complementary medicine, 101, 156 Computational Biology, 129, 156 Computed tomography, 94, 157, 191 Computerized axial tomography, 157, 191 Computerized tomography, 62, 63, 157 Conception, 157, 164, 195 Concomitant, 44, 85, 106, 157 Connective Tissue, 151, 156, 157, 164, 165, 175, 177, 191 Consciousness, 157, 159, 188, 194 Contamination, 37, 157 Contraindications, ii, 157 Contralateral, 157, 164 Control group, 9, 157

Contusion, 61, 157 Conus, 69, 157 Conventional therapy, 157 Conventional treatment, 48, 157 Convulsants, 33, 157 Convulsions, 150, 157 Coordination, 34, 154, 157 Coronary, 157, 158, 177 Coronary Thrombosis, 158, 177 Cortices, 60, 158 Cortisone, 158, 159, 186 Cranial, 37, 38, 85, 154, 158, 183 Cryofixation, 158 Cryopreservation, 5, 158 Cultured cells, 107, 158 Curative, 158, 196 Cyclic, 31, 83, 152, 158, 183, 186, 191 Cyclin, 81, 158 Cyclophosphamide, 33, 65, 90, 158, 170 Cytokine, 11, 13, 38, 77, 158, 172, 196 Cytomegalovirus, 20, 158, 165 Cytomegalovirus Infections, 158, 165 Cytoplasm, 149, 150, 154, 158, 162, 178, 179, 191 Cytosine, 158, 188 Cytoskeletal Proteins, 152, 158 Cytoskeleton, 158, 172, 177 Cytostatic, 26, 158 Cytotoxic, 4, 12, 15, 20, 158, 189 Cytotoxicity, 48, 155, 158 D Daunorubicin, 159, 160 De novo, 6, 21, 48, 77, 81, 89, 159 Degenerative, 157, 159 Deletion, 4, 22, 25, 71, 149, 159, 174 Dementia, 145, 159 Denaturation, 159, 185 Dendrites, 159, 180, 188 Dendritic, 4, 11, 38, 159, 176 Dendritic cell, 4, 11, 38, 159 Density, 9, 30, 159, 181 Dentate Gyrus, 42, 159, 169 Deuterium, 159, 169 Dexamethasone, 33, 159 Diagnostic procedure, 111, 118, 159 Diffusion, 7, 20, 41, 91, 151, 159 Difluoromethylornithine, 106, 159 Digestion, 93, 150, 159, 174, 195, 199 Digestive tract, 159, 193, 194 Diploid, 49, 159, 184 Direct, iii, 9, 32, 35, 44, 72, 155, 159, 190, 195

206

Glioblastoma Multiforme

Discrete, 11, 159 Distal, 160 Dose-limiting, 31, 160 Dose-rate, 27, 160 Dosimetry, 39, 59, 160 Doxorubicin, 33, 160 Drive, ii, vi, 17, 45, 46, 97, 160 Drug Evaluation, 12, 160 Drug Interactions, 106, 122, 160 Drug Resistance, 24, 160 Drug Tolerance, 160, 197 Duodenum, 150, 160, 182, 195 E Edema, 7, 160 Effector, 145, 148, 156, 160, 173, 183 Effector cell, 148, 160, 173 Efficacy, 5, 12, 17, 20, 26, 28, 31, 33, 35, 39, 40, 41, 75, 98, 99, 104, 106, 160, 198 Electrode, 6, 160 Electrolyte, 160, 186, 193 Electrons, 149, 160, 173, 175, 181, 189 Elementary Particles, 160, 161, 175, 180, 188 Emaciation, 145, 161 Embryo, 153, 154, 161, 171 Encephalitis, 161 Encephalomyelitis, 78, 161 Endemic, 161, 194 Endocytosis, 47, 161 Endogenous, 28, 152, 161, 198 Endometrial, 42, 161 Endometrium, 161 Endothelial cell, 18, 43, 151, 161, 164, 197 Endothelium, 17, 161, 184 Endothelium, Lymphatic, 161 Endothelium, Vascular, 161 Enhancer, 21, 161 Entorhinal Cortex, 161, 169 Environmental Exposure, 161, 181 Environmental Health, 128, 130, 161 Environmental Pollutants, 162, 185 Enzymatic, 147, 152, 156, 162, 185 Eosinophils, 162, 168, 174 Ependymal, 162, 166 Ependymal tumors, 162, 166 Epidemic, 162, 194 Epidermal, 15, 16, 40, 44, 47, 50, 51, 54, 58, 62, 64, 65, 73, 76, 87, 162, 176 Epidermal Growth Factor, 15, 16, 40, 44, 47, 50, 54, 58, 62, 65, 73, 76, 87, 162 Epidermis, 162, 167 Epidermoid carcinoma, 162, 194

Epidural, 95, 162 Epigastric, 162, 182 Epinephrine, 146, 162, 180, 199 Epithelial, 145, 151, 162 Epithelial Cells, 162 Epithelium, 150, 161, 162 Erythrocyte Volume, 151, 162 Erythrocytes, 151, 152, 162, 192 Erythropoietin, 36, 163 Escalation, 31, 37, 42, 95, 163 Estradiol, 163 Estramustine, 106, 163 Estrogen, 163, 192, 196 Etoposide, 99, 105, 106, 107, 163 Eukaryotic Cells, 158, 163, 171 Evoke, 163, 195 Excisional, 19, 163 Exhaustion, 148, 163 Exocrine, 163, 182 Exogenous, 161, 163, 166 Exon, 67, 147, 163 Exotoxin, 62, 163 External-beam radiation, 163, 173, 189, 201 Extracellular, 39, 66, 147, 149, 157, 161, 163, 164, 172, 176, 178, 193 Extracellular Matrix, 39, 157, 163, 164, 172, 176 Extracellular Matrix Proteins, 163, 176 Extracellular Space, 163 Extraction, 9, 18, 163 Eye Infections, 145, 164 F Family Planning, 129, 164 Fast Neutrons, 164, 180 Fat, 151, 164, 174, 185, 193 Fatigue, 33, 164 Feces, 153, 164 Fenretinide, 12, 164 Ferritin, 84, 164 Fetus, 163, 164, 199 Fibrinogen, 164, 184, 197 Fibroblast Growth Factor, 53, 164 Fibroblasts, 5, 11, 164 Fibrosarcoma, 76, 164 Fibrosis, 164, 191 Fine-needle aspiration, 67, 164, 179 Fissure, 159, 164 Fixation, 158, 164, 192 Fluorescence, 9, 31, 67, 75, 165 Fold, 10, 17, 20, 43, 164, 165 Foramen, 155, 165, 183

207

Fossa, 154, 165 Fractionation, 42, 53, 68, 102, 106, 165 Free Radicals, 149, 165 Fungi, 5, 164, 165, 177, 199, 201 G Gamma knife, 31, 68, 69, 165 Gamma Rays, 165, 189 Ganciclovir, 20, 31, 52, 93, 165 Ganglia, 145, 165, 180, 183, 195 Gas, 152, 159, 165, 169, 176, 180, 188 Gastric, 115, 162, 165 Gastrin, 165, 169 Gastrointestinal, 153, 162, 165, 176, 195, 196, 198 Gastrointestinal tract, 153, 165, 198 Gene Amplification, 50, 54, 60, 64, 165 Gene Expression, 19, 23, 24, 26, 27, 29, 36, 45, 67, 75, 89, 112, 114, 115, 166 Gene Expression Profiling, 23, 89, 166 Gene Targeting, 47, 166 Gene Therapy, 12, 20, 21, 26, 31, 33, 35, 46, 47, 52, 73, 74, 117, 145, 166 Gene-modified, 5, 166 Genetic Code, 166, 181 Genetic testing, 166, 185 Genetics, 19, 21, 54, 58, 66, 68, 71, 81, 84, 113, 166, 178 Genomics, 22, 23, 32, 79, 166 Genotype, 24, 25, 36, 147, 166, 183 Germ Cells, 166, 176, 193 Gland, 158, 166, 175, 182, 184, 187, 192, 195, 197 Glial Fibrillary Acidic Protein, 57, 166 Glial tumors, 5, 8, 16, 166 Gliosarcoma, 5, 33, 167 Glucocorticoid, 159, 167, 186 Glucokinase, 167, 169 Glucose, 53, 61, 151, 167, 168, 169, 172, 183, 193 Glufosfamide, 64, 167 Glycine, 147, 167, 180, 192 Glycolysis, 36, 167 Glycoprotein, 149, 153, 163, 164, 167, 197, 198 Governing Board, 167, 186 Grade, 4, 10, 13, 19, 21, 23, 28, 33, 40, 42, 44, 50, 55, 98, 104, 112, 114, 167 Grading, 18, 33, 167 Graft, 77, 146, 167, 171 Graft Rejection, 167, 171 Grafting, 167, 171 Gram-negative, 167, 179

Granular Cell Tumor, 57, 167 Granule, 42, 159, 168, 191 Granulocyte, 4, 168 Growth factors, 11, 13, 36, 44, 112, 114, 168, 177 Guanine, 48, 83, 168, 188 H Habitual, 154, 168 Health Physics, 168, 174 Hematologic malignancies, 168, 174 Heme, 147, 168, 179, 186 Hemoglobin, 162, 168, 174, 186 Hemoglobin A, 168, 186 Hemoglobinopathies, 166, 168 Hemostasis, 168, 172 Hepatocellular, 14, 168 Hepatocellular carcinoma, 14, 168 Herbicide, 86, 168 Heredity, 165, 166, 168 Herpes, 20, 31, 35, 36, 43, 44, 52, 93, 168 Herpes Zoster, 168 Heterodimers, 39, 168, 172 Heterogeneity, 19, 71, 112, 114, 146, 169 Heterogenic, 169 Heterogenous, 29, 169 Heterotrophic, 165, 169 Hexokinase, 43, 169 Hippocampus, 70, 159, 169, 188, 195 Histocompatibility, 80, 169 Histology, 41, 169 Homologous, 23, 146, 166, 169, 188, 192, 196 Hormone, 45, 158, 162, 163, 165, 169, 172, 173, 176, 191, 197 Humoral, 38, 167, 169 Humour, 169 Hybrid, 155, 169 Hydrogen, 8, 145, 152, 153, 159, 163, 169, 174, 178, 180, 181, 183, 188 Hydrogen Peroxide, 8, 153, 169, 174 Hydrolysis, 155, 169, 185, 187 Hydrophobic, 40, 169 Hydroxyproline, 147, 156, 169 Hyperfractionation, 86, 169 Hyperplasia, 94, 170 Hypersensitivity, 146, 170, 192 Hypertrophy, 170 Hyperventilation, 57, 170 Hypnotic, 150, 170, 196 Hypoglycemic, 94, 170 Hypothermia, 83, 170 Hypoxia, 6, 7, 11, 12, 21, 27, 36, 43, 170

208

Glioblastoma Multiforme

Hypoxic, 6, 11, 21, 37, 94, 170 I Ifosfamide, 106, 170 Immune response, 4, 36, 38, 74, 146, 148, 158, 167, 170, 171, 172, 175, 192, 195, 199, 200 Immune Sera, 170 Immune system, 148, 150, 160, 170, 171, 175, 200 Immunization, 36, 170, 171, 192 Immunocompromised, 26, 170 Immunodeficiency, 40, 69, 145, 170 Immunoelectrophoresis, 149, 170 Immunogenic, 6, 80, 170 Immunoglobulin, 148, 170, 172, 178 Immunohistochemistry, 27, 90, 170 Immunologic, 5, 11, 114, 170, 189 Immunology, 38, 48, 58, 98, 146, 171 Immunosuppressive, 5, 158, 167, 170, 171 Immunosuppressive therapy, 171 Immunotherapy, 4, 6, 11, 38, 53, 58, 74, 77, 150, 171 Implant radiation, 171, 172, 173, 189, 201 Implantation, 31, 157, 171 In situ, 17, 74, 75, 171 In Situ Hybridization, 75, 171 Incision, 171, 173 Induction, 5, 6, 12, 29, 35, 40, 41, 44, 49, 75, 76, 171 Infarction, 158, 171, 177 Infection, 46, 145, 149, 150, 158, 161, 164, 168, 170, 171, 175, 181, 182, 195, 200 Inflammation, 149, 161, 164, 168, 171, 185 Infusion, 64, 71, 85, 171 Initiation, 4, 5, 171, 198 Inoperable, 89, 171 Inorganic, 155, 171 Insertional, 22, 171 Insulin, 23, 89, 98, 172 Insulin-dependent diabetes mellitus, 172 Insulin-like, 23, 89, 98, 172 Integrins, 45, 172 Interferon, 33, 63, 71, 73, 75, 80, 172 Interferon-alpha, 80, 172 Interleukin-1, 17, 47, 76, 172 Interleukin-13, 47, 172 Interleukin-2, 58, 77, 172 Intermediate Filaments, 22, 172 Internal radiation, 172, 173, 189, 201 Interstitial, 72, 77, 152, 163, 172, 173, 201 Intoxication, 173, 200

Intracellular, 29, 171, 172, 173, 176, 186, 191 Intracranial tumors, 17, 112, 114, 173 Intravenous, 31, 47, 93, 171, 173 Intrinsic, 35, 43, 75, 146, 150, 173 Invasive, 6, 12, 14, 19, 23, 25, 45, 47, 74, 173, 175 Iodine, 84, 173 Ion Channels, 149, 173 Ionization, 173 Ionizing, 43, 81, 99, 147, 161, 168, 173, 189 Ions, 145, 152, 153, 160, 169, 173 Irinotecan, 33, 173 Irradiation, 9, 27, 37, 43, 66, 76, 78, 83, 92, 98, 152, 173, 180, 201 Isoenzyme, 169, 173 K Karyotype, 57, 173 Kb, 50, 128, 173 Killer Cells, 103, 173 Kilobase, 25, 173 Kinetic, 173, 174 L Latency, 40, 174 Latent, 13, 44, 174, 186 Lesion, 174, 199 Lethal, 19, 43, 174 Leucine, 39, 174 Leukemia, 33, 46, 160, 166, 168, 174 Leukocytes, 150, 151, 162, 172, 174, 178, 198 Life cycle, 165, 174 Ligament, 174, 187 Ligands, 172, 174 Linear Energy Transfer, 37, 174 Linkages, 19, 168, 174 Lipid, 155, 172, 174, 181 Lipid Peroxidation, 174, 181 Lipophilic, 174, 185 Liposomes, 73, 174 Liver, 77, 93, 145, 150, 152, 158, 163, 164, 168, 169, 174, 186, 191 Liver scan, 174, 191 Localization, 4, 29, 49, 61, 78, 170, 174 Localized, 4, 19, 50, 78, 158, 165, 171, 174, 184, 199 Lomustine, 87, 102, 174 Loss of Heterozygosity, 25, 174 Luciferase, 12, 175 Lymph, 79, 94, 154, 161, 169, 175, 195 Lymph node, 79, 94, 154, 175

209

Lymphatic, 161, 171, 175, 177, 193, 194, 197 Lymphatic system, 175, 193, 194, 197 Lymphocyte, 145, 148, 172, 173, 175, 176 Lymphocyte Count, 145, 175 Lymphoid, 148, 175 Lymphokine, 53, 103, 175 Lymphoma, 33, 35, 46, 168, 175 M Macrophage, 4, 79, 94, 148, 172, 175 Magnetic Resonance Imaging, 7, 41, 79, 91, 175, 191 Magnetic Resonance Spectroscopy, 18, 87, 175 Major Histocompatibility Complex, 4, 80, 175 Malignancy, 14, 23, 24, 45, 50, 175 Malignant tumor, 14, 15, 24, 115, 176 Mammary, 176, 196 Matrix metalloproteinase, 26, 176 Maximum Tolerated Dose, 37, 160, 176 Measles Virus, 33, 94, 176 Mechlorethamine, 176, 186 Mediate, 13, 43, 47, 173, 176 Mediator, 6, 42, 43, 172, 176 Medical Records, 30, 176 MEDLINE, 129, 176 Medulloblastoma, 42, 63, 176 Meiosis, 39, 176, 196 Melanin, 176, 183, 199 Melanocytes, 176 Melanoma, 37, 74, 98, 103, 152, 176 Membrane Proteins, 174, 176 Meninges, 112, 114, 154, 176 Meningioma, 19, 71, 90, 112, 113, 176 Mental, iv, 3, 33, 128, 130, 154, 159, 164, 176, 188, 191 Mesenchymal, 162, 177 Meta-Analysis, 64, 177 Metabolite, 177, 184, 186 Metaphase, 25, 177 Metastasis, 4, 31, 55, 62, 75, 80, 93, 95, 176, 177 Metastasize, 8, 177, 192 Metastatic, 17, 30, 37, 40, 47, 57, 64, 67, 70, 80, 177, 192 Metastatic cancer, 47, 177 Methyltransferase, 83, 177 MI, 95, 143, 177 Microbe, 177, 197 Microbiology, 48, 98, 145, 177 Microfilaments, 172, 177

Microglia, 149, 177 Microorganism, 155, 177, 200 Microtubules, 39, 172, 177, 182 Migration, 16, 42, 45, 92, 94, 177 Mitochondrial Swelling, 177, 179 Mitogen-Activated Protein Kinase Kinases, 178 Mitogen-Activated Protein Kinases, 15, 112, 178 Mitosis, 39, 149, 178 Mitotic, 42, 112, 114, 163, 178, 196, 200 Modeling, 24, 35, 178 Modification, 5, 11, 75, 147, 178, 188 Molecular Probes, 31, 178 Monitor, 5, 11, 12, 26, 38, 153, 178, 180 Monoclonal, 18, 39, 47, 112, 113, 173, 178, 189, 201 Monoclonal antibodies, 18, 39, 47, 178 Monocytes, 172, 174, 178, 196 Mononuclear, 7, 178, 198 Morbillivirus, 176, 178 Morphological, 18, 112, 114, 161, 176, 179 Morphology, 18, 55, 58, 88, 99, 112, 114, 179 Motility, 16, 91, 179 Motion Sickness, 179 Mucins, 179 Mucositis, 179, 197 Multimodality treatment, 94, 179 Muscle Fibers, 146, 179 Mycoplasma, 5, 179 Myocardium, 177, 179 Myofibrils, 152, 179 Myoglobin, 179, 186 N Nausea, 115, 179 NCI, 1, 7, 10, 32, 127, 155, 179 Necrosis, 80, 82, 112, 114, 149, 166, 171, 177, 179 Needle biopsy, 55, 164, 179 Neoplasia, 25, 77, 179 Neoplasm, 83, 167, 179, 191, 199 Neoplastic, 4, 14, 42, 44, 175, 179, 181 Nerve, 146, 150, 155, 159, 176, 179, 180, 181, 190, 191, 195, 198 Nervous System, 16, 42, 50, 74, 82, 154, 176, 179, 180, 182, 195 Neural, 16, 44, 147, 169, 177, 180 Neurodegenerative Diseases, 16, 180 Neurologic, 134, 167, 180 Neurologist, 16, 180

210

Glioblastoma Multiforme

Neurology, 10, 40, 57, 61, 65, 69, 79, 81, 83, 87, 89, 94, 95, 98, 101, 103, 105, 107, 112, 113, 180 Neuronal, 10, 42, 180 Neurons, 42, 43, 112, 113, 159, 165, 180, 188, 195, 196 Neuropeptides, 152, 180 Neurotransmitter, 145, 147, 167, 173, 180, 191, 195 Neutron Capture Therapy, 56, 180 Neutrons, 56, 147, 152, 164, 173, 180, 189 Nimodipine, 107, 180 Nitrogen, 33, 146, 158, 163, 165, 180 Norepinephrine, 146, 180 Nuclear, 37, 49, 95, 112, 114, 150, 152, 161, 163, 165, 166, 179, 180, 199 Nuclei, 147, 160, 166, 175, 178, 180, 185, 188 Nucleic acid, 29, 113, 114, 158, 166, 171, 180, 181, 188 O Oligodendroglial, 181 Oligodendroglioma, 25, 30, 41, 114, 181 Oncogene, 22, 82, 181 Oncogenic, 22, 47, 69, 89, 172, 181, 188 Oncologist, 16, 181 Oncolysis, 181 Oncolytic, 17, 181 Opacity, 159, 181 Opportunistic Infections, 145, 181 Orbit, 181 Orbital, 94, 181 Organ Culture, 90, 181 Osteonecrosis, 54, 181 Overdose, 157, 181 Oxidation, 145, 149, 174, 181 Oxidative Stress, 8, 29, 181 Oxygenation, 6, 21, 84, 181 P Paclitaxel, 99, 102, 105, 106, 107, 182 Paediatric, 64, 74, 182 Palliative, 182, 196 Pancreas, 14, 145, 151, 172, 182, 198 Pancreatic, 14, 182 Pancreatic cancer, 14, 182 Pancreatic Juice, 15, 182 Parasitic, 150, 182 Partial remission, 182, 190 Particle, 182, 198 Patch, 157, 182 Pathogenesis, 21, 40, 182 Pathologic, 149, 151, 158, 170, 182

Pathologic Processes, 149, 182 Pathophysiology, 6, 51, 64, 182 Pelvic, 182, 187 Penicillamine, 35, 182 Penicillin, 148, 182, 199 Peptide, 31, 38, 49, 50, 147, 164, 182, 185, 187 Perfusion, 7, 77, 170, 182 Pericytes, 17, 182 Peripheral blood, 7, 172, 182 Peripheral Nervous System, 180, 182, 195 Peritoneal, 66, 183 Peritoneal Cavity, 66, 183 Peritoneum, 183 PH, 57, 60, 62, 63, 82, 86, 88, 103, 183 Pharmacodynamic, 7, 183 Pharmacokinetic, 12, 13, 33, 37, 105, 183 Pharmacologic, 183, 197 Phenotype, 16, 22, 28, 58, 63, 98, 103, 113, 183 Phenylalanine, 183, 199 Phorbol, 183, 187 Phorbol Esters, 183, 187 Phosphodiesterase, 83, 183 Phospholipids, 164, 183, 187 Phosphorus, 152, 183, 184 Phosphorylase, 152, 183 Phosphorylated, 20, 49, 178, 183 Phosphorylates, 183, 187 Phosphorylating, 20, 183 Phosphorylation, 44, 178, 184, 187 Photodynamic therapy, 8, 29, 184 Photosensitizer, 9, 29, 184 Photosensitizing Agents, 184, 185 Physiologic, 146, 151, 184, 190 Physiology, 7, 184 Pigment, 176, 179, 184 Pilot study, 35, 184 Pituitary Gland, 164, 184 Plants, 146, 150, 152, 155, 167, 168, 179, 180, 184, 198 Plasma, 37, 148, 149, 151, 154, 161, 164, 168, 179, 184, 192 Plasma Volume, 151, 184 Plasmid, 47, 166, 184, 199 Plasmin, 149, 184 Plasminogen, 90, 149, 184 Plasminogen Activators, 184 Platelets, 152, 184 Platinum, 155, 184 Pleomorphic, 93, 185 Pneumonia, 157, 185

211

Podophyllotoxin, 163, 185, 196 Poisoning, 173, 179, 185 Polychlorinated Biphenyls, 69, 185 Polymerase, 30, 185 Polymerase Chain Reaction, 30, 185 Polymorphic, 24, 25, 155, 159, 185 Polymorphism, 24, 185 Polypeptide, 147, 156, 162, 164, 179, 184, 185, 187, 201 Polyploidy, 71, 185 Polyposis, 82, 185 Polysaccharide, 148, 185 Pons, 152, 185 Porfimer sodium, 8, 185 Porphyrins, 67, 186 Posterior, 154, 155, 182, 186, 191 Postnatal, 186, 194 Postoperative, 28, 86, 186 Potassium, 17, 186 Potentiate, 28, 36, 186 Practicability, 186, 198 Practice Guidelines, 130, 186 Precancerous, 30, 154, 186 Preclinical, 4, 11, 31, 33, 35, 37, 40, 186 Precursor, 49, 155, 158, 160, 162, 180, 183, 184, 186, 199 Predisposition, 42, 186 Prednisone, 186 Premalignant, 186 Primitive neuroectodermal tumors, 166, 176, 186 Probe, 22, 113, 186 Procarbazine, 33, 52, 71, 102, 106, 186 Prodrug, 20, 186 Prognostic factor, 53, 73, 82, 187 Progression, 4, 9, 13, 19, 22, 23, 24, 25, 31, 33, 36, 38, 40, 42, 48, 68, 84, 113, 148, 187, 190 Progressive, 84, 93, 153, 159, 160, 163, 179, 180, 187, 199 Promoter, 20, 21, 43, 45, 187 Prophylaxis, 187, 199 Prospective study, 67, 187 Prostate, 42, 151, 164, 187, 198 Prostatic Neoplasms, 163, 187 Protein C, 62, 146, 147, 150, 164, 187 Protein Conformation, 147, 187 Protein Isoforms, 147, 187 Protein Kinase C, 92, 178, 187 Protein Kinases, 15, 114, 178, 187 Protein S, 37, 151, 166, 187, 191

Protein-Serine-Threonine Kinases, 178, 187 Proteolytic, 45, 156, 164, 184, 187 Protocol, 5, 10, 34, 82, 186, 187 Protons, 147, 169, 173, 175, 188, 189 Proto-Oncogene Proteins, 182, 188 Proto-Oncogene Proteins c-mos, 182, 188 Proto-Oncogenes, 13, 188 Psychic, 176, 188, 192 Psychoactive, 188, 200 Public Policy, 129, 188 Publishing, 51, 188 Pulmonary, 151, 170, 188, 199 Pulmonary Ventilation, 170, 188 Pulse, 178, 188 Purines, 188, 192 Pyramidal Cells, 159, 188 Pyrazoloacridine, 33, 188 Pyrimidines, 70, 188, 192 Q Quality of Life, 33, 34, 35, 39, 71, 188 Quiescent, 30, 188 R Race, 173, 177, 189 Radiation oncologist, 181, 189 Radioactive, 151, 169, 171, 172, 173, 174, 178, 180, 181, 189, 191, 196, 199, 201 Radiobiology, 174, 189 Radioimmunotherapy, 189 Radiolabeled, 39, 173, 189, 201 Radiological, 12, 189 Radiology, 19, 30, 73, 89, 102, 189 Radionuclide Imaging, 25, 189 Radiosensitization, 8, 29, 189 Radiosensitizers, 28, 70, 189 Randomized, 8, 13, 52, 87, 106, 160, 189 Randomized clinical trial, 52, 189 Reagent, 175, 190 Recombinant, 5, 33, 47, 63, 75, 112, 113, 190, 199 Recombination, 166, 190 Rectum, 156, 159, 165, 187, 190 Recur, 7, 190 Recurrence, 7, 9, 38, 55, 98, 190 Refer, 1, 156, 164, 165, 168, 174, 180, 189, 190, 197 Refraction, 190, 194 Refractory, 32, 60, 90, 190 Regeneration, 146, 164, 190 Regimen, 33, 46, 107, 155, 160, 190 Relapse, 50, 52, 81, 190 Remission, 103, 190

212

Glioblastoma Multiforme

Reoperation, 65, 190 Resected, 13, 18, 190 Resection, 8, 38, 39, 52, 67, 87, 115, 190 Residual disease, 12, 190 Respiration, 152, 157, 178, 190 Response rate, 33, 190 Retina, 155, 157, 190 Retinoid, 13, 191 Retinol, 13, 191 Retrospective, 52, 191 Retroviral vector, 166, 191 Retrovirus, 74, 191 Ribosome, 191, 198 Risk factor, 187, 191 S Salivary, 158, 182, 191, 195 Salivary glands, 158, 191 Sarcoma, 80, 186, 191, 193 Scans, 8, 191 Schizoid, 191, 200 Schizophrenia, 191, 200 Schizotypal Personality Disorder, 191, 200 Sclera, 155, 157, 191 Sclerosis, 89, 191 Screening, 31, 32, 112, 113, 155, 191 Second Messenger Systems, 191 Secondary tumor, 115, 177, 192 Secretion, 5, 90, 153, 162, 169, 172, 177, 179, 191, 192, 199 Sedimentation, 192, 198 Segregation, 66, 190, 192 Seizures, 167, 192, 194 Selective estrogen receptor modulator, 192, 196 Semen, 187, 192 Semisynthetic, 152, 163, 192, 196 Sensitization, 28, 192 Sequencing, 74, 185, 192 Serine, 44, 45, 178, 187, 188, 192 Serous, 161, 192 Serum, 13, 15, 36, 83, 84, 156, 170, 192, 198 Sex Characteristics, 146, 192 Shock, 65, 192, 198 Side effect, 30, 115, 121, 123, 146, 150, 158, 160, 192, 197 Signs and Symptoms, 190, 193 Skeleton, 193 Skull, 78, 181, 193, 194, 196 Small intestine, 160, 169, 193 Smooth muscle, 94, 152, 182, 193, 195 Social Environment, 188, 193 Sodium, 67, 123, 193

Soft tissue, 151, 164, 193 Soft tissue sarcoma, 164, 193 Solid tumor, 24, 31, 40, 44, 115, 148, 160, 174, 193 Soma, 188, 193 Somatic, 42, 146, 169, 176, 178, 182, 193, 196 Somatic cells, 176, 178, 193 Somnolence, 33, 193 Sorbitol, 169, 193 Specialist, 135, 193 Species, 146, 155, 162, 169, 173, 176, 177, 178, 179, 182, 189, 193, 198, 200 Specificity, 14, 19, 146, 193 Spectroscopic, 19, 175, 193 Spectrum, 46, 177, 194 Sperm, 155, 194, 198 Spinal cord, 16, 88, 91, 149, 150, 152, 154, 155, 157, 161, 162, 176, 179, 180, 182, 194, 195 Spleen, 93, 158, 175, 194 Sporadic, 50, 84, 180, 194 Squamous, 6, 50, 88, 162, 167, 194 Squamous cell carcinoma, 88, 162, 168, 194 Squamous cells, 167, 194 Staging, 191, 194 Statistically significant, 33, 194 Status Epilepticus, 89, 194 Steady state, 13, 194 Stem Cells, 16, 22, 163, 194 Stereotactic, 31, 68, 80, 91, 99, 103, 107, 194 Stereotactic biopsy, 80, 194 Stereotactic radiosurgery, 68, 91, 99, 103, 107, 194 Sterility, 11, 158, 195 Stimulus, 11, 160, 173, 174, 195, 196 Stomach, 145, 159, 165, 169, 179, 183, 193, 194, 195 Strand, 185, 195 Stress, 29, 84, 94, 178, 179, 181, 186, 195 Subacute, 171, 195 Subclinical, 171, 192, 195 Subcutaneous, 4, 12, 14, 20, 160, 195 Subiculum, 169, 195 Submaxillary, 162, 195 Substance P, 177, 192, 195 Substrate, 48, 50, 195 Suppression, 11, 13, 26, 42, 75, 76, 115, 195 Suppressive, 4, 195 Supratentorial, 6, 19, 56, 72, 74, 84, 88, 105, 195

213

Survival Rate, 44, 195 Sympathetic Nervous System, 180, 195 Symphysis, 154, 187, 195 Symptomatic, 39, 195 Synapse, 146, 195, 198 Synaptic, 146, 180, 195 Synergistic, 17, 62, 196 Synthetic retinoid, 12, 164, 196 Systemic, 17, 20, 31, 38, 151, 162, 171, 173, 189, 196, 198, 201 T Tamoxifen, 71, 192, 196 Tarsus, 54, 196 Technetium, 62, 196 Telomerase, 10, 74, 75, 196 Temozolomide, 52, 59, 67, 71, 81, 85, 90, 92, 196 Temporal, 169, 196 Teniposide, 102, 196 Thalidomide, 59, 90, 196 Therapeutics, 27, 32, 35, 41, 47, 49, 122, 196 Thermal, 152, 180, 185, 196 Thiotepa, 107, 196 Threonine, 178, 187, 188, 192, 196 Threshold, 16, 196 Thrombin, 164, 187, 197 Thrombolytic, 184, 197 Thrombomodulin, 187, 197 Thrombosis, 172, 187, 197 Thymidine, 20, 31, 52, 93, 152, 197 Thymidine Kinase, 20, 31, 52, 93, 197 Thymus, 170, 175, 197 Thyroid, 173, 197, 199 Tolerance, 6, 43, 145, 197 Tomography, 81, 101, 175, 197 Tone, 157, 197 Tonic, 157, 197 Tooth Preparation, 145, 197 Topical, 169, 197 Topoisomerase inhibitors, 147, 173, 197 Topotecan, 85, 93, 197 Toxic, iv, 28, 33, 48, 146, 150, 158, 159, 161, 163, 185, 196, 197, 198 Toxicity, 6, 20, 31, 38, 39, 40, 44, 45, 46, 48, 50, 62, 66, 102, 107, 160, 176, 197 Toxicology, 130, 197 Toxin, 62, 75, 112, 113, 197 Trace element, 151, 198 Transcriptase, 191, 196, 198 Transcription Factors, 26, 44, 49, 198

Transduction, 14, 15, 16, 26, 35, 40, 42, 43, 73, 112, 114, 198 Transfection, 15, 35, 151, 166, 198 Transfer Factor, 170, 198 Translating, 17, 198 Translation, 32, 43, 147, 198 Translational, 10, 26, 32, 35, 198 Transmitter, 145, 149, 173, 176, 180, 198 Transplantation, 12, 16, 72, 77, 170, 175, 198 Trauma, 179, 198 Treatment Outcome, 98, 103, 198 Tropism, 44, 198 Tubulin, 39, 177, 198 Tumor marker, 14, 19, 27, 151, 198 Tumor Necrosis Factor, 196, 198 Tumor suppressor gene, 4, 7, 13, 80, 174, 199 Tumorigenic, 4, 42, 199 Tumour, 50, 84, 181, 199 Tyrosine, 4, 13, 16, 50, 58, 76, 199 U Ulcer, 199 Ulceration, 115, 199 Uracil, 188, 199 Uranium, 196, 199 Urethra, 187, 199 Urine, 151, 162, 199 Uterus, 154, 161, 199 V Vaccination, 4, 38, 199 Vaccines, 199, 200 Vacuoles, 161, 199 Vagina, 154, 199 Valine, 182, 199 Vascular, 35, 51, 54, 64, 84, 94, 112, 114, 155, 161, 171, 184, 199 Vascular endothelial growth factor, 51, 54, 64, 84, 199 Vector, 20, 31, 36, 43, 45, 49, 93, 172, 198, 199 Vein, 43, 173, 180, 199 Venous, 187, 199 Ventricle, 169, 188, 199 Venules, 151, 152, 161, 200 Verapamil, 107, 200 Vertebrae, 194, 200 Vertebral, 62, 95, 200 Vesicular, 18, 168, 200 Veterinary Medicine, 129, 200 Vinblastine, 198, 200 Vinca Alkaloids, 200

214

Glioblastoma Multiforme

Vincristine, 33, 102, 106, 186, 198, 200 Viral, 17, 20, 26, 31, 46, 47, 161, 181, 188, 191, 198, 199, 200 Viral vector, 20, 31, 200 Virulence, 150, 197, 200 Virus, 17, 20, 31, 33, 36, 43, 46, 52, 65, 69, 89, 93, 145, 150, 161, 172, 191, 198, 200 Viscera, 193, 200 Vitro, 11, 12, 14, 16, 20, 22, 23, 24, 25, 26, 28, 29, 32, 35, 43, 44, 45, 48, 50, 61, 71, 75, 87, 90, 166, 171, 185, 200 Vivo, 9, 11, 16, 18, 22, 23, 24, 25, 26, 28, 30, 32, 40, 43, 44, 45, 46, 47, 48, 49, 50, 62, 73, 87, 90, 166, 171, 200

W War, 47, 176, 200 White blood cell, 145, 148, 168, 174, 175, 200 Withdrawal, 63, 200 Wound Healing, 164, 172, 176, 200 X Xenograft, 50, 148, 200 X-ray, 14, 59, 157, 165, 173, 180, 189, 191, 194, 201 X-ray therapy, 173, 201 Y Yeasts, 165, 183, 201 Z Zymogen, 187, 201

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216

Glioblastoma Multiforme