Acute Myelogenous Leukemia - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

ACUTE MYELOGENOUS LEUKEMIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FE...

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ACUTE

MYELOGENOUS LEUKEMIA 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., 1960Acute Myelogenous Leukemia: 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: 0-497-00020-2 1. Acute Myelogenous Leukemia-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 acute myelogenous leukemia. 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 ACUTE MYELOGENOUS LEUKEMIA .......................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Acute Myelogenous Leukemia ...................................................... 4 E-Journals: PubMed Central ....................................................................................................... 62 The National Library of Medicine: PubMed ................................................................................ 65 CHAPTER 2. NUTRITION AND ACUTE MYELOGENOUS LEUKEMIA .............................................. 117 Overview.................................................................................................................................... 117 Finding Nutrition Studies on Acute Myelogenous Leukemia ................................................... 117 Federal Resources on Nutrition ................................................................................................. 123 Additional Web Resources ......................................................................................................... 124 CHAPTER 3. ALTERNATIVE MEDICINE AND ACUTE MYELOGENOUS LEUKEMIA ........................ 125 Overview.................................................................................................................................... 125 National Center for Complementary and Alternative Medicine................................................ 125 Additional Web Resources ......................................................................................................... 139 General References ..................................................................................................................... 140 CHAPTER 4. DISSERTATIONS ON ACUTE MYELOGENOUS LEUKEMIA.......................................... 141 Overview.................................................................................................................................... 141 Dissertations on Acute Myelogenous Leukemia ........................................................................ 141 Keeping Current ........................................................................................................................ 142 CHAPTER 5. PATENTS ON ACUTE MYELOGENOUS LEUKEMIA .................................................... 143 Overview.................................................................................................................................... 143 Patents on Acute Myelogenous Leukemia ................................................................................. 143 Patent Applications on Acute Myelogenous Leukemia.............................................................. 145 Keeping Current ........................................................................................................................ 151 CHAPTER 6. BOOKS ON ACUTE MYELOGENOUS LEUKEMIA ........................................................ 153 Overview.................................................................................................................................... 153 Chapters on Acute Myelogenous Leukemia ............................................................................... 153 CHAPTER 7. PERIODICALS AND NEWS ON ACUTE MYELOGENOUS LEUKEMIA .......................... 155 Overview.................................................................................................................................... 155 News Services and Press Releases.............................................................................................. 155 Academic Periodicals covering Acute Myelogenous Leukemia.................................................. 157 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 159 Overview.................................................................................................................................... 159 U.S. Pharmacopeia..................................................................................................................... 159 Commercial Databases ............................................................................................................... 160 Researching Orphan Drugs ....................................................................................................... 160 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 165 Overview.................................................................................................................................... 165 NIH Guidelines.......................................................................................................................... 165 NIH Databases........................................................................................................................... 167 Other Commercial Databases..................................................................................................... 169 The Genome Project and Acute Myelogenous Leukemia ........................................................... 169 APPENDIX B. PATIENT RESOURCES ............................................................................................... 173 Overview.................................................................................................................................... 173 Patient Guideline Sources.......................................................................................................... 173 Finding Associations.................................................................................................................. 175 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 177 Overview.................................................................................................................................... 177 Preparation................................................................................................................................. 177

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Finding a Local Medical Library................................................................................................ 177 Medical Libraries in the U.S. and Canada ................................................................................. 177 ONLINE GLOSSARIES................................................................................................................ 183 Online Dictionary Directories ................................................................................................... 186 ACUTE MYELOGENOUS LEUKEMIA DICTIONARY......................................................... 187 INDEX .............................................................................................................................................. 247

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with acute myelogenous leukemia 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 acute myelogenous leukemia, 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 acute myelogenous leukemia, 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 acute myelogenous leukemia. Abundant guidance is given on how to obtain free-ofcharge 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 acute myelogenous leukemia, 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 acute myelogenous leukemia. 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. LEUKEMIA

STUDIES

ON

ACUTE

MYELOGENOUS

Overview In this chapter, we will show you how to locate peer-reviewed references and studies on acute myelogenous leukemia.

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

Osteonecrosis of the Maxilla as a Complication to Chemotherapy: A Case Report Source: SCD. Special Care in Dentistry. 22(4): 142-146. July-August, 2002. Contact: Available from Special Care Dentistry. 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2660. Summary: Numerous oral complications have been documented as a consequence of chemotherapy for the treatment of cancer. One not so well documented consequence of this treatment is avascular necrosis or osteonecrosis (bone tissue death) of the underlying bone. In this case report, the authors discuss osteonecrosis of the maxilla (upper jaw) in a 48 year old female patient who was treated for acute myelogenous

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Acute Myelogenous Leukemia

leukemia. The patient had successfully completed both induction and consolidation chemotherapy without steroid administration. The authors review the possible causes of the osteonecrosis and the difficulties in diagnosis in this case. The authors conclude that early recognition of potential sources of infection is important when dealing with immunocompromised patients. Meticulous oral home care and the need for preventing oral complications throughout treatment needs to be stressed. Dentists also should be part of the health care team for all patients undergoing chemotherapy to carefully monitor oral health regardless of whether the patients report any symptoms. 9 figures. 24 references. •

Oral Manifestations of Acute Myelomonocytic Leulemia: A Case Report and Review of the Classification Source: Journal of Periodontology. 73(6): 664-668. June 2002. Contact: Available from American Academy of Periodontology. Suite 800, 737 North Michigan Avenue, Chicago, IL 60611-2690. (312) 573-3220. Fax (312) 573-3225. Summary: Oral signs and symptoms may indicate a serious underlying systemic disease. The most frequently observed oral findings of leukemia are mucosal bleeding and ulceration, petechiae, and gingival hyperplasia (overgrowth of the gums). This case report describes a 53 year old male who presented with gingival enlargement and bleeding, fatigue, and recent weight loss as initial manifestations of acute myelomonocytic leukemia. In this case patient, a gingival biopsy was performed, revealing the presence of a hypercellular infiltrate of atypical myeloid and monocytic cells. Flow cystometry results confirmed that the infiltrate was of a myelomonocytic origin, and a diagnosis of acute myelomonocytic leukemia was rendered. The patient responded well to a chemotherapeutic induction regimen, with regression of gingival enlargement and remission of disease. The patient continued with consolidation chemotherapy and an autologous bone marrow transplant, but eventually died 22 months after initial diagnosis. The authors stress that oral health care professionals, especially periodontists, must recognize that gingival enlargement may represent an initial manifestation of an underlying systemic disease. Acute myelogenous leukemia is a hematological disorder with a predilection for gingival involvement. 3 figures. 24 references.

Federally Funded Research on Acute Myelogenous Leukemia The U.S. Government supports a variety of research studies relating to acute myelogenous leukemia. 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 acute myelogenous leukemia.

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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).

Studies

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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 acute myelogenous leukemia. The following is typical of the type of information found when searching the CRISP database for acute myelogenous leukemia: •

Project Title: A MOUSE MODEL FOR HUMAN GASTROINTESTINAL STROMAL TUMOR Principal Investigator & Institution: Besmer, Peter; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): The overall objective of this proposal is to investigate: 1) mechanisms leading to the formation of gastrointestinal stromal tumor (GIST) and 2) the consequences of therapeutic intervention, by using a mouse model we have recently developed for this disease. The Kit receptor tyrosine kinase encoded at the murine W locus. Kit loss of function mutations result in major deficiencies in several major cell systems during embryogenesis and in the postnatal animal including gametogenesis, hematopoiesis, melanogenesis, and interstitial cells of Cajal (ICC) in the gastrointestinal tract. Normal Kit receptor mediated functions include cell proliferation, cell survival, cell adhesion, cell migration, secretory responses, and differentiation. In addition, in human neoplasia oncogenic activation of Kit is thought to have roles in gastro intestinal stromal tumors (GIST), mastocytosis/mast cell leukemia, acute myelogenous leukemia, and germ cell tumors. Activating Kit mutations are found in all of these neoplasms. Based on the finding of familial cases of GIST syndrome we have developed a mouse model for familial GIST syndrome by targeted mutation of the Kit receptor tyrosine kinase gene using a knock-in strategy. We now propose to use this mouse model to investigate mechanism of the development of GIST, to study the consequences of therapeutic intervention in mice with GIST and to elucidate mechanisms of signaling by oncogenetically activated Kit receptors. We furthermore propose to investigate the effect of the KitV558del mutation on the development of ICC networks during embryonic development and on embryonic heart development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ABERRANT LARG AND RHOA ACTIVATION IN HUMAN LEUKEMIAS Principal Investigator & Institution: Der, Channing J.; Professor; Pharmacology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (Adapted from the investigator's abstract) The leukemia-associated Rho guanine nucleotide exchange factor (LARG) was recently identified as a fusion partner of the mixed lineage leukemia (MLL) protein in acute myeloid leukemia. LARG is a novel member of the rapidly expanding Dbl family of oncoproteins that promote malignant transformation by activating Ras-related Rho family GTPases. Like other Dbl family proteins, LARG contains a Dbl homology (DH) domain that functions as a guanine nucleotide exchange factor and activator of Rho GTPases. The DH domain is followed by a pleckstrin homology (PH) domain that presumably regulates DH domain function. LARG also contains a regulator of G-protein signaling (RGS) domain, suggesting that it may link G protein-coupled receptor signaling to Rho GTPases. Our

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preliminary studies determined that LARG is an activator of RhoA and can cause transformation of NIH 3T3 mouse fibroblasts. We have proposed four specific aims to perform detailed structure-function analyses of LARG. Specific aim 1 will determine the roles of the DH and PH domains in mediating LARG activation of RhoA. In particular, whether the PH domain regulates DH domain function in a phosphatidylinositol 3kinase dependent fashion will be determined. Specific aim 2 will evaluate the role of the RGS domain in linking LARG with G protein coupled receptor signaling. This includes a determination of which heterotrimeric G alpha subunit(s) is regulated by the RGS domain and which G alpha subunit(s) in turn regulates LARG DH domain activation. Specific aim 3 will determine if the tumor-associated MLL-LARG fusion protein is an aberrantly activated form of LARG and can promote growth transformation of epithelial cells and lL-3 independent growth of 32D myeloid cells. Finally, Specific Aim 4 will involve a determination of the crystal structure of the DH/PH domains of LARG complexed with its GTPase target, RhoA, and the determination of the structural basis for DH domain recognition of GTPases. Although the number of Dbl family oncoproteins continue to increase at a rapid pace, to date, LARG is the only functional Dbl protein found to be mutated in human cancer. Our studies will provide a comprehensive, structural, biochemical, and biological analysis of LARG function and assess a role for aberrant LARG activation of RhoA in AML development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ARP--GENE TARGET OF THE ALL1 GENE IN ACUTE LEUKEMIAS Principal Investigator & Institution: Croce, Carlo M.; Director Kimmel Cancer Center; Kimmel Cancer Center; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2003 Summary: The ALL-1 gene, the human homologue of the Drosophila trithorax gene, is directly involved in human acute leukemias associated with abnormalities at chromosome 11q23. Using the differential display method, we have isolated genes which are downregulated or upregulated in ALL-1 double knockout mouse embryonal stem (ES) cells including one, designated ARP, which is a novel homeotic gene containing a short motif shared with several homeobox genes. Utilizing a bacteriallysynthesized ALL-1 polypeptide encompassing the AT-hook motifs, we identified a 0.5 kb ARP DNA-fragment which preferentially bound to the polypeptide. Within this DNA, a region of -100 bp was protected by the polypeptide from digestion with ExoIII and DNase I. Whole mount in situ hybridization to early mouse embryos of 9.5-10.5 days indicated a complex pattern of ARP expression, spatially overlapping with the expression of ALL-1. These results suggest that ARP is upregulated by the ALL-1 protein, possibly through direct interaction with an upstream DNA sequence of the ARP gene. Expression of ARP is shut off in acute leukemias carrying a t(4;11) or a t(9;11) chromosome translocation suggesting that the 11q23 abnormalities create chimeric products with a dominant negative effect. We intend to identify and characterize gene targets of ALL-1 and to determine their role in hematopoietic differentiation, in embryonal development and in leukemogenesis. Acute lymphoblastic and acute myelogenous leukemias will be investigated for the expression, rearrangements and mutations of ALL-1 target genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

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Project Title: ASSESSMENT OF NOVEL MOLECULAR MARKERS IN AML Principal Investigator & Institution: Gilliland, Gary; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 13-MAY-2003; Project End 31-MAR-2009 Summary: (provided by applicant): Significant advances have been made in the classification and treatment strategies of acute myeloid leukemia (AML) based on karyotype (Mrozek et al., 2000). However, it is clear that cytogenetic translocations, inversions and deletions result in changes at the genetic level which in turn are responsible, at least in part, for malignant transformation (Bloomfield and Caligiuri, 2001). Indeed, consistent molecular abnormalities in the absence of an abnormal karyotype are now starting to emerge in AML with some early evidence for an association with clinical outcome. However, some of these prognostic results, including our own, have been inconsistent. This is likely due to inclusion of factors with confounding prognostic significance, such as age, cytogenetics and variations in treatment within each study. In this proposal, we wish to assess the frequency and predictive value of novel molecular abnormalities in adult AML patients that are enrolled in CALGB treatment protocols (e.g., CALGB 19808 and 10201) and are relatively homogeneous with regard to other important prognostic factors such as cytogenetics, age and treatment. We hypothesize that consistent molecular defects, like certain karyotypes, can be predictive of clinical outcome, can ultimately result in further risk stratification for AML treatment, and can lend insight into treatment approaches for patients with AML. The ultimate goal of the current study is to identify those patients for whom standard therapy will likely result in cure and those patients for whom standard therapy will likely fail, so that therapy can be tailored according to risk, as is currently being done within the CALGB for core binding factor-associated AML. This is a six-year proposal designed to perform definitive analyses on selected pilot studies. The work proposed for CALGB 20202 (which is Project 1 of this LCSC application) follow smaller pilot CALGB studies that are performed and funded by a multitude of investigators using materials from the CALGB Leukemia Tissue Bank (LTB), CALGB 9665. Once these smaller pilot studies are completed and it is determined that they merit further definitive validation, the mechanism described in the current Project 1 will be utilized. As such, this proposal will not attempt to define all the specific analyses to be carried out over the entire six-year funding period, but rather will detail two studies that are currently planned, and provide evidence for the mechanism by which additional studies will be formulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BENZENE METABOLITES AND HEMATOTOXICITY Principal Investigator & Institution: Monks, Terrence J.; Professor and Chair; Div/Pharmoacology & Toxicology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: (Adapted from applicant's abstract): Benzene, a major industrial chemical and environmental pollutant, causes a variety of hematological disorders in man, including aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia. While it is clear that benzene must be metabolized to cause its acute hematotoxic effects, no single metabolite of benzene reproduces these effects in vivo. Coadministration of hydroquinone (HQ) and phenol (PHE), however, does lead to bone marrow suppression in rodents. A pharmacokinetic interaction between these two

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benzene metabolites results in increased concentrations of both metabolites in bone marrow. Peroxidase and/or phenoxy-radical mediated oxidation of HQ then initiates redox cycling and formation of the reactive electrophile, 1,4-benzoquinone, which is considered the ultimate hematotoxic metabolite of benzene. However, 1,4-benzoquinone readily undergoes glutathione (GSH) conjugation to form 2-(glutathion-Syl)hydroquinone, 2,5-bis-(glutathion-S-yl)hydroquinone, 2,6-bis-(glutathion-Syl)hydroquinone, and 2,3,5-tris-(glutathion-S-yl)hydroquinone. Preliminary data indicate that these GSH conjugates are present in the bone marrow of rats and mice following coadministration of hydroquinone and phenol. Moreover, the majority of HQGSH conjugates present in bone marrow are formed in situ and are metabolized to more reactive thiol conjugates via a previously unidentified mercapturic acid pathway. Because these quinol-thioether metabolites have enhanced capability to both redox cycle and arylate tissue macromolecules, we hypothesize that quinol-thioether metabolites contribute to benzene-mediated hematotoxicity and that the mechanism(s) likely involve the production of reactive oxygen species and/or interaction with proteins that specifically recognize GSH/cysteine and GSH/cysteine containing molecules. Such metabolite specific interactions interfere with growth- and differentiation-related signaling. We therefore propose to (i) assess the acute hematotoxicity of HQ-GSH conjugates in rodent hematopoietic tissue, (ii) determine changes in the production and/or function of hematopoietic growth factors in response to HQ-GSH conjugates, (iii) test the hypothesis that metabolite-induced changes in gamma-glutamyl transpeptidase activity (GGT), dipeptidase activity, cysteine transport, and GSH concentrations, precipitate sphingolipid turnover, the generation of ceramide and the induction of apoptosis, and (iv) test the hypothesis that specific proteins involved in the synthesis (GST), transport (GS-X pump), and metabolism (GGT, dipeptidases) of the peptidyl leukotrienes are targets of HQ-GSH conjugates and interfere with granulocytic cell differentiation. Because benzene reduces the number of myeloid stem cells in bone marrow and induces incomplete granulocytic differentiation, our studies will provide a comprehensive understanding of the mechanisms by which reactive polyphenolic metabolites of benzene cause perturbations in growth- and differentiation-related signaling and how such changes culminate in benzene-mediated hematotoxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BENZODIAZEPINE RECEPTOR AND DRUG RESISTANCE IN AML Principal Investigator & Institution: Banker, Deborah E.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2004 Summary: We are investigating molecular bases of drug resistance as markers of clinical outcome in acute myeloid leukemia (AML) and testing various drug-sensitizing strategies in hopes of improving cure rates for patients with this disease. Relevant chemotherapeutics induce apoptosis and leukemic blasts become drug resistant by downregulating apoptotic responses to these drugs. As a result of anti-apoptotic activities, expression of Bcl-2 family proteins is associated with failure to achieve remission, with short disease-free survival, and with drug-resistant relapse in AML. Bcl2 proteins are constituents of mitochondrial pore complexes (PTPC) where they block apoptosis by antagonizing mitochondrial pore dissolution that otherwise occurs after lytotoxic treatments. Like Bcl-2, peripheral benzodiazepine receptors (pBzR) reside in PTPC of normal and leukemic blood cells and can protect transfected leukemia cells from apoptosis. However, the association of pBzR expression with clinical outcome has not been directly tested. If high pBzR expression predicts clinical failures in AML, pBzR

Studies

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would be a rational target for molecular anti-leukemia therapies. PK11195 is a highaffinity pBzR antagonist that can block the PTPC protection afforded by Bcl-2 proteins, and can thereby overcome drug resistance. However, whether pBzR or Bcl-2 expresson levels determine the efficacy of PK11195 is unknown. We propose laboratory analyses that will determine the variability of BzR expression in a large number of cell samples collected from AML patients in IRB-approved clinical trials from which complete clinical data is available. We will use standard statistical analyses to determine whether pBzR is an independent prognostic marker in AML. We also propose laboratory analyses of PK11195 efficacy in primary AML cell samples treated with different relevant drugs and in isogenic cell lines over-expressing different anti-apoptotic proteins. NOD/SCID mice will be used as an in vivo model to further test PK11195 efficacy in sensitizing engrafted AML cells. In vitro analyses of normal bone marrow samples and of non-leukemia cells in engrafted mice will examine possible PK11195 toxicities: Data collected in these studies will improve our understanding of the molecular bases of drug resistance in AML. Furthermore, if drug-sensitizing by PK11195 is documented and low toxicity is confirmed in these experiments, novel treatment strategies that include PK11195 will be warranted for AML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMICAL STRATEGIES TO INCREASE LEUKEMIA RESPONSE Principal Investigator & Institution: Gandhi, Varsha; Associate Professor; Clinical Investigation; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 15-SEP-1992; Project End 31-JUL-2006 Summary: (provided by applicant): This proposal is an extension of CA57629 that has been focused on understanding the metabolism, mechanism of action, and interaction of nucleoside analogs. With the success rate of analogs in leukemias, several laboratories including ours have investigated the mechanisms of cell death by these agents. The steps include formation of triphosphate of the analog, incorporation into replicating DNA, inhibition of ribonucleotide reductase (with newer analogs) and finally inhibition of DNA synthesis. Continued inhibition of DNA synthesis proceeds to cell death through apoptosis. When tested in cell lines, which are actively cycling and replicating DNA, such scenario seems to be in place. However, when one tries to validate this process during therapy, the outcome is conflicting and intriguing. The biology of leukemia cells in the body is very different from cell lines in culture. Leukemia cells in peripheral blood are generally non- or slow- cycling and with a very small percent of cells in S-phase (0-5%). Nonetheless after 5-days of effective nucleoside analog therapy, there is a massive cytoreduction (1 to 3-log decrease). Our hypothesis is built around these premises to suggest that in addition to conventional S-phase mediated pathway, there may he additional pathways that result in non-S-phase cell death during therapy. To test this hypothesis, we want to pursue three specific aims that are focused toward different mode of cell death by analogs. First, we plan to define the elements of cell death caused by conventional DNA synthesis inhibition pathway during therapy. Using nelarabine and clofarabine, two of the most successful new nucleoside analogs in the clinic, we plan to investigate the role of cellular pharmacokinetics and cellular pharmacodynamics in cell death. These parameters will be compared with clinical response to these therapies. Second, we plan to identify mitochondria induced cell death of leukemia cells during therapy. Nucleoside analogs may affect mitochondria directly and/or indirectly to induce cell death in circulating leukemia cells during therapy. Direct effect such as mitochondrial respiratory function involving ATP synthase,

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adenosine nucleotide translocator (ANT), and early decrease in mitochondnal membrane potential will be accessed to elucidate the role of mitochondria induced apoptosis. Indirect effect will include release of cytochrome c, and late effect on membrane potential. Finally, we will investigate the role of receptor-mediated cell death of leukemia cells during therapy. Following our lead in cell lines that analog incorporation results in induction of fas ligand followed by fas-mediated cell death of non-Sphase population, we plan to pursue the role of fas in cell death during therapy. We feel that knowledge gained through these aims will assist us in designing optimal therapy of leukemia with nucleoside analogs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BROAD SPECTRUM MDR MODULATION IN AML Principal Investigator & Institution: Baer, Maria R.; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2003; Project Start 10-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): Multidrug resistance (MDR) is a major cause of treatment failure in acute myeloid leukemia (AML). MDR is frequently associated with energy-dependent drug efflux, and efflux may be blocked by competitive inhibition with non-cytotoxic substrates, termed MDR modulators. Pharmacological modulation of MDRis effective in laboratory models, but clinical application has been disappointing. Trials of pharmacological modulation of MDR in AML have targeted P-glycoprotein (Pgp), the best-characterized MDR-associated transport protein, but additional transport proteins, including muitidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP), are also likely to contribute to the clinical MDR phenotype. Pharmacological MDR modulation also promotes apoptosis independently of drug efflux, but this effect remains largely unexplored. The overall goal of this proposal is to develop clinical MDR modulation approaches in AML which take into account both the multiple efflux proteins expressed in AML cells and the drug efflux-independent effects of modulators. This requires determining the relevance of expression and function of MRP-1 and BCRP, in addition to Pgp, in AML and the spectrum of activity of available clinically applicable modulators. The studies will utilize the existing Cancer and Leukemia Group B (CALGB) repository of pre-treatment samples from patients > 60 years old with AML occurring de novo and following antecedent myelodysplastic syndromes, a population with a high incidence of clinical MDR, treated on a single protocol, CALGB9720. The specific aims are: 1. To determine the incidence and clinical significance of Pgp, MRP-1 and BCRP expression and function in an AML patient population with a high incidence of clinical drug resistance; 2. To compare the effects of diverse available clinically applicable modulators, including PSC-833, cyclosporine A, Biricodar (VX-710), VX-853, the fumitremorgin C analogue KO143, and the novel taxane-derived agents IDN5109 and tRA96023, on drug retention in AML cells that have been characterized with respect to Pgp, MRP-1 and BCRP expression and function; 3. To compare the drug transport-independent effects of PSC-833, cyclosporineA, biricodar, VX-853, KO143, IDN5109 and tRA96023, onAML cell survival, measured by the apoptotic response. The study is expected to provide essential information for the design of future clinical trials of broad-spectrum MDR modulation in AML and other malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CELL CYCLE REGULATION AND LEUKEMOGENESIS BY CBFBSMMHC Principal Investigator & Institution: Friedman, Alan D.; Associate Professor; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The AML1 or CBFbeta subunits of Core Binding Factor are mutated or translocated in 30% of acute myeloid leukemia (AML) cases, lnv(16) encodes CBFbeta-SMMHC, linking CBFbeta to Smooth Muscle Myosin Heavy Chain. Inhibition of CBF blocks differentiation and slows G1 to S cell cycle progression. Mutations, which stimulate G1 may prevent cell cycle inhibition by CBF oncoproteins and potentiate their ability to impede differentiation. Aim 1: To identify the regulatory pathway responsible for variation in AML1 expression during the cell cycle and to determine whether AML1 regulates the cell cycle in normal progenitors. The effect of expressing an siRNA from a retroviral vector in normal or AML1(+/-) progenitors on cell cycle kinetics will be assessed. Endogenous AML1 levels increase sharply as 32D c13 cells enters S, and this is also observed with exogenous AML1, implicating regulated protein stability. The role of cdks and other kinases, protein:protein interaction, and ubiquitination in this process will be determined. Aim 2: To determine whether CBFbeta-SMMHC and loss of p15INK4b cooperate to induce AML, whether loss of p15 specifically affects myeloid progenitor proliferation, and whether lack of p15 prevents cell cycle inhibition from reduced AML1 activity. CBFbeta-SMMHC cooperates with loss of p16p19 to induce lymphoid leukemias in mice. The p15 promoter is inactivated by methylation in 80% of AMLs, whereas p16p19 abnormalities are rare. Marrow from C57BL/6 p15 (-/-) mice will be transduced with CBFbeta-SMMHC and transplanted. The cell cycle characteristics of myeloid, lymphoid, and erythroid progenitors from p15 (+/+), (+/-), and (-/-) mice will be compared. The effect of AML1 siRNA and of CBFbeta-SMMHC on p15 (-/-) progenitor cell cycle kinetics will be assessed. Aim 3: To determine whether the CBFbeta-SMMHC Assembly Competence Domain is required for transformation, to identify residues critical for ACD function, and to determine their role in corepressor binding. Deletion of a 28 residue segment, the ACD, near the Cterminus of CBFbeta-SMMHC prevents multimerization, inhibition of AML1 transactivation, and inhibition of cell proliferation. We propose to evaluate this deletion in the AML model developed in Aim 2, to identify point mutations in the ACD which prevent multimerization, to assess their effect on AML1 transactivation and on proliferation, and to determine whether they bind mSin3a or HDAC8, as does CBFbetaSMMHC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHARACTERIZATION OF HUMAN LEUKEMIC STEM CELLS Principal Investigator & Institution: Bonnet, Dominique A.; Assistant Professor/Chief; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Understanding the processes that regulate the developmental program of normal stem cells and how aberrations in this program initiate leukemic proliferation remain a major challenge in biology. Progress to address these major questions in the human hematopoietic system has been hampered, until recently, by the lack of in vivo assays for normal and leukemic stem cells. The only way to conclusively assay stem cells is to follow their repopulating capacity. The recent development of methods to transplant human hematopoietic cells into immune-deficient mice provides an

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important approach to characterize stem cells and to develop animal models for hematopoietic diseases including leukemia. The development of an in vivo model that replicates many aspects of human AML and allows the identification of a novel leukemic stem cell (termed the SCID-Leukemia Initiating Cell, SL-IC) based on the ability of that cell to initiate AML in NOD/SCID mice provides the foundation of an assay to define the biological and molecular properties of such new leukemic stem cells. The major long-term objectives of my research program are to further characterize human leukemic stem cells. The research project proposed here will focus on three objectives: 1) determine the existence of an heterogeneity at the leukemic stem cell level (both Lin-CD34+ and Lin-CD341o/- subfractions have leukemic stem cell properties); 2) evaluate the biological properties of the leukemic stem cell pool (i.e., self-renewal, proliferation and differentiation capacities, response to cytokines and/or stromal cell environment); 3) to study the gene expression pattern of six regulatory molecules (AML1, PU.1, GATA- 1, Hox A5, Hox B4 and SCL/tal-1), known to be involved in the early stage of hematopoietic development and/or in the physiopathology of leukemia, before and after induction of differentiation of the leukemic stem cell fraction. The information obtained from these studies will gave us a more complete understanding of the nature of the leukemic stem cells, their biological properties, and the early molecular factors involved in the maintenance and/or differentiation of such leukemic stem cells. Furthermore, the knowledge gained about leukemic stem cells will allow us to devise new therapeutic strategies such as cell purging strategy, gene suicide therapy, antisense therapy and others, targeted specifically to the leukemic stem cell pool. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CMYB DURING EARLY MYELOPOIESIS Principal Investigator & Institution: Choi, John K.; Pathology and Lab Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: (Applicant's Description): The applicant's career goal to combine research with clinical practice of hematopathology is a logical outcome of his c o n t inued interests in carcinogenesis, cellular differentiation, and transcription factors. While he has had a productive research experience with skeletal myocytes and B cell transcription factors, this proposal represents a significant change in research subject and uses many technical approaches that are novel to him. The expression of the hematopoieticrestricted transcription factor c-myb can be disrupted using antisense oligonucleotides and this leads to cell cycle arrest or apoptosis of leukemic cells. Based on these findings, clinical trials of antisense oligonucleotide based therapy against leukemic cells are in progress. Although c-myb is a rational target, it is still less than perfect for treatment of leukemias because it is also expressed by normal hematopoietic cells and is essential for their normal development. A better fundamental understanding of c-myb biology may identify additional and possibly better targets. MYB may play a role in leukemogenesis by physically interacting with transcription co-factors and activating specific genes that promote cellular proliferation. These co-factors and c-myb activated genes are potential targets for antisense based therapies against leukemias. It is possible that some of these targets are essential for cell cycle progression in some leukemic cells but dispensable in normal hematopoietic progenitors. To test this, the expression of known c-myb activated genes and interacting proteins will be suppressed using antisense approaches and cellular proliferation of normal and leukemic cells will be measured. Novel c-myb activated genes will be identified using differential display. The expression of these genes will be suppressed using an antisense approach and the effect on cellular

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proliferation will be measured. In some leukemias, c-myb may be mutated resulting in altered protein interaction or gene activation. Primary leukemias will be screened for spontaneous c-myb mutations and these mutants will be analyzed for their effects on cellular proliferation using cell counting or tritiated thymidine incorporation, gene activation using RT-PCR or northern blot analysis, and co-factor interaction using coimmunoprecipitation or mammalian two hybrid assay. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COOPERATING GENES IN INV(16) ACUTE MYELOID LEUKEMIA Principal Investigator & Institution: Castilla, Lucio; Program in Molecular Medicine; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Acute myeloid leukemias (AML) arise from the uncontrolled clonal expansion of hematopoietic progenitor cells. Different subtypes of AML are associated with specific chromosomal translocations. For example, the subtype M4Eo is associated with the chromosome 16 break-and-join inversion of the genes that code for the fusion gene CBFb-MYH11. Within subtypes, additional mutations have also been found in other genes including Ras, p53, and NFl. These mutations could play a role in CBFB-MYH11 mediated AML.We generated the Cbfb-MYH11 knock-in mouse, mimicking the presence of CBFb-MYH11 in human AML-M4Eo. We have shown that Cbfb-MYH11 plays a role in leukemogenesis by blocking hematopoietic differentiation. We hypothesize that AML is the result of a process that involves two-events: 1. The creation of a fusion gene that alters hematopoietic stem cell differentiation and 2. the introduction of one or more other mutations that are associated with apoptosis and/or proliferation. To test these hypotheses we will identify genes that synergize with CbfbMYH11 to develop AML. We will first combine retroviral insertional mutagenesis in our knock in mice with inverse PCR to identify genes altered in AML (Aim 1). We will then use retroviral transduction of identified genes and transplantation experiments to test for a transforming role of these genes. As an alternative approach to test our hypotheses, we will use genetic crosses and retroviral transduction experiments to evaluate the functional interactions between Ras associated genes and Cbfb-MYH11 in AML development (Aim 2). Our long-term goals are to understand the genetic mechanisms that determine AML, and to provide targets for the design of improved therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COOPERATING GENETIC EVENTS IN MYELOID LEUKEMIA DEVELOPME Principal Investigator & Institution: Largaespada, David A.; Associate Professor; None; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2003 Summary: (adapted from the investigator's abstract) Cancer develops as a result of the accumulation of multiple genetic changes in somatic cells, all of which cooperate in inducing the transformed phenotype. In acute myeloid leukemia (AML) the number and nature of these "cooperating" oncogenic mutations is most often unknown. The BXH-2 mouse offers a model system ideal for the elucidation of interacting gene mutations. In this model, a Murine Leukemia Virus (MuLV) induces AML by acting as an insertional mutagen. The number of different gene whose expression is altered by proviral insertion and which contribute to leukemia development in BXH-2 mice is

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likely to be large. At least eight different loci have been identified which are mutated by proviral insertion in multiple BXH-2 leukemias, but none of these loci is involved in more than 15% of the leukemias. Therefore, new and more efficient methods for identifying and cloning these cancer genes have been developed. These techniques include the selection of tumor-specific, somatically-acquired proviruses near CpG islands, which greatly enriches for proviruses near genes involved in leukemogenesis, and the development of a highly efficient inverse PCR-based approach for cloning proviral insertion sites. The combination of these two technologies allows rapid progress toward the goal of understanding the complex network of genes mutated during myeloid leukemia development. These procedures have been used to identify mutations in two genes likely to impact the same cell signaling pathway: Nf1 and Cdc251. It is the goal of this proposal to define the overlap between the oncogenic effects of these mutations and discover other proteins involved in this pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CLINICAL RESEARCH SUPPORT COMPONENT Principal Investigator & Institution: Stone, Richard M.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAR-2003 Summary: (provided by applicant): The ultimate objective of the research projects in this program project application is to improve the therapeutic results for patients with myeloid malignancies including acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. To achieve this objective, tumor cells and other relevant clinical samples from patients will be collected, catalogued, and distributed to the relevant projects for analysis of the expected therapeutic targets and other molecules that might be important in prognosis or pathophysiology. Secondly, a clinical infrastructure is required to carry out the clinical trials described in Project 5 and additional clinical studies that will emanate from the developmental approaches outlined in Projects 1, 8, 9 & 10. Clinical Research Core resources are required to carry out these functions which extend beyond direct patient care and the clinical laboratory. Without the clinical research support provided in the Core it would be impossible to coordinate the proper collection of multiple research specimens, the adherence to novel complex therapeutic schedules and timely follow-up of patients enrolled on research studies. Also critical to this success of the project is the collaboration of individuals in the Core with the staff from the Biostatistics Core who will provide a quality control system for specimen tracking, computerized data entry, quality of control data and will assist in the design and analysis of the clinical research protocols. The purpose of the Clinical Research Support Core is to provide the following services that will be utilized by all the clinical research studies: 1. To collect research specimens and coordinate patient follow-up at Dana- Farber Partners Cancer Center and collaborating institutions. 2. To act as liaison with outside physicians, hospitals, and biotechnology companies to coordinate the collection of research specimens and follow-up data. 3. To insure that study parameters are followed, ancillary specimens are collected on time and processed properly, confirm eligibility, and patient registration. 4. To insure the accuracy of submitted data from outside sources. 5. To provide data management for the collection of individual patient information. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEPSIPEPTIDE: A NOVEL HISTONE DEACYTLASE INHIBITOR IN L Principal Investigator & Institution: Byrd, John C.; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 07-JUN-2002; Project End 31-MAR-2004 Summary: (provided by applicant): A fine balance between the enzymatic activity of histone acetyltransferase and histone deacetylase (HDAC) governs levels of posttranslation acetylation of histone lysine residues. Recognition of this regulatory mechanism for gene transcriptional activation is growing. In cell transformation, acetylation is profoundly altered, and accumulation of hypoacetylated histone species occurs. Depsipeptide is a novel HDAC inhibitor completing phase I development in solid tumors; clinical activity has been noted. Studies by our group have shown selective cytotoxicity of depsipeptide toward acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) cells compared to normal hematopoetic cells. This cytotoxic effect occurs via an uncommonly exploited pathway of apoptosis, and the effect appears to be related to increasing histone H3 and H4 acetylation. We have demonstrated the ability of depsipeptide to induce gene transcription, cell differentiation, and expression of adhesion/co-stimulatory molecules in human myeloid cell lines and transformed lymphocytes. Synergy with decitabine and up-regulation of the 1D10 antigen was also noted. Based upon these data, we propose to perform the first clinical trial of depsipeptide in leukemia patients in two separate cohorts (AML and CLL). The objectives of our proposal are to 1) determine the safety of administering depsipeptide to two cohorts of leukemia patients (AML and CLL) 2) determine the dose at which a 100 percent increase in the baseline histone acetylation occurs, which will define a minimal effective pharmacologic dose (MEPD) 3) examine the biologic effect of depsipeptide on leukemia cells treated in vivo in patients with CLL and AML with respect to differentiation (AML) and co-stimulatory/adhesion molecule expression(AML and CLL). The specific relationship of these processes to lysine-specific H4 alterations, inhibition of HDAC enzyme activity, and enhanced ex vivo sensitivity to monoclonal antibodies will be assessed. By utilizing this novel study design that target MEPD, we may achieve significant biological effects, while avoiding excess doses of depsipeptide. The clinical and laboratory results of this trial will provide pharmacokinetic and pharmacodynamic information for additional correlative efforts in both single agent phase II and combination phase I studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEREGULATION OF MYELOPOIESIS BY ZINC FINGER PROTEIN EVI1 Principal Investigator & Institution: Perkins, Archibald S.; Associate Professor; Pathology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-JAN-2004 Summary: As is the case with most human cancers, acute myeloid leukemia (AML) is the result of multiple genetic events, each of which leads to loss of a particular aspect of cellular growth control. Two key aspects of this loss of control involve unrestrained proliferation and a block to differentiation. While circumstantial support for the importance of the latter has come from the analysis of leukemic cell phenotype and the efficacy of differentiation therapy, we do not as yet have a clear molecular understanding of how this is manifested or caused. Evi-1 is a leukemogenic zinc finger transcriptional repressor that is thought to act by interfering with cellular maturation of myeloid cells. We have shown that Evi-1 can blunt the accumulation of C/ebpalpha

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mRNA during myelopoiesis; C/ebpalpha encodes a transcriptional regulatory protein that is essential for the generation of mature granulocytes. However, transcripts of other myeloid-essential regulatory proteins are unaffected by Evi-1. We therefore hypothesize that EVI-1 affects the expression of a very limited subset of genes that play a regulatory role in myeloid maturation. We further hypothesize that the repression of these genes by EVI-1 results in the block to differentiation. We will approach this by identifying and characterizing differences in transcription between Evi-1-expressing myeloid progenitor cells and control myeloid progenitor cells. The differentially expressed genes may be known or novel, and may be direct or indirect targets of Evi-1 action. Furthermore, we propose to test the importance of these transcriptional differences between Evi-1 expressing cells and control cells by assessing their ability to override the Evi-1 induced interference with myelopoiesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA METHYLATION AS A DIAGNOSTIC MARKER IN AML Principal Investigator & Institution: Plass, Christoph; Associate Professor, Department of Medic; Molecular Virology, Immunology & Medical Genetics; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (Provided by applicant): Aberrant DNA methylation in the promoter region of genes is found in a variety of human cancers and is thought to be associated with gene silencing. Restriction Landmark Genomic Scanning (RLGS) is currently the only technique that allows the scanning of thousands of promoter sequences for aberrant DNA methylation in human cancer. Aberrant DNA methylation was recently shown to be a major contributor and an early event in tumorigenesis, especially in the development of acute myeloid leukemia (AML). In this application we propose to investigate the role of DNA methylation in AML with special emphasis on clinical correlates. The samples that will be used for this study will come from the CALGB Leukemia Tissue Bank. Our hypothesis is that epigenetic changes (DNA methylation) are equally important as genetic alterations in leukemogenesis but have been underestimated in its extend. Since methylation changes could affect the transcription of genes it is likely that these epigenetic differences contribute to the molecular defects that underlie normal karyotype AML. Subsequently, aberrantly methylated targets can be used to identify novel diagnostic or prognostic biomarkers in AML. To test this hypothesis our specific aims are (1) to study methylation profiles in a subset of normal karyotype AML with blast counts >50 percent. (2) Rigorous statistical and bioinformatical analysis will identify diagnosis and relapse specific methylation events, candidate subclass predicting methylation events and finally methylation targets that correlate with clinical data such as duration of complete remission. (3) A small subset of highly informative methylation targets will be studied in detail by bisulfite sequencing. MS-PCR tests will be developed that allow (4) screening of larger patient samples. Statistical analysis will be performed to determine the value of a methylation event as a diagnostic biomarker or as a marker with predictive value. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ELIMINATION OF CHEMOTHERAPY IN NEWLY-DIAGNOSED APL Principal Investigator & Institution: Estey, Elihu; Leukemia; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005

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Summary: (provided by applicant): Administration of all-transretinoic acid (ATRA) + myelotoxic chemotherapy results in long-term remission in 70% of patients with newly diagnosed acute promyelocytic leukemia (APL). It is becoming clear however that this approach is associated with development, several years later, of myelodysplastic syndromes and AML. The demonstration of the effectiveness of arsenic trioxide (ATO) in APL makes it feasible to assess, in newly diagnosed APL, whether the combination of ATO + ATRA will enable elimination of myelotoxic therapy. To test this hypothesis (SA#1) we will conduct a trial of ATO + ATRA, with myelotoxic therapy added only if minimal residual disease (MRD), as judged by the standard manual PCR assay, persists or recurs. For safety monitoring we will use a published Bayesian "multiple outcome" design that allows early termination if the rates of either CR, or PCR negativity at 6 months from CR date, are too low. More effective means of measuring MRD would obviously make similar trials more feasible in the future, and SA#2 tests the hypothesis that use of high sensitivity quantitative real-time PCR, rather than the standard assay, and blood rather than marrow will increase the accuracy of current methods. Similarly, understanding of mechanisms underlying resistance to ATRA would increase the possibility of eliminating myelotoxic therapy, and SA#3 tests the hypothesis that addition of ATO to ATRA, while decreasing the overall relapse rate, increases the frequency of missense mutations in the PML-RAR( gene among patients who do relapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION OF AML-1/RUNX1 IN EARLY HEMATOPOIESIS Principal Investigator & Institution: Keller, Gordon M.; Professor; Gene and Cell Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Translocations of the transcription factor AML1/Runxl account for more than 30 percent of acute myelogenous leukemia and 2530 percent of acute lymphoblastic leukemia. Gene targeting studies have demonstrated that AML1/Runxl is essential for the establishment of the definitive, but not primitive hematopoietic system. More recent gene expression analyses suggest that Runxl may play a role at a developmental stage earlier than predicted from knock-out experiments. The goals of this proposal are to further define the earliest stages of hematopoietic development regulated by Runxl and subsequently to identify and characterize genes involved in these commitment steps. The experiments in the first aim are designed to define the precise stage of hematopoietic development affected by Runxl deficiency. The focus of the second aim will be to further investigate the consequences of forced expression of Runxl on the developmental potential of wild type ES cells. The third aim will identify genes that function at the developmental stage(s) regulated by Runxl. The results from these studies will provide new insights into the cellular and molecular events involved in the establishment of the definitive hematopoietic system and the role of Runxl in this process. These findings, in particular the third aim, will ultimately shed new light on the critical events involved in the onset of leukemia following translocations at the AML1/Runxl locus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL ANALYSIS OF THE HUMAN LEUKEMIA GENE E2APBX1 Principal Investigator & Institution: Kamps, Mark P.; Pathology; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 10-APR-1992; Project End 31-MAR-2007 Summary: (provided by applicant): PBX, MEIS/PREP, and HOX genes encode interacting transcription factors that regulate development. Their mutation produces oncogenes that cause human leukemia and other tumors. Pbx, Meis/Prep, and Hox proteins are also implicated as subordinate oncoproteins functionally required for leukemogenesis by other human oncogenes. Thus, understanding oncogenesis by individual Pbx, Meis/Prep or Hox oncogenes will yield a broader understanding of human leukemia in general. This proposal focuses on understanding how Pbx proteins control development and hematopoiesis (Aims 1 and 2) and how the human E2a-Pbxl oncogene causes AML and preB ALL (Aims 3 and 4). Health-relatedness: Just as understanding oncogenesis by signal transduction oncoproteins led to the development of therapeutic inhibitors of cell proliferation, so also understanding the biochemical mechanism of oncoproteins that block hematopoietic differentiation will establish a rational to generate drugs that inhibit their function and promote differentiation. Because oncogenes that promote proliferation and inhibit differentiation cooperate to cause leukemia, drugs that inhibit proliferation and promote differentiation should cooperate to cure leukemia. Aim 1. Determine how Pbx homodimerization (in the absence of DNA) and Pbx:Meis/Prep heterodimerization regulate DNA-binding and nuclear import of Pbx proteins. Determine how Pbx proteins function as transcriptional coactivators. Aim 2. Using knockout technology, determine the role of Pbx2 in mouse development in general, and in regulating lineage commitment, differentiation progression, and gene transcription during hematopoiesis in particular. Make conditional Pbx2/Pbxl, or Pbx2/Pbx3 mice to determine the effect of double knockouts on hematopoietic differentiation. Aim 3: Use conditional E2a-ER-Pbxl to determine how E2 about-Pbxl prevents transcription of myeloid differentiation genes, focusing, mechanistically, on MRP8. Determine whether direct E2a-Pbxl targets reestablish a differentiation block in conditionally-immortalized E2a-ER-Pbxl myeloblasts and are activated in human t(l;19) pre-B ALL (L-Myc is one such target). Aim 4: Establish the cellular impact of E2a-Pbxl in models of pre-B cell leukemia induced by coexpression of Ras6l L plus E2a-Pbxl, or in transgenic mice expressing wild-type or conditional E2a-ERPbxl genes driven by the early, hematopoietic specific, Vav promoter. Identify the biochemical domains of E2a-Pbxl required to cause pre-B ALL, and begin to identify a genetic mechanism by which E2a-ER-Pbxl causes pre-B cell ALL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUSION PROTEINS IN THE MOLECULAR PATHOGENESIS OF APL Principal Investigator & Institution: Pandolfi, Pier Paolo; Professor; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 01-JUN-1997; Project End 31-MAY-2005 Summary: (Adapted from the investigator's abstract) APL is associated with reciprocal translocations always involving the RAR[1] locus which variably fuses to the PML, PLZF, NPM or NuMA genes (referred to as X genes), two aberrant fusion genes are thus generated which encode X-RAR[1] and RAR[1]-X fusion proteins. We hypothesize that the various X/RAR[1] fusion proteins disrupt the genetic events synergistically cooperate with X/RAR[1] leading to APL. We will test this hypothesis in vivo, by a

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direct genetic approach, with the following Specific Aims: 1) To define the leukemogenic potential of the fusion proteins of APL in transgenic mice (TM). Hemopoiesis, leukemogenesis, and response to RA and As2O3 treatments will be analyzed in X/RAR[1] and RAR[1]/X TM in which the expression of the transgene is restricted to the myeloid/promyelocytic hemopoietic compartment through the use of a human Cathepsin-G (hCG) minigene expression vector. hCG-X-RAR[1] and RAR[1]-X lines will be intercrossed to elucidate the possible cooperative roles of these molecules in leukemogenesis. 2) To establish the role of X and RAR[1] proteins in APL promotion and progression. We will test whether the reduction to heterozygosity of X and/or RAR[1] in APL, or their functional inactivation by the fusion products is a crucial event in APL leukemogenesis. To this end, we will interbreed hCG-X/RAR[1] and RAR[1]/X TM with PML, PLZF or RAR[1] Knock-Out mice to reproduce in vivo the genetic complexity observed in the APL blast, and study hemopoiesis and leukemogenesis in the resulting transgene combinations. 3) To define the mechanisms of leukemogenesis and transcriptional repression in APL. We will study in vivo, in TM, as well as in vitro, in transcriptional and cell culture assays, the biochemical and oncogenic activities of X/RAR[1] and RAR[1] proteins harboring mutations in ligand binding, repressive and activating domains. 4) To study leukemogenesis and the concept of dominance/interference by X-RAR[1] on X function utilizing an in vivo "Knock-in" approach. We will introduce the PLZF-RAR[1] fusion gene in the PLZF locus in mouse ES cells by a Knock-in approach. We will study the resulting phenotype and leukemogenesis by the PLZF-RAR[1] fusion protein in vivo, in mice and/or chimeras generated from these ES cells, as well as in vitro, in ES cells differentiation experiments. 5) To identify target genes of the oncogenic activity the various X-RAR[1] and RAR[1]-X fusion proteins. We will utilize purified promyelocytic cell populations from our TM to identify, on a comparative basis, target genes relevant for their oncogenic functions utilizing microarray and chromatin immunoprecipitation techniques. 6) To identify additional genetic events contributing to APL pathogenesis. Retroviral insertional mutagenesis in PML-RAR[1] and PLZF-RAR[1] TM, and Spectral Karyotyping (SKY) will be utilized to identify additional genetic events in APL leukemogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC ANALYSIS OF MYELOPROLIFERATIVE DISEASE Principal Investigator & Institution: Cowell, John K.; Chairman, Department of Cancer Genetics; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-JAN-2004 Summary: Myeloproliferative disorders (MPDs) result from the abnormal proliferation of myeloid precursor cells in the bone marrow. Understanding the genetic events which result in MPDs will not only improve our understanding of the disease process, but will also provide insights into the normal developmental control in early progenitor cells. A variant form of this disease is associated with T-cell leukemia/lymphoma and peripheral blood eosinophilia. The clinical course of the disease is particularly aggressive with rapid progression of the disease to acute myelogenous leukemia or stem cell leukemia. The involvement of both myeloid and T-cell lineages in this disease strongly suggest a primitive origin for the cells involved, before the commitment to a particular lineage. These tumors invariably show a highly specific, reciprocal chromosome translocation involving chromosomes 8 and 13. This specific translocation is always involved with this biphenotypic tumor indicating that genes located at the translocation breakpoints play an important role in disease development. The genes involved in this rearrangement have now been identified as FGFR1 in chromosome

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region 8p11 and a zinc finger gene, ZNF198, of unknown function, in 13q12. The molecular conequences of this rerrangement have been shown to be identical in all of the four cases we have analyzed. As a result of the rearrangement a fusion gene is generated which is under the control of the ZNF198 promoter. This novel gene carries the zinc finger motif of ZNF198 fused to the tyrosine kinase domain of FGFR1. Because of the highly specific nature of this rearrangement and its consistent presence in all of the tumors analyzed to date, this rearrangement must clearly be important in leukemogenesis in these patients. Our goals therefore are (1) to transform normal cells using the fusion gene in order to establish a functional assay in vitro, (2) to create a transgenic mouse line expressing the fusion protein and so establish an in vivo model to study the biological consequences of the translocation and (3) since the fusion gene may act as a dominant-negative we will also investigate the normal function of ZNF198 in order to compare its activity with that of the fusion gene. As a result of our improved understanding of the genetic events which give rise to this MPD, it may eventually be possible to design novel therapeutic approaches to this disease directed against the aberrant gene(s) and its product. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MANIPULATION OF T CELLS--PRECLINICAL MODELS Principal Investigator & Institution: Dipersio, John F.; Cheif, Division of Oncology; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Applicant's Description Verbatim): Allogeneic bone marrow transplantation is a curative therapy for hematologic malignancies, marrow failure states, and selected inherited metabolic diseases. Unfortunately, BMT is associated with significant morbidity and mortality related to graft vs. host disease (GvHD). Attempts to mitigate GvHD using T-cell depletion resulted in increased rates of graft failure, post-transplant lymphoproliferative diseases, leukemia relapse and opportunistic infections. We propose to genetically modify T-cells using novel cell surface chimeric suicide genes. We will test the expression and purification of novel fusion suicide genes in vitro and in vivo using instructive transgenic and "knock-in" murine pre-clinical models. The optimal method and potential role of genetically manipulated T-cells to mitigate GvHD while maintaining engraftment and graft vs. leukemia can only be defined by developing new reagents and novel pre-clinical murine transplant models. We propose to generate important new reagents to study T-cell transduction by suicide genes and to use a number of well-defined pre-clinical models to develop a rational approach and a clear foundation for future clinical trials. In Aim I, we will design methods to optimize transduction, selection, and expansion of transduced T-cells, using OKT3 and 11-3 and CD3/CD28 magnetic beads. In addition, we will generate novel second-generation suicide genes designed to optimize detection and killing in response to prodrug. We will also test the survival and function of transduced murine and human T cells using in vivo using allogeneic transplant models and several murine SCID models. Aims II and III, we will use the chimeric suicide genes developed in Aim I to generate informative transgenic and knock-in pre-clinical murine models in which these suicide genes will be expressed in all (Aim II) or in subsets (Aim III) of peripheral T-cells. Allogeneic bone marrow transplantation will be performed using the transgenic and knock-in mice developed in Aims II and III to further develop the optimal method of suicide in vivo, its effect on GvHD and engraftment, and its possible role in clinical trials. In Aim 1V, we will utilize three novel murine leukemia models in which the effects of genetically modified T-cells and their in vivo suicide on GvHD, engraftment and graft vs. leukemia

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can be compared to animals receiving unmanipulated T-cells and T-cell depleted BM. These studies will provide new insights into the pathophysiology of GvHD and its effective treatment. Issues regarding the use of genetically manipulated T-cells to control GvHD can best be investigated through the use of informative animal models and the comprehensive studies described in this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ZEBRAFISH

GENETICS

OF

MYELOID

NEOPLASIA--MUTAGENESIS

IN

Principal Investigator & Institution: Look, a Thomas.; Professor of Pediatrics; DanaFarber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Forward genetic screening in the zebrafish affords an unparalleled opportunity to discover genes required in human blood cell development, and whose alteration can lead to premalignant states or overt leukemia. This proposal tests two linked hypotheses: (i) genome-wide ethylnitrosourea (ENU) mutagenesis screens in the zebrafish can be used to identify dominant and recessive mutations that cause a deficiency or abnormal distribution of circulating granulocytes, implicating genes important in vertebrate myelopoiesis; and (ii) a subset of the genes discovered by this method will have human counterparts that contribute to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), or to one of the congenital neutropenias that predispose to these malignancies. In preliminary studies, the zebrafish myeloperoxidase (zMpo) gene was cloned to be used in these screens as a granulocyte developmental marker, and its specificity for cells of the granulocytic lineage was demonstrated by RNA in situ analysis during development and adulthood in the fish. Also, detailed morphologic histochemical, electron microscopic and in situ analysis of cells in normal zebrafish blood and kidney (the hematopoietic organ of adult zebrafish) have been performed, and the results will serve as normal benchmarks for the analysis of myeloid cell development in mutant zebrafish lines recovered during screening. Mutant fish identified by in situ hybridization following ENU mutagenesis (Aim 1) will be analyzed to determine the cell developmental stage at which the mutation occurred (stem vs committed progenitor vs mature) (Aim 2). Next, the chromosomal location of each mutation will be mapped on the zebrafish genome, and examined for synteny with known regions of loss-ofheterozygosity (LOH) in human MDS/AML (Aim 3). Positional cloning (Aim 4) will focus on genes most likely to have deleted or mutated counterparts in these two neoplasias, both characterized by disordered granulocytic development. These zebrafish mutants may also have human homologues among the mutated genes contributing to recessive congenital blood diseases associated with granulocytopenia that can predispose to MDS/AML. Mutant zebrafish lines that harbor mutations in homologues of previously unidentified MDS/AML tumor suppressor genes will also serve as animal models to help identify genes in pathways leading to myeloid malignancy. A long-range goal is to use these models as a starting point for second-generation modifier screens to identify suppressors and enhancers of the genes causing myelopoietic defects, which may then be exploited as targets for therapeutic development. MDS and AML are currently extremely difficult to treat and are generally only curable with myeloablative therapy followed by hematopoietic stem cell transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENOMIC PROFILING OF CHILDHOOD DE NOVO AND RELAPSED AML Principal Investigator & Institution: Dahl, Gary V.; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Provided by applicant): Acute myelogenous leukemia (AML) accounts for approximately 20 percent of cases of childhood leukemias. In contrast to lymphoblastic leukemias, the cure rate for childhood AML is still less than 50 percent. We propose to apply the powerful new technology of gene expression profiling to AML specimens from more than 600 children with de novo AML treated on the Pediatric Oncology Group (POG) Study #9421. Our hypothesis is that global gene expression profiles will provide new insights into genetic determinants of response to therapy and clinical behavior of childhood AML. The specific aims of this proposal are: (1) Gene expression profiling of childhood de novo AML specimens from patients enrolled in POG Study #9421. A total of 621 banked specimens are available. The microarrays for this project will contain 48,000 human genes. The profiles of gene expression of childhood AML will be compared to our existing databases including adult AML, lymphomas, and several types of carcinomas. In addition, gene expression clusters will be analyzed with reference to histopathological classification and cytogenetic abnormalities. It is likely that this approach will reveal clusters of genes which will re-define subclasses of childhood AML. (2) Prognostic significance of genes involved in drug resistance and apoptotic pathways. Modulation of drug resistance by high dose cyclosporine and high dose cytarabine were the two therapeutic questions addressed by #9421, resulting in 4 study cohorts. Although early in follow-up, there is a trend to increased survival with high dose cyclosporine. Drug transporters and other genes known to be involved in therapeutic responses will be examined for prognostic importance in each treatment cohort. We hypothesize that MDR1 will lose prognostic importance in the cyclosporine cohorts. The relationship of individual and clustered gene expression to complete remission, duration of remission, and survival will be assessed for the entire set of genes on the arrays. (3) Gene expression profiling of specimens from patients with relapsed pediatric AML enrolled in POG #9421 and #9720. Serial specimens at diagnosis and relapse are available in at least 39 cases, providing a great opportunity to identify genes which may be selected or induced by therapy. The outcome of these studies may guide the next generation of biologic and therapeutic studies in childhood AML, and make a significant contribution to the diagnosis, prognosis and development of rational therapeutics in this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GVL TO REDUCE AML RELAPSE AFTER MURINE ALLOGENEIC BMT Principal Investigator & Institution: Blazar, Bruce R.; Director; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2007 Summary: (provided by applicant): Allo-BMT has been an effective therapy for patients with myeloid malignancies due to a GVL effect. One approach designed to minimize GVHD side-effects is donor BM T cell depletion (TCD). Although TCD reduces GVHD, TCD can result in T-cell immune deficiency post-BMT. In Aim 1, we hypothesize that targeting the innate immune system (NK cells), which returns later post-BMT, will be the optimal approach to decrease AML recurrence after allo-BMT. Strategies are

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proposed to increase NK cells and block NK inhibitory receptors which will decrease AML recurrence by blocking the "off signal" delivered by AML cells to NK cells (Aim 1). In Aim 2, we hypothesize that the profound T-cell immunodeficiency post-BMT can be circumvented by strategies which protect the thymus against conditioning cells from conditioning regimen-induced injury. We will build upon this and determine whether DC vaccines will induce long-lasting memory cell responses in KGF treated recipients. We hypothesize that fusions of DCs and AML cells may be preferable to AML-lysate pulsed DCs due to superior loading of the MHC class I pathway via an endogenous rather than exogenous route. In another approach, we will induce DCs in vivo to present AML antigens by infusing AML-derived heat-shock proteins (hsps). Hsps associated with tumor peptides that are taken up by APCs can chaperone these peptides into MHC class I pathways and facilitate DCs maturation. We envision a sequential strategy in which thymus protective agents are given pre-BMT followed by approaches which stimulate the innate system early post-BMT and others that are directed toward stimulating the adaptive system late post-BMT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOXA9 GENE AS A THERAPEUTIC TARGET IN LEUKEMIA Principal Investigator & Institution: Lawrence, Hugh Jeffrey.; Professor of Medicine; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 12-APR-2001; Project End 31-MAR-2004 Summary: (provided by applicant) A growing body of evidence supports the notion that misexpression of the HOXA9 homeobox gene is a common and critical event in myeloid leukemogenesis. Enforced expression of HOXA9 in murine marrow cells is clearly leukemogenic, and the gene is aberrantly upregulated in a large majority of cases of human acute myelogenous leukemia (AML). In a recent survey of 6,800 human genes in acute leukemia, HOXA9 expression was shown to be highly specific for AML and was the single best marker for a poor outcome. The major hypothesis of this grant is that aberrant activation of HOXA9 is a frequent downstream consequence of many, if not most, oncogenic events that lead to AML, and that this activation is critical to the induction and maintenance of the malignant phenotype. An additional key hypothesis is that HOXA9 overexpression contributes to the drug resistance phenotype. The focus of this application is to explore strategies to inhibit HOXA9 expression and/or function as a novel therapeutic approach for AML. This project has 3 major aims: i) to test the in vitra biologic effects of over-expression of HOXA9 in a factor-dependent nonleukemogenic myeloid cell line engineered to express high levels of HOXA9 in a tetracycline-regulatable manner, and to use this inducible cell line model to test strategies to block HOXA9 expression. ii) to develop an in vivo model of a Tetregulatable HOXA9-driven AML in mice, which can be used to test treatment the strategies developed in Aim #1 in a whole animal, and iii) to study the ability of antiHOXA9 strategies to alter the proliferation, differentiation and chemotherapeutic sensitivity of fresh leukemic cells from patients, and of human myeloid leukemic cell lines that show high levels of endogenous HOXA9 expression. The specific strategies to be tested include the use of conventional antisense oligonucleotides, double-stranded DNA decoys, and double-stranded RNA to induce RNA interference. We anticipate that therapies targeting the expression and/or function of HOX proteins could have a major role in the clinical treatment of leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MICROARRAY TECHNOLOGY TO PROFILE CPG ISLAND METHYLATION Principal Investigator & Institution: Futscher, Bernard W.; Associate Professor; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 22-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant): The long-term objective of this research project is to adapt microarray-based technology to measure CpG island methylation in human cancer cells. CpG islands are approximately 1kb stretches of DNA that have a high CG content, are enriched in the dinucleotide 5'-CG -3', are found at the 5' end of about 50% of all human genes, and participate in the transcriptional regulation of these genes. The cytosines in the CpG dinucleotides of CpG islands are unmethylated in normal tissue; however, CpG islands become aberrantly methylated during oncogenesis and has been linked to the transcriptional repression of the associated gene. In addition, from the limited number of CpG islands and tumors that have been analyzed to date, it appears that patterns of aberrant methylation occur in a tumor-specific and stage-specific fashion, suggesting that CpG island methylation profiles may be useful as a tumorspecific fingerprint to monitor disease activity and burden. Thus, a multiplexed assay where the cytosine methylation status of thousands of CpG islands can be determined simultaneously would be useful in the molecular profiling of human tumors, and will likely provide insights into the biology of cancer. To this end we have formed a multidisciplinary team to use human CpG island microarrays (CGI arrays) as a tool for determining CpG island methylation profiles in cancer, and from these profiles identify characteristic patterns of CpG island methylation that correlate with the tumor's clinical phenotype. The 4 integrated specific aims that follow are designed to reach our objective. 1) Construct CpG island microarrays for use in CpG island methylation analysis. 2) Optimize methylation analysis using CpG island microarrays 3) Determine CpG island methylation signatures in AML cell lines and in AML samples obtained from patients with known clinical outcome. 4) Develop and implement a public database for the dissemination and mining of the CGI array data Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MICRODETECTION ASSAY FOR DRUG RESISTANT TUMORS Principal Investigator & Institution: Beck, William T.; Professor and Head; Pharmaceutics/Pharmacodynamics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 15-APR-1987; Project End 31-JAN-2004 Summary: (Applicant's Abstract) Despite recent advances in cancer genetics and treatment, anticancer drug resistance remains a formidable problem. The long-term goal of this project has been the development of microdetection assays that will ultimately permit individualization of therapy. Through the years, the applicant has focused on understanding the mechanisms of tumor cell resistance to natural product drugs, and has defined both P-glycoprotein-associated multidrug resistance (Pgp-MDR) and altered topoisomerase II-associated MDR, with the idea that a focus on a few targets might permit exploitation for diagnosis or therapy. It is now clear that resistance, even to a single anticancer drug, is a multifactorial phenomenon with multiple genetic changes. Given this panoply of changes, the task of identifying "the" gene(s) responsible for the phenotype is very challenging. However, if these changes represent a reproducible pattern of gene expression, then it might not matter knowing which gene(s) cause the phenotype if what is desired is knowing whether an expression pattern accurately

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represents the phenotype. Recent advances in cDNA array technology now make it possible, after all these years; to develop a true "microdetection" assay that can theoretically detect drug resistant tumor cells. However, application of this methodology to identify a small proportion of therapy resistant cells in an otherwise sensitive tumor population remains problematic. The applicant will develop the idea in this application that marrying methods of gene array, drug action, and analysis of specific genes will be able to provide a profile of such a subpopulation of drug resistant cells. Accordingly, the hypothesis to be tested is that tumor cells from therapy-resistant patients display coordinate expression of drug-resistant genes that can be detected by their molecular and cellular signatures. The specific aims are: 1) define the basis for the apparent coordinate regulation of the MDR1, MRP, and other genes in relapsed AML through study of MRP regulation, and 2) use gene array methodology to identify patterns of gene expression associated with therapy resistance in AML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR POPULATIONS

EPIDEMIOLOGY

OF

APL

IN

HISPANIC

Principal Investigator & Institution: Lopez-Berestein, Gabriel G.; Associate Professor; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 16-AUG-2002; Project End 31-JUL-2007 Summary: Unexplained high frequency (24-30%) of acute pro-myelocytic leukemia (APL) has been reported among Hispanic populations. The aim of this joint project between the University of Texas MD Anderson Cancer Center (MDACC), the Instituto de Enfermedades Neplasicas (IEN) in Lima Peru, and the Puerto Rico Cancer Center (PRCC), University of Puerto Rico is to obtain preliminary epidemiologic cytogenetic, and molecular parameters that would allow to establish the feasibility of larger comparative multi-country study. For this purpose, the newly diagnosed APL patients admitted to the three centers will be asked to participate in an epidemiologic survey and will be examined for each of the 4 genes (PLM, PLZF, NPM and NuMA) that could fuse to retinoic acid receptor-alpha (RARalpha) and the retinoic acid specific catabolic enzyme CYP26. We will look for the similarities and differences among the partner proteins in these patients that may explain the high incidence and/or distinct clinical outcome in response to retinoic acid (RA) therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETIC CHANGES IN LEUKEMIA IN INFANTS Principal Investigator & Institution: Felix, Carolyn A.; Associate Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 15-DEC-1998; Project End 31-MAR-2007 Summary: (provided by applicant): Translocations of the MLL gene with one of many partner genes are associated with clinically aggressive leukemias in infants. The objective of this work is to understand the etiology and consequences of these translocations. The genomic breakpoint sequences suggest that DNA damage is involved in the translocation process but the etiologic agent(s) is unknown. An inactivating NQO1 polymorphism confers genetic susceptibility and DNA damage from benzoquinone, which is detoxified by NQO1, may interfere with DNA topoisomerase II. The first hypothesis is that DNA topoisomerase II mediates chromosomal breakage that results in translocations, that benzoquinone contributes to the breakage, and that translocations form when the breakage is repaired. The second hypothesis is that gene

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expression patterns reflecting primary and secondary molecular alterations will vary with the partner gene and affect biology and prognosis. Aim I examines the der(1l) and der(other) breakpoint junction sequences for evidence of associations of NQO1 genotypes with specific damage patterns. These experiments will show the sequence motifs affected by the damage and the panhandle PCR approaches will lead readily to new partner genes. Aims 2 and 3 combine molecular biology, biochemistry and mass spectrometry to study the genomic breakpoint sequences in cellular and in vitro model systems. Assays to determine whether benzoquinone damages the genomic breakpoint sequences in a DNA topoisomerase II dependent manner and to characterize the nature of the damage address the etiologic question. If the first hypothesis is correct, the results may show specific benzoquinone-related damage that leads to translocations. Aim 4 uses oligonucleotide arrays to discern effects of different partner genes on gene expression patterns. The partner genes hCDCrel and SEPTIN2 are members a distinct gene family involved in infant AML. Aim 5 exploits retroviral gene transfer to investigate the transforming capabilities of MLL-SEPTIN fusions in syngeneic mice. If the second hypothesis is correct, leukemias with various MLL translocations will be distinguishable by their gene expression patterns. This multidisciplinary research plan to elucidate the etiology and consequences of MLL translocations may inform new approaches to treatment and prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEUKEMIA

MOLECULAR

PATHOLOGY

OF

ACUTE

PROMYELOCYTIC

Principal Investigator & Institution: Chang, Kun-Sang S.; Associate Professor; Laboratory Medicine; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-1992; Project End 31-JUL-2005 Summary: (Adapted from the investigator's abstract) In the past few years, significant progress has been made in understanding the molecular pathology of acute promyelocytic leukemia (APL). Both cell culture and animal models support the suggestion that the PML-RARA fusion protein resulting from the t(15;17) is responsible for the development of APL. However, our studies indicate that loss of function of PML, a growth and transformation suppressor disrupted in APL may also contribute to the pathogenesis of APL. Our major focus during the previous funding period was to understand the biological function of PML. Several new findings have resulted from these studies. (a) PML plays a role in regulating cell cycle progression and apoptosis. These important properties of PML are just beginning to emerge and the molecular mechanism of how PML regulates cell cycle progression and apoptosis is not well understood. (b) Our studies suggest that PML is a substrate of cyclin-dependent kinases, this further supporting a role for PML in cell cycle control. How phosphorylation of PML affects growth suppression and apoptosis is unknown. (c) Our studies provided significant insight into the transcriptional regulatory function of PML. We found that PML represses Sp1-dependent transcription of target genes involved in the G1 to S transition, and that PML represses transactivation of NFkappaB target promoters. (d) PML recruits histone deacetylase and silences transcription of target genes by deacetylation of the promoter. We propose to continue to pursue the following specific aims: (1) to study the mechanism of PML regulation of cell cycle progression. Hypothesis to be tested: PML regulates cell cycle progression by inducing a GI arrest through its effects on transactivation of genes involved in the G1/S checkpoint. (2) To study the molecular basis of PML induced apoptosis. Hypothesis to be tested: PML

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27

induces apoptosis by (i) de-repression of the antiapoptotic effects of NFKB; (ii) induced expression of p53; and (iii) functional interaction with Bax. (3) To study PML phosphorylation and the biologic significance. Hypothesis to be tested: Phosphorylation and dephosphorylation of the PML protein play an important role in the regulation of cell cycle progression, apoptosis, and transcription regulation. Studies outlined in this proposal will provide important information toward understanding cell cycle regulation and apoptosis. Results obtained from these studies will further expand our knowledge in understanding the molecular pathology of acute promyelocytic leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR TAXONOMY OF PEDIATRIC AND ADULT ACUTE LEUKEMIA Principal Investigator & Institution: Willman, Cheryl L.; Director, Univ Cancer Research and Treat; Pathology; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JAN-2005 Summary: Although remarkable advances have been made in the treatment of the acute leukemias, particularly resistant forms of leukemia remain. In 1999, 28,000 children and adults in the U.S. will be diagnosed with leukemia and 21,000 will die of their disease. This variability in clinical response is due in part to the tremendous heterogeneity of the disease itself. Traditionally classified solely on the basis of morphology and cytochemistry, the acute lymphoid or lymphoblastic leukemias (ALL) and the acute myeloid leukemias (AML) are characterized by highly variable clinical and biologic behavior, immunophenotypes, and chromosomal abnormalities. Striking differences in outcome may be seen in cases with the same cytogenetic profile, implying that more subtle genetic abnormalities also impact disease biology and response. We hypothesize that cDNA microarray technology will yield quantitative, orderly, and systematic gene expression profiles that can be used to design more clinically relevant classification schemes and to predict therapeutic response. By conducting correlative science studies accompanying NCI-sponsored clinical trials in children and adults affected by acute leukemia for the Pediatric Oncology Group, Children's Cancer Study Group, and Southwest Oncology Group, and by maintaining the largest leukemia tissue repositories in the world, we are poised to propose the following specific aims: 1. To Further Optimize cDNA Microarray Technology for Studies in Primary Human Leukemia Samples. 2. To Characterize the Molecular Variations Among Highly Selected Acute Leukemia Cases Using at Least 30,000 Genes. Cases have been selected using two approaches: 1) therapeutic response/resistance and 2) the presence of specific cytogenetic abnormalities. Study sets in AML include: 1) patients with "primary resistant" disease; 2) patients in long-term remission; 3) paired pre-treatment and relapse samples; 4) patients responding or failing specific treatment regimens; and 4) cases selected by genotype [t(8.21), inv(16), t(15;17), t(4;11), t(9;11), and complex]. In ALL, cases are being selected prospectively using two approaches: 1) the presence of residual disease vs. complete molecular response during the treatment course using automated quantitative molecular monitoring methods; and 2) by genotype [hyperdiploid, t(12;21), t(9;22), t(1;19), and t(4;11)]. 3. To Apply Multivariate Clustering Methods to Group Acute Leukemias That are Coherent in their Expression Patterns. 4. To Use Automated Quantitative "Real-Time" PCR Technologies to Validate cDNA Microarray Analyses. 5. To Use High Performance Computing and Informatics Technologies to Link Large Genomic Data Sets with Clinical Databases. All leukemia samples have associated clinical databases containing detailed patient information, laboratory data (cytogenetics,

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correlative scientific studies), and therapeutic response data. Our experienced clinical trials biostatisticians will work with the UNM High Performance Computing Center (a National Supercomputing Facility) and Sandia National Laboratory (both world leaders in massively scalable parallel computing, statistics, informatics, and visualization tools) to meet this aim. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOUSE MODELS FOR FAMILIAL PLATELET DISORDER Principal Investigator & Institution: Speck, Nancy A.; Professor; Biochemistry; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 20-JAN-2001; Project End 31-DEC-2005 Summary: Mutations in the RUNX1 gene (also known as AML1) cause a rare familial platelet disorder with propensity to develop acute myelogenous leukemia (FPD/AML). FPD/AML patients have reduced platelet numbers, defects in platelet function, and decreased numbers of hematopoietic progenitors in their bone marrow and peripheral blood. FPD/AML patients also have a propensity to progress to acute myelogenous leukemia. The mutations found in FPD/AML pedigrees involve only one copy of the RUNX1 gene. RUNX1 encodes a DNA-binding subunit of the heterodimeric corebinding factors (CBFs). The "Runt" domain in Runx1 mediates DNA-binding and heterodimerization with the non-DNA-binding CBFbeta subunit. Mutations in FPD/AML patients include missense and nonsense mutations in the Runt domain, creation of a cryptic splice acceptor site within the Runt domain, and an intragenic deletion. Biallelic point mutations in the Runx1 Runt domain were also recently documented in approximately 25% of M-0, AML, defining a new subgroup in this disease. The similar clinical phenotypes of FPD/AML patients suggest that haploinsufficiency is the underlying mechanism in all cases of the disease. However, the severity of platelet defects in FPD/AML families varies, suggesting that subtle phenotypic variation may be conferred by the different FPD/AML RUNX1 alleles. The goals of this project are to understand how mutations found in the Runx1 Runt domain in FPD/AML and AML M-0, patients affect the functions of the Runx1 protein, both in vitro and in vivo. The Specific Aims are: 1. Determine how mutations in the Runx1 Runt domain found in FPD/AML and M-0, AML patients affect DNA-binding, CBFP heterodimerization, and the Runt domain structure. 2. Determine whether point mutations in the Runx1 Runt domain found in FPD/AML patients result in haploinsufficiency, in the generation of partially functional Runx1 alleles, or in transdominant negative Runx1 alleles. 3. Generate and characterize mouse models for FPD/AML that mimic the hematopoietic progenitor defects, platelet defects, and propensity for AML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MURINE MODELS OF FLT3 MEDIATED LEUKEMIAS Principal Investigator & Institution: Gilliland, D Gary.; Associate Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAR-2003 Summary: (provided by applicant): Acute myelogenous leukemia (AML) is characterized by chromosomal translocations or point mutations that involve transcription factors, such as PML/RARa, AML1/ETO and C/EBPa. However, these gene arrangements and mutations are not sufficient to cause leukemia, and the nature of the additional required mutations has been elusive. It has recently been discovered that

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the FLT3 receptor tyrosine kinase is constitutively activated in 20-25% of AML as a consequence internal tandem repeat mutations (ITD). Furthermore, the FLT-ITD may occur simultaneously with each of the transcription factor mutations above. We hypothesize that the FLT3-ITD provides proliferative and/or survival signals to hematopoietic progenitors, and causes the acute leukemia phenotype through cooperation with transcription factor mutations that impair hematopoietic differentiation. We further hypothesize that FLT3-ITD leukemias can be treated with FLT3-specific small molecule inhibitors. In Specific Aim 1, we will analyze the transforming properties of FLT3-ITD in murine bone marrow transplantation assays. Specific Aims 2-4 will test the cooperative effect of FLT3-ITD with PML/RARa, AML1/ETO, or mutant C/EBPa, respectively, in murine models of leukemia. In Specific Aim 5, a FLT3-ITD "knock-in" mouse will be generated, in part to facilitate analysis of the structural requirements of cooperating transcription factor mutants. In each of these contexts, we will assess the therapeutic efficacy of a FLT3-specific small molecule inhibitor. Collectively, these experiments will determine the pathophysiologic significance of constitutive activation of FLT3 in human AML, and validate novel therapeutic approaches that target the FLT3-ITD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: NOVEL GENE REARRANGED WITH THE RAR ALPHA LOCUS Principal Investigator & Institution: Waxman, Samuel; Wiener Professor/ Medical Director; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-JAN-2003 Summary: (adapted from the investigator's abstract) The promyelocytic leukemia zinc finger (PLZF) protein is transcription factor, highly expressed in hematopoietic progenitor cells, that is fused to the retinoic acid receptor-a (RAR a) in t(11;17)associated acute promyelocytic leukemia (APL). The t(11;17) APL is a distinct syndrome which, unlike the more common t(15;17) APL is unresponsive to retinoic acid or chemotherapy. PLZF-RARa which is generated in t(11;17) APL is an aberrant retinoid receptor which like the PML-RARa fusion of t(15;17) was a dominant negative inhibitor of wild-type RARa. Hence a common mechanism in leukemogenesis is disruption of retinoic acid signaling. The fusion of RARa to the PLZF may select for an aggressive clinical phenotype due to the disruption of the important function of PLZF in normal myeloid development. PLZF is a sequence specific DNA-binding transcriptional repressor and a growth suppressor inducing G1/S arrest and programmed cell death in myeloid cells. The PLZF protein contains an evolutionarily conserved motif called a POZ (poxvirus zinc finger) domain, found in other zinc finger proteins implicated in neoplasia, development and differentiation. The POZ domain appears to be necessary for PLZF protein to dimerize and repress gene transcription and for the transcriptional and biological effects of PLZF and the PLZF-RARa chimera. The mode of action and molecular target proteins of the POZ domains are unknown. The proposed research will: 1. Determine of how PLZF controls myeloid cell growth and differentiation by elucidation of PLZF target genes which bind the PLZF protein in vitro and in vivo such as IL-6, cyclin A and other to be identified by whole genome PCR. 2. Define how an evolutionarily conserved protein motif, the POZ domain, functions in transcriptional regulation, though mutagenesis of conserved residues and identification of partner proteins using the yeast two hybrid system. 3. Define protein-protein interaction networks that play a role in normal myelopoiesis and leukemogenesis (PML-PLZF, NCor-PLZF). 4. Extend knowledge of gene regulation in early hematopoiesis through characterization of the cis-acting sequences controlling expression of PLZF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL TARGETS FOR THE TREATMENT OF AML Principal Investigator & Institution: Dranoff, Glenn; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAR-2003 Summary: (provided by applicant): Advances in molecular genetics have led to improved understanding of the pathogenesis of acute myelogenous leukemia (AML) and the mechanisms underlying the generation of a host anti-tumor immune response in these patients. While a large number of tumor antigens that elicit humoral and/or cellular reactions in cancer patients have been defined through innovative cloning strategies and biochemical approaches, relatively little is known about the antigenic targets in AML. To learn more about antileukemia immune responses, we propose to determine the immunogenicity of a novel leukemia antigen and to identify additional promising targets for vaccination studies. First, we will conduct a Phase I clinical trial evaluating the biologic activity and toxicity of vaccination with the novel antigen MAIAP. This gene product is a new member of the inhibitor of apoptosis protein (IAP)

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family. The expression in AML cells of two other members of this family, survivin and XIAP, has been correlated with poor prognosis, likely reflecting the ability of IAPs to antagonize caspase activity and thereby promote cell survival. Although we initially identified MAIAP as a tumor antigen in a melanoma patient responding to vaccination with irradiated, autologous GM-CSF secreting tumor cells, MAIAP is frequently expressed in primary AML and is thus an attractive vaccine target for this disease. In the second part of this project, we will identify additional novel AML antigens by studying in detail the anti-leukemia immune response elicited in patients by vaccination with irradiated, autologous AML cells engineered to secrete GM-CSF or the infusion of donor lymphocytes following allogeneic bone marrow transplantation. Lastly, to complement these immunologic approaches, we will conduct a Phase I clinical trial to determine the safety and biologic activity of novel flt3 inhibitors. The frequent occurrence of flt3 mutations in AML cells together with the striking clinical activity of the STI571 bcr-abl kinase inhibitor in CML suggest that targeted pharmacologic therapy for AML may be possible. If the immunotherapeutic and pharmacologic approaches demonstrate biologic activity and safety, we plan to evaluate them in combination as well. The specific aims of this project are: 1. To determine the safety and biologic activity of vaccination with MAIAP in patients with AML. 2. To identify novel AML antigens through antibodybased expression cloning strategies. 3. To determine the toxicity and biologic activity of novel flt3 inhibitors in patients with AML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NUP98-HOXA9 AND AML Principal Investigator & Institution: Van Deursen, Jan M.; Associate Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-JAN-2003 Summary: (adapted from the investigator's abstract) The t(7;11) in patients with acute myeloid leukemia (AML) generates a fusion gene encoding the amino-terminal NUP98, an FG repeat-containing nuclear pore complex protein (NPC), and the carboxy-terminus of HOXA9, a homeotic transcription factor. The NUP98 portion of NUP98-HOXA9 contains 37 of the 38 FG repeat motif of NUP98. The HOXA9 part contains the HOXA9 DNA-binding domain and a TRP-containing motif that mediates interactions between HOXA9 and other transcription factors. The long term objective is to understand the exact mechanism by which NUP98-HOXA9 contributes to leukemia. To achieve this goal, the functionally critical motifs in the NUP98 and HOXA9 portions of NUP98HOXA9 that mediate its ability to transform NIH3T3 cell will be defined, as will the proteins that interact with these motifs. The ability of each NUP98-HOXA9 isoform to induce AML in vivo will be tested by genetically engineering mice to express the chimeric proteins. Further, these mice will be bred onto a BXH2 genetic background to identify mutations that cooperate with NUP98-HOXA9 to induce AML. Finally, the normal in vivo functions of NUP98 and HOXA9 will be studied by examining phenotypic effects of loss- or gain-of-function mutations in mice. These studies should further our understanding of the molecular mechanism of oncogenesis in an expanding subgroup o AML patients with translocations that link nucleoporins to nuclear proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS AND THERAPY OF ACUTE PROMYELOCYTIC LEUKEMIA Principal Investigator & Institution: Kogan, Scott C.; Assistant Professor; George Williams Hooper Foundation; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 19-FEB-1999; Project End 31-JAN-2004 Summary: A differentiation block is a cardinal attribute of nearly all human cancers and leukemias. For this reason, a major focus of clinical oncology trials has been to utilize differentiating agents, such as retinoic acid, to reverse the maturational defects characteristic of malignant cells. The most successful example of differentiation therapy has been the use of retinoic acid to treat acute pro-myelocytic leukemia, a form of leukemia associated with fusion of the retinoic acid receptor alpha gene encoding the Pml nuclear protein. In acute promyelocytic leukemia, the leukemic cells are blocked at the pro-myelocyte stage of differentiation but can be induced to develop into mature neutrophils by treatment with retinoic acid. The broad, long-term objectives of the proposed work are to elucidate the mechanism controlling the differentiation of blood cells, to understand how multiple genetic alterations combine to result in leukemia, and to utilize this knowledge to improve oncologic therapy. An animal model of acute promyelocytic leukemia was created by expression of a PMLRARalpha transgene in murine myeloid cells. The specific research proposed in this application is intended to utilize this model to fulfill three specific aims: 1) elucidate the mechanisms by which the chimeric PmlRaralpha protein impairs the differentiation of myeloid cells, 2) identify genetic events that cooperative with PmlRaralpha in leukemogenesis and define the role of these additional events, and 3) elucidate the mechanisms by which retinoic acid reverses the PmlRaralpha proteins will be determined. The ability of PmlRaralpha to alter the expression of genes that may regulate neutrophil differentiation will be assessed. The nature of the vents that cooperate with PmlRaralpha will be studied in the mouse model; cooperative events will be isolated with molecular cytogenetic and proviral tagging methods. The ability of retinoic acid to reduce PmlRaralpha protein levels and to induce transcriptional changes will also be evaluated in the mice. This proposal provides the additional mentored research career development required by the candidate to achieve his immediate career goal of becoming an independent investigator and will enable the candidate to develop a productive career as an academic hematopathologist, spending a portion of his time diagnosing hematologic disorders, devoting major efforts to research in leukemia pathogenesis, and utilizing this knowledge to improve therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Steuber, C P.; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: The concept of the pediatric cooperative cancer group was introduced over 30 years ago because of the rarity of pediatric malignant diseases and the vital importance of controlled trials to improve the outcome for such patients. For such a group to succeed, the collaborative contributions of individuals from a large variety of specialties and fields of research are absolutely essential. This multimodal organized approach to the treatment of childhood cancer through the cooperative group has welldemonstrated its value. The Section of Pediatric Hematology-Oncology at Baylor

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College of Medicine has been involved in the genesis of this kind of clinical research and has participated in the activities at even level. The current goals of the Section regarding cancer prevention, treatment, and research have lead to the recent development of the Texas Children's Cancer Center. The Center is a joint effort of Texas Children's Hospital and Baylor College of Medicine and is committed to providing the finest possible patient care, education and research in the areas of pediatric and adolescent cancer and hematological disorders. Major expansion of the clinic and research lab facility is underway. New faculty are being recruited to expand the current research program in the areas of gene therapy, bone marrow transplantation, molecular biology, clinical pharmacology, and experimental therapeutics. Additional personnel including data managers, pediatric nurse practitioners, and research personnel have been recruited to support the new faculty members and the expanded programs. In addition, outreach efforts are making the Center known to communities in Texas that would benefit from a service dedicated to the treatment of children with cancer. The development of the Texas Children's Cancer Center will enhance Baylor's contributions to the Pediatric Oncology Group (POG) by expanding the research and treatment programs that have so successfully contributed to POG throughout the years, by developing new and innovative treatment and research programs, and by increasing study populations for those programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Link, Michael P.; Professor; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The overall goal of this research proposal is for Stanford University, the University of Arizona, and the Kaiser Permanente Medical Centers of the South San Francisco Bay Area to continue their active involvement in Pediatric Oncology Group research activities. Stanford faculty and the University of Arizona faculty have already assumed key leadership positions in POG and have or have had major roles in the scientific and administrative aspects of the Group. Further, Stanford, the University of Arizona, and Kaiser have maintained excellent performance ratings in their participation in POG studies and have received commendations for the large numbers of evaluable patients placed on therapeutic protocols. Specifically: l) We plan to continue to enter patients on appropriate POG studies where they exist. The number of patient entries from Stanford has increased each year as appropriate POG studies become available. We anticipate that between 65 and 80 patients will be entered on front-line therapeutic studies each year from Stanford in addition to patients who will be entered from the affiliates; in addition, 40-50 patients or more will be entered on POG non-therapeutic studies. 2) We anticipate that the activities of individual investigators from Stanford and the University of Arizona will continue and increase during the period of this research proposal. Currently, our faculty serve as study coordinators for front- line therapeutic studies in lymphoma and leukemia, and they have coordinated and analyzed data from recently closed protocols in osteosarcoma, lymphoma, leukemia, and Ewing's sarcoma. Our faculty also serve key scientific and administrative roles as Group Vice Chair, Disease and Discipline Committee Chairmen and CoChairmen, as members of Disease and Discipline Core Committees, and as members of the Executive Committee. Thus, our faculty are in position to influence the future direction of the scientific activities of POG. 3) We anticipate that involvement of Stanford faculty in the laboratory scientific activities of POG will continue. The

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laboratories of Drs. Link and Cleary have served as immunology reference laboratories and molecular biologic reference laboratories for leukemia studies of POG. 4) We anticipate that non-POG related laboratory and clinical research conducted at Stanford University and its affiliates will become increasingly relevant to POG activities. Some of these activities have already been incorporated into POG laboratory and therapeutic studies and others are targeted for incorporation into future POG studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Meyer, William H.; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: Children's Hospital of Oklahoma (CHO) at the University of Oklahoma is a member institution of the Pediatric Oncology Group. One of our primary goals is the enrollment of the majority of pediatric patients with cancer in the state of Oklahoma in a cooperative cancer program (POG). Participation in group studies guarantees optimal care for these patients and the opportunity to study in depth the natural history of childhood cancer, develop effective therapeutic regimens, and evaluate the toxicity. and effectiveness of new anti-cancer agents in the treatment of childhood cancer. In addition to the POG studies, institutional non- therapeutic protocols have been developed, i.e., evaluation of leukemic therapy on the central nervous system of newly diagnosed leukemic patients and longitudinal evaluation of coping mechanisms with stress among patients and parents of children with cancer. For all these programs, patient resources and scientific expertise are available in Children's Hospital of Oklahoma. The team at the University of Oklahoma is multidisciplinary. It consists of pediatric hematologistsoncologists, radiation therapists, radiologists, pediatric surgeons, immunologists,

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pathologists and psychologists. All protocols are reviewed by the Institutional Review Board and informed consent is obtained on all patients entered into these protocols. Protocol compliance remains a high priority. The evaluability rate for the last four years averaged 92.5%. St. Francis Hospital of Tulsa was previously considered a branch of CHO. At the request of the POG Operations Office, Tulsa has applied to become an affiliate institution. The University of New Mexico is also affiliated with the University of Oklahoma. It serves an economically disadvantaged population (native American Indians) which needs to be included in the population studied by cooperative cancer groups. The Pathology Department at the University of New Mexico has special expertise in molecular diagnostic hematopathology and in solid tumors which can benefit the research efforts of the Pediatric Oncology Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Kung, Faith H.; Associate Professor; Pediatrics; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: This proposal represents a request to support continued participation in the pediatric Oncology Group (POG). This cooperative research is devoted to the investigation of chemotherapeutic, immunological and molecular biological approaches to the treatment of acute leukemia and other neoplastic diseases of childhood. Significant disease free survival has been achieved and contributions have been made in clinical pharmacology, tumor immunology and biology of cancer. However the real objective of these studies is the eradication of neoplastic diseases by treatment. Studies are being designed to reflect an increasing intensity of attack on the neoplastic cell. The cooperative group technique permits prompt evaluation in series of reasonable size of promising leads in chemotherapy. These leads or new approaches are often suggested by the results of the group's own work in clinical oncology. Thus, a completed protocol often suggests new avenues to be explored in new protocols. POG led in the investigation in the immunophenotyping of acute lymphoblastic leukemia, NTX polyglutamates accumulation in leukemic cells, and N-myc gene amplication in neuroblastoma, correlated the findings with patient outcome, and then incorporated them in new treatment protocols designed to improve the survival of children with cancer. The Division of pediatric Hematology/Oncology at the University of California, San Diego has 24 years experience (10 years in CALGB and 14 in POG) in cooperative clinical trials. In the past 5 years the 4 consortium member institutions had entered 332 patients on both therapeutic and non- therapeutic studies and the satellites, 211 patients. Our investigators served on 12 committees, designed/coordinated 16 group protocol studies. We also contributed to 15 group publications/presentations. Our investigators will continue to design and chair therapeutic protocols,and serve on committees. Dr. Yu's laboratory will continue to explore new immunotherapeutic agents for Group use, and serve as the Group Reference Laboratory. We plan to continue our active participation in all phases of POG activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

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

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

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Grier, Holcombe E.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1986; Project End 31-DEC-2002 Summary: The principal activity of this grant is to improve the care and treatment of children with cancer by participating in the Pediatric Oncology Group (POG). The three specific goals of the participation of the Dana-Farber Cancer Institute/Children's Hospital (DFCI/CH) and Maine Children's Cancer Program (MCCP) are to 1) enter and follow children with malignancies on appropriate Pediatric Oncology Group (POG) protocols 2) provide leadership in planning and executing POG protocols and 3) provide pilot clinical studies and scientific leadership to POG. 1) Patient entry: the referral patterns at the two institutions has not changed and the commitment to POG protocols remains high. Therefore, patients accrual will continue at the high level previously noted over the last grant period. 2) Leadership within POG: Drs. Weinstein and Grier respectively are the disease chairs for the Myeloid and Sarcoma Committees. The disease committee chairs have primary responsibility for all scientific and clinical activities within POG. Investigators from these institutions are currently or were in the last cycle chairs for 7 separate POG protocols and co chairs of 35 more. They also have 18 positions on disease or discipline committees within POG. Enthusiasm remains strong, and involvement at the current level will continue. 3) Pilot POG protocols and scientific leadership: Scientific leadership is detailed in part above. Dr. Arceci provided scientific leadership for and analyzed the samples of the MEC protocol (#9222) that piloted the use of multidrug resistance reversal agents (cyclosporine) in relapsed AML. This protocol provided the background for the about to open group wide AML up-front protocol (#9394) that will randomize whether or not patients will receive cyclosporine during maintenance therapy. DFCI ALL protocols have provided the background for one of the arms of the proposed new T- cell protocol (#9404). In addition, the background for the current stereotactic protocol (#9373) was in part developed at the Joint Center for Radiation Therapy and the DFCI. Finally, POG has embarked on a major effort to study the autologous transplant protocols for ALL (#9421) developed at the DFCl. Finally Dr. Lipshultz ran at DFCI/CH the pilot studies of late cardiac toxicity from anthracyclines that provides the background data for the randomized trial of enalapril for patients with elevated after load. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Luchtman-Jones, Lori; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: The Washington University Medical Center in St. Louis is one of the 39 full member institutions, 48 affiliate, 12 consortia and 9 CCOP institutions of the Pediatric Oncology Group who has pooled their patient resources and scientific expertise to study the natural history of childhood cancer, develop and compare effective therapeutic regimens and investigate the toxicity and effectiveness of new anticancer agents in the treatment of children with cancer. Additionally tumor specimens and occasionally normal tissue and blood samples are collected to determine more about the basic cancer biology and pathology of the disease. Group studies are ongoing in epidemiology, cancer control, pharmacology and pharmacokinetics. The investigators at the Washington University Medical Center include pediatric oncologists, radiologists,

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radiation oncologists, cytogenetists, neurologists, surgeons, and pathologists. All children with malignant disease are placed on cooperative group protocols if they are eligible and if informed consent is obtained. Data accessioned at the time the patient is placed on study protocol, during the study, and when off therapy is submitted to the Group Statistical Office for data analysis, interpretation and eventual publication. The investigators at Washington University Medical Center serve in multiple administrative and research capacities for the Group. The diagnostic studies, pathological findings, surgical procedure and therapeutic plan for all new patients and patients who relapse are discussed at the weekly Tumor Board Conference. The Principal Investigator has a phase I contract and works with 16 other POG institutions to establish the maximum tolerated dose of a new agent along with the pharmacology and, if indicated, the biologic response of the agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Lauer, Stephen J.; Professor of Pediatrics; Pediatrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-MAR-2003 Summary: The Pediatric Oncology Program at Emory University is the only comprehensive children's cancer center in Georgia and one of the largest of its kind in the Southeast. It serves a racially, ethnically, and socioeconomically diverse population from metropolitan Atlanta, the State of Georgia, and other states including Alabama, Arkansas, the Carolinas, Florida, and Mississippi. Since the inception of the Pediatric Oncology Group (POG), Emory is consistently one of the largest single-institution contributors to POG clinical and laboratory studies. Emory is a center for Phase I and pilot POG trials and has initiated numerous protocols that have subsequently been implemented by POG. The specific aims of the Emory POG Program are: l) to continue as a major source of patients for POG-sponsored Phase I, pilot, groupwide, and intergroup studies; 2) to provide leadership by its investigators as POG Study Coordinators, Co- coordinators, and Core Committee members; 3) to develop innovative institutional clinical trials on which to base future POG investigations; and 4) to maintain strong basic and translational research programs in pediatric oncology. To address these aims, Emory investigators are Coordinators for several major POG studies, including standard-risk new ALL (#9405), high-risk new ALL (#9006), salvage chemotherapy in relapsed neuroblastoma (#9140), and chemotherapy vs. autologous bone marrow transplantation (ABMT) in AML (#8821). Emory POG members actively participate in POG Core Committees, Subcommittees, and new protocol development. Institutional pilot studies include therapy of relapsed AML with idarubicin and chlordeoxyadenosine, treatment of relapsed solid tumors with high-dose busulfan/melphalan and ABMT, transplantation of haploidentical CD34+ cells for relapsed ALL or AML, and vincristine plus dose-escalated cyclophosphamide and infusions of peripheral blood-derived progenitor cells in refractory solid tumors. Complementary laboratory research activities include molecular biology of ALL (mechanisms of IL-6- mediated autocrine growth and aberrations in tumor-suppressor genes); in vitro sensitivity of leukemia cells to antineoplastic agents mid biological response modifiers; mechanisms of resistance of AML cells to alkylating agents; molecular neuro-oncology; and xenogeneic models to evaluate normal and neoplastic human hematopoiesis. Investigators at Emory are participating in the POG laboratory study of methotrexate metabolism by ALL cells (ALinC #16) and coordinate the study of alterations in p53 tumor-suppressor gene pathways in relapsed ALL (SIMAL #l0). Taken

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together, these activities of the Emory POG Program will continue to contribute to our knowledge of the biology, therapy, and prevention of neoplastic diseases in infancy, childhood and adolescence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: PEDIATRIC ONCOLOGY GROUP ACTIVITIES Principal Investigator & Institution: Winick, Naomi J.; Professor of Pediatrics; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: This grant application seeks continued support for the Pediatric Oncology Group (POG) activities of The University of Texas Southwestern Medical Center (UT Southwestern) Consortium, which consists of UT Southwestern (Dallas), Cook-Ft. Worth Children's Medical Center (Ft. Worth), and Scott & White Clinic (Temple). Since joining POG in 1981, this partnership of children's cancer treatment and research centers in

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North Texas has grown to become POG's largest contributing member with regard to patients enrolled on therapeutic studies (over 100 annually). During the current grant cycle, consortium investigators have held administrative and scientific leadership positions on major Group committees, including Executive Committee, Principal Investigator's Committee, New ALL Committee, T-cell Committee, and Lymphoid Relapse Committee. UT Southwestern Consortium investigators have also served or are serving as study coordinators on multiple POG treatment protocols studying ALL (newly diagnosed patients with B-lineage and T-cell disease as well as following relapse), non-Hodgkin's lymphoma, bone marrow transplantation and new agents being explored in Phase I-II trials. UT Southwestern Consortium investigators have also had prominent roles in the arenas of data management, protocol development, molecular and pharmacologic monitoring in authorized POG reference laboratories, and supportive care. Results of pilot projects conducted at UT Southwestern have been instrumental in the construct of group-wide treatment strategies, especially involving use of methotrexate for B-lineage ALL. To support the UT Southwestern Consortium's continued commitment to POG research during the next 5 years, this new grant proposal describes personnel and facilities in the 3 consortium centers. Specifically, during 1996-2000 the Consortium aims to advance POG research by: (l) enrolling as many patients as possible on POG treatment, biological classification, and epidemiology protocols; (2) collecting, recording, and submitting research data in an accurate and timely fashion; (3) providing administrative and scientific expertise to the Group through continued active participation on major committees, including service as disease committee chairs and protocol coordinators; and (4) continuing to conduct innovative in-house pilot studies for subsequent use by the Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY GROUP MEMBERSHIP Principal Investigator & Institution: Schwartz, Cindy L.; Associate Professor; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: The aim of this research is to improve the treatment of childhood cancer through participation in organized clinical trials with fellow members of the Pediatric Oncology Group. In addition, we intend to expand our understanding of these diseases by collaborative laboratory investigations. Multiple projects are described which reflect the intense commitment of our faculty to work within the Pediatric Oncology Group. Our faculty are leaders of the POG commitments in ALL phenotyping, Neuropathology, Bone Tumors, Hodgkins disease, Rhabdomyosarcoma, Radiation Oncology, Bone Marrow Transplantation, Myeloid disease, Germ Cell Tumors, Late Effects of Childhood Cancer Therapy, and Multiple Drug Resistance. Pediatrics is the program that describes patient accrual and protocol activity within the division of Pediatric Oncology at Johns Hopkins under the supervision of Dr. Cindy Schwartz as POG PI. The disciplines of Radiation Oncology, Pathology, Pediatric Surgery, Orthopedic Surgery, Neurosurgery and Nursing also play a major role in patient accrual and protocol activity. In addition, Fairfax Hospital under the direction of Dr. Jay Greenberg is an active affiliate of our institution. With the limited numbers of children admitted with any single oncologic diagnosis to an individual institution, it is clear that cooperative clinical research is required if significant advances are to be made. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

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Project Title: PEDIATRIC ONCOLOGY GROUP STUDIES Principal Investigator & Institution: Mclean, Thomas W.; Pediatrics; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-DEC-2002 Summary: The overall objective of the proposed research effort is to continue work towards determining the optimum care for children with all types of cancer. The research mechanism involves participation by pediatric investigators at the Bowman Gray School of Medicine in the development and execution of collaborative multidisciplinary clinical protocols of the pediatric Oncology Group. The proposed research grant will support the continued participation of the Bowman Gray School of Medicine as a full member of the pediatric Oncology Group. Our accomplishments in the past grant period are described in detail in the proposal. Our institutional goals for the five year period of this grant include: (1) continuing our high level of patient accrual and excellent clinical contributions to the POG including our outstanding patient evaluability and protocol compliance which has merited a letter of commendation from the operations office at every 6-month analysis in the past (2) maintaining our institutional involvement in POG leukemia studies and our representation on the new ALL core committee (3) continuation and further development of our multi-disciplinary institutional commitment to POG Hodgkin's disease activities (4) a major role on the

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POG cytogenetics committee including optimal use of our new reference laboratory status (5) increased institutional development of late effects studies in collaboration with the POG late effects efforts (6) expansion of our efforts in neuro-oncology including increased enrollment on brain tumor studies and investigator roles on the POG brain tumor committee (7) use of in situ studies of tumor cell ploidy in collaboration with POG and other investigators (8) continued contributions to the administrative aspects of the POG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER CTR

PEDIATRIC

ONCOLOGY

GROUP--MIDWEST

CHILDREN'S

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

Project Title: PEDIATRIC ONCOLOGY GROUP--THE CAROLINAS CONSORTIUM Principal Investigator & Institution: Barredo, Julio C.; Professor; Pediatrics; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-JUN-1996; Project End 31-DEC-2002 Summary: (Adapted from the applicant's description): The institutions included in this proposal have been part of the Pediatric Oncology Group (POG) and received good performance scores during the past five years. There are two primary goals of this proposed research; the first is to accrue patients to the Group clinical trials in order to determine the optimal care of children with all types of cancers. The second is to

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contribute scientific expertise to the Group in areas of both patient care and tumor biology. This proposed research will allow participation in POG activities through a consortium effort of East Carolina University (ECU) School of Medicine, Carolinas Medical Center, Medical University of South Carolina (MUSC), Greenville Hospital, Presbyterian Hospital, and Memorial Mission Hospital (The Carolinas' Consortium). In addition to these clinical activities, their scientific efforts in next five years will include: (1) development of new protocols for the treatment of children with cancer focusing mainly on pediatric lymphomas; (2) expansion of studies of minimal marrow residual disease (using RT-PCR analysis) and assessment of new purging techniques in neuroblastoma; (3) participation in the laboratory evaluation of folylpolyglutamate synthetase (FPGS) in lymphoblasts of newly diagnosed patients; and (4) evaluation of the role hematopoietic growth factors in the treatment of pediatric malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACOGENETIC STUDIES OF ACUTE MYELOID LEUKEMIA Principal Investigator & Institution: Moysich, Kirsten B.; Assistant Professor; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2004; Project Start 21-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Many academic institutions and Cooperative Groups maintain extensive archives of tumor tissue from patients with matching treatment and clinical outcome information. Such archives have been utilized for molecular characterizations of specific tumors, as well as prognostic studies aimed at investigating the effect of acquired genetic alterations on clinical outcome measures. There is increasing interest in utilizing these tumor archives in pharmacogenetic studies, which are concerned with assessing the associations between constitutional genetic polymorphisms and treatment-related toxicity and prognosis. Little effort has focused on the appropriateness of using diseased tissue as a source of genomic DNA in pharmacogenetic studies. We believe that an important first step in pharmacogenetic studies that utilize stored tumor tissue as a source of genomic DNA should be to demonstrate concordance between polymorphism measured in diseased and paired non-diseased tissue. Since our long-term interest lies in conducting a pharmacogenetic investigation of acute myeloid leukemia, we propose in our primary specific aim to systematically investigate the utility of using archived bone marrow samples for an investigation on the prognostic significance of a panel of genes involved in the pharmacodynamics of AML chemotherapy in a well-characterized group of AML patients. In our secondary specific aim, we propose to utilize the data generated from this methodological investigation for a pilot study on the role of this panel of polymorphisms relevant to AML treatment in toxicity and clinical outcome measures among AML patients. Specifically, we will compare genetic polymorphism data between paired bone marrow and buccal cells from 100 AML patients from Roswell Park Cancer Institute. In the pilot study component of this research we will assess role of genetic polymorphisms encoding for proteins involved in metabolism of chemotherapeutic agents used in the treatment of AML, protection from oxidative damage generated by chemotherapeutic agents, and drug resistance in clinical outcome measures among AML patients. Data generated from this research will guide the design of large-scale pharmacogenetic studies of AML by a) providing data on the appropriateness of using existing bone marrow tissue banks, and b) direct sample size considerations by providing data on potential misclassification of genotype data in bone marrow tissue, as well as preliminary data on the effect of genetic polymorphisms on clinical outcomes.

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

Project Title: PILOT--MOLECULAR EPIDEMIOLOGY OF APL IN HISPANICS Principal Investigator & Institution: Lopez-Enriquez, Alberto; University of Puerto Rico Med Sciences Medical Sciences Campus San Juan, Pr 00936 Timing: Fiscal Year 2002; Project Start 16-AUG-2002; Project End 31-JUL-2007 Summary: Unexplained high frequency (24-30%) of acute pro-myelocytic leukemia (APL) has been reported among Hispanic populations. The aim of this joint project between the University of Texas MD Anderson Cancer Center (MDACC), the Instituto de Enfermedades Neoplasicas (IEN) in Lima, Peru and the Puerto Rico Cancer Center (PRCC), University of Puerto Rico is to obtain preliminary epidemiologic cytogenetic, and molecular parameters that would allow to establish the feasibility of larger comparative multi-country study. For this purpose, the newly diagnosed APL patients admitted to the three centers will be ask to participate in an epidemiologic survey and will be examined for each of the 4 genes (PML, PLZF, NPM and NuMA) that could fuse to retinoic acid receptor/alpha (RARalpha) and the retinoic acid specific catabolic enzyme CYP26. We will look for the similarities and differences among the partner proteins in these patients that may explain the high incidence and/or distinct clinical outcome in response to retinoic acid (RA) therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PLZF ONCOPROTEIN COMPLEXES SPECIFIC INTERACTION BLOCKER Principal Investigator & Institution: Watt, Paul M.; Tvw Telethon Institute-Child Health Res for Child Health Research Subiaco, Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Several crucial oncoprotein interactions occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a target-specific therapy of leukaemia. The ability to isolate specific blockers of particular protein/protein interactions also provides an opportunity to uncouple complex genetic pathways in mammalian systems, which are relatively intractable to genetic analysis. The dissection of pathways using specific blockers may ultimately provide a useful avenue for identifying and characterizing new drug targets. We have chosen to target one of the known interactions of the oncoprotein, PLZF in the search for specific inhibitors. Complexes containing PLZF are involved in the development of Acute Promyelocytic Leukemia (APL) and Acute Myeloid Leukemia (AML). A genetic selection will be used to identify naturally derived peptide sequences which are capable of blocking PLZF/ETO interactions and which do not interfere with other interactions involving the PLZF protein. This technique termed 'dual-bait/reporter reverse two hybrid screening' allows one to select for or against specific blockers of known interactions in yeast cells. The affinity and specificity of the interaction blockers derived from the screen will be determined using the novel yeast genetic system and by ex vivo assays of functional effects of candidate peptides on repression and growth inhibitory activity of PLZF. Finally, isolation of specific blockers of PLZF interactions may provide leads or the development of new therapeutic agents for the treatment of APL and AML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: POLYMORPHISM OF MULTI-DRUG-RESISTANCE PROTEIN-1 Principal Investigator & Institution: Ho, Rodney J.; Professor; Pharmaceutics; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 10-JAN-2002; Project End 31-DEC-2005 Summary: (provided by applicant): The long-term goal of this program is to elucidate the genetic and functional correlates of drug transporters that influence inter-individual variations in drug disposition and therapeutic outcome. Variations in the 170 kd membrane bound, efflux transporter P-glycoprotein (P-gp, often referred to as multidrug resistance protein-1 or MDR-1) in adult subjects produce up to a 7-fold difference in bioavailability of digoxin, a P-gp substrate. P-gp is expressed in tissues central to in vivo drug disposition, including the liver, gut, blood-brain barrier, placenta, and kidney. While a number of genetic variants of MDR-1 have been demonstrated in continuous cell-lines, their frequency and clinical significance has not been fully established. A more robust and reliable RT-PCR method was developed recently to simultaneously quantitate MDR-1 mRNA and isolate 3.8 kb cDNA from total cellular RNA. As a result, an efficient cloning and expression of MDR-1 cDNA in an expression vector is now feasible. We will use these cDNA vectors to systematically evaluate functional variation of a large series of cDNA from leukemia patients. With this proposal, we will identify genetic variations that produce significant effects on the efflux function of Pgp with the following aims: Aim 1: to identify genetic variants of MDR- 1 from DNA and RNA isolated from leukemic (AML and MDS) patients. Aim 2: to determine functional significance of genetic variants identified from the leukemic patients By integrating the results of Aims 1 and 2, we can begin to define the role of genetic variations on the P-gp efflux function. The proposed studies will elucidate the role of MDR-1 genetic polymorphism in functional P-gp variations and may shed light on their modulation of systemic and CNS availability and disposition of drugs from a wide range of therapeutic classes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROFILING SPECTROMETRY

OF

PROTEIN

MODIFICATIONS

BY

MASS

Principal Investigator & Institution: Graeber, Thomas G.; Doe Ctr -Genomics & Proteomics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 12-MAY-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The cellular signaling circuitry has many types of regulation, from transcriptional control to regulation of protein degradation. These processes are often modulated by enzymatic modification of the proteins involved, and thus the modification of proteins is an integral part of most signal transduction pathways. In this project we plan to develop methods for detecting modifications within the proteome. Our initial focus will be on detecting tyrosine phosphorylation of proteins in cancer. We plan to develop methods for enriching cellular extracts for modified proteins directly coupled to methods for mass spectrometry-based detection and identification of these proteins. We also plan to demonstrate the usefulness of these "modification profiling" techniques by applying them to the study of specific biological questions. Misregulated tyrosine phosphorylation is a characteristic of many types of cancer, and several successful anticancer therapies are designed to inhibit activated tyrosine kinases associated with particular cancers. Thus, knowledge of additional examples of tyrosine kinase activities linked to cancer can ultimately be translated into

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new clinical therapies. This project will initially allow for the scholarly development of the candidate under the mentorship of the sponsor Dr. David Eisenberg, and the collaborators Dr. Joseph Loo and Dr. Charles Sawyers, and will ultimately result in an independent research project. The methods for collecting protein modification data to be developed in this project will complement existing methods for measuring gene expression data, assisting in one of the fundamental goals of genomics and proteomics to understand the circuitry of the cell. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGNOSTIC IMPLICATIONS OF FLT3 MUTATIONS IN AML Principal Investigator & Institution: Meshinchi, Soheil; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 08-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Activating mutations in the Flt3 receptor gene are the most common somatic mutation in AML and cause constitutive activation of the Flt3 receptor tyrosine kinase. Presence of these mutations (Flt3 internal tandem duplication, FIt3/ITD and Flt3 point mutations, FIt3/PM) may lead to lower rate of remission induction and increased rate of relapse. The aim of this project is to evaluate diagnostic marrow specimens from pediatric and adult AML patients treated on national multiinstitutional trials (CCG, POG and SWOG) for Flt3 activating mutations and to correlate FLT3 mutations with other biologic markers. Initially, presence of Flt3 activating mutations will be determined and correlated with clinical characteristics and outcome in an attempt to define the prognostic significance of these mutations. Clinical significance of the FIt3/ITD mutations will further be characterized by determination of the ITD allelic ratio and Loss of Heterozygosity (LOH) of Chromosome 13. We have created a collaborative network with our pediatric and adult colleagues where the information generated on Flt3 activating mutations will be merged and correlated with the data on ckit activating mutations, minimal residual disease and RNA expression profile in order to better define the biology of this mutation. We will also perform Flt3 mutational analysis as a part of national phase III AML trials in Adults (SWOG SO106) and pediatrics (COG AML trial- under development) in a prospective fashion to determine whether therapy intensification would alter the prognostic significance of Flt3 mutations. This grant project will undertake an extensive evaluation of Flt3 mutations in the largest patient population tested to date and will correlate the data with other biologic markers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: QUANTITATIVE HOX EXPRESSION AS PROGNOSTIC MARKER IN AML Principal Investigator & Institution: Drabkin, Harry A.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-OCT-2003 Summary: (provided by applicant): Homeodomain containing genes encode transcription factors that act during development to control pattern formation, differentiation and proliferation. Based on data from our laboratory and work of others, the quantitative analysis of HOX gene expression promises to be a powerful new tool in the prognostic assessment of patients with acute myelogenous leukemia (AML). To date, characteristic chromosomal alterations have been the gold standard for prognosis

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in AML. However, 50 percent of AML patients lack cytogenetic changes and another 1020 percent have alterations considered to be of intermediate importance. Thus, a majority of patients with AML lack sufficient prognostic markers upon which definitive therapeutic decisions can be made. Our studies indicate that the patterns of quantitative HOX gene expression are in near total concordance with favorable and adverse chromosomal features. In addition, these expression patterns extend to the subset of patients with normal cytogenetics and other intermediate changes and are predictive of outcome. We propose to confirm and extend our initial observations on the importance of HOX gene expression in AML. In the R21, we will refine our quantitative assays to include the complete set of HOXA, HOXB and important TALE (PBX, MEIS) family members and validate the analytic performance of these assays. We will also explore the analysis of selected extended HOX and paraHox genes in AML for inclusion in the subsequent R33. The R33 phase will determine the role of quantitative HOX expression as a prognostic marker in AML, the association of HOX expression patterns with specific chromosomal features as well as resistant or relapsed disease, and should permit us to identify the most useful subset of HOX genes based on our analysis of large numbers of patients and disease phenotypes. Lastly, we will determine whether there is a relationship between HOX expression and another new predictor of outcome involving internal tandem duplications or mutations of the FLT3 receptor. Importantly, the HOX genes are more than markers of lineage, or differentiation. Rather, they are integrally involved in the pathogenesis of acute leukemia in both mice and man. Thus, their analysis provides insight into the disease process, and its heterogeneity, while providing new important prognostic information. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECOMBINANT ANTICD33 ANTIBODY FOR AML Principal Investigator & Institution: Scheinberg, David A.; Chairman, Molecular Pharmacology & Chemi; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 26-SEP-1991; Project End 31-OCT-2003 Summary: (Adapted from Investigator's Abstract): The long-term goals of this program are to create monoclonal antibody based therapeutic agents for myeloid leukemia and to use studies in this model to understand basic principles of immunotherapy and resistance to immunotherapy in order to apply the concepts to other systems. Over the last 7 years of this R01, the investigators have constructed several new recombinant CDR grafted humanized anti-CD33 monoclonal antibodies (HuM 195) and characterized their biology, biochemistry, radiobiology, and radio- chemistry. The first alpha-emitting antibodies were characterized and have now entered human clinical trials. The interactions of HuM 195, in K cells and IL-2 were evaluated and this combination has also begun human trials. Phase II and III studies of the unmodified HuM 195 have begun internationally. Work has been completed toward understanding a new pglycoprotein mediated "immunological resistance" first described as part of this R01. This renewal is intended to build on several aspects of the prior work and proposes continued exploration of the newly discovered "immunological resistance." The investigators have recently observed that MDR HL60 cells were also cross-resistant to HuM 195-based immunotoxins, radioconjugates, and complement-mediated killing. Preliminary data suggest that p-glycoprotein may mediate this resistance by increasing intracellular pH (pHi). In Aim #1 the investigators propose to study and explain this new pHi mediated immunological resistance by conducting electrophysical studies on individual cells and on populations. The structure and function studies of the membrane

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attack complex will also be performed. Manipulations of pHi will be done in cells from patients with PNH, a human disease associated with excessive complement mediated lysis. In Aim #2, the investigators will focus on understanding resistance to the immunotoxin Hum 195-gelonin and will explore how MDR cells resist targeted alpha radiations. In Aim #3 the investigators will study methods to bypass the resistance to both toxins and isotopes in vitro, ex vivo, and in vivo. It is anticipated that these studies will result in data that can be applied quickly to human clinical problems in clinical trials and to other tumor systems as well. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOIC ACID PARADOX AND PROMYELOCYTIC LEUKEMIA Principal Investigator & Institution: Dmitrovsky, Ethan; Andrew G. Wallace Professor of Pharmacol; Pharmacology and Toxicology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 01-MAR-1994; Project End 31-MAY-2006 Summary: Acute promyelocytic leukemia (APL; FAB M3) cells have a balanced translocation t(15;17) (q22;12-21) rearranging the retinoic acid receptoralpha (RARalpha) and promyelocytic leukemia (PML) genes. Two features distinguish APL: (1) APL cells express PML/RARalpha that results from this translocation and (2) alltransretinoic acid (RA) treatment of APL induces complete clinical remissions. Paradoxically, these responses are linked to PML/RARalpha expression. Prior work from our laboratory and others indicate that PML/RARalpha functions as a dominantnegative transcription factor whose, effects are overcome by pharmacological RA dosages leading to degradation of PML/RARalpha protein. Target genes are activated by RA to signal terminal growth suppression and differentiation. Identification of these target genes is the subject of our current work. A hallmark of the APL differentiation program is the rapid proteolysis of PML/RARalpha by RA via proteasomal degradation. Using microarray analyses, direct evidence was found for an RA inducible mechanism for ubiquitin-dependent PML/RARalpha degradation. A gene cluster prominently induced by RA-treatment of APL cells was that of the ubiquitin-ligase system. A component is UBE1L, an E1-like ubiquitin-activating enzyme. UBE1L induction provides a mechanistic basis for PML/RARalpha degradation by RA. We hypothesize that UBE1L is an RA-target gene leading to PML/RARalpha degradation. This relieves dominant-negative effects of PML/RARalpha and permits differentiation to proceed. We confirmed this by co-transfecting UBE1L with PML/RARalpha. This leads to PML/RARalpha degradation even without RA-treatment. For this competing renewal application of NIH R0-1 CA62275-07, we propose to confirm that UBE1L is a direct retinoid target gene. that triggers PML/RARalpha degradation and overcomes the differentiation block in APL cells through three specific aims. First, to study comprehensively the retinoid regulation of UBE1L in RA sensitive and resistant APL cells and determine whether UBE1L is a direct RA target gene. Second, to conduct mechanistic co-transfection studies to elucidate how UBE1L triggers PML/RARalpha degradation. Third, to establish the in vivo relevancy of these findings by conducting UBE1L stable transfection studies in RA sensitive and resistant APL cells that contain wild-type or mutant PML/RARalpha species. Cellular, biochemical, and molecular genetic techniques are used to investigate mechanisms of RA action, using preclinical experimental models of APL. Through successful completion of these aims, a fuller understanding of APL RA response should derive in this important model for differentiation therapy. These findings are relevant to retinoid-based differentiation therapy of other human malignancies.

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

Project Title: ROLE LEUKEMOGENESIS

OF

AML1/ETO

IN

HEMATOPOIESIS

AND

Principal Investigator & Institution: Mulloy, James C.; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 16-MAY-2001; Project End 31-JAN-2003 Summary: The AML 1/ETO fusion protein is causally implicated in the pathogenesis of 40% of acute myeloid leukemias of the M2 subtype, and accounts for 12% of human AMLs overall. The fusion gene is compromised of the amino-terminal portion of the AML1 (CBFA2) gene on chromosome 21 and the nearly full coding region of ETO gene on chromosome 8. Aml1/Eto interferes with the function of the transcription factor, CBF, in a dominant negative fashion, presumably by its ability to bind to the heterodimeric transcription partner CBF beta and repress transcription through CBF enhancer elements. Mice deficient in AML1 or CBF BETA lack definitive hematopoiesis, and these mice die during embryogenesis. Similarly, mice engineered to express a leukemic fusion protein that interferes with CBF function die from a similar phenotype, complicating the development of an animal model of AML. Recent advances in retroviral gene delivery systems, hematopoietic stem cell biology, and immunodeficient animal development have made it possible to overexpress genes of interest in human and murine stem cells and use these cells to reconstitute the immune system of recipient animals. The ultimate objective of this work is the development of murine model AML, specifically of AML associated with expression of AML1/ETO (Specific Aim 1). A murine retovirus optimized for expression in stem cells will be used, and the green fluorescent protein will be co-expressed from the same mRNA using an IRES element, to facilitate identification of transduced cells. Both human and murine stem cells will be used in these studies, and the appropriate animal model will be chosen to allow the growth of transformed cells in vivo. In vitro studies will also be performed to determine the effects of AML1/ETO over-expression on normal hematopoiesis (Specific Aim 2). Using specific combinations of cytokines and stromal layers, the investigator will determine which hematopoietic lineage is affected by AML1/ETO expression. Mutants of AML1/ETO will also be included in the system, to decipher which signaling pathways are important in AML1/ETO-induced leukemia in vivo. mRNA from human stem cells expressing AML1/ETO will be used for differential hybridization screening of high-density microarrays to identify target genes regulated by AML1/ETO (Specific Aim 3). These target genes will be evaluated for their contribution for the phenotype elicited by expression of AML1/ETO in human stem cells, using the assays mentioned above. Taken together, these data will provide detailed information on the functional role of AML1/ETO in both hematopoeisis and leukemogenesis. The establishment of a small animal model of AML will greatly enhance our ability to develop and test treatment strategies and drugs that may be useful in the therapy of AML. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF MYELOID ELF-1 LIKE FACTOR IN HEMATOPOIESIS Principal Investigator & Institution: Hedvat, Cyrus V.; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 05-APR-2001; Project End 31-MAR-2006 Summary: (Adapted from applicant?s abstract) The ETS family of transcription factors play key roles in the regulation of hematopoiesis. ETS factors regulate critical events in

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hematopoietic development as demonstrated by the profound defects observed in mice deficient in these genes. The aberrant expression of ETS family members has been linked to the pathogenesis of several types of human and murine leukemia as well as other malignancies. MEF (myeloid elf-1 like factor) is a member of the ETS family cloned from a human megakaryocytic leukemia cell line (CMK). MEF activates transcription of genes important in hematopoiesis including the cytokines GM-CSF and IL-3. MEF interacts with the transcription factor AML1, and the AML1/ETO fusion protein, the product of the (8;21) translocation in acute myelogenous leukemia, and cooperates with AML1 in the regulation of the IL-3 promoter. To evaluate the role that MEF plays in hematopoietic cell development and function, the regulatory pathways central to MEF function will be defined. 1) A tetracycline-inducible MEF expression hematopoietic cell model will be used for differential gene expression analysis with DNA microarrays to identify target genes, which will be validated, and their regulation studied. 2) The functional domains of MEF that regulate the interaction with AML1B and cyclin A will be characterized and their role in regulating target gene expression will be studied. 3) the phenotype of MEF deficient mice generated by homologous recombination will be characterized to define the role of MEF in the development of the hematopoietic, as well as other, systems. Gross, microscopic, and cell-type specific functional abnormalities will be assessed with particular attention to the hematopoietic system. This work will contribute to defining the relationship between mechanisms of cellular development and differentiation and the establishment of disease. Work in the area of hematopathology where diagnostic skills will be developed. Experience in the analysis of mouse models, the use of emerging microarray technology to study and diagnose disease, and clinical diagnostic development will lead to an independent career as a physician scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE TRANSFORMATION

OF

THE

PNH

PHENOTYPE

IN

LEUKEMIC

Principal Investigator & Institution: Bessler, Monica; Barnes-Jewish Hospital Ms 90-94212 St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 20-JAN-2001; Project End 31-DEC-2005 Summary: (adapted from the applicant's abstract): Paroxysmal nocturnal hemoglobinuria (PNH) is a blood disorder, which is caused by the clonal expansion of a hematopoietic progenitor cell that carries a somatic mutation in the X-linked PIGA gene. It presented classically with hemoglobinuria due to intravascular hemolysis, thrombotic complications, and pancytopenia. The PIGA gene encodes a protein subunit of a glycosyltransferase essential in the synthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. Patients with PNH therefore have a proportion of blood cells deficient in all GPI-linked surface molecules. PNH is frequently found in patients with aplastic anemia (AA) and in patients with myelodysplasia (MDS). Although not a neoplastic disease on its own, patients with PNH have an increased risk of developing acute myeloid leukemia (AML). Promoted by the clinical association of PNH with AA, MDS, and AML, we raised the hypothesis that a PIGA gene mutation alone does not cause clonal expansion or leukemic transformation. But due to their inability to like certain proteins to the cell surface through a GPI-anchor PNH cells escape immuno surveillance and cell death that causes bone marrow aplasia in AA and controls neoplastic cell growth in early leukemogenesis. In the proposed research we will use a mouse model that closely mimics the human disease and investigate the association of PNH with MDS and AML. We will obtain mice with blood cells lacking GPI-linked

52


proteins by disrupting the murine Piga gene in early hematopoietic progenitor cells in the bone marrow using the Cre-loxP system. By this approach we will generate two types of mice, one with all blood cells deficient in GPI-linked proteins whereas the other will have both PIGA (+) and PIGA(-) circulating blood cells. We will then compare PIGA(+) and PIGA(-) hematopoiesis in these mice in vitro and in vivo under a variety of circumstances, including the administration of stimuli that trigger cell death along with agents known to cause leukemia transformation. Competition between cells expressing wild type Piga and those expressing the recombined Piga allele will enable us to uncover even subtle differences in cell death and proliferation in any stages of hematopoietic differentiation. These experiments will demonstrate whether PIGA(-) blood cells are more resistant to specific stimuli that activate apoptotic cell death and whether mice with PIGA(-) blood cells develop leukemia earlier and more frequent compared to mice with phenotypically normal blood cells. In this way we hope to identify the factors that differentially influence growth and death of PNH and normal hematopoietic progenitor cells and to elucidate mechanisms that may lead to leukemia transformation in patients with PNH. The availability of a mouse model for PNH will provide us with a powerful tool to test new therapeutic agents for the treatment of PNH, PNH/MDS, PNH,AML and possibly other clonal blood disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SRCAP TRANSCRIPTION

REGULATION

OF

CREB

AND

GR-MEDIATED

Principal Investigator & Institution: Chrivia, John C.; Associate Pharmacological & Physiol Scis; St. Louis University St. Louis, Mo 63110

Professor;

Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): CREB-binding protein (CBP) functions as a coactivator for many transcription factors and is able to respond to extracellular signals to specifically regulate gene expression. Mutations within CBP have been found in patients with mental retardation and growth defects (Rubinstein-Taybi syndrome) and have been demonstrated in patients with acute myelogenous leukemia. Several viruses that cause diseases in humans (HTLV-l, HIV-1, CMV, HBV, and adenovirus) also use CBP to regulate gene expression. Regulation of transcription by CBP occurs in part through its ability to function as a histone acetylase transferase (HAT), and in part through contact with other molecules which themselves function as HATs or which function as general transcription factors such as TBP. Recent work indicates that CBP contacts a specific subset of proteins to activate transcription at different promoters. We have identified a novel protein termed SRCAP (SNF2-Related-CBP-Activator Protein) that binds to a region within CBP shown to be important for CBP to function as a coactivator for CREB. SRCAP regulates the ability of CREB and CBP to activate transcription and we have found that SRCAP regulates transcription of several promoters (PEPCK, somatostatin, and enkephalin) that utilize CREB and CBP to activate transcription. In addition, we have found that SRCAP enhances glucocorticoid receptormediated transcription of the MMTV-promoter. Recent studies indicate that SRCAP (like CBP) is targeted by several viral proteins. These include: the HCV core protein that inhibits CREB-mediated transcription; the HCV NS5A protein that in conjunction with SRCAP represses transcription of the p21 gene; the adenovirus protein, DBP, that blocks CBP-SRCAP interaction and inhibits transcription mediated by SRCAP; and the adenovirus protein, Ela that binds CBP and blocks binding of CBP to SRCAP. The proposed studies will determine whether interaction of CBP and SRCAP is needed for CREB-mediated transcription of endogenous genes. They will determine the

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mechanism(s) through which SRCAP activates CREB-mediated transcription and by which SRCAP activates GR-transcription of the MMTV promoter. These studies will also determine whether SRCAP binding proteins regulate the ATPase and transcriptional activities of SRCAP. For example, we have found that the Dead box RNA helicase protein (DBX) binds to SRCAP and represses CREB-mediated transcription. We propose to determine whether this repression of CREB-mediated transcription occurs through formation of a DBX-SRCAP complex. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STAT ACTIVATION IN LEUKEMIAS Principal Investigator & Institution: Zuckerman, Kenneth S.; Professor; Internal Medicine; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2006 Summary: (Applicant's Abstract) The first purpose of this project is to understand the molecular mechanisms responsible for the constitutive activation of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signal transduction pathways in some cases of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML). The second purpose of this project is to determine the importance of constitutive JAK2/STAT5 activation in development and maintenance of the leukemic phenotype, both in vitro and in vivo. The primary hypotheses being tested are that specific activating mutations that lead to constitutive activation of JAK/STAT signal transduction pathways are responsible for the development and/or maintenance of leukemic cell survival and proliferation, and that, in leukemic cells expressing constitutively activated STAT5, inhibition of STAT5 activation or function. Three specific aims are proposed to test these hypotheses. Specific Aim 1 is to determine the mechanism(s) of constitutive activation in the HEL/Dami and Meg-01 human leukemic cell lines. Specific Aim 2 is to determine whether constitutive JAK/STAT signaling pathway activation plays an important role in maintenance of the leukemic phenotype of primary human AML cells. Specific Aim 3 is to determine the ability of double-stranded "decoy" oligonucleotides containing the STAT5 binding domain to inhibit the unregulated survival and proliferation of leukemic cells in vivo. The models to be tested include: (1) human HEL/Dami and Meg-01 cell lines implanted in sublethally irradiated NOD/SCID mice; (2) tet-off bcr/abl transgenic mice, which develop leukemia when mice are deprived of tetracycline in their drinking water (obtained from Dan Tenen); and (3) mice transplanted with bone marrow cells transfected with TEL/JAK2 or TEL/ABL retroviruses, which result in development of leukemias that have constitutively activated STAT5. These studies should lead to new understanding approaches for treatment of leukemias in which STAT activation plays a role in maintenance of the leukemic phenotype. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: TARGETING FLT3 AS A NOVEL SPECIFIC THERAPY FOR LEUKEMIA Principal Investigator & Institution: Levis, Mark J.; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Leukemia remains a deadly disease in both adults and children. The majority of patients still die, and new treatments are urgently needed. There is now substantial data indicating that the receptor tyrosine kinase FLT3 plays a

54


role in a significant fraction of leukemias. FLT3, which is expressed in most cases of acute myeloid and acute lymphocytic leukemia (AML and ALL), is constitutively activated by internal tandem duplication (ITD) mutations of the juxtamembrane region, by point mutations in the kinase domain, and by co-expression of FLT3 ligand (FL). 30% or more of AML cases harbor an activating mutation of FLT3, and this subset of patients has been shown to have a worse prognosis. Preliminary data presented here provides evidence that a FLT3 tyrosine kinase inhibitor is specifically cytotoxic to AML cells harboring FLT3 activating mutations. This proposal's scientific objective is the development of a FLT3 tyrosine kinase inhibitor for use in the treatment of leukemia. The immediate goal is to characterize the responses of different types of leukemias to the inhibitors in order to predict which patients may benefit from this therapy. The specific aims will be to test human leukemia cell lines and primary leukemic blasts for cytotoxic response to FLT3 inhibitors, with and without chemotherapy, and to correlate this cytotoxic response with changes in downstream signaling proteins and gene expression. Similar correlative studies will be performed on samples from patients receiving the inhibitor as part of a clinical trial. A FLT3 inhibitor has tremendous potential as an alternative or adjunct to conventional therapy for acute leukemias. This proposal has two goals. The first is to address the urgent need for new leukemia therapies. The second is to allow the principal investigator, Dr. Mark Levis, to develop into a laboratory-based researcher whose focus is to translate basic science research into clinical applications. With the guidance of a mentor who has expertise in the pathogenesis of leukemia, along with a structured educational program and a supportive academic environment, the principal investigator will use the support provided by this award to complete the transition to independent clinician scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TARGETING LEUKEMIAS WITH BCL2 BH3 HELICAL PEPTIDES Principal Investigator & Institution: Satterthwait, Arnold C.; Associate Professor; Burnham Institute 10901 N Torrey Pines Rd La Jolla, Ca 920371005 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Malignancies are often characterized by defects in programmed cell death (PCD) pathways contributing to blocks in responses to irradiation and chemotherapy. These defects are frequently manifested by imbalances in the Bcl-2 superfamily of proteins that link survival and death signals to the core PCD machinery. Bcl-2 is over-expressed in about 50% of all cancers. Most chronic lymphocytic leukemias (CLLs) and many Acute Myelogenous Leukemias (AMLs) and Acute Lymphocytic Leukemias (ALLs) over-express anti-apoptotic Bcl-2. Functional studies in vitro suggest an important role for Bcl-2 family proteins in maintaining the survival of these leukemic cells and promoting their resistance to chemotherapy. We hypothesize that apoptosis is controlled by the heterodimerization of competing Bcl-2 family inhibitors, inducers and effectors which ultimately determine whether the inducers channel apoptotic proteins through mitochondrial membranes. Heterodimerization occurs via BH3-domain binding pockets. Preliminary experiments from our laboratory reproducibly demonstrates that a constrained alpha-helical Bak BH3-domain peptide (16 mer) from the pro-apoptotic protein Bak, but not a wild-type unconstrained peptide, overrides block(s) to apoptosis in freshly isolated leukemia cells. The alpha-helical structure is essential for high affinity binding of BH3 peptides, and therefore constrained BH3 peptides are more potent than unconstrained linear peptides. We propose to (1) test various strategems for improving the activity of the Bak BH3 peptide as well as for synthesizing constrained helical BH3 peptides from additional

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55

effectors (Bax, Bak) and an inducer (Bid), (2) assess their pro-apoptotic activities and the sensitivities of CLL and AML cells from untreated and relapsed/refractory individuals, (3) identify the targets of pro-apoptotic BH3 peptides by comparing affinities for Bcl-2 family proteins and (4) link a potent pro-apoptotic peptide to membrane permeable peptides for tests against leukemic cells. BH3 peptides could provide powerful tools for proof of concept data in support of efforts to generate small-molecule compounds that mimic Bcl-2 family proteins for the treatment of leukemia and for identifying mechanisms of cell survival and resistance to chemotherapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE BTB POCKET AS A NOVEL CANCER THERAPY TARGET Principal Investigator & Institution: Melnick, Ari M.; Belfer Scholar; Developmtl & Molecular Biology; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): The BTB domain transcription factors regulate the phenotype of normal and malignant cells by virtue of their repression of specific genetic programs. In particular two BTB proteins, Bcl-6 and PLZF play critical roles in nonHodgkin? s lymphomas and retinoid resistant APL respectively. Both of these proteins repress target genes by interacting with co-repressors that recruit histone deacetylases. The BTB domain is required for transcriptional repression by these two proteins and thus represents the major functional motif of Bcl-6 and PLZF. We performed detailed structure-function studies on Bcl-6 and PLZF including crystallographic analysis of the BTB domains of both proteins, and found that a conserved charged pocket is the BTB docking site for co-repressors. Pocket mutants that abrogate co-repressor binding are unable to mediate transcriptional repression and are severely impaired for biological effects, demonstrating the central importance of the charged pocket for the entire proteins? functions. We also identified the reciprocal co-repressor consensus sequence that binds to the BTB pocket. Based on these findings, we hypothesize that the BTB domain charged pocket represents a potential target for development of specifically targeted transcriptional therapy agents that bind to the pocket motif. To validate the BTB pocket as a potential drug target, we intend to introduce the minimal pocket binding peptide into cells using protein transduction domains as carriers. Using this methodology we will determine the effect of these peptides in binding the BTB pocket in vivo, blocking co-repressor interaction in vivo, blocking transcriptional repression, and, most importantly, inhibiting the well characterized cell biological effects of PLZF and Bcl-6 as well as derepressing the target genes silenced by these proteins. In addition, we propose here to develop two high throughput screening assays which can be used in the future to identify compounds that occupy the BTB charged pocket and block corepressor interactions. We expect this research to ultimately lead to the development of a new class of drugs which could provide targeted therapy of non-Hodgkin? s lymphomas as well as retinoid resistant acute promyelocytic leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: THE PLZF PROTEIN OF T(11;17)-PROMYELOCYTIC LEUKEMIA Principal Investigator & Institution: Licht, Jonathan D.; Professor and Vice Chairman; Ruttenberg Cancer Center; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 01-APR-1993; Project End 31-JAN-2008

56


Summary: The promyelocytic leukemia zinc finger (PLZF) protein is a transcription factor, expressed in hematopoietic progenitor cells, fused to the retinoic acid receptoralpha (RAR alpha) in t(11;17)-associated acute promyelocytic leukemia (APL). Over the past 9 years, through two periods of funding, our group characterized t(11;17) APL as a distinct syndrome, unresponsive to retinoic acid. We determined that the PLZFRARalpha fusion generated in t(11;17) is a dominant negative form of PAR that actively recruits corepressors and histone deacteylase molecules to RAR target genes. The study of the PLZF fusion protein helped solidify the model of aberrant transcriptional repression as a pathogenic basis of leukemia. Though progress has been gratifying, many questions remain. The nature of the critical target genes of the retinoid receptor blocked by the fusion proteins of APL is not certain. The way in which genes are repressed is incompletely understood. Histone deacetylases are critically involved but other modes of chromatin modification, chromatin remodeling and epigenetic silencing of repressed genes are likely. The PLZF protein represses through a number of corepressors attracted though the BTB/POZ Domain. Further structure of this domain will yield further insights and potential therapeutic modalties in the disease. APL in animal models occurs after a considerable delay, indicating that other mutations are required for the disease to occur. One such cooperating mutation may be the mutation of the fit3 receptor tyrosine kinase molecule. One mode of cooperation may be the ability of the APL fusion proteins to abrogate the p53 pathway and prevent premature cellular senescence in response to activation of ras/map kinasse pathways. PML is a modulator of p53 function and PLZF may be as well. The proposed research will: 1. Determine of how PLZF controls myeloid cell growth and differentiation by elucidation of PLZF target genes which bind the PLZF protein in vitro and in vivo such as IL-6, cyclin A and other to be identified by whole genome PCR. 2. Define how an evolutionarily conserved protein motif, the POZ domain, functions in transcriptional regulation, though mutagensis of conserved residues and identification of partner proteins using the yeast two hybrid system. 3. Define protein-protein interaction networks that play a role in normal myelopoiesis and leukemogenesis (PML-PLZF, N-Cor-PLZF) 4. Extend knowledge of gene regulation in early hematopoiesis through characterization of the cisacting sequences controlling expression of PLZF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE RISK OF CANCER IN FANCONI ANEMIA HETEROZYGOTES Principal Investigator & Institution: Berwick, Marianne; Professor and Chief; SloanKettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: Fanconi anemia (FA) homozygotes have an increased cancer predisposition. In addition to the extraordinarily high frequency of AML in FA patients (actuarial risk of 52 percent for the development of MDS and/or AML by 40 years of age), FA patients exhibit malignancies of a variety of organ systems, most commonly gastrointestinal and gynecologic. The high incidence of nonhematologic malignancy in FA patients is especially striking because of the predicted early death from hematologic causes associated with the syndrome. Thus patients are unusually young when they develop cancer, and the incidence of malignancy probably would be considerably higher if patients had a longer life expectancy. There is evidence that heterozygote carriers of homozygous recessive familial cancer syndromes, such as Fanconi anemia, ataxia telangiectasia and xeroderma pigmentosum, are at increased risk for cancer. It is now possible to ascertain the carrier status by means of molecular tests rather than impute carrier status through probabilities, and thus it may be possible to arrive at a definitive

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answer to the role of heterozygosity among Fanconi anemia carriers. This study will directly address the etiology of cancer that involves the role of Fanconi anemia heterozygosity. The major aim of this retrospective cohort study will be to evaluate whether FA heterozygotes are at increased risk for developing cancer. In order to address this aim this study will use the extensive resources of the International Fanconi Anemia Registry at Rockefeller University. The sample will consist of 758 Fanconi anemia heterozygote grandparents of FA probands and 758 grandparents who do not carry an FA allele. Risk factor information will be obtained by questionnaire, blood will be collected for DNA analysis, and diagnostic pathology information will be collected using a systematic approach. Analyses will be undertaken to evaluate the role of Fanconi anemia heterozygosity for cancer. If carriers are found to be at increased risk, this information can be used to target individuals for cancer prevention strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF CREB IN LEUKEMOGENESIS Principal Investigator & Institution: Sakamoto, Kathleen M.; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2004; Project Start 20-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Leukemia is the most common form of childhood cancer. Children with acute myeloid leukemia (AML) have less than 50% overall survival despite aggressive chemotherapy and bone marrow transplantation. Therefore, it is critical to understand the molecular pathogenesis of AML. We demonstrated that CREB is overexpressed in bone marrow cells from patients with AML but not in normal bone marrow or bone marrow from patients without active leukemia. Furthermore, CREB overexpression was associated with an increased risk of relapse and decreased event-free survival in patients with AML. Our preliminary results suggest that AML is a heterogeneous disease that is not well understood. We hypothesize that there is an uncoupling of differentiation and CREB expression in myeloid leukemia cells. We propose to study the role of CREB in normal and malignant myeloid cells to identify novel mechanisms of leukemogenesis and improve our understanding of the molecular pathways regulating myeloid cell proliferation and differentiation. In Specific Aim 1, we will characterize CREB expression and activation in primary normal myeloid cells and myeloid leukemia cells. Experiments are proposed to determine the expression of CREB in normal mouse embryos at different stages of hematopoietic development. We will also examine CREB expression in normal myeloid progenitor cells at different stages of myeloid differentiation. Finally, we will examine whether CREB is activated in primary leukemia cells. In Specific Aim 2, we will further characterize the biological phenotype of CREB overexpression and down regulation in myeloid leukemia cell lines and primary normal myeloid cells. Our preliminary results demonstrated that CREB overexpression leads to increased proliferation and survival of myeloid leukemia cells. CREB down regulation using RNA interference (RNAi) suppresses the growth and survival of leukemia cells. To study signaling pathways upstream of CREB, we will overexpress activated kinases and use RNAi technology to inhibit expression of kinases. In Specific Aim 3, we will characterize the phenotype of transgenic mice in which CREB overexpression is targeted to myeloid cells. Defects in hematopoiesis and development of leukemia will be determined in both CREB transgenic mice and a mouse bone marrow transplant model. These studies will define the role of CREB in both normal and malignant myelopoiesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF CYCLIN A1 IN ACUTE MYELOID LEUKEMIA Principal Investigator & Institution: Wolgemuth, Debra J.; Professor; Obstetrics and Gynecology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): We have identified a novel mammalian A-type cyclin, cyclin AI, that our targeted mutagenesis in mice revealed to be essential for the progression of male germ cells into meiosis. Human cyclin AI is also highly expressed in myeloid leukemia cell lines and in leukemic cells from patients with acute myeloid leukemias, in the promyelocytic form (APL) in particular. We have tested the hypothesis that the aberrant high levels of cyclin AI were causal in the leukemic phenotype, i.e., acting as an oncogene. Transgenic mice in which cyclin AI was expressed under the control of the human cathepsin G promoter in myeloid precursor cells were generated. They exhibited abnormal myelopoiesis and developed acute myeloid leukemia with low penetrance and long latency. Interestingly, in the transgenic mouse model and in human NB4 cells, the localization of cyclin A1 is predominantly cytoplasmic, distinct from its nuclear localization in germ cells. We wish to understand the cellular mechanisms in myelopoiesis that are altered in the presence of elevated levels of cyclin A1 that is now mostly cytoplasmic. The distinct cytoplasmic localization of cyclin A1 will be studied, testing the hypothesis that this property contributes to the tumorigenesis. We will also address the role of cyclin A1 during normal hematopoiesis by studying hematopoietic parameters in mice that are null for the cyclin A1 gene. The hypothesis that cyclin A1 will have distinct Cdk partners, other interacting partners, and substrates in normal versus leukemic cells will be tested using immunoprecipitation and a yeast 2-hybrid screen. As high levels of cyclin A1 protein have been shown to be characteristic of APL, we will ask whether manipulating the expression of cyclin A1 will affect the development of the leukemia. We will test this idea by performing genetic studies in which we will manipulate the expression of cyclin A1 in the fusion oncogene X-RARalpha transgenic animal models of APL. The question is whether these mice will be more resistant to the development of leukemia in the absence of cyclin AI. These studies will provide important insight into the etiology of myeloid leukemia, the role of cell cycle control in the oncogenic process, and the development of new and potentially highly tissue-specific target molecules for pharmacologic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE VARIABLE EXPRESSION OF CD33 ON LEUKEMIC STEM CELLS Principal Investigator & Institution: Becker, Michael William.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 22-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This is an application for a K08 award. The candidate is a junior faculty member in the Blood and Marrow Transplantation Program at the University of Michigan Medical Center. Dr. Becker's long term goal is to become an independent laboratory investigator in the field of leukemogenesis and stem cell biology. This application details a four point program that will provide the necessary tools for Dr. Becker to develop his research career such that he can achieve this goal. First, Dr. Becker will obtain advanced conceptual and theoretical training in molecular biology and developmental biology with particular emphasis on carcinogenesis and stem cell biology by participating in several courses in the University of Michigan graduate school. Second, Dr. Becker will acquire additional research skills and

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techniques through the completion of his research project regarding the expression of CD33 on leukemic stem cells in Acute Myelogenous Leukemia. Dr. Becker has already achieved impressive preliminary data that have been submitted for publication in a leading peer reviewed journal. Third, Dr. Becker will acquire advanced communication skills, both written and oral, required for a successful career through participation in BMT research seminars and conferences, participation in national meetings and the preparation of manuscripts. Fourth, the applicant's progress throughout the award will be monitored by an advisory committee of senior researchers and academic leaders. The applicant's sponsor guarantees that 80% of Dr. Becker's effort will be devoted to his research for the period of this award. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPEUTIC STRATEGIES IN DISORDERS OF HEMATOPOIESIS Principal Investigator & Institution: Gabrilove, Janice L.; Professor and Chief; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2003; Project Start 23-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): This is a "Midcareer Investigator Award in PatientOriented Research: PA-00-005" entitled Therapeutic Strategies in Disorders of Hematopoiesis. The formation of blood cells represents a complex interaction between stem cells, ceils making up the stromal microenvironment and growth regulatory proteins, which are presented in soluble and localized forms. These interactions give rise to an enormous number and diversity of cells that function in widely separated parts of the body to transport oxygen, defend against infectious agents and provide stimulus for clotting. Abnormalities that impair the process of blood cell development, such as Myelodysplasia and Acute Myelogenous Leukemia (AML); as well as Cancer, can lead to life threatening illness as welt as lineage specific myelosuppression or pancytopenia resulting in significant morbidity and mortality. This proposal focuses on the development, conduct and mentoring of scientifically based, hypothesis-driven pilot clinical investigations, designed to exploit inherent biological features of these specific diseases. Three distinct central hypotheses underlie the Candidate's present (currently funded) and new (to be supported by K24) clinical research efforts: 1) the therapeutic application of agents that interfere or reverse transcriptional repression will be of clinical utility in AML and MDS respectively; 2) inhibition of autocrine and microenvironmentally presented growth factors, which contribute to delays in programmed cell death, characteristic of disorders such as chronic lymphocytic leukemia (CLL), represents a novel therapeutic approach of potential utility; and 3) cytokines inhibitory for erythropoiesis contribute to anemia of cancer; strategies to overcome cytokine inhibition should augment red blood cell production in cancer patients and further reduce the clinical problem of anemia in this population. An important part of this application concerns the active mentorship of key junior faculty and hematology/oncology fellows who have chosen to pursue academic clinical research as a career path. This mentorship program consists of: 1) participation in specific curriculum in conjunction with the NIH funded Clinical Research Training Program (K30), for which the candidate serves as the Principal investigator, and IRB course on conduct in Clinical Research; 2) direct oversight, including weekly meetings for: (a) protocol and IND development; (b) accrual, data and regulatory review; (c) manuscript and presentation preparation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TOPOISOMERASE I INHIBITORS IN LEUKEMIA AND SOLID TUMORS Principal Investigator & Institution: Kaufmann, Scott H.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-APR-1997; Project End 31-MAR-2005 Summary: (Applicant's Abstract) Two topoisomerase I (topo I) poisons, topotecan (TPT) and irinotecan (CPT-l1), are currently licensed for use in the U.S. Clinical responses to these agents are highly variable. Although preclinical studies have identified numerous factors that can affect the action of topo I poisons in vitro, few of these parameters have been examined in tumor samples or correlated with clinical response. Studies supported by this grant have investigated 1) mechanisms of resistance to topo I poisons in clinical leukemia specimens and 2) effects of combining topo I poisons with other agents. In pursuing the first goal, we have demonstrated during the current funding period that topo I content in acute myelogenous leukemia specimens varies widely but correlates with other markers of proliferation (e.g., PCNA); that the TPT concentration required to stabilize topo I-DNA complexes in acute leukemia specimens ex vivo varies over a 30fold range irrespective of topo I content; and that this variation in TPT concentration required to stabilize topo I-DNA cleavage complexes can been recapitulated in a tissue culture model. Additional tissue culture studies have demonstrated enhanced sensitivity to TPT or SN-38 (the active metabolite of CPT-11) when activity of the DNA damage checkpoint kinase ATR is inhibited. While addressing the second goal, we have demonstrated that cytotoxic effects are more than additive when SN-38 is combined with the quinazoline-based kinase inhibitor CI1033 or with gemcitabine. Further studies have demonstrated that the SN-38/CI1033 synergy reflects enhanced drug accumulation as a result of CI1033-mediated inhibition of the ABC cassette transporter BCRP. To build on these results, we now propose to 1) evaluate the relationship between response of three well-defined cohorts of solid tumor patients receiving single-agent CPT-11 or TPT and various tumor cell parameters that have been implicated in drug resistance in preclinical models (including topo I content, p53 status, proliferative index, levels of anti-apoptotic Bcl-2 family members, and expression of replication checkpoint proteins); 2) use the recently developed tissue culture model to determine the mechanistic basis for the observation that different TPT concentrations are required to stabilize topo I-DNA complexes in different leukemia specimens; and 3) examine the mechanistic basis for the unanticipated synergy of the gemcitabine + SN-38 combination and determine the effect of combining SN-38 with other agents currently undergoing early clinical testing. Collectively, these studies should provide insight into factors that affect response to topo I poisons in the clinical setting and aid in the rational integration of topo I poisons into multidrug regimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TREATMENT OF CHILDHOOD CANCER Principal Investigator & Institution: Brecher, Martin L.; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: Cooperative trials in pediatric cancer patients have played a major role in the remarkable improvement in cure of childhood cancers. Because most childhood cancers are rare, it is only through this mechanism that adequate numbers of patients can be accrued in reasonable lengths of time for randomized controlled studies. The Department of Pediatrics at Roswell Park Cancer Institute (RPCI) has actively

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participated in cooperative group trials via the Pediatric Oncology Group (POG) to answer treatment questions which would be impossible to answer were we to conduct only single institution studies. Some pediatric solid tumors are so rare that national intergroup studies are required. We also participate in these intergroup studies. RPCI investigators are coordinators for a number of POG protocols including front-line studies for the treatment of advanced Hodgkin's disease, advanced small non- cleaved cell lymphoma, non-rhabdomyosarcoma soft tissue sarcomas, acute lymphoblastic leukemia in relapse, the National Wilms Tumor Study, brain tumors in infants, and the Intergroup Ewing's Sarcoma Study. Roswell Park investigators have also developed POG phase II studies of continuous infusion 5-fluouracil and the combination of cisplatin, ifosfamide and etoposide. Roswell Park investigators chair the Wilms Tumor Committee, the Neuroscience Subcommittee of the Brain Tumor Committee, and cochair the Pathology Discipline Core Committee, as well as being active on a number of other POG Core Committees. They have made major contributions over the last few years in the areas of solid tumor oncology, neuro- oncology and the treatment of lymphoid malignancies. We are strongly committed to the interdisciplinary approach to pediatric cancer and have established collaboration with the necessary clinical specialties including Radiation Medicine, Pediatric Surgery, Pediatric Neurology, Neurosurgery, and Orthopedic Surgery, as well as with researchers in immunology, pharmacology and molecular biology. As more children are cured of their cancers, the identification and prevention, when feasible, of complications of therapy have become imperative. We have been a major contributor to the identification and understanding of the long-term medical and psychosocial effects of the treatment of leukemia, Hodgkin's disease, and a number of solid tumors, both through the cooperative group mechanism and through institutional studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIA Principal Investigator & Institution: Griffin, James D.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The long-term goals of this Program are to understand the pathogenesis of acute myeloid leukemias and use this information to develop novel therapeutic strategies to cure these disorders. A central hypothesis is that AML's are caused by multiple oncogenes that cooperate to cause leukemia. Thus, different leukemia oncogenes are likely to disrupt various cellular processes. An essential event is blocking differentiation, most likely by disrupting the transcription factor network that regulates myelopoiesis. The focus of this project is to understand the contribution of mutations in FLT3 to the pathogenesis of AML, and use this information to develop novel therapeutic strategies. FLT3 is a tyrosine kinase transmembrane receptor normally expressed in immature myeloid cells and required for proper development of hematopoietic stem cells, B cells, dendritic cells, and NK cells. Mutations in this receptor have been discovered in 20-30% of AMLs and are believed to cause constitutive activation of the receptor. Most of the mutations are in the juxtamembrane domain immediately inside the cell membrane, and involve in-frame, tandem, duplications of usually short stretches of DNA. In this project, we will determine the mechanism whereby these JM domain duplications activate the receptor, examine the mechanism of activation of a point mutation that also activates the receptor (D835Y), and compare the transforming functions of mutant FLT3 to those of another common tyrosine kinase oncogene of myeloid leukemias, BCR/ABL. Finally, small

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molecule kinase inhibitors are now available for both FLT3 and BCR/ABL and they will be studied to determine mechanisms of action on leukemic cells, modes of resistance, and opportunities for incorporation into novel combination chemotherapies. Successful completion of the studies proposed in this project will result in improved understanding of the pathogenesis of AML and the development of novel treatment strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

A pilot study of high-throughput, sequence-based mutational profiling of primary human acute myeloid leukemia cell genomes. by Ley TJ, Minx PJ, Walter MJ, Ries RE, Sun H, McLellan M, DiPersio JF, Link DC, Tomasson MH, Graubert TA, McLeod H, Khoury H, Watson M, Shannon W, Trinkaus K, Heath S, Vardiman JW, Caligiuri MA, Bloomfield CD, Milbrandt JD, Mardis ER, Wilson RK.; 2003 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=283582

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Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO. by Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=109300

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Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26. by Morishita K, Parganas E, William CL, Whittaker MH, Drabkin H, Oval J, Taetle R, Valentine MB, Ihle JN.; 1992 May 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=48987

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Acute myeloid leukemia induction by amphotropic murine retrovirus (4070A): clonal integrations involve c-myb in some but not all leukemias. by Wolff L, Koller R, Davidson W.; 1991 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=241365

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Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. by Schoch C, Kohlmann A, Schnittger S, Brors B, Dugas M, Mergenthaler S, Kern W, Hiddemann W, Eils R, Haferlach T.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126615

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

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

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Altered myelopoiesis and the development of acute myeloid leukemia in transgenic mice overexpressing cyclin A1. by Liao C, Wang XY, Wei HQ, Li SQ, Merghoub T, Pandolfi PP, Wolgemuth DJ.; 2001 Jun 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34442

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Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. by Miyoshi H, Ohira M, Shimizu K, Mitani K, Hirai H, Imai T, Yokoyama K, Soeda E, Ohki M.; 1995 Jul 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=307102

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AML1 /ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. by Miyamoto T, Weissman IL, Akashi K.; 2000 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16578

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AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. by Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, Burel SA, Lagasse E, Weissman IL, Akashi K, Zhang DE.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56972

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An activated receptor tyrosine kinase, TEL/PDGF[beta]R, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. by Grisolano JL, O'Neal J, Cain J, Tomasson MH.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170948

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Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. by Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ.; 1988 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279827

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Cutaneous Infection Caused by Cylindrocarpon lichenicola in a Patient with Acute Myelogenous Leukemia. by Iwen PC, Tarantolo SR, Sutton DA, Rinaldi MG, Hinrichs SH.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87389

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DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the HIV-2 enhancer. by Fu GK, Grosveld G, Markovitz DM.; 1997 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19999

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Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics. by Virtaneva K, Wright FA, Tanner SM, Yuan B, Lemon WJ, Caligiuri MA, Bloomfield CD, de la Chapelle A, Krahe R.; 2001 Jan 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14719

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Fusion of the NUP98 gene with the LEDGF/p52 gene defines a recurrent acute myeloid leukemia translocation. by Hussey DJ, Moore S, Nicola M, Dobrovic A.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60524

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Human AML1 /MDS1 /EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: A model for human AML. by Cuenco GM, Nucifora G, Ren R.; 2000 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=26509

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Identification and Characterization of an Activating TrkA Deletion Mutation in Acute Myeloid Leukemia. by Reuther GW, Lambert QT, Caligiuri MA, Der CJ.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86471

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Interleukin 1 as an autocrine growth factor for acute myeloid leukemia cells. by Cozzolino F, Rubartelli A, Aldinucci D, Sitia R, Torcia M, Shaw A, Di Guglielmo R.; 1989 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286914

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Isolation and analysis of the 21q+ chromosome in the acute myelogenous leukemia 8;21 translocation: evidence that c-mos is not translocated. by Drabkin HA, Diaz M, Bradley CM, Le Beau MM, Rowley JD, Patterson D.; 1985 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397059

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Isolation of a yeast artificial chromosome spanning the 8;21 translocation breakpoint t(8;21)(q22;q22.3) in acute myelogenous leukemia. by Gao J, Erickson P, Gardiner K, Le Beau MM, Diaz MO, Patterson D, Rowley JD, Drabkin HA.; 1991 Jun 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51771

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Liver infection caused by Coniothyrium fuckelii in a patient with acute myelogenous leukemia. by Kiehn TE, Polsky B, Punithalingam E, Edwards FF, Brown AE, Armstrong D.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=269503

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Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia. by Blanco JG, Dervieux T, Edick MJ, Mehta PK, Rubnitz JE, Shurtleff S, Raimondi SC, Behm FG, Pui CH, Relling MV.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56962

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NUP98 --HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice. by Kroon E, Thorsteinsdottir U, Mayotte N, Nakamura T, Sauvageau G.; 2001 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133485

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Participation of the cytokines interleukin 6, tumor necrosis factor-alpha, and interleukin 1-beta secreted by acute myelogenous leukemia blasts in autocrine and paracrine leukemia growth control. by Oster W, Cicco NA, Klein H, Hirano T, Kishimoto T, Lindemann A, Mertelsmann RH, Herrmann F.; 1989 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329675

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Pulmonary Infection Caused by Gymnascella hyalinospora in a Patient with Acute Myelogenous Leukemia. by Iwen PC, Sigler L, Tarantolo S, Sutton DA, Rinaldi MG, Lackner RP, McCarthy DI, Hinrichs SH.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88727

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Recurrent Self-Limited Fungemia Caused by Yarrowia lipolytica in a Patient with Acute Myelogenous Leukemia. by Chang CL, Park TH, Lee EY, Lim YT, Son HC.; 2001 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=87906

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Signal transduction and transforming properties of the TEL --TRKC fusions associated with t(12;15)(p13;q25) in congenital fibrosarcoma and acute myelogenous leukemia. by Liu Q, Schwaller J, Kutok J, Cain D, Aster JC, Williams IR, Gilliland DG.; 2000 Apr 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=302017

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The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein. by Melnick AM, Westendorf JJ, Polinger A, Carlile GW, Arai S, Ball HJ, Lutterbach B, Hiebert SW, Licht JD.; 2000 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110824

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The partial tandem duplication of ALL1 in acute myeloid leukemia with normal cytogenetics or trisomy 11 is restricted to one chromosome. by Caligiuri MA, Strout MP, Oberkircher AR, Yu F, de la Chapelle A, Bloomfield CD.; 1997 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20539

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The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1 /CBF[alpha]2 transcription factor. by McNeil S, Zeng C, Harrington KS, Hiebert S, Lian JB, Stein JL, van Wijnen AJ, Stein GS.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24742

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Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. by Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D, Konopleva M, Zhao S, Estey E, Andreeff M.; 2001 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=200930

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Timed sequential chemotherapy with concomitant Granulocyte Colony-Stimulating Factor for high-risk acute myelogenous leukemia: a single arm clinical trial. by He XY, Elson P, Pohlman B, Lichtin A, Hussein M, Andresen S, Kalaycio M.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113260

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Vancomycin-resistant Aureobacterium species cellulitis and bacteremia in a patient with acute myelogenous leukemia. by Nolte FS, Arnold KE, Sweat H, Winton EF, Funke G.; 1996 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=229168

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.

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

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To generate your own bibliography of studies dealing with acute myelogenous leukemia, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “acute myelogenous leukemia” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for acute myelogenous leukemia (hyperlinks lead to article summaries): •

A case of acute myelogenous leukemia: myelodysplastic syndrome with t(2;11)(p21;q23) without MLL rearrangement. Author(s): Gozzetti A, Tozzuoli D, Crupi R, Raspadori D, Fabbri A, Lauria F. Source: Cancer Genetics and Cytogenetics. 2003 July 15; 144(2): 177-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12850382

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A case of treatment-related myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemotherapy with autologous stem cell transplantation for non-Hodgkin's lymphoma. Author(s): Jang GD, Kim SW, Suh CW, Kim EK, Bahng HS, Jeong YH, Park IG, Kim WK, Kim SH, Suh EJ, Park CJ, Ji HS, Lee JS. Source: Journal of Korean Medical Science. 2002 August; 17(4): 555-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172056

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A homoharringtonine-based regimen for childhood acute myelogenous leukemia. Author(s): Tang J, Xue H, Pan C, Chen J, Gu L, Zhao H. Source: Medical and Pediatric Oncology. 2003 July; 41(1): 70-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764750

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A phase I study of idarubicin dose escalation with amisfostine and high-dose cytarabine in patients with relapsed acute myelogenous leukemia and myelodysplastic syndromes. Author(s): Garcia-Manero G, Faderl S, Giles F, Thomas D, Cortes J, O'Brien S, Davis J, Kantarjian HM, Estey E. Source: Haematologica. 2002 August; 87(8): 804-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12161355

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A randomized trial of liposomal daunorubicin and cytarabine versus liposomal daunorubicin and topotecan with or without thalidomide as initial therapy for patients with poor prognosis acute myelogenous leukemia or myelodysplastic syndrome. Author(s): Cortes J, Kantarjian H, Albitar M, Thomas D, Faderl S, Koller C, GarciaManero G, Giles F, Andreeff M, O'Brien S, Keating M, Estey E. Source: Cancer. 2003 March 1; 97(5): 1234-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12599230

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Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia. Author(s): Lensch MW, Tischkowitz M, Christianson TA, Reifsteck CA, Speckhart SA, Jakobs PM, O'Dwyer ME, Olson SB, Le Beau MM, Hodgson SV, Mathew CG, Larson RA, Bagby GC Jr. Source: Blood. 2003 July 1; 102(1): 7-16. Epub 2003 March 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12637330

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Acute myelogenous leukemia and glycogen storage disease 1b. Author(s): Pinsk M, Burzynski J, Yhap M, Fraser RB, Cummings B, Ste-Marie M. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 December; 24(9): 756-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12468919

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Acute myelogenous leukemia associated with extreme symptomatic thrombocytosis and chromosome 3q translocation: case report and review of literature. Author(s): Chang VT, Aviv H, Howard LM, Padberg F. Source: American Journal of Hematology. 2003 January; 72(1): 20-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12508263

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Acute myelogenous leukemia complicated by acute necrotizing ulcerative gingivitis due to Aspergillus terreus. Author(s): Khoury H, Poh CF, Williams M, Lavoie JC, Nevill TJ. Source: Leukemia & Lymphoma. 2003 April; 44(4): 709-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12769350

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Acute myelogenous leukemia following mitoxantrone treatment for multiple sclerosis. Author(s): Mogenet I, Simiand-Erdociain E, Canonge JM, Pris J. Source: The Annals of Pharmacotherapy. 2003 May; 37(5): 747-8. Retraction In: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708958

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Acute myelogenous leukemia following treatment with cyclosporin A in a nephrotic patient. Author(s): Ikeda Y, Sakemi T, Matsuzaki M, Sano M. Source: Intern Med. 2002 September; 41(9): 722-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12322800

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Acute myelogenous leukemia in an adult with thrombocytopenia with absent radii syndrome. Author(s): Go RS, Johnston KL. Source: European Journal of Haematology. 2003 April; 70(4): 246-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12656750

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Acute myelogenous leukemia M5b developed during clinical remission of Castleman disease. Author(s): Tomonari A, Shirafuji N, Tojo A, Iseki T, Ooi J, Komiya I, Tani K, Asano S. Source: International Journal of Hematology. 2003 April; 77(3): 274-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12731671

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Acute myelogenous leukemia with internal tandem duplication of the Flt3 gene appearing or altering at the time of relapse: a report of two cases. Author(s): Hovland R, Gjertsen BT, Bruserud O. Source: Leukemia & Lymphoma. 2002 October; 43(10): 2027-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12481903

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Acute myelogenous leukemia with the t(3;12)(q26;p13) translocation: case report and review of the literature. Author(s): Voutsadakis IA, Maillard N. Source: American Journal of Hematology. 2003 February; 72(2): 135-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12555218

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Adult onset acute myelogenous leukemia and electromagnetic fields in Los Angeles County: bed-heating and occupational exposures. Author(s): Oppenheimer M, Preston-Martin S. Source: Bioelectromagnetics. 2002 September; 23(6): 411-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12210558

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Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy. Author(s): Mattiuzzi GN, Kantarjian H, Faderl S, Lim J, Kontoyiannis D, Thomas D, Wierda W, Raad I, Garcia-Manero G, Zhou X, Ferrajoli A, Bekele N, Estey E. Source: Cancer. 2004 February 1; 100(3): 581-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14745876

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Analysis of acute myelogenous leukemia: preparation of samples for genomic and proteomic analyses. Author(s): Gjertsen BT, Oyan AM, Marzolf B, Hovland R, Gausdal G, Doskeland SO, Dimitrov K, Golden A, Kalland KH, Hood L, Bruserud O. Source: Journal of Hematotherapy & Stem Cell Research. 2002 June; 11(3): 469-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12183832

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Antiproliferative effects of a non-beta-oxidizable fatty acid, tetradecylthioacetic acid, in native human acute myelogenous leukemia blast cultures. Author(s): Tronstad KJ, Bruserud O, Berge K, Berge RK. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 November; 16(11): 2292-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12399975

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Assessment of differences in patient populations selected for excluded from participation in clinical phase III acute myelogenous leukemia trials. Author(s): Mengis C, Aebi S, Tobler A, Dahler W, Fey MF. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 November 1; 21(21): 3933-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581417

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BAVC regimen and autograft for acute myelogenous leukemia in second complete remission. Author(s): Meloni G, Vignetti M, Avvisati G, Capria S, Micozzi A, Giona F, Mandelli F. Source: Bone Marrow Transplantation. 1996 October; 18(4): 693-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8899182

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BAX and PKCalpha modulate the prognostic impact of BCL2 expression in acute myelogenous leukemia. Author(s): Kornblau SM, Vu HT, Ruvolo P, Estrov Z, O'Brien S, Cortes J, Kantarjian H, Andreeff M, May WS. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 April; 6(4): 1401-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10778970

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BCL-2 expression does not not correlate with patient outcome in pediatric acute myelogenous leukemia. Author(s): Naumovski L, Martinovsky G, Wong C, Chang M, Ravendranath Y, Weinstein H, Dahl G. Source: Leukemia Research. 1998 January; 22(1): 81-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9585084

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Bcl-2 protein expression in normal human bone marrow precursors and in acute myelogenous leukemia. Author(s): Porwit-MacDonald A, Ivory K, Wilkinson S, Wheatley K, Wong L, Janossy G. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1995 July; 9(7): 1191-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7543174

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Behenoyl cytarabine-associated reversible encephalopathy in a patient with acute myelogenous leukemia. Author(s): Cho SG, Moon H, Lee JH, Lee SY, Kim CC, Lee KS. Source: Journal of Korean Medical Science. 1999 February; 14(1): 89-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10102531

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Beneficial effects of post-transfusional hepatitis in acute myelogenous leukemia may be mediated by lipopolysaccharides, tumor necrosis factor alpha and interferon gamma. Author(s): Treon SP, Broitman SA. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 October; 6(10): 1036-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1405756

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Benefit of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia. Author(s): Schiller G, Gajewski J, Lee M, Ho W, Territo M, Champlin R. Source: Leukemia & Lymphoma. 1994 September; 15(1-2): 85-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7858506

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Bilateral breast involvement in acute myelogenous leukemia. Author(s): Khoury NJ, Hanna Al-Kass FM, Jaafar HN, Taher AT, Shamseddine AI. Source: European Radiology. 2000; 10(6): 1031. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10879725

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Bilateral breast relapse in acute myelogenous leukemia. Author(s): Monteleone PM, Steele DA, King AK, Konefal S, Kelleher JF. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2001 February; 23(2): 126-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11216705

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Bilateral orbital granulocytic sarcoma (chloroma) preceding the blast phase of acute myelogenous leukemia: CT findings. Author(s): Bulas RB, Laine FJ, Das Narla L. Source: Pediatric Radiology. 1995; 25(6): 488-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7491213

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Blasts from patients with acute myelogenous leukemia express functional receptors for stem cell factor. Author(s): Broudy VC, Smith FO, Lin N, Zsebo KM, Egrie J, Bernstein ID. Source: Blood. 1992 July 1; 80(1): 60-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1377054

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Bleeding risk and platelet transfusion refractoriness in patients with acute myelogenous leukemia who undergo autologous stem cell transplantation. Author(s): Toor AA, Choo SY, Little JA. Source: Bone Marrow Transplantation. 2000 August; 26(3): 315-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10967572

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Bone marrow necrosis associated with relapse of acute myelogenous leukemia following unrelated hematopoeitic stem cell transplantation using an immunoablative regimen. Author(s): Venkateswaran L, Duerst R, Haut P, Kletzel M, Chou P. Source: Medical and Pediatric Oncology. 2002 February; 38(2): 148-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11813193

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Bone marrow purging studies in acute myelogenous leukemia using the recombinant anti-CD33 immunotoxin HuM195/rGel. Author(s): Duzkale H, Pagliaro LC, Rosenblum MG, Varan A, Liu B, Reuben J, Wierda WG, Korbling M, McMannis JD, Glassman AB, Scheinberg DA, Freireich EJ. Source: Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2003 June; 9(6): 364-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12813444

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Bone marrow transplantation for childhood acute myelogenous leukemia. Author(s): Lin KH, Jou ST, Chen RL, Lin DT, Lin KS. Source: Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1994 September-October; 35(5): 415-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7942028

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Bone marrow transplantation for children less than 2 years of age with acute myelogenous leukemia or myelodysplastic syndrome. Author(s): Woolfrey AE, Gooley TA, Sievers EL, Milner LA, Andrews RG, Walters M, Hoffmeister P, Hansen JA, Anasetti C, Bryant E, Appelbaum FR, Sanders JE. Source: Blood. 1998 November 15; 92(10): 3546-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9808546

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Bone marrow transplantation for children with acute myelogenous leukemia. Author(s): Dinndorf P, Bunin N. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 1995 August; 17(3): 211-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7620920

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Bone marrow transplantation vs. high-dose cytorabine-based consolidation chemotherapy for acute myelogenous leukemia. A long-term follow-up study of quality-of-life measures of survivors. Author(s): Wellisch DK, Centeno J, Guzman J, Belin T, Schiller GJ. Source: Psychosomatics. 1996 March-April; 37(2): 144-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8742543

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Brain granulocytic sarcoma at the site of previous cerebral hemorrhage in a patient with acute myelogenous leukemia. Author(s): Enani MA, Harakati MS, Almohareb FI, Rahman NU, Fawzy EM. Source: International Journal of Hematology. 1993 August; 58(1-2): 119-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8219108

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Busulfan plus etoposide as a preparative regimen for autologous bone marrow transplantation for acute myelogenous leukemia: an update. Author(s): Linker CA, Damon LE, Ries CA, Rugo HS, Wolf JL. Source: Seminars in Oncology. 1993 August; 20(4 Suppl 4): 40-8; Quiz 49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8342075

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CAM-cytarabine, aclarubicin plus macrophage colony-stimulating factor in the treatment of acute myelogenous leukemia with trilineage dysplasia: usefulness of in vitro apoptosis in leukemic cells. Author(s): Mori M, Hatake K, Tanaka M, Takatoku M, Matsumoto Y, Uchida M, Kametaka M, Nagai T, Terui Y, Tomizuka H, Muroi K, Ozawa K. Source: Leukemia & Lymphoma. 2001 July; 42(3): 387-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11699403

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Challenging and unusual cases: Case 1. Simultaneous presentation of acute myelogenous leukemia and myocardial infarction. Author(s): Pervez H, Potti A, Mehdi SA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 April 1; 21(7): 1416-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663736

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Characterization of t(11;19)(q23;p13.3) by fluorescence in situ hybridization analysis in a pediatric patient with therapy-related acute myelogenous leukemia. Author(s): Cheng L, Ramesh KH, Radel E, Ratech H, Wei D, Cannizzaro LA. Source: Cancer Genetics and Cytogenetics. 2001 August; 129(1): 17-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11520560

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Chemotherapy for acute myelogenous leukemia in the elderly with cytarabine, mitoxantrone, and granulocyte-macrophage colony-stimulating factor. Author(s): Kalaycio M, Pohlman B, Elson P, Lichtin A, Hussein M, Tripp B, Andresen S. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 2001 February; 24(1): 58-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11232951

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Cholesterol catabolism in patients with acute myelogenous leukemia and hypocholesterolemia: suppressed levels of a circulating marker for bile acid synthesis. Author(s): Tatidis L, Vitols S, Gruber A, Paul C, Axelson M. Source: Cancer Letters. 2001 September 20; 170(2): 169-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11463495

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Clinical significance of low protein phosphatase-1 activity of blasts in acute myelogenous leukemia with high white cell counts. Author(s): Nishikawa M, Yamamoto M, Watanabe Y, Kita K, Shiku H. Source: International Journal of Oncology. 2001 March; 18(3): 559-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11179487

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Close correlation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, an intracellular active metabolite, to the therapeutic efficacy of N(4)-behenoyl-1-beta-Darabinofuranosylcytosine therapy for acute myelogenous leukemia. Author(s): Yamauchi T, Kawai Y, Goto N, Kishi S, Imamura S, Yoshida A, Urasaki Y, Fukushima T, Iwasaki H, Tsutani H, Masada M, Ueda T. Source: Japanese Journal of Cancer Research : Gann. 2001 September; 92(9): 975-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11572766

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Coexistence of inversion 16 and the Philadelphia chromosome in patients with acute myelogenous leukemia. Author(s): Siddiqui AD, Sheikh ZS, Liu D, Seiter K. Source: Leukemia & Lymphoma. 2002 May; 43(5): 1137-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12148898

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Colon cancer with meningeal carcinomatosis and myelodysplastic syndrome in a patient who underwent intensive chemotherapy for acute myelogenous leukemia: a case report. Author(s): Nagashima T, Muroi K, Kunitama M, Izumi T, Ohtsuki T, Komatsu N, Fukayama M, Ozawa K. Source: Japanese Journal of Clinical Oncology. 2001 May; 31(5): 221-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11450998

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Comparative genomic hybridization and multiplex-fluorescence in situ hybridization: an appraisal in elderly patients with acute myelogenous leukemia. Author(s): Dalley CD, Neat MJ, Foot NJ, Burridge M, Byrne L, Amess JA, Rohatiner AZ, Lister A, Young BD, Lillington DM. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2002; 3(6): 290-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12522451

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Comparison of allogeneic stem cell transplantation, high-dose cytarabine, and autologous peripheral stem cell transplantation as postremission treatment in patients with de novo acute myelogenous leukemia. Author(s): Tsimberidou AM, Stavroyianni N, Viniou N, Papaioannou M, Tiniakou M, Marinakis T, Skandali A, Sakellari I, Yataganas X; The Hellenic Cooperative Group. Source: Cancer. 2003 April 1; 97(7): 1721-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12655529

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Comparison of fludarabine-containing salvage chemotherapy regimens for relapsed/refractory acute myelogenous leukemia. Author(s): Thomas MB, Koller C, Yang Y, Shen Y, O'Brien S, Kantarjian H, Davis J, Estey E. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 May; 17(5): 990-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12750721

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Comparison of outcome in acute myelogenous leukemia patients with translocation (8;21) found by standard cytogenetic analysis and patients with AML1/ETO fusion transcript found only by PCR testing. Author(s): Sarriera JE, Albitar M, Estrov Z, Gidel C, Aboul-Nasr R, Manshouri T, Kornblau S, Chang KS, Kantarjian H, Estey E. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 January; 15(1): 57-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11243400

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Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL. Author(s): Miller MK, Strauchen JA, Nichols KT, Phelps RG. Source: The American Journal of Dermatopathology. 2001 August; 23(4): 334-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11481527

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Congenital acute myelogenous leukemia presenting as palpable renal masses in a neonate. Author(s): Butani L, Paulson TE. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 March; 25(3): 240-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621244

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Conservative treatment for patients over 80 years with acute myelogenous leukemia. Author(s): Latagliata R, Alimena G, Carmosino I, Breccia M, Borza PA, Bongarzoni V, Copia C, Spadea A, Pinazzi B, Frattarelli N, Ferrara F, Petti MC, Mandelli F. Source: American Journal of Hematology. 2002 December; 71(4): 256-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12447953

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Constitutive activation of STAT transcription factors in acute myelogenous leukemia. Author(s): Spiekermann K, Biethahn S, Wilde S, Hiddemann W, Alves F. Source: European Journal of Haematology. 2001 August; 67(2): 63-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11722592

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CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Author(s): Kelly LM, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM, Williams I, Amaral SM, Curley DP, Duclos N, Neuberg D, Scarborough RM, Pandey A, Hollenbach S, Abe K, Lokker NA, Gilliland DG, Giese NA. Source: Cancer Cell. 2002 June; 1(5): 421-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12124172

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Cutaneous infection caused by Cylindrocarpon lichenicola in a patient with acute myelogenous leukemia. Author(s): Iwen PC, Tarantolo SR, Sutton DA, Rinaldi MG, Hinrichs SH. Source: Journal of Clinical Microbiology. 2000 September; 38(9): 3375-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10970386

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Cytokine induction of a human acute myelogenous leukemia cell line (KG-1) to a CD1a+ dendritic cell phenotype. Author(s): Hulette BC, Rowden G, Ryan CA, Lawson CM, Dawes SM, Ridder GM, Gerberick GF. Source: Archives of Dermatological Research. 2001 March; 293(3): 147-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11357229

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De novo acute myelogenous leukemia with trilineage myelodysplasia associated with t(8;21)(q22;q22). Author(s): Fujisawa S, Togawa J, Tanaka M, Koharazawa H, Aoba M, Fujita H, Murata T, Kanamori H, Matsuzaki M, Mohri H, Ishigatsubo Y. Source: Intern Med. 1999 July; 38(7): 607-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10435370

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Deletion of 3'-CBFB gene in association with an inversion (16)(p13q22) and a loss of the Y chromosome in a 2-year-Old child with acute myelogenous leukemia-M4. Author(s): Batanian JR, Huang Y, Fallon R. Source: Cancer Genetics and Cytogenetics. 2000 September; 121(2): 216-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11063812

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Deletion of a critical internalization domain in the G-CSFR in acute myelogenous leukemia preceded by severe congenital neutropenia. Author(s): Hunter MG, Avalos BR. Source: Blood. 1999 January 15; 93(2): 440-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9885205

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Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia. Author(s): Lezon-Geyda K, Najfeld V, Johnson EM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 June; 15(6): 954-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11417483

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Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute myelogenous leukemia in 1st remission. Author(s): Gale RP, Park RE, Dubois RW, Herzig GP, Hocking WG, Horowitz MM, Keating A, Kempin S, Linker CA, Schiffer CA, Wiernik PH, Weisdorf DJ, Rai KR. Source: Leukemia Research. 1999 August; 23(8): 709-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10456668

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Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. Author(s): Choudhury BA, Liang JC, Thomas EK, Flores-Romo L, Xie QS, Agusala K, Sutaria S, Sinha I, Champlin RE, Claxton DF. Source: Blood. 1999 February 1; 93(3): 780-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9920826

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Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. Author(s): Lillington DM, Micallef IN, Carpenter E, Neat MJ, Amess JA, Matthews J, Foot NJ, Young BD, Lister TA, Rohatiner AZ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 May 1; 19(9): 2472-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11331326

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Detection of minimal residual disease by mutant p53 immunocytochemistry in acute myelogenous leukemia. Author(s): Kattamis AC, Tsangaris GT, Vamvoukakis J, Moschovi M, Grafakos S, Tzortzatou-Stathopoulou F. Source: Medical and Pediatric Oncology. 2000 February; 34(2): 153-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10657882

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Detection of minimal residual disease in a patient having acute myelogenous leukemia with t(16;21)(p11;q22) treated by allogeneic bone marrow transplantation. Author(s): Okoshi Y, Shimizu S, Kojima H, Obara N, Mukai HY, Komeno T, Hasegawa Y, Mori N, Nagasawa T. Source: Acta Haematologica. 2001; 105(1): 45-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11340253

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Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. Author(s): Pearlman M, Jendiroba D, Pagliaro L, Keyhani A, Liu B, Freireich EJ. Source: Leukemia Research. 2003 July; 27(7): 617-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12681361

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Diabetes insipidus as a presenting symptom of acute myelogenous leukemia. Author(s): Frangoul HA, Shaw DW, Hawkins D, Park J. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2000 September-October; 22(5): 457-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11037861

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Differentiation therapy in acute myelogenous leukemia (non-APL). Author(s): Waxman S. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 March; 14(3): 491-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10720148

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Discordant detection of monosomy 7 by GTG-banding and FISH in a patient with Shwachman-Diamond syndrome without evidence of myelodysplastic syndrome or acute myelogenous leukemia. Author(s): Sokolic RA, Ferguson W, Mark HF. Source: Cancer Genetics and Cytogenetics. 1999 December; 115(2): 106-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10598142

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Disseminated candidiasis in a patient with acute myelogenous leukemia. Author(s): Grabowski R, Dugan E. Source: Cutis; Cutaneous Medicine for the Practitioner. 2003 June; 71(6): 466-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12839257

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Disseminated infection due to Scedosporium apiospermum in a patient with acute myelogenous leukemia. Author(s): Ann Pharmacother. 2004 Jan;38(1):176-7 Source: Leukemia & Lymphoma. 2003 February; 44(2): 369-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742821

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Donor leukocyte infusions in acute myelogenous leukemia. Author(s): Porter DL. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 June; 17(6): 1035-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764364

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Dose-escalation study of single dose mitoxantrone in combination with timed sequential chemotherapy in patients with refractory or relapsing acute myelogenous leukemia. Author(s): Thomas X, Cambier N, Taksin AL, Reman O, Vekhoff A, Pautas C, Leblond V, Soler-Michel P, Ecstein-Fraisse E, Archimbaud E. Source: Leukemia Research. 2000 November; 24(11): 957-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11086179

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Double minutes and c-MYC amplification in acute myelogenous leukemia: Are they prognostic factors? Author(s): Bruckert P, Kappler R, Scherthan H, Link H, Hagmann F, Zankl H. Source: Cancer Genetics and Cytogenetics. 2000 July 1; 120(1): 73-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10913679

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Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Author(s): Lunghi P, Tabilio A, Dall'Aglio PP, Ridolo E, Carlo-Stella C, Pelicci PG, Bonati A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 September; 17(9): 1783-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970778

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Drug concentration-dependent expression of multidrug resistance-associated protein and P-glycoprotein in the doxorubicin-resistant acute myelogenous leukemia sublines. Author(s): Choi CH, Kim HS, Rha HS, Jeong JH, Park YH, Min YD, Kee KH, Lim DY. Source: Molecules and Cells. 1999 June 30; 9(3): 314-9. Erratum In: Mol Cells 1999 August 31; 9(4): Following 958. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10420992

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Early lymphocyte recovery is a predictive factor for prolonged survival after autologous hematopoietic stem cell transplantation for acute myelogenous leukemia. Author(s): Porrata LF, Litzow MR, Tefferi A, Letendre L, Kumar S, Geyer SM, Markovic SN. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 July; 16(7): 1311-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12094255

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Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of caspases-8, 7, and 3 and BID cleavage in human acute myelogenous leukemia cell line HL-60. Author(s): Lamothe B, Aggarwal BB. Source: Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research. 2002 February; 22(2): 269-79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11911810

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Effect of granulocyte-macrophage colony-stimulating growth factor on interferon and tumor necrosis factor production in whole blood cell cultures of patients with acute myelogenous leukemia. Author(s): Kaminska T, Hus I, Dmoszynska A, Kandefer-Szerszen M. Source: Arch Immunol Ther Exp (Warsz). 2001; 49 Suppl 2: S83-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11665752

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Effect of rhGM-CSF on the kinetics of hematopoiesis in long-term marrow cultures from patients with acute myelogenous leukemia. Author(s): Montesinos JJ, Sanchez-Valle E, Miranda-Peralta E, Gutierrez-Romero M, Mayani H. Source: Leukemia & Lymphoma. 2002 December; 43(12): 2383-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12613528

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Effect of slow lymphocyte recovery and type of graft-versus-host disease prophylaxis on relapse after allogeneic bone marrow transplantation for acute myelogenous leukemia. Author(s): Kumar S, Chen MG, Gastineau DA, Gertz MA, Inwards DJ, Lacy MQ, Tefferi A, Litzow MR. Source: Bone Marrow Transplantation. 2001 November; 28(10): 951-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11753550

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Effects of angiogenic regulators on in vitro proliferation and cytokine secretion by native human acute myelogenous leukemia blasts. Author(s): Bruserud O, Glenjen N, Ryningen A. Source: European Journal of Haematology. 2003 July; 71(1): 9-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801293

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Effects of azoles on human acute myelogenous leukemia blasts and T lymphocytes derived from acute leukemia patients with chemotherapy-induced cytopenia. Author(s): Bruserud O. Source: International Immunopharmacology. 2001 November; 1(12): 2183-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11710547

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Effects of cytarabine and various anthracyclins on platelet activation: characterization of in vitro effects and their possible clinical relevance in acute myelogenous leukemia. Author(s): Foss B, Ulvestad E, Hervig T, Bruserud O. Source: International Journal of Cancer. Journal International Du Cancer. 2002 January 1; 97(1): 106-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11774251

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Effects of signal transduction inhibitor 571 in acute myelogenous leukemia cells. Author(s): Scappini B, Onida F, Kantarjian HM, Dong L, Verstovsek S, Keating MJ, Beran M. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2001 December; 7(12): 3884-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11751479

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Effects of TNFalpha on the growth and sensitivity to cytosine arabinoside of blast progenitors in acute myelogenous leukemia with special reference to the role of NFkappaB. Author(s): Wu Z, Shen L, Inatomi Y, U M, Miyashita T, Toyama K, Miyauchi J. Source: Leukemia Research. 2003 November; 27(11): 1009-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859994

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Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Author(s): Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P, Latagliata R, Mariani G, Rossini A, Battistini A, Lo-Coco F, Peschle C. Source: Blood. 2002 October 15; 100(8): 2980-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12351411

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Enterocolitis as initial presentation of acute myelogenous leukemia exacerbated by induction chemotherapy with idarubicin-cytosine arabinoside. Author(s): Wood RA. Source: Mayo Clinic Proceedings. 2002 October; 77(10): 1133. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12374257

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Establishment of a cell line with AML1-MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia. Author(s): Inokuchi K, Hamaguchi H, Taniwaki M, Yamaguchi H, Tanosaki S, Dan K. Source: Genes, Chromosomes & Cancer. 2001 October; 32(2): 182-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11550287

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Estimation of radiographic doses in a case-control study of acute myelogenous leukemia. Author(s): Preston-Martin S, Pogoda JM. Source: Health Physics. 2003 February; 84(2): 245-59. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553655

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Evaluation of the clinical relevance of the expression and function of P-glycoprotein, multidrug resistance protein and lung resistance protein in patients with primary acute myelogenous leukemia. Author(s): Tsimberidou AM, Paterakis G, Androutsos G, Anagnostopoulos N, Galanopoulos A, Kalmantis T, Meletis J, Rombos Y, Sagriotis A, Symeonidis A, Tiniakou M, Zoumbos N, Yataganas X. Source: Leukemia Research. 2002 February; 26(2): 143-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11755464

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Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Author(s): Martino R, Caballero MD, Simon JA, Canals C, Solano C, Urbano-Ispizua A, Bargay J, Leon A, Sarra J, Sanz GF, Moraleda JM, Brunet S, San Miguel J, Sierra J; AML and alloPBSCT Subcommittees of the Spanish Group for Hematopoietic Transplantation. Source: Blood. 2002 September 15; 100(6): 2243-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12200391

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Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia. Author(s): Styczynski J, Wysocki M, Debski R, Juraszewska E, Malinowska I, Stanczak E, Ploszynska A, Stefaniak J, Mazur B, Szczepanski T. Source: Leukemia & Lymphoma. 2002 September; 43(9): 1843-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685842

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Expression of CD86 in acute myelogenous leukemia is a marker of dendritic/monocytic lineage. Author(s): Re F, Arpinati M, Testoni N, Ricci P, Terragna C, Preda P, Ruggeri D, Senese B, Chirumbolo G, Martelli V, Urbini B, Baccarani M, Tura S, Rondelli D. Source: Experimental Hematology. 2002 February; 30(2): 126-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11823047

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Expression of Fc(epsilon)-receptors by human acute myelogenous leukemia (AML) blasts: studies of high- and low- (CD23) affinity receptor expression and the effects of IgE-mediated receptor ligation on functional AML blast characteristics. Author(s): Bruserud O, Gjertsen BT, Ulvestad E. Source: Leukemia Research. 2002 May; 26(5): 515-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11916528

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Extensive neoplastic cardiac infiltration in a patient with acute myelogenous leukemia: role of echocardiography. Author(s): Makaryus AN, Tung F, Liu W, Mangion J, Kort S. Source: Echocardiography (Mount Kisco, N.Y.). 2003 August; 20(6): 539-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859368

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Facial cellulitis-like Sweet's syndrome in acute myelogenous leukemia. Author(s): Tercedor J, Rodenas JM, Henraz MT, Garcia-Mellado V, Gutierrez-Salmeron MT, Naranjo R. Source: International Journal of Dermatology. 1992 August; 31(8): 598-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1428459

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Factors associated with transfusion requirements during treatment for acute myelogenous leukemia. Author(s): Favre G, Fopp M, Gmur J, Tichelli A, Fey MF, Tobler A, Schatzmann E, Gratwohl A. Source: Annals of Hematology. 1993 October; 67(4): 153-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8218536

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Fas-independent and nonapoptotic cytotoxicity mediated by a human CD4(+) T-cell clone directed against an acute myelogenous leukemia-associated DEK-CAN fusion peptide. Author(s): Ohminami H, Yasukawa M, Kaneko S, Yakushijin Y, Abe Y, Kasahara Y, Ishida Y, Fujita S. Source: Blood. 1999 February 1; 93(3): 925-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9920842

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Fatal Bacillus cereus meningoencephalitis in an adult with acute myelogenous leukemia. Author(s): Marley EF, Saini NK, Venkatraman C, Orenstein JM. Source: Southern Medical Journal. 1995 September; 88(9): 969-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7660218

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Fatal reactivation of hepatitis B virus following cytotoxic chemotherapy for acute myelogenous leukemia: fibrosing cholestatic hepatitis. Author(s): Kojima H, Abei M, Takei N, Mukai Y, Hasegawa Y, Iijima T, Nagasawa T. Source: European Journal of Haematology. 2002 August; 69(2): 101-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12366713

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Feasibility study of autologous peripheral blood stem cell transplantation for the treatment of childhood acute myelogenous leukemia. Author(s): Horikoshi Y, Mimaya J, Amano K, Kawano Y, Watanabe A, Watanabe T, Sekine I, Nishikawa K, Tsunematsu Y, Endo M, Eguchi H, Koyama T, Kawakami K, Oka T, Matsushita T, Koizumi S, Fujimoto T, Takaue Y. Source: Japanese Journal of Clinical Oncology. 2000 March; 30(3): 137-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10798541

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Feasibility, toxicity, and biologic response of interleukin-2 after consolidation chemotherapy for acute myelogenous leukemia: a report from the Children's Cancer Group. Author(s): Sievers EL, Lange BJ, Sondel PM, Krailo MD, Gan J, Liu-Mares W, Feig SA. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1998 March; 16(3): 914-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9508173

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Filgrastim treatment of acute myelogenous leukemia (M7) relapse after allogeneic peripheral stem cell transplantation resulting in both graft-versus-leukemia effect with cytogenetic remission and chronic graft-versus-host disease manifesting as polyserositis and subsequent bronchiolitis obliterans with organizing pneumonia. Author(s): Law L, Tuscano J, Wun T, Ahlberg K, Richman C. Source: International Journal of Hematology. 2002 November; 76(4): 360-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12463601

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Financial analysis of patients with newly diagnosed acute myelogenous leukemia on protocol or standard therapy. Author(s): Berman E, Little C, Teschendorf B, Jones M, Heller G. Source: Cancer. 2002 September 1; 95(5): 1064-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209692

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Flt3 in acute myelogenous leukemia: biology, prognosis, and therapeutic implications. Author(s): Voutsadakis IA. Source: Medical Oncology (Northwood, London, England). 2003; 20(4): 311-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716027

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Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Author(s): Estey E, Plunkett W, Gandhi V, Rios MB, Kantarjian H, Keating MJ. Source: Leukemia & Lymphoma. 1993 March; 9(4-5): 343-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8394169

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Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. Author(s): Gandhi V, Estey E, Keating MJ, Plunkett W. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1993 January; 11(1): 116-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8418222

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Fluorescence in situ hybridization detection of AML-1/ETO rearrangement in a case of acute myelogenous leukemia with complicated cytogenetic abnormalities. Author(s): Obama K, Tara M, Niina K. Source: International Journal of Hematology. 2003 January; 77(1): 91-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12568306

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Fulminant hepatitis type B after chemotherapy in a serologically negative hepatitis B virus carrier with acute myelogenous leukemia. Author(s): Ishiga K, Kawatani T, Suou T, Tajima F, Omura H, Idobe Y, Kawasaki H. Source: International Journal of Hematology. 2001 January; 73(1): 115-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11372746

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Functional characterization of fibroblastic cells in long-term marrow cultures from patients with acute myelogenous leukemia. Author(s): Mayani H, Guilbert LJ, Janowska-Wieczorek A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 October; 7(10): 1564-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8412319

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Functional expression of c-kit by acute myelogenous leukemia blasts is enhanced by tumor necrosis factor-alpha through posttranscriptional mRNA stabilization by a labile protein. Author(s): Brach MA, Buhring HJ, Gruss HJ, Ashman LK, Ludwig WD, Mertelsmann RH, Herrmann F. Source: Blood. 1992 September 1; 80(5): 1224-30. Retraction In: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1381241

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Fusarium solani infection in a patient with acute myelogenous leukemia--a case report. Author(s): Kumar RR, Kumar BR, Shafiulla M, Lakshmaiah KC, Sridhar H. Source: Indian J Pathol Microbiol. 1997 October; 40(4): 555-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9444872

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Fusion of AML1/Runx1 to copine VIII, a novel member of the copine family, in an aggressive acute myelogenous leukemia with t(12;21) translocation. Author(s): Ramsey H, Zhang DE, Richkind K, Burcoglu-O'Ral A, Hromas R. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 August; 17(8): 1665-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12886257

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Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Author(s): Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K. Source: Genes, Chromosomes & Cancer. 1999 November; 26(3): 192-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10502316

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Fusion of the platelet-derived growth factor receptor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Author(s): Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H. Source: Blood. 1997 December 1; 90(11): 4271-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9373237

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G-CSF priming in acute myelogenous leukemia. Author(s): Murashige N, Kami M, Takaue Y. Source: The New England Journal of Medicine. 2003 November 20; 349(21): 2071-2; Author Reply 2071-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627794

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Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes. Author(s): Tsimberidou A, Estey E, Cortes J, Thomas D, Faderl S, Verstovsek S, GarciaManero G, Keating M, Albitar M, O'Brien S, Kantarjian H, Giles F. Source: Cancer. 2003 March 15; 97(6): 1481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12627513

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Gene rearrangements in bone marrow cells of patients with acute myelogenous leukemia. Author(s): Schmetzer HM, Braun S, Wiesner D, Duell T, Gerhartz HH, Mittermueller J. Source: Acta Haematologica. 2000; 103(3): 125-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10940650

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Genetic heterogeneity in familial acute myelogenous leukemia: evidence for a second locus at chromosome 16q21-23.2. Author(s): Horwitz M, Benson KF, Li FQ, Wolff J, Leppert MF, Hobson L, Mangelsdorf M, Yu S, Hewett D, Richards RI, Raskind WH. Source: American Journal of Human Genetics. 1997 October; 61(4): 873-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9382098

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Genetic reversion in an acute myelogenous leukemia cell line from a Fanconi anemia patient with biallelic mutations in BRCA2. Author(s): Ikeda H, Matsushita M, Waisfisz Q, Kinoshita A, Oostra AB, Nieuwint AW, De Winter JP, Hoatlin ME, Kawai Y, Sasaki MS, D'Andrea AD, Kawakami Y, Joenje H. Source: Cancer Research. 2003 May 15; 63(10): 2688-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12750298

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Genetic studies on a family with acute myelogenous leukemia. Author(s): Feng B, Lei J, Lin Z, Hao J, Chen W. Source: Cancer Genetics and Cytogenetics. 1999 July 15; 112(2): 134-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10686940

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Gleditsia sinensis fruit extract is a potential chemotherapeutic agent in chronic and acute myelogenous leukemia. Author(s): Chow LM, Chui CH, Tang JC, Teo IT, Lau FY, Cheng GY, Wong RS, Leung TW, Lai KB, Yau MY, Gou D, Chan AS. Source: Oncol Rep. 2003 September-October; 10(5): 1601-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883747

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Glutathione system, topoisomerase II level and multidrug resistance phenotype in acute myelogenous leukemia before treatment and at relapse. Author(s): Massaad-Massade L, Ribrag V, Marie JP, Faussat AM, Bayle C, Dreyfus F, Gouyette A. Source: Anticancer Res. 1997 November-December; 17(6D): 4647-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9494583

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Granulocyte colony-stimulating factor following chemotherapy in elderly patients with newly diagnosed acute myelogenous leukemia. Author(s): Maslak PG, Weiss MA, Berman E, Yao TJ, Tyson D, Golde DW, Scheinberg DA. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 January; 10(1): 32-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8558934

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Granulocyte colony-stimulating factor-combined marrow-ablative chemotherapy and autologous blood cell transplantation for the treatment of patients with acute myelogenous leukemia in first remission. The Fukouka Bone Marrow Transplant Group. Author(s): Harada M, Akashi K, Hayashi S, Eto T, Takamatsu Y, Teshima T, Hirota Y, Taniguchi S, Nagafuji K, Mizuno S, Gondo H, Niho Y. Source: International Journal of Hematology. 1997 October; 66(3): 297-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9401275

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Granulocyte-macrophage colony stimulating factor (GM-CSF) priming in the treatment of elderly patients with acute myelogenous leukemia. Author(s): Frenette PS, Desforges JF, Schenkein DP, Rabson A, Slapack CA, Miller KB. Source: American Journal of Hematology. 1995 May; 49(1): 48-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7741138

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Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. Author(s): Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA, Schulman P, Lee EJ, Moore JO, Powell BL, Schiffer CA. Source: The New England Journal of Medicine. 1995 June 22; 332(25): 1671-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7760868

88


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Granulocyte-macrophage colony-stimulating factor in association to timed-sequential chemotherapy with mitoxantrone, etoposide, and cytarabine for refractory acute myelogenous leukemia. Author(s): Archimbaud E, Fenaux P, Reiffers J, Cordonnier C, Leblond V, Travade P, Troussard X, Tilly H, Auzanneau G, Marie JP, et al. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 March; 7(3): 372-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8445942

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Granulocyte-macrophage colony-stimulating factor with induction treatment of acute myelogenous leukemia. Author(s): Adkins DR, Brown RA, DiPersio JF. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1997 February; 15(2): 862-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9053516

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Granulocytic sarcoma in MLL-positive infant acute myelogenous leukemia: fluorescence in situ hybridization study of childhood acute myelogenous leukemia for detecting MLL rearrangement. Author(s): Park KU, Lee DS, Lee HS, Kim CJ, Cho HI. Source: American Journal of Pathology. 2001 December; 159(6): 2011-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11733351

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Granulocytic sarcoma of the breast preceding acute myelogenous leukemia: a case report. Author(s): Joo M, Lee HK, Kang YK, Kim JH. Source: Journal of Korean Medical Science. 2000 August; 15(4): 457-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10983697

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Granulocytic sarcoma of the ovary in patients with acute myelogenous leukemia. Author(s): Yamamoto K, Akiyama H, Maruyama T, Sakamaki H, Onozawa Y, Kawaguchi K. Source: American Journal of Hematology. 1991 November; 38(3): 223-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1951322

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Granulocytic sarcoma presenting as a diffuse renal mass before hematological manifestations of acute myelogenous leukemia. Author(s): Bagg MD, Wettlaufer JN, Willadsen DS, Ho V, Lane D, Thrasher JB. Source: The Journal of Urology. 1994 December; 152(6 Pt 1): 2092-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7966684

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Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice. Author(s): Ailles LE, Gerhard B, Kawagoe H, Hogge DE. Source: Blood. 1999 September 1; 94(5): 1761-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10477702

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Growth in children after bone marrow transplantation for acute myelogenous leukemia as compared to acute lymphocytic leukemia. Author(s): Alter CA, Thornton PS, Willi SM, Bunin N, Moshang T Jr. Source: J Pediatr Endocrinol Metab. 1996 January-February; 9(1): 51-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8887133

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Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium. Author(s): Sandler ES, Hagg R, Coppes MJ, Mustafa MM, Gamis A, Kamani N, Wall D. Source: Medical and Pediatric Oncology. 2000 October; 35(4): 403-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11025470

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Hepatic granuloma due to Propionibacterium acnes in a patient with acute myelogenous leukemia. Author(s): Ullmann AJ, Helmreich-Becker I, Maeurer MJ, Han SR, Heussel CP, Koehler HH, Fischer T, Huber C. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2000 January; 30(1): 219-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10619766

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Herpes zoster-like Sweet's syndrome in acute myelogenous leukemia. Author(s): Chiang CT, Chan HL, Kuo TT, Wang PN. Source: International Journal of Dermatology. 1997 September; 36(9): 717-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9352420

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Herpetic geometric glossitis in a pediatric patient with acute myelogenous leukemia. Author(s): Theriault A, Cohen PR. Source: American Journal of Clinical Oncology : the Official Publication of the American Radium Society. 1997 December; 20(6): 567-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9391541

90


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Heterogeneity in CBF beta/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia. Author(s): Shurtleff SA, Meyers S, Hiebert SW, Raimondi SC, Head DR, Willman CL, Wolman S, Slovak ML, Carroll AJ, Behm F, et al. Source: Blood. 1995 June 15; 85(12): 3695-703. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7780153

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Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation-inducing agent. Author(s): Andreeff M, Stone R, Michaeli J, Young CW, Tong WP, Sogoloff H, Ervin T, Kufe D, Rifkind RA, Marks PA. Source: Blood. 1992 November 15; 80(10): 2604-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1421378

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High affinity interleukin-3 receptor expression on blasts from patients with acute myelogenous leukemia correlates with cytotoxicity of a diphtheria toxin/IL-3 fusion protein. Author(s): Alexander RL, Ramage J, Kucera GL, Caligiuri MA, Frankel AE. Source: Leukemia Research. 2001 October; 25(10): 875-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11532521

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High dose ara-C combined with autologous peripheral blood stem cell transplantation in the treatment of acute myelogenous leukemia: the question is still not answered. Author(s): Bruserud O, Ernst P. Source: Stem Cells (Dayton, Ohio). 2000; 18(6): 459-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11072036

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High levels of Ca(2+)-independent endonuclease activity capable of producing nucleosomal-size DNA fragmentation in non-adherent marrow mononuclear cells from patients with myelodysplastic syndromes and acute myelogenous leukemia. Author(s): Kawabata H, Anzai N, Ueda Y, Masutani H, Hirama T, Yoshida Y, Okuma M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 January; 10(1): 67-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8558941

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High levels of constitutive WAF1/Cip1 protein are associated with chemoresistance in acute myelogenous leukemia. Author(s): Zhang W, Kornblau SM, Kobayashi T, Gambel A, Claxton D, Deisseroth AB. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1995 September; 1(9): 1051-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9816079

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High remission rate, short remission duration in patients with refractory anemia with excess blasts (RAEB) in transformation (RAEB-t) given acute myelogenous leukemia (AML)-type chemotherapy in combination with granulocyte-CSF (G-CSF). Author(s): Estey EH, Kantarjian HM, O'Brien S, Kornblau S, Andreeff M, Beran M, Pierce S, Keating M. Source: Cytokines Mol Ther. 1995 March; 1(1): 21-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9384660

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High-dose cytarabine and recombinant human granulocyte colony-stimulating factor for the treatment of resistant acute myelogenous leukemia. Author(s): Schiller G, Emmanoulides C, Iastrebner MC, Lee M, Naeim F. Source: Leukemia & Lymphoma. 1996 February; 20(5-6): 427-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8833398

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High-dose cytosine arabinoside and daunorubicin induction therapy for adult patients with de novo non M3 acute myelogenous leukemia: impact of cytogenetics on achieving a complete remission. Author(s): Stein AS, O'Donnell MR, Slovak ML, Nademanee A, Dagis A, Schmidt GM, Parker PM, Snyder DS, Smith EP, Somlo G, Margolin KA, Arber D, Niland J, Forman SJ. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 July; 14(7): 1191-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10914541

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High-dose liposomal daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia. Author(s): Cortes J, Estey E, O'Brien S, Giles F, Shen Y, Koller C, Beran M, Thomas D, Keating M, Kantarjian H. Source: Cancer. 2001 July 1; 92(1): 7-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11443603

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Highly complex karyotypic changes in acute myelogenous leukemia: a case report. Author(s): Heller A, Rubtsov N, Kytola S, Karamysheva TV, Sablina OV, Degtyareva MM, Starke H, Metzke H, Claussen U, Liehr T. Source: International Journal of Oncology. 2003 July; 23(1): 139-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12792786

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Histamine and interleukin-2 in acute myelogenous leukemia. Author(s): Hellstrand K, Mellqvist UH, Wallhult E, Carneskog J, Kimby E, Celsing F, Brune M. Source: Leukemia & Lymphoma. 1997 November; 27(5-6): 429-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9477124

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HLA-identical sibling bone marrow transplants vs chemotherapy for acute myelogenous leukemia in first remission. Author(s): Gale RP, Buchner T, Zhang MJ, Heinecke A, Champlin RE, Dicke KA, Gluckman E, Good RA, Gratwohl A, Herzig RH, Keating A, Klein JP, Marmont AM, Prentice HG, Rowlings PA, Sobocinski KA, Speck B, Weiner RS, Horowitz MM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 November; 10(11): 1687-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8892667

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Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a model for human AML. Author(s): Cuenco GM, Nucifora G, Ren R. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 February 15; 97(4): 1760-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10677531

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Hypereosinophilic syndrome terminating in acute myelogenous leukemia. Author(s): Higuchi W, Koike T, Ihizumi T, Shibata A. Source: Acta Haematologica. 1993; 90(3): 165-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8291379

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Hypermethylation of p15(INK4B) gene in a patient with acute myelogenous leukemia evolved from paroxysmal nocturnal hemoglobinuria. Author(s): Uchida T, Ohashi H, Kinoshita T, Saito H, Taguchi R, Hotta T, Murate T. Source: Blood. 1998 October 15; 92(8): 2981-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9763591

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Idarubicin, cytarabine, and topotecan in patients with refractory or relapsed acute myelogenous leukemia and high-risk myelodysplastic syndrome. Author(s): Lee ST, Jang JH, Suh HC, Hahn JS, Ko YW, Min YH. Source: American Journal of Hematology. 2001 December; 68(4): 237-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11754412

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Identification of a novel human gene, ZFP91, involved in acute myelogenous leukemia. Author(s): Unoki M, Okutsu J, Nakamura Y. Source: International Journal of Oncology. 2003 June; 22(6): 1217-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738986

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Identification of ins(8;21) with AML1/ETO fusion in acute myelogenous leukemia M2 by molecular cytogenetics. Author(s): Urioste M, Martinez-Ramirez A, Cigudosa JC, Mateo MS, Martinez P, Contra T, Benitez J. Source: Cancer Genetics and Cytogenetics. 2002 February; 133(1): 83-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11890995

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Images in cardiovascular medicine. Constrictive pericarditis in a patient with relapsed acute myelogenous leukemia after allogeneic bone marrow transplantation. Author(s): Wong R, Durand JB, Luna MA, Couriel DR, Gajewski JL. Source: Circulation. 2004 March 9; 109(9): E146-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15007019

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Impact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children's Cancer Group. Author(s): Alonzo TA, Kobrinsky NL, Aledo A, Lange BJ, Buxton AB, Woods WG. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 November; 24(8): 627-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439034

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In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Author(s): Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N, Shigesada K, Ito Y, Benson KF, Raskind WH, Rossier C, Antonarakis SE, Israels S, McNicol A, Weiss H, Horwitz M, Scott HS. Source: Blood. 2002 February 15; 99(4): 1364-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11830488

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In vitro cytotoxicity of the LDE: daunorubicin complex in acute myelogenous leukemia blast cells. Author(s): Dorlhiac-Llacer PE, Marquezini MV, Toffoletto O, Carneiro RC, Maranhao RC, Chamone DA. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2001 October; 34(10): 1257-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11593299

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In vitro effects of interleukin-12 on the growth of blast progenitors in acute myelogenous leukemia. Author(s): Miyauchi J. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 December; 15(12): 1996-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11753626

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In vivo effects of IL-4, IL-10, and amifostine on cytokine production in patients with acute myelogenous leukemia. Author(s): Tao M, Li B, Nayini J, Sivaraman S, Song S, Larson A, Toofanfard M, Chen H, Venugopal P, Preisler HD. Source: Leukemia & Lymphoma. 2001 March; 41(1-2): 161-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11342369

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Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog. Author(s): Zhang Y, Dawson MI, Ning Y, Polin L, Parchment RE, Corbett T, Mohamed AN, Feng KC, Farhana L, Rishi AK, Hogge D, Leid M, Peterson VJ, Zhang XK, Mohammad R, Lu JS, Willman C, VanBuren E, Biggar S, Edelstein M, Eilender D, Fontana JA. Source: Blood. 2003 November 15; 102(10): 3743-52. Epub 2003 July 31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893763

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Intensive postremission chemotherapy in Taiwanese adults with acute myelogenous leukemia. Author(s): Hsu HC, Gau JP, Liu JM, Chau WK, Ho CH. Source: Adv Ther. 2001 March-April; 18(2): 67-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11446270

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Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Author(s): Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, Akiyama T, Kuroda H, Kawano Y, Kobune M, Kato J, Hirayama Y, Sakamaki S, Kohda K, Miyake K, Niitsu Y. Source: Nature Medicine. 2003 September; 9(9): 1158-65. Epub 2003 August 03. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12897778

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Interleukin-7 (IL-7) in patients receiving intensive chemotherapy for acute myelogenous leukemia: studies of systemic IL-7 Levels and IL-7 responsiveness of circulating T lymphocytes. Author(s): Wendelbo O, Glenjen N, Bruserud O. Source: Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research. 2002 October; 22(10): 105765. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12433286

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Intraocular leukemia as the primary manifestation of relapsing acute myelogenous leukemia. Author(s): Kassam F, Gale JS, Sheidow TG. Source: Can J Ophthalmol. 2003 December; 38(7): 613-6. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14740808

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Intravenous itraconazole for prophylaxis of systemic fungal infections in patients with acute myelogenous leukemia and high-risk myelodysplastic syndrome undergoing induction chemotherapy. Author(s): Mattiuzzi GN, Kantarjian H, O'Brien S, Kontoyiannis DP, Giles F, Zhou X, Lim J, Bekele BN, Faderl S, Cortes J, Pierce S, Leitz GJ, Raad I, Estey E. Source: Cancer. 2004 February 1; 100(3): 568-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14745874

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Investigation on marking method for phenomenon on regrowth drug resistance in relapsed acute myelogenous leukemia. Author(s): Chen Y, He M, Wu Y, Li H, Yu D. Source: J Tongji Med Univ. 2001; 21(4): 286-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12539549

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Is myelodysplastic related acute myelogenous leukemia a distinct entity from de novo acute myelogenous leukemia? Potential for targeted therapies. Author(s): Rosenfeld C, Kantarjian H. Source: Leukemia & Lymphoma. 2001 May; 41(5-6): 493-500. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11378567

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Is there an association between total-body irradiation and secondary acute myelogenous leukemia/myelodysplastic syndrome in patients with relapsed/refractory Hodgkin's disease treated with autologous stem-cell transplantation? Author(s): Fung HC, Nademanee AP, Bhatia S, Forman SJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 August 1; 19(15): 3585-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11481369

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Isolated granulocytic sarcoma followed by acute myelogenous leukemia type FAB-M2 associated with inversion 16 and trisomies 9 and 22. Author(s): Morel F, Herry A, Le Bris MJ, Le Calvez G, Marion V, Berthou C, De Braekeleer M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 December; 16(12): 2458-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454755

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Isolated IgA deficiency after chemotherapy for acute myelogenous leukemia in an infant. Author(s): Uram R, Rosoff PM. Source: Pediatric Hematology and Oncology. 2003 September; 20(6): 487-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14631625

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Jaundice following high--dose arabinoside cytosine in a child with acute myelogenous leukemia. Author(s): Wysocki M, Nowaczyk-Michalak A, Pilecki O, Trybus L, Balcar-Boron A. Source: Acta Haematol Pol. 1992; 23(3): 197-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1492544

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Karyotype is prognostically more important than the FAB system's distinction between myelodysplastic syndrome and acute myelogenous leukemia. Author(s): Estey EH, Keating MJ, Dixon DO, Trujillo JM, McCredie KB, Freireich EJ. Source: Hematol Pathol. 1987; 1(4): 203-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3504436

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Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Author(s): Morrison FS, Kopecky KJ, Head DR, Athens JW, Balcerzak SP, Gumbart C, Dabich L, Costanzi JJ, Coltman CA, Saiki JH, et al. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 July; 6(7): 708-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1625490

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Leptin in human acute myelogenous leukemia: studies of in vivo levels and in vitro effects on native functional leukemia blasts. Author(s): Bruserud O, Huang TS, Glenjen N, Gjertsen BT, Foss B. Source: Haematologica. 2002 June; 87(6): 584-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12031914

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Leukemia blast-induced T-cell anergy demonstrated by leukemia-derived dendritic cells in acute myelogenous leukemia. Author(s): Narita M, Takahashi M, Liu A, Nikkuni K, Furukawa T, Toba K, Koyama S, Takai K, Sanada M, Aizawa Y. Source: Experimental Hematology. 2001 June; 29(6): 709-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11378266

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Leukemic cells within skin lesions of psoriasis in a patient with acute myelogenous leukemia. Author(s): Metzler G, Cerroni L, Schmidt H, Soyer HP, Sill H, Kerl H. Source: Journal of Cutaneous Pathology. 1997 August; 24(7): 445-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9274964

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Leukemic hypopyon in acute myelogenous leukemia. Author(s): Matano S, Ohta T, Nakamura S, Kanno M, Sugimoto T. Source: Annals of Hematology. 2000 August; 79(8): 455-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10985367

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Lipoprotein receptors in acute myelogenous leukemia: failure to detect increased lowdensity lipoprotein (LDL) receptor numbers in cell membranes despite increased cellular LDL degradation. Author(s): Rudling M, Gafvels M, Parini P, Gahrton G, Angelin B. Source: American Journal of Pathology. 1998 December; 153(6): 1923-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9846982

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Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Author(s): Mattiuzzi GN, Estey E, Raad I, Giles F, Cortes J, Shen Y, Kontoyiannis D, Koller C, Munsell M, Beran M, Kantarjian H. Source: Cancer. 2003 January 15; 97(2): 450-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12518369

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Liver dysfunction in patients with acute myelogenous leukemia: studies on patients not infected with hepatitis C virus during intense therapy. Author(s): Kawatani T, Tajima F, Ishiga K, Suou T, Kawasaki H. Source: J Med. 1998; 29(1-2): 45-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9704292

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Long term follow-up of patients with acute myelogenous leukemia who received the daunorubicin, vincristine, and cytosine arabinoside regimen. Author(s): Beguin Y, Sautois B, Forget P, Bury J, Fillet G. Source: Cancer. 1997 April 1; 79(7): 1351-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9083157

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Long-term bone marrow culture-derived stromal fibroblasts as a potential target for gene therapy in acute myelogenous leukemia. Author(s): Min YH, Li GX, Jang JH, Suh HC, Kim JS, Cheong JW, Lee ST, Hahn JS, Ko YW. Source: Leukemia Research. 2002 April; 26(4): 369-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11839380

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Long-term outcome in acute myelogenous leukemia autografted with mafosfamidepurged marrow in a single institution: adverse events and incidence of secondary myelodysplasia. Author(s): Abdallah A, Egerer G, Weber-Nordt RM, Korbling M, Haas R, Ho AD. Source: Bone Marrow Transplantation. 2002 July; 30(1): 15-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12105772

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Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of adult acute myelogenous leukemia in first complete remission. Author(s): Collisson EA, Lashkari A, Malone R, Paquette R, Emmanouilides C, Territo MC, Schiller GJ. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 November; 17(11): 2183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12931210

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Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for older patients with acute myelogenous leukemia. Author(s): Schiller G, Lee M. Source: Leukemia & Lymphoma. 1997 March; 25(1-2): 111-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9130619

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Long-term results in non randomized patients with acute myelogenous leukemia: a single institution experience. Author(s): Deliliers GL, Annaloro C, Oriani A, Della Volpe A, Boschetti C, Cortelezzi A, Maiolo AT. Source: Ann Ital Med Int. 1998 July-September; 13(3): 146-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9859570

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Loss of DCC gene expression is of prognostic importance in acute myelogenous leukemia. Author(s): Inokuchi K, Yamaguchi H, Hanawa H, Tanosaki S, Nakamura K, Tarusawa M, Miyake K, Shimada T, Dan K. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2002 June; 8(6): 1882-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12060632

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Loss of heterozygosity in childhood de novo acute myelogenous leukemia. Author(s): Sweetser DA, Chen CS, Blomberg AA, Flowers DA, Galipeau PC, Barrett MT, Heerema NA, Buckley J, Woods WG, Bernstein ID, Reid BJ. Source: Blood. 2001 August 15; 98(4): 1188-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11493469

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Low and maximally phosphorylated levels of the retinoblastoma protein confer poor prognosis in newly diagnosed acute myelogenous leukemia: a prospective study. Author(s): Kornblau SM, Andreeff M, Hu SX, Xu HJ, Patel S, Theriault A, Koller C, Kantarjian H, Estey E, Deisseroth AB, Benedict WF. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1998 August; 4(8): 1955-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9717825

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Low curative potential of bone marrow transplantation for highly aggressive acute myelogenous leukemia with inversioin inv (3)(q21q26) or homologous translocation t(3;3) (q21;q26). Author(s): Reiter E, Greinix H, Rabitsch W, Keil F, Schwarzinger I, Jaeger U, Lechner K, Worel N, Streubel B, Fonatsch C, Mitterbauer G, Kalhs P. Source: Annals of Hematology. 2000 July; 79(7): 374-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10965785

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Low-dose cytarabine and aclarubicin in combination with granulocyte colonystimulating factor (CAG regimen) for previously treated patients with relapsed or primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation. Author(s): Saito K, Nakamura Y, Aoyagi M, Waga K, Yamamoto K, Aoyagi A, Inoue F, Nakamura Y, Arai Y, Tadokoro J, Handa T, Tsurumi S, Arai H, Kawagoe Y, Gunnji H, Kitsukawa Y, Takahashi W, Furusawa S. Source: International Journal of Hematology. 2000 April; 71(3): 238-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10846828

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Low-dose total body irradiation and G-CSF without hematopoietic stem cell support in the treatment of relapsed or refractory acute myelogenous leukemia (AML), or AML in second or subsequent remission. Author(s): Shulman LN, Tarbell NJ, Storen E, Marcus K, Mauch PM. Source: International Journal of Radiation Oncology, Biology, Physics. 1998 December 1; 42(5): 1113-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9869237

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Malignant counterpart of myeloid dendritic cell (DC) belonging to acute myelogenous leukemia (AML) exhibits a dichotomous immunoregulatory potential. Author(s): Fujii S, Shimizu K, Koji F, Kawano F. Source: Journal of Leukocyte Biology. 2003 January; 73(1): 82-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12525565

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Malignant progenitors from patients with CD87+ acute myelogenous leukemia are sensitive to a diphtheria toxin-urokinase fusion protein. Author(s): Frankel AE, Beran M, Hogge DE, Powell BL, Thorburn A, Chen YQ, Vallera DA. Source: Experimental Hematology. 2002 November; 30(11): 1316-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423685

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Management of acute myelogenous leukemia in the elderly. Author(s): Rathnasabapathy R, Lancet JE. Source: Cancer Control : Journal of the Moffitt Cancer Center. 2003 NovemberDecember; 10(6): 469-77. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14652523

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Masked MLL gene rearrangement was disclosed in the clinical course and sequential development of chromosome abnormality in a patient with therapy related acute myelogenous leukemia. Author(s): Hashimoto S, Toba K, Izumi N, Sato N, Takahashi H, Ozawa T, Moriyama M, Aoki S, Furukawa T, Narita M, Takahashi M, Aizawa Y. Source: Leukemia Research. 2003 March; 27(3): 285-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12537982

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MDR modulation in acute myelogenous leukemia: is it dead? Author(s): Karp JE. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 April; 15(4): 666-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11368374

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Metastatic gastric adenocarcinoma following allogeneic stem cell transplantation in a patient with acute myelogenous leukemia. Author(s): Tsimberidou AM, Medina J, Earl M, Sierra M, Shriki JE, Bueso-Ramos C, Giralt S, Beran M, Giles FJ, Garcia-Manero G. Source: Bone Marrow Transplantation. 2003 March; 31(5): 413-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634736

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Microsporidial endophthalmitis in a patient with acute myelogenous leukemia. Author(s): Yoken J, Forbes B, Maguire AM, Prenner JL, Carpentieri D. Source: Retina (Philadelphia, Pa.). 2002 February; 22(1): 123-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11884897

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Microvenular hemangioma in a boy with acute myelogenous leukemia. Author(s): Chang SE, Roh KH, Lee MW, Choi JH, Sung KJ, Moon KC, Koh JK, Yoon GS. Source: Pediatric Dermatology. 2003 May-June; 20(3): 266-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12787280

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Minimally differentiated acute myelogenous leukemia (AML-M0) granulocytic sarcoma presenting in the oral cavity. Author(s): Amin KS, Ehsan A, McGuff HS, Albright SC. Source: Oral Oncology. 2002 July; 38(5): 516-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12110349

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Mitoxantrone and prolonged infusion gemcitabine as salvage therapy in patients with acute myelogenous leukemia. Author(s): Apostolidou E, Estey E, Cortes J, Garcia-Manero G, Faderl S, Thomas D, Tsimberidou A, Kantarjian H, Giles FJ. Source: Leukemia Research. 2003 April; 27(4): 301-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12531220

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MLL gene rearrangement in acute myelogenous leukemia after exposure to tegafur/uracil. Author(s): Fukushima T, Yoshio N, Noto Y, Kida H. Source: International Journal of Hematology. 2002 February; 75(2): 178-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11939265

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MmTRA1b/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia. Author(s): Yokoyama A, Yamashita T, Shiozawa E, Nagasawa A, Okabe-Kado J, Nakamaki T, Tomoyasu S, Kimura F, Motoyoshi K, Honma Y, Kasukabe T. Source: Leukemia Research. 2004 February; 28(2): 149-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654079

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Molecular and cytogenetic remission in a case of subtype M4E acute myelogenous leukemia with minimal monochemotherapy: high sensitivity or spontaneous remission? Author(s): Martelli MP, Latagliata R, Spadea A, Avvisati G, Mancini M, Romano A, Luzi G, Petti MC. Source: European Journal of Haematology. 2000 September; 65(3): 203-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11007057

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Molecular targets in acute myelogenous leukemia. Author(s): Stirewalt DL, Meshinchi S, Radich JP. Source: Blood Reviews. 2003 March; 17(1): 15-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12490207

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Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis. Author(s): Park WH, Lee MS, Park K, Kim ES, Kim BK, Lee YY. Source: International Journal of Cancer. Journal International Du Cancer. 2002 September 20; 101(3): 235-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209973

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Mylotarg combined with topotecan and cytarabine in patients with refractory acute myelogenous leukemia. Author(s): Cortes J, Tsimberidou AM, Alvarez R, Thomas D, Beran M, Kantarjian H, Estey E, Giles FJ. Source: Cancer Chemotherapy and Pharmacology. 2002 December; 50(6): 497-500. Epub 2002 October 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12451477

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Mylotarg, fludarabine, cytarabine (ara-C), and cyclosporine (MFAC) regimen as postremission therapy in acute myelogenous leukemia. Author(s): Tsimberidou AM, Estey E, Cortes JE, Garcia-Manero G, Faderl S, Verstovsek S, Thomas DA, Ferrajoli A, Keating MJ, O'Brien S, Kantarjian HM, Giles FJ. Source: Cancer Chemotherapy and Pharmacology. 2003 December; 52(6): 449-52. Epub 2003 September 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680159

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NCCN Practice Guidelines for Acute Myelogenous Leukemia. Author(s): Appelbaum FR, Baer MR, Carabasi MH, Coutre SE, Erba HP, Estey E, Glenn MJ, Kraut EH, Maslak P, Millenson M, Miller CB, Saba HI, Stone R, Tallman MS; National Comprehensive Cancer Network. Source: Oncology (Huntingt). 2000 November; 14(11A): 53-61. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11195419

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Neutropenic colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside. Author(s): Hogan WJ, Letendre L, Litzow MR, Tefferi A, Hoagland HC, Pruthi RK, Kaufmann SH. Source: Mayo Clinic Proceedings. 2002 August; 77(8): 760-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12173711

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Neutrophilic eccrine hidradenitis unassociated with chemotherapy in a patient with acute myelogenous leukemia. Author(s): Roustan G, Salas C, Cabrera R, Simon A. Source: International Journal of Dermatology. 2001 February; 40(2): 144-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11328400

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New strategies for the treatment of acute myelogenous leukemia: differentiation induction--present use and future possibilities. Author(s): Bruserud O, Gjertsen BT. Source: Stem Cells (Dayton, Ohio). 2000; 18(3): 157-65. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10840068

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New strategies in the treatment of acute myelogenous leukemia (AML): in vitro culture of aml cells--the present use in experimental studies and the possible importance for future therapeutic approaches. Author(s): Bruserud O, Gjertsen BT, Foss B, Huang TS. Source: Stem Cells (Dayton, Ohio). 2001; 19(1): 1-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11209086

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New strategies in the treatment of acute myelogenous leukemia: mobilization and transplantation of autologous peripheral blood stem cells in adult patients. Author(s): Bruserud O, Tjonnfjord G, Gjertsen BT, Foss B, Ernst P. Source: Stem Cells (Dayton, Ohio). 2000; 18(5): 343-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11007918

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Nonmyeloablative preparative regimens: how relevant for acute myelogenous leukemia? Author(s): Storb R. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 April; 15(4): 662-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11368372

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Novel presentation of acute myelogenous leukemia as symptomatic galactorrhea. Author(s): Ales N, Flynn J, Byrd JC. Source: Annals of Internal Medicine. 2001 August 21; 135(4): 303-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11511155

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Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Author(s): Konopleva M, Tsao T, Ruvolo P, Stiouf I, Estrov Z, Leysath CE, Zhao S, Harris D, Chang S, Jackson CE, Munsell M, Suh N, Gribble G, Honda T, May WS, Sporn MB, Andreeff M. Source: Blood. 2002 January 1; 99(1): 326-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11756188

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Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Author(s): Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM, Jordan CT. Source: Blood. 2001 October 15; 98(8): 2301-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11588023

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Ocular adnexal granulocytic sarcoma as the first sign of acute myelogenous leukemia relapse. Author(s): Yaghouti F, Nouri M, Mannor GE. Source: American Journal of Ophthalmology. 1999 March; 127(3): 361-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10088758

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Ocular presentation and successful outcome of invasive sphenoid sinus aspergillosis in acute myelogenous leukemia. Author(s): Carta A, Cesana C. Source: Haematologica. 1998 December; 83(12): 1116-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9949629

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Oculomotor nerve invasion of acute myelogenous leukemia demonstrated by magnetic resonance imaging. Author(s): Tabata M, Yoshida M, Takahashi H, Toshima M, Takatoku M, Tsunoda J, Kikuno M, Hatake K, Miura Y. Source: Leukemia & Lymphoma. 1998 July; 30(3-4): 411-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9713972

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Oncogenes, protooncogenes, and tumor suppressor genes in acute myelogenous leukemia. Author(s): Hijiya N, Gewirtz AM. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 1995 May; 17(2): 101-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7749759

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Oral Fusarium infection in a granulocytopenic patient with acute myelogenous leukemia: a case report. Author(s): Myoken Y, Sugata T, Kyo T, Fujihara M. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 1995 May; 24(5): 237-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7616464

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Orbital granulocytic sarcoma in acute myelogenous leukemia. Author(s): Lakhkar BN, Banavali S, Philip P. Source: Indian J Pediatr. 2000 March; 67(3): 234-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10838728

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Outcome assessment of age group-specific (+/- 50 years) post-remission consolidation with high-dose cytarabine or bone marrow autograft for adult acute myelogenous leukemia. Author(s): Bassan R, Raimondi R, Lerede T, D'emilio A, Buelli M, Borleri G, Personeni A, Bellavita P, Rodeghiero F, Barbui T. Source: Haematologica. 1998 July; 83(7): 627-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9718868

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Outcomes in patients treated with gemtuzumab ozogamicin for relapsed acute myelogenous leukemia. Author(s): Lang K, Menzin J, Earle CC, Mallick R. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 2002 May 15; 59(10): 941-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12040733

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Overexpression of Bcl-2 or Bcl-xL inhibits Ara-C-induced CPP32/Yama protease activity and apoptosis of human acute myelogenous leukemia HL-60 cells. Author(s): Ibrado AM, Huang Y, Fang G, Liu L, Bhalla K. Source: Cancer Research. 1996 October 15; 56(20): 4743-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8840993

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Overexpression of cyclin E in acute myelogenous leukemia. Author(s): Iida H, Towatari M, Tanimoto M, Morishita Y, Kodera Y, Saito H. Source: Blood. 1997 November 1; 90(9): 3707-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9345056

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Paternal isodisomy 7q secondary to monosomy 7 at recurrence in a Down syndrome child with acute myelogenous leukemia. Author(s): Picos-Cardenas VJ, Meza-Espinoza JP, Gutierrez-Angulo M, Esparza-Flores MA, Ayala-Madrigal ML, Hansmann I, Gonzalez GJ. Source: Cancer Genetics and Cytogenetics. 2002 April 15; 134(2): 138-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12034527

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Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia. Author(s): Rizzieri DA, Ibom VK, Moore JO, DeCastro CM, Rosner GL, Adams DJ, Foster T, Payne N, Thompson M, Vredenburgh JJ, Gasparetto C, Long GD, Chao NJ, Gockerman JP. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 February; 9(2): 663-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12576433

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Pilot study of gemtuzumab ozogamicin, liposomal daunorubicin, cytarabine and cyclosporine regimen in patients with refractory acute myelogenous leukemia. Author(s): Apostolidou E, Cortes J, Tsimberidou A, Estey E, Kantarjian H, Giles FJ. Source: Leukemia Research. 2003 October; 27(10): 887-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860007

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Platelet-derived growth factor (PDGF) in human acute myelogenous leukemia: PDGF receptor expression, endogenous PDGF release and responsiveness to exogenous PDGF isoforms by in vitro cultured acute myelogenous leukemia blasts. Author(s): Foss B, Ulvestad E, Bruserud O. Source: European Journal of Haematology. 2001 October; 67(4): 267-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11860452

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Potential involvement of the AML1-MTG8 fusion protein in the granulocytic maturation characteristic of the t(8;21) acute myelogenous leukemia revealed by microarray analysis. Author(s): Shimada H, Ichikawa H, Ohki M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 May; 16(5): 874-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11986950

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Prognostic factors in elderly patients with acute myelogenous leukemia: a single center study in Japan. Author(s): Nannya Y, Kanda Y, Oshima K, Kaneko M, Yamamoto R, Chizuka A, Hamaki T, Suguro M, Matsuyama T, Takezako N, Miwa A, Togawa A. Source: Leukemia & Lymphoma. 2002 January; 43(1): 83-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11908740

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Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group. Author(s): Casillas JN, Woods WG, Hunger SP, McGavran L, Alonzo TA, Feig SA; Children's Cancer Group. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 August; 25(8): 594-600. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902910

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Prognostic value of AML 1/ETO fusion transcripts in patients with acute myelogenous leukemia. Author(s): Cho EK, Bang SM, Ahn JY, Yoo SM, Park PW, Seo YH, Shin DB, Lee JH. Source: Korean J Intern Med. 2003 March; 18(1): 13-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12760263

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Progress and controversies in the treatment of pediatric acute myelogenous leukemia. Author(s): Arceci RJ. Source: Current Opinion in Hematology. 2002 July; 9(4): 353-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12042711

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Prolonged administration of all-trans retinoic acid in combination with intensive chemotherapy and G-CSF for adult acute myelogenous leukemia: single-centre pilot study in different risk groups. Author(s): Bassan R, Chiodini B, Lerede T, Giussani U, Oldani E, Buelli M, Rossi A, Viero P, Rambaldi A, Barbui T. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2002; 3(4): 193-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189565

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Quality of life in patients with acute myelogenous leukemia in prolonged first complete remission after bone marrow transplantation (allogeneic or autologous) or chemotherapy: a cross-sectional study of the EORTC-GIMEMA AML 8A trial. Author(s): Zittoun R, Suciu S, Watson M, Solbu G, Muus P, Mandelli F, Stryckmans P, Peetermans M, Thaler J, Resegotti L, Dardenne M, Willemze R. Source: Bone Marrow Transplantation. 1997 August; 20(4): 307-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9285546

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Quantitation of minimal residual disease in acute myelogenous leukemia and myelodysplastic syndromes in complete remission by molecular cytogenetics of progenitor cells. Author(s): Engel H, Drach J, Keyhani A, Jiang S, Van NT, Kimmel M, Sanchez-Williams G, Goodacre A, Andreeff M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1999 April; 13(4): 568-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10214863

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Quantitation of minimal residual disease in t(8;21)-positive acute myelogenous leukemia patients using real-time quantitative RT-PCR. Author(s): Sugimoto T, Das H, Imoto S, Murayama T, Gomyo H, Chakraborty S, Taniguchi R, Isobe T, Nakagawa T, Nishimura R, Koizumi T. Source: American Journal of Hematology. 2000 June; 64(2): 101-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10814988

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Quantitative expression of proliferating cell nuclear antigen by western blot (PCNAWB) in peripheral blasts correlates with remission induction in patients with acute myelogenous leukemia. Author(s): Del Giglio A, Drach J, Kornblau SM, Patel S, Novaes M, Khetan R, Sawaya N, Dorlhiac-Llacer P, Chamone DF, Andreeff M, et al. Source: Leukemia & Lymphoma. 1995 October; 19(3-4): 235-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8535214

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Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia. Author(s): Drabkin HA, Parsy C, Ferguson K, Guilhot F, Lacotte L, Roy L, Zeng C, Baron A, Hunger SP, Varella-Garcia M, Gemmill R, Brizard F, Brizard A, Roche J. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 February; 16(2): 186-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11840284

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Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia. Author(s): Solary E, Drenou B, Campos L, de Cremoux P, Mugneret F, Moreau P, Lioure B, Falkenrodt A, Witz B, Bernard M, Hunault-Berger M, Delain M, Fernandes J, Mounier C, Guilhot F, Garnache F, Berthou C, Kara-Slimane F, Harousseau JL; Groupe Ouest Est Leucemies Aigues Myeloblastiques. Source: Blood. 2003 August 15; 102(4): 1202-10. Epub 2003 March 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663440

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Raltitrexed, a novel folate-based thymidylate synthase inhibitor, for the treatment of acute leukemia: is this drug active against acute myelogenous leukemia? Author(s): Takemura Y, Kobayashi H, Miyachi H. Source: International Journal of Hematology. 2000 July; 72(1): 112-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10979221

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Reactive oxygen species-specific mechanisms of drug resistance in paraquat-resistant acute myelogenous leukemia sublines. Author(s): Choi CH, Kim HS, Kweon OS, Lee TB, You HJ, Rha HS, Jeong JH, Lim DY, Min YD, Kim MS, Chung MH. Source: Molecules and Cells. 2000 February 29; 10(1): 38-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10774745

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Real-time quantitative reverse transcription-polymerase chain reaction for the detection of AML1-MTG8 fusion transcripts in t(8;21)-positive acute myelogenous leukemia. Author(s): Kondo M, Kudo K, Kimura H, Inaba J, Kato K, Kojima S, Matsuyama T, Horibe K. Source: Leukemia Research. 2000 November; 24(11): 951-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11086178

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Recurrence of acute myelogenous leukemia with the same AML1/ETO breakpoint as at diagnosis after complete remission lasting 15 years: analysis of stored bone marrow smears. Author(s): Tsukamoto N, Karasawa M, Tanaka Y, Yokohama A, Uchiumi H, Matsushima T, Murakami H, Nojima Y. Source: International Journal of Hematology. 2003 November; 78(4): 362-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14686496

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Recurrent self-limited fungemia caused by Yarrowia lipolytica in a patient with acute myelogenous leukemia. Author(s): Chang CL, Park TH, Lee EY, Lim YT, Son HC. Source: Journal of Clinical Microbiology. 2001 March; 39(3): 1200-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11230460

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Relapse of acute myelogenous leukemia as a cerebellar myeloblastoma showing megakaryoblastic differentiation. Author(s): Lorsbach RB, Folkerth RD, Pinkus GS. Source: Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 1999 December; 12(12): 1186-91. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10619274

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Remission induction by granulocyte colony-stimulating factor in hypoplastic acute myelogenous leukemia complicated by infection. A case report and review of the literature. Author(s): Takamatsu Y, Miyamoto T, Iwasaki H, Makino S, Tamura K. Source: Acta Haematologica. 1998; 99(4): 224-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9644302

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Resonance in periodic chemotherapy: a case study of acute myelogenous leukemia. Author(s): Andersen LK, Mackey MC. Source: Journal of Theoretical Biology. 2001 March 7; 209(1): 113-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11237575

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Retroviral marking of acute myelogenous leukemia progenitors that initiate longterm culture and growth in immunodeficient mice. Author(s): Ailles LE, Humphries RK, Thomas TE, Hogge DE. Source: Experimental Hematology. 1999 November; 27(11): 1609-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10560908

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Role of drugs in cutaneous eruptions after chemotherapy for acute myelogenous leukemia. Author(s): Mansouri S, Dubertret L, Bastuji-Garin S, Dombret H, Roujeau JC, Aractingi S. Source: Archives of Dermatology. 1998 July; 134(7): 881-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9681363

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Secondary acute myelogenous leukemia with MLL gene rearrangement following radioimmunotherapy (RAIT) for non-Hodgkin's lymphoma. Author(s): Nabhan C, Peterson LA, Kent SA, Tallman MS, Dewald G, Multani P, Gordon LI. Source: Leukemia & Lymphoma. 2002 November; 43(11): 2145-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12539741

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Secondary myelodysplastic syndrome and acute myelogenous leukemia are significant complications following autologous stem cell transplantation for lymphoma. Author(s): Howe R, Micallef IN, Inwards DJ, Ansell SM, Dewald GW, Dispenzieri A, Gastineau DA, Gertz MA, Geyer SM, Hanson CA, Lacy MQ, Tefferi A, Litzow MR. Source: Bone Marrow Transplantation. 2003 August; 32(3): 317-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12858205

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Selective bowel decontamination for the prevention of infection in acute myelogenous leukemia: a prospective randomized trial. Author(s): Lee DG, Choi SM, Choi JH, Yoo JH, Park YH, Kim YJ, Lee S, Min CK, Kim HJ, Kim DW, Lee JW, Min WS, Shin WS, Kim CC. Source: Korean J Intern Med. 2002 March; 17(1): 38-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12014211

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Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia. Author(s): Glenjen N, Mosevoll KA, Bruserud O. Source: International Journal of Cancer. Journal International Du Cancer. 2002 September 1; 101(1): 86-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209593

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Solitary embolic cutaneous aspergillosis in the immunocompromised patient with acute myelogenous leukemia - a propos another case caused by Aspergillus flavus. Author(s): Krunic AL, Medenica M, Busbey S. Source: International Journal of Dermatology. 2003 December; 42(12): 946-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14636189

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Spontaneous medial rectus hemorrhage in a patient with acute myelogenous leukemia. Author(s): Thuente DD, Neely DE. Source: J Aapos. 2002 August; 6(4): 257-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12185355

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Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using alltrans retinoic acid. Author(s): Pan XQ, Zheng X, Shi G, Wang H, Ratnam M, Lee RJ. Source: Blood. 2002 July 15; 100(2): 594-602. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091353

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Successful treatment of invasive aspergillosis in two patients with acute myelogenous leukemia. Author(s): Singer MS, Seibel NL, Vezina G, Choi SS, Dinndorf PA. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 March; 25(3): 252-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12621247

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Survival-weighted health profile for long-term survivors of acute myelogenous leukemia. Author(s): Hsu C, Wang JD, Hwang JS, Tien HF, Chang SM, Cheng AL, Chen YC, Tang JL. Source: Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. 2003 August; 12(5): 503-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13677495

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Systemic antifungal prophylaxis reduces invasive fungal in acute myelogenous leukemia: a retrospective review of 833 episodes of neutropenia in 322 adults. Author(s): Rex JH, Anaissie EJ, Boutati E, Estey E, Kantarjian H. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 June; 16(6): 1197-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12040453

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Targeting FLT3 kinase in acute myelogenous leukemia: progress, perils, and prospects. Author(s): Heinrich MC. Source: Mini Reviews in Medicinal Chemistry. 2004 March; 4(3): 255-71. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15032673

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The angioregulatory phenotype of native human acute myelogenous leukemia cells: influence of karyotype, Flt3 abnormalities and differentiation status. Author(s): Glenjen N, Hovland R, Wergeland L, Wendelbo O, Ernst P, Bruserud O. Source: European Journal of Haematology. 2003 September; 71(3): 163-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12930316

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The latest treatment advances for acute myelogenous leukemia. Author(s): Colvin GA, Elfenbein GJ. Source: Medicine and Health, Rhode Island. 2003 August; 86(8): 243-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14582219

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Therapy-related myelodysplastic syndrome or acute myelogenous leukemia in patients with acute promyelocytic leukemia (APL). Author(s): Garcia-Manero G, Kantarjian HM, Kornblau S, Estey E. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 September; 16(9): 1888. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12200720

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Timed sequential therapy of acute myelogenous leukemia in adults: a phase II study of retinoids in combination with the sequential administration of cytosine arabinoside, idarubicin and etoposide. Author(s): Bolanos-Meade J, Karp JE, Guo C, Sarkodee-Adoo CB, Rapoport AP, Tidwell ML, Buddharaju LN, Chen TT. Source: Leukemia Research. 2003 April; 27(4): 313-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12531222

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Timed-sequential chemotherapy with concomitant granulocyte colony-stimulating factor for newly diagnosed de novo acute myelogenous leukemia. Author(s): He XY, Pohlman B, Lichtin A, Rybicki L, Kalaycio M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 June; 17(6): 1078-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764371

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Transcription of AML1/ETO in bone marrow and cord blood of individuals without acute myelogenous leukemia. Author(s): Basecke J, Cepek L, Mannhalter C, Krauter J, Hildenhagen S, Brittinger G, Trumper L, Griesinger F. Source: Blood. 2002 September 15; 100(6): 2267-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12229881

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Translocation (11;16)(q23;p13) acute myelogenous leukemia and myelodysplastic syndrome. Author(s): Glassman AB, Hayes KJ. Source: Ann Clin Lab Sci. 2003 Summer; 33(3): 285-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956443

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Treatment of acute myelogenous leukemia. Author(s): Estey EH. Source: Oncology (Huntingt). 2002 March; 16(3): 343-52, 355-6; Discussion 357, 362, 3656. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046392

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Treatment of refractory and relapsed acute myelogenous leukemia. Author(s): Stanisic S, Kalaycio M. Source: Expert Review of Anticancer Therapy. 2002 June; 2(3): 287-95. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12113052

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Ultrastructural peroxidase cytochemistry of leukemic cells. I. Classification of acute myelogenous leukemia. Author(s): Wada J. Source: The Keio Journal of Medicine. 1980 December; 29(4): 163-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6947116

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Uncertainties in the standard care of acute myelogenous leukemia. Author(s): Rowe JM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 April; 15(4): 677-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11368379

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Unique molecular and cellular features of acute myelogenous leukemia stem cells. Author(s): Jordan CT. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 April; 16(4): 559-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11960332

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Unstimulated human acute myelogenous leukemia blasts secrete matrix metalloproteinases. Author(s): Matsuzaki A, Janowska-Wieczorek A. Source: Journal of Cancer Research and Clinical Oncology. 1997; 123(2): 100-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9030248

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Untreated chronic lymphocytic leukemia concurrent with or followed by acute myelogenous leukemia or myelodysplastic syndrome. A report of five cases and review of the literature. Author(s): Lai R, Arber DA, Brynes RK, Chan O, Chang KL. Source: American Journal of Clinical Pathology. 1999 March; 111(3): 373-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10078113

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Unusual histopathology of mucormycosis in acute myelogenous leukemia. Author(s): Mamlok V, Cowan WT Jr, Schnadig V. Source: American Journal of Clinical Pathology. 1987 July; 88(1): 117-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3474878

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Unusual rheumatological and cardiological manifestations of acute myelogenous leukemia in a patient with Klinefelter's syndrome. Author(s): Dow G, Reid GD, Horsman DE, Barnett MJ. Source: Leukemia & Lymphoma. 1993 March; 9(4-5): 419-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8348077

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Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. Author(s): Estey E, Thall P, Andreeff M, Beran M, Kantarjian H, O'Brien S, Escudier S, Robertson LE, Koller C, Kornblau S, et al. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1994 April; 12(4): 671-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7512125

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Use of hematopoietic growth factors in the treatment of acute myelogenous leukemia. Author(s): Ganser A, Heil G. Source: Current Opinion in Hematology. 1997 May; 4(3): 191-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9209835

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Use of the polymerase chain reaction to detect hypermethylation in the calcitonin gene. A new, sensitive approach to monitor tumor cells in acute myelogenous leukemia. Author(s): Fukuhara T, Hooper WC, Baylin SB, Benson J, Pruckler J, Olson AC, Evatt BL, Vogler WR. Source: Leukemia Research. 1992 October; 16(10): 1031-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1405705

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Validation of flow-cytometric determination of Ki67 expression as a measure of growth factor response in acute myelogenous leukemia. Author(s): Gore SD, Weng LJ, Burke PJ. Source: Experimental Hematology. 1993 December; 21(13): 1702-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7694870

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Vancomycin-resistant Aureobacterium species cellulitis and bacteremia in a patient with acute myelogenous leukemia. Author(s): Nolte FS, Arnold KE, Sweat H, Winton EF, Funke G. Source: Journal of Clinical Microbiology. 1996 August; 34(8): 1992-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8818896

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Variable cytotoxicity of diphtheria toxin 388-granulocyte-macrophage colonystimulating factor fusion protein for acute myelogenous leukemia stem cells. Author(s): Feuring-Buske M, Frankel A, Gerhard B, Hogge D. Source: Experimental Hematology. 2000 December; 28(12): 1390-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11146161

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What is the best induction regimen for acute myelogenous leukemia? Author(s): Rowe JM. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 September; 12 Suppl 1: S16-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9777889

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What's new in the causes of hemorrhage in acute myelogenous leukemia? Author(s): Rossle A, Ostermann H. Source: Pathology, Research and Practice. 1990 June; 186(3): 415-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2198555

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CHAPTER 2. NUTRITION AND ACUTE MYELOGENOUS LEUKEMIA Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and acute myelogenous leukemia.

Finding Nutrition Studies on Acute Myelogenous Leukemia 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 “acute myelogenous leukemia” (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 “acute myelogenous leukemia” (or a synonym): •

A case of acute myeloid leukemia with t(7;11)(p15;p15) mimicking myeloid crisis of chronic myelogenous leukemia. Author(s): Division of Hematology, Suzuka General Hospital, Mie, Japan. [email protected] Source: Kawakami, K Miyanishi, S Nishii, K Usui, E Murata, T Shinsato, I Shiku, H Int-JHematol. 2002 July; 76(1): 80-3 0925-5710

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A comparison of cytokinetically based versus intensive chemotherapy for childhood acute myelogenous leukemia. Source: Dahl, G V Kalwinsky, D K Mirro, J Look, A T Hamatol-Bluttransfus. 1987; 3083-7 0440-0607

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A phase II study of Homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: a pediatric oncology group study. Author(s): Department of Pediatric Hematology/Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada. [email protected] Source: Bell, B A Chang, M N Weinstein, H J Med-Pediatr-Oncol. 2001 August; 37(2): 103-7 0098-1532

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A randomized comparison of intensive maintenance treatment for adult acute myelogenous leukemia using either cyclic alternating drugs or repeated courses of the induction-type chemotherapy: AML-6 trial of the EORTC Leukemia Cooperative Group. Source: Jehn, U Zittoun, R Suciu, S Fiere, D Haanen, C Peetermans, M Lowenberg, B Willemze, R Solbu, G Stryckmans, P Hamatol-Bluttransfus. 1990; 33277-84 0440-0607

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Aclacinomycin-A in the induction treatment of childhood acute myelogenous leukemia. Source: Fink, F M Grumayer, E R Kardos, G Revesz, T Gadner, H Schuler, D HamatolBluttransfus. 1987; 30393-8 0440-0607

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Acute myelogenous leukemia after treatment for malignant germ cell tumors in children. Author(s): Department of Pediatric Hematology and Oncology, Heinrich-HeineUniversity Dusseldorf, Medical Center, Dusseldorf, Germany. [email protected] Source: Schneider, D T Hilgenfeld, E Schwabe, D Behnisch, W Zoubek, A Wessalowski, R Gobel, U J-Clin-Oncol. 1999 October; 17(10): 3226-33 0732-183X

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Amsacrine and continuous-infusion high-dose cytosine arabinoside as induction therapy for patients with newly-diagnosed acute myelogenous leukemia. Author(s): Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. Source: Ghaddar, H M Pierce, S Kantarjian, H M Freireich, E J Keating, M J Estey, E H Leuk-Lymphoma. 1996 June; 22(1-2): 71-6 1042-8194

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Antibody therapy for residual disease in acute myelogenous leukemia. Author(s): Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, 1275 York Avenue, New York, NY 10021, USA. [email protected] Source: Jurcic, J G Crit-Rev-Oncol-Hematol. 2001 April; 38(1): 37-45 1040-8428

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Autologous bone marrow transplantation for acute myelogenous leukemia using 4hydroperoxycyclophosphamide and VP-16 purged bone marrow. Author(s): Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021. Source: Gulati, S Acaba, L Yahalom, J Reich, L Motzer, R Crown, J Doherty, M Clarkson, B Berman, E Atzpodien, J et al. Bone-Marrow-Transplant. 1992 August; 10(2): 129-34 0268-3369

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Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Author(s): First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Source: Gondo, H Harada, M Miyamoto, T Takenaka, K Tanimoto, K Mizuno, S Fujisaki, T Nagafuji, K Hayashi, S Eto, T Taniguchi, S Akashi, K Harada, N Yamasaki, K Shibuya, T Matsuishi, E Ohno, Y Makino, S Takamatsu, Y Murakawa, M Teshima, T Hirota, Y Okamura, T Kinukawa, N Niho, Y et al. Bone-Marrow-Transplant. 1997 November; 20(10): 821-6 0268-3369

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Autologous transplantation with peripheral blood stem cells collected after granulocyte colony-stimulating factor in patients with acute myelogenous leukemia. Author(s): Fred Hutchinson Cancer Research Center. Seattle, WA 98104, USA. Source: Demirer, T Petersen, F B Bensinger, W I Appelbaum, F R Fefer, A Rowley, S Sanders, J Chauncey, T Storb, R Lilleby, K Buckner, C D Bone-Marrow-Transplant. 1996 July; 18(1): 29-34 0268-3369

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CECA-cyclophosphamide, etoposide, carboplatin and cytosine arabinoside--a new salvage regimen for relapsed or refractory acute myelogenous leukemia. Author(s): Section of Molecular Hematology and Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, USA. [email protected] Source: Kornblau, S M Kantarjian, H O'Brien, S Andreeff, M Koller, C A Beran, M Keating, M Estey, E Leuk-Lymphoma. 1998 January; 28(3-4): 371-5 1042-8194

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CHOP treatment of childhood acute myelogenous leukemia with monocytic differentiation: a report on five cases. Source: Urasinski, T Podraza, W Hamatol-Bluttransfus. 1987; 30403-5 0440-0607

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Combination of mitoxantrone and etoposide in patients aged over 60 years with untreated acute myelogenous leukemia. Author(s): Department of Internal Medicine, University of Tubingen, FRG. Source: Ehninger, G Fackler Schwalbe, E Freund, M Heil, G Henke, M Hoelzer, D Hoffmann, R Kurrle, E Link, H Losch, A et al. Hamatol-Bluttransfus. 1990; 33316-7 04400607

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Combination therapy with mitoxantrone and etoposide in adult acute myelogenous leukemia. Author(s): Dept. of Internal Medicine-Poliklinik, University, Heidelberg, FRG. Source: Knauf, W U Ho, A D Korbling, M Hunstein, W Hamatol-Bluttransfus. 1990; 33314-5 0440-0607

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Continuous infusion high-dose cytosine arabinoside without anthracyclines as induction and intensification therapy in adults under age 50 with newly diagnosed acute myelogenous leukemia. Source: Estey, E Keating, M J Plunkett, W McCredie, K B Freireich, E J Semin-Oncol. 1987 June; 14(2 Suppl 1): 58-63 0093-7754

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Double intensification with amsacrine/high dose ara-C and high dose chemotherapy with autologous bone marrow transplantation produces durable remissions in acute myelogenous leukemia. Author(s): Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston 77030. Source: Spinolo, J A Dicke, K A Horwitz, L J Jagannath, S Zander, A R Auber, M L Spitzer, G Bone-Marrow-Transplant. 1990 February; 5(2): 111-8 0268-3369

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Effects of interferon and retinoic acid on the growth and differentiation of clonogenic leukemic cells from acute myelogenous leukemia patients treated with recombinant leukocyte-alpha A interferon. Source: Gallagher, R E Lurie, K J Leavitt, R D Wiernik, P H Leuk-Res. 1987; 11(7): 609-19 0145-2126

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High-dose cytosine arabinoside and retinol in the treatment of acute myelogenous leukemia in childhood. Source: Lie, S O Slordahl, S H Hamatol-Bluttransfus. 1987; 30399-402 0440-0607

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Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia. Author(s): Department of Internal Medicine, University of Heidelberg, Germany. Source: Haas, R Ho, A D Del Valle, F Fischer, J T Ehrhardt, R Dohner, H Witt, B Huberts, H Kaplan, E Hunstein, W Semin-Oncol. 1993 December; 20(6 Suppl 8): 20-6 0093-7754

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Improved survival for patients with acute myelogenous leukemia. Author(s): Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. Source: Mitus, A J Miller, K B Schenkein, D P Ryan, H F Parsons, S K Wheeler, C Antin, J H J-Clin-Oncol. 1995 March; 13(3): 560-9 0732-183X

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In vitro effects of R-verapamil on the cytokine environment and T-lymphocyte proliferation when human T-lymphocyte activation takes place in the presence of acute myelogenous leukemia blasts. Author(s): Section for Hematology, Medical Department B, Haukeland University Hospital, University of Bergen, Norway. Source: Bruserud, O Cancer-Chemother-Pharmacol. 1996; 39(1-2): 71-8 0344-5704

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In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. Author(s): Department of Hematology/Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA. [email protected]. Source: Stein, A S O'Donnell, M R Chai, A Schmidt, G M Nademanee, A Parker, P M Smith, E P Snyder, D S Molina, A Stepan, D E Spielberger, R Somlo, G Margolin, K A Vora, N Lipsett, J Lee, J Niland, J Forman, S J J-Clin-Oncol. 1996 August; 14(8): 2206-16 0732-183X

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In vivo use of all-trans retinoic acid prior to induction chemotherapy improves complete remission rate and increases rhodamine 123 uptake in patients with de novo acute myeloid leukemia. Author(s): Department of Hematology, Ankara University, School of Medicine, Sihhiye, Turkey. Source: Ustun, C Beksac, M Dalva, K Koc, H Konuk, N Ilhan, O Ozcan, M Topcuoglu, P Sertkaya, D Hayran, M Med-Oncol. 2002; 19(1): 59-67 1357-0560

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Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia. Author(s): Section for Hematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway. Source: Bruserud, O Gjertsen, B T Huang, Ts Oncologist. 2000; 5(6): 454-62 1083-7159

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Induction therapy for acute myelogenous leukemia in patients over 60 years with intermediate-dose cytosine arabinoside, mitoxantrone and etoposide. Author(s): Leukemia/Bone Marrow Transplantation Program of British Columbia, Vancouver General Hospital, Canada. Source: Shepherd, J D Reece, D E Barnett, M J Klingemann, H G Nantel, S H Sutherland, H J Phillips, G L Leuk-Lymphoma. 1993 February; 9(3): 211-5 1042-8194

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Intensive sequential chemotherapy for children with acute myelogenous leukemia. Author(s): Division of Pediatric Oncology and Biostatistics, Dana-Farber Cancer Institute, Boston. Source: Grier, H E Gelber, R D Clavell, L A Camitta, B M Link, M P Garcea, M J Weinstein, H J Hamatol-Bluttransfus. 1990; 33193-7 0440-0607

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Mitoxantrone and VP-16 in refractory acute myelogenous leukemia. Source: Ho, A D Lipp, T Ehninger, G Meyer, P Freund, M Illiger, H J Korbling, M Hamatol-Bluttransfus. 1987; 30339-42 0440-0607

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Mitoxantrone in the treatment of acute myelogenous leukemia: a review. Author(s): Service d'Hematologie, Hopital Edouard Herriot, Lyon, France. Source: Thomas, X Archimbaud, E Hematol-Cell-Ther. 1997 August; 39(4): 63-74 12693286

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New developments in the treatment of acute myeloid leukemia: focus on topotecan. Author(s): M.D. Anderson Cancer Center, Houston, TX 77030, USA. Source: Kantarjian, H Semin-Hematol. 1999 October; 36(4 Suppl 8): 16-25 0037-1963

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Pharmacokinetics of mitoxantrone, etoposide and cytosine arabinoside in leukemic cells during treatment of acute myelogenous leukemia--relationship to treatment outcome and bone marrow toxicity. Author(s): Department of Internal Medicine, Karolinska Hospital, Stockholm, Sweden. Source: Gruber, A Liliemark, E Tidefelt, U Paul, C Bjorkholm, M Peterson, C Liliemark, J Leuk-Res. 1995 October; 19(10): 757-61 0145-2126

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Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC833 in relapsed or refractory acute myelogenous leukemia. Author(s): Section of Molecular Hematology and Therapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. [email protected] Source: Kornblau, S M Estey, E Madden, T Tran, H T Zhao, S Consoli, U Snell, V Sanchez Williams, G Kantarjian, H Keating, M Newman, R A Andreeff, M J-Clin-Oncol. 1997 May; 15(5): 1796-802 0732-183X

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Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia. Author(s): Department of Microbiology, University Hospital Mainz, Germany. Source: Schonbohn, H Schuler, M Kolbe, K Peschel, C Huber, C Bemb, W Aulitzky, W E Ann-Hematol. 1995 October; 71(4): 161-8 0939-5555

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Prognostic factors in childhood acute myelogenous leukemia. Source: Grier, H E Gelber, R D Camitta, B M Delorey, M J Link, M P Price, K N Leavitt, P R Weinstein, H J J-Clin-Oncol. 1987 July; 5(7): 1026-32 0732-183X

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Rapid engraftment after autologous transplantation utilizing marrow and recombinant granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in patients with acute myelogenous leukemia. Author(s): Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA. Source: Demirer, T Buckner, C D Appelbaum, F R Petersen, F B Rowley, S Weaver, C H Lilleby, K Sanders, J Chauncey, T Storb, R et al. Bone-Marrow-Transplant. 1995 June; 15(6): 915-22 0268-3369

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Remission induction and postremission therapy in acute myelogenous leukemia: British MRC Study. Author(s): Department of Haematological Medicine, University of Cambridge, UK. Source: Rees, J K Gray, R G Hamatol-Bluttransfus. 1990; 33243-8 0440-0607

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Role of suramin as an IL-1 inhibitor in suppression of acute myelogenous leukemia progenitor proliferation. Author(s): Department of Clinical Investigation, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA. Source: Estrov, Z Talpaz, M Estey, E H Strassmann, G Exp-Hematol. 1995 September; 23(10): 1080-7 0301-472X

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Secondary acute myelogenous leukemia following safe exposure to etoposide. Author(s): Department of Pediatrics, University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock 72202, USA. [email protected] Source: Stine, K C Saylors, R L Sawyer, J R Becton, D L J-Clin-Oncol. 1997 April; 15(4): 1583-6 0732-183X

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Strategies in the treatment of acute myelogenous leukemia. Author(s): Division of Hematology/Oncology, Emory University, Atlanta, GA 30322. Source: Vogler, W R Leuk-Res. 1992 December; 16(12): 1143-53 0145-2126

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Sweet's syndrome in acute myelogenous leukemia presenting as periorbital cellulitis with an infiltrate of leukemic cells. Author(s): Department of Medicine, Division of Dermatology, University of Louisville, KY, USA. Source: Morgan, K W Callen, J P J-Am-Acad-Dermatol. 2001 October; 45(4): 590-5 01909622

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The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia. Author(s): Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. Source: Vey, N Giles, F J Kantarjian, H Smith, T L Beran, M Jeha, S Clin-Cancer-Res. 2000 February; 6(2): 731-6 1078-0432

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Therapeutic options for acute myelogenous leukemia. Author(s): Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095, USA. [email protected] Source: Estey, E H Cancer. 2001 September 1; 92(5): 1059-73 0008-543X

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Therapy of acute myelogenous leukemia in adults. Author(s): Dept. of Hematology I, University, Rome, Italy. Source: Petti, M C Broccia, G Caronia, F Di Raimondo, F Fioritoni, G Ladogana, S Leone, G Liso, V Musso, M Neri, A et al. Hamatol-Bluttransfus. 1990; 33249-53 0440-0607

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Therapy-related acute myelogenous leukemia associated with 11q23 chromosomal abnormalities and topoisomerase II inhibitors: report of four additional cases and brief commentary. Author(s): Leukemia/Bone Marrow Transplantation Program of British Columbia, Vancouver General Hospital, Canada. Source: Bredeson, C N Barnett, M J Horsman, D E Dalal, B I Ragaz, J Phillips, G L LeukLymphoma. 1993 September; 11(1-2): 141-5 1042-8194

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Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem. Author(s): Department of Human Biotechnologies and Hematology, University La Sapienza of Rome, Cattedra di Ematologia, Via Benevento 6-00161, Rome, Italy. [email protected] Source: Latagliata, Roberto Petti, Maria Concetta Fenu, Susanna Mancini, Marco Spiriti, Maria Antonietta Aloe Breccia, Massimo Brunetti, Gregorio A Avvisati, Giuseppe Lo Coco, Francesco Mandelli, Franco Blood. 2002 February 1; 99(3): 822-4 0006-4971

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Time sequential chemotherapy for primary refractory or relapsed adult acute myeloid leukemia: results of the phase II Gemia protocol. Author(s): Servei d'Hematologia Clinica, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni M Claret, 167, 08025 Barcelona, Spain. 5059@hsp. santpau.es. Source: Martino, R Guardia, R Altes, A Sureda, A Brunet, S Sierra, J Haematologica. 1999 Mar; 84(3): 226-30 0390-6078

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Treatment of acute myelogenous leukemia in children: results of the Italian Cooperative Study AIEOP/LAM 8204. Source: Amadori, S Ceci, A Comelli, A Madon, E Masera, G Nespoli, L Paolucci, G Zanesco, L Covelli, A Mandelli, F J-Clin-Oncol. 1987 September; 5(9): 1356-63 0732-183X

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Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Author(s): Stanford University Medical Center, Stanford, CA, USA. Source: Advani, R Saba, H I Tallman, M S Rowe, J M Wiernik, P H Ramek, J Dugan, K Lum, B Villena, J Davis, E Paietta, E Litchman, M Sikic, B I Greenberg, P L Blood. 1999 February 1; 93(3): 787-95 0006-4971

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Vitamins Vitamin K Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. ALTERNATIVE MEDICINE AND ACUTE MYELOGENOUS LEUKEMIA Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to acute myelogenous leukemia. 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 acute myelogenous leukemia 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 “acute myelogenous leukemia” (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 acute myelogenous leukemia: •

A case of treatment-related myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemotherapy with autologous stem cell transplantation for non-Hodgkin's lymphoma. Author(s): Jang GD, Kim SW, Suh CW, Kim EK, Bahng HS, Jeong YH, Park IG, Kim WK, Kim SH, Suh EJ, Park CJ, Ji HS, Lee JS. Source: Journal of Korean Medical Science. 2002 August; 17(4): 555-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172056

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A homoharringtonine-based regimen for childhood acute myelogenous leukemia. Author(s): Tang J, Xue H, Pan C, Chen J, Gu L, Zhao H. Source: Medical and Pediatric Oncology. 2003 July; 41(1): 70-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764750

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A phase II study of Homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: a pediatric oncology group study. Author(s): Bell BA, Chang MN, Weinstein HJ. Source: Medical and Pediatric Oncology. 2001 August; 37(2): 103-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11496347

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A phase II study of VP-16, intermediate-dose Ara-C and carboplatin (VAC) in advanced acute myelogenous leukemia and blastic chronic myelogenous leukemia. Author(s): Amadori S, Picardi A, Fazi P, Testi AM, Petti MC, Montefusco E, Mandelli F. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 May; 10(5): 766-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8656669

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A phase III trial of high-dose cytosine arabinoside with or without etoposide in relapsed and refractory acute myelogenous leukemia. A Southeastern Cancer Study Group trial. Author(s): Vogler WR, McCarley DL, Stagg M, Bartolucci AA, Moore J, Martelo O, Omura GA. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1994 November; 8(11): 1847-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7967730

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A randomized comparison of intensive maintenance treatment for adult acute myelogenous leukemia using either cyclic alternating drugs or repeated courses of the induction-type chemotherapy: AML-6 trial of the EORTC Leukemia Cooperative Group. Author(s): Jehn U, Zittoun R, Suciu S, Fiere D, Haanen C, Peetermans M, Lowenberg B, Willemze R, Solbu G, Stryckmans P. Source: Haematol Blood Transfus. 1990; 33: 277-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1691132

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Aclacinomycin A and etoposide (VP-16-213): an effective regimen in previously treated patients with refractory acute myelogenous leukemia. Author(s): Rowe JM, Chang AY, Bennett JM. Source: Blood. 1988 April; 71(4): 992-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3162695

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Acute myelogenous leukemia after treatment for malignant germ cell tumors in children. Author(s): Schneider DT, Hilgenfeld E, Schwabe D, Behnisch W, Zoubek A, Wessalowski R, Gobel U. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1999 October; 17(10): 3226-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10506623

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Acute myelogenous leukemia in Down's syndrome: report of a single pediatric institution using a BFM treatment strategy. Author(s): Zubizarreta P, Felice MS, Alfaro E, Fraquelli L, Casak S, Quinteros R, Cygler A, Gallego M, Perez LE, Sackmann-Muriel F. Source: Leukemia Research. 1998 May; 22(5): 465-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9652734

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Amsacrine and continuous-infusion high-dose cytosine arabinoside as induction therapy for patients with newly-diagnosed acute myelogenous leukemia. Author(s): Ghaddar HM, Pierce S, Kantarjian HM, Freireich EJ, Keating MJ, Estey EH. Source: Leukemia & Lymphoma. 1996 June; 22(1-2): 71-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8724530

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Autologous bone marrow transplantation for acute myelogenous leukemia using 4hydroperoxycyclophosphamide and VP-16 purged bone marrow. Author(s): Gulati S, Acaba L, Yahalom J, Reich L, Motzer R, Crown J, Doherty M, Clarkson B, Berman E, Atzpodien J, et al. Source: Bone Marrow Transplantation. 1992 August; 10(2): 129-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1525601

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Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination. Author(s): Lemoli RM, Gasparetto C, Scheinberg DA, Moore MA, Clarkson BD, Gulati SC. Source: Blood. 1991 April 15; 77(8): 1829-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2015406

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Autologous bone marrow transplantation in late first complete remission improves outcome in acute myelogenous leukemia. Author(s): Miggiano MC, Gherlinzoni F, Rosti G, Bandini G, Visani G, Fiacchini M, Ricci P, Testoni N, Motta MR, Geromin A, Rizzi S, Belardinelli A, Mangianti S, Manfroi S, Tura S. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 March; 10(3): 402-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8642854

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Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Author(s): Gondo H, Harada M, Miyamoto T, Takenaka K, Tanimoto K, Mizuno S, Fujisaki T, Nagafuji K, Hayashi S, Eto T, Taniguchi S, Akashi K, Harada N, Yamasaki K, Shibuya T, Matsuishi E, Ohno Y, Makino S, Takamatsu Y, Murakawa M, Teshima T, Hirota Y, Okamura T, Kinukawa N, Niho Y, et al.

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Autologous transplantation with peripheral blood stem cells collected after granulocyte colony-stimulating factor in patients with acute myelogenous leukemia. Author(s): Demirer T, Petersen FB, Bensinger WI, Appelbaum FR, Fefer A, Rowley S, Sanders J, Chauncey T, Storb R, Lilleby K, Buckner CD. Source: Bone Marrow Transplantation. 1996 July; 18(1): 29-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8831992

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BAVC regimen and autograft for acute myelogenous leukemia in second complete remission. Author(s): Meloni G, Vignetti M, Avvisati G, Capria S, Micozzi A, Giona F, Mandelli F. Source: Bone Marrow Transplantation. 1996 October; 18(4): 693-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8899182

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BAVC regimen and autologous bone marrow transplantation in patients with acute myelogenous leukemia in second remission. Author(s): Meloni G, De Fabritiis P, Petti MC, Mandelli F. Source: Blood. 1990 June 15; 75(12): 2282-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2350575

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Bilateral breast relapse in acute myelogenous leukemia. Author(s): Monteleone PM, Steele DA, King AK, Konefal S, Kelleher JF. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2001 February; 23(2): 126-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11216705

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Busulfan plus etoposide as a preparative regimen for autologous bone marrow transplantation for acute myelogenous leukemia: an update. Author(s): Linker CA, Damon LE, Ries CA, Rugo HS, Wolf JL. Source: Seminars in Oncology. 1993 August; 20(4 Suppl 4): 40-8; Quiz 49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8342075

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CECA-cyclophosphamide, etoposide, carboplatin and cytosine arabinoside--a new salvage regimen for relapsed or refractory acute myelogenous leukemia. Author(s): Kornblau SM, Kantarjian H, O'Brien S, Andreeff M, Koller CA, Beran M, Keating M, Estey E. Source: Leukemia & Lymphoma. 1998 January; 28(3-4): 371-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9517508

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Combination of mitoxantrone and etoposide in patients aged over 60 years with untreated acute myelogenous leukemia.


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Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen. Author(s): Ho AD, Lipp T, Ehninger G, Illiger HJ, Meyer P, Freund M, Hunstein W. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1988 February; 6(2): 213-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3422260

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Combination therapy with mitoxantrone and etoposide in adult acute myelogenous leukemia. Author(s): Knauf WU, Ho AD, Korbling M, Hunstein W. Source: Haematol Blood Transfus. 1990; 33: 314-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1969834

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Dose-escalation study of single dose mitoxantrone in combination with timed sequential chemotherapy in patients with refractory or relapsing acute myelogenous leukemia. Author(s): Thomas X, Cambier N, Taksin AL, Reman O, Vekhoff A, Pautas C, Leblond V, Soler-Michel P, Ecstein-Fraisse E, Archimbaud E. Source: Leukemia Research. 2000 November; 24(11): 957-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11086179

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Double intensification with amsacrine/high dose ara-C and high dose chemotherapy with autologous bone marrow transplantation produces durable remissions in acute myelogenous leukemia. Author(s): Spinolo JA, Dicke KA, Horwitz LJ, Jagannath S, Zander AR, Auber ML, Spitzer G. Source: Bone Marrow Transplantation. 1990 February; 5(2): 111-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1690035

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Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Author(s): Lunghi P, Tabilio A, Dall'Aglio PP, Ridolo E, Carlo-Stella C, Pelicci PG, Bonati A. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 September; 17(9): 1783-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970778

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Evaluation of the clinical relevance of the expression and function of P-glycoprotein, multidrug resistance protein and lung resistance protein in patients with primary acute myelogenous leukemia. Author(s): Tsimberidou AM, Paterakis G, Androutsos G, Anagnostopoulos N, Galanopoulos A, Kalmantis T, Meletis J, Rombos Y, Sagriotis A, Symeonidis A, Tiniakou M, Zoumbos N, Yataganas X. Source: Leukemia Research. 2002 February; 26(2): 143-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11755464

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Gleditsia sinensis fruit extract is a potential chemotherapeutic agent in chronic and acute myelogenous leukemia. Author(s): Chow LM, Chui CH, Tang JC, Teo IT, Lau FY, Cheng GY, Wong RS, Leung TW, Lai KB, Yau MY, Gou D, Chan AS. Source: Oncol Rep. 2003 September-October; 10(5): 1601-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883747

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Granulocyte colony-stimulating factor following chemotherapy in elderly patients with newly diagnosed acute myelogenous leukemia. Author(s): Maslak PG, Weiss MA, Berman E, Yao TJ, Tyson D, Golde DW, Scheinberg DA. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 January; 10(1): 32-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8558934

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Granulocyte-macrophage colony-stimulating factor in association to timed-sequential chemotherapy with mitoxantrone, etoposide, and cytarabine for refractory acute myelogenous leukemia. Author(s): Archimbaud E, Fenaux P, Reiffers J, Cordonnier C, Leblond V, Travade P, Troussard X, Tilly H, Auzanneau G, Marie JP, et al. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 March; 7(3): 372-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8445942

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Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium. Author(s): Sandler ES, Hagg R, Coppes MJ, Mustafa MM, Gamis A, Kamani N, Wall D.


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High-dose cytosine arabinoside remission induction for acute myelogenous leukemia: comparison of two regimens of remission maintenance. Author(s): Curtis JE, Messner HA, Minden MD, Lipton JH, Lockwood GA, Tritchler DL, McCulloch EA. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 November; 6(11): 1192-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1434804

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High-dose retinol in children with acute myelogenous leukemia in remission. Author(s): Lie SO, Wathne KO, Petersen LB, Slordahl SH, Norum KR. Source: European Journal of Haematology. 1988 May; 40(5): 460-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3163976

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Homoharringtonine in combination with cytarabine for patients with acute myelogenous leukemia. Author(s): Feldman E, Arlin Z, Ahmed T, Mittelman A, Puccio C, Chun H, Cook P, Baskind P. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 November; 6(11): 1189-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1434803

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Homoharringtonine is safe and effective for patients with acute myelogenous leukemia. Author(s): Feldman E, Arlin Z, Ahmed T, Mittelman A, Puccio C, Chun H, Cook P, Baskind P. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 November; 6(11): 1185-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1434802

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Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia. Author(s): Haas R, Ho AD, Del Valle F, Fischer JT, Ehrhardt R, Dohner H, Witt B, Huberts H, Kaplan E, Hunstein W. Source: Seminars in Oncology. 1993 December; 20(6 Suppl 8): 20-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8290968

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Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group. Author(s): Creutzig U, Ritter J, Schellong G.

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Impact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children's Cancer Group. Author(s): Alonzo TA, Kobrinsky NL, Aledo A, Lange BJ, Buxton AB, Woods WG. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 November; 24(8): 627-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439034

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Improved survival for patients with acute myelogenous leukemia. Author(s): Mitus AJ, Miller KB, Schenkein DP, Ryan HF, Parsons SK, Wheeler C, Antin JH. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1995 March; 13(3): 560-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7884416

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In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. Author(s): Stein AS, O'Donnell MR, Chai A, Schmidt GM, Nademanee A, Parker PM, Smith EP, Snyder DS, Molina A, Stepan DE, Spielberger R, Somlo G, Margolin KA, Vora N, Lipsett J, Lee J, Niland J, Forman SJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1996 August; 14(8): 2206-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8708709

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Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Author(s): Kaufmann SH. Source: Cancer Research. 1989 November 1; 49(21): 5870-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2790800

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Induction therapy for acute myelogenous leukemia in patients over 60 years with intermediate-dose cytosine arabinoside, mitoxantrone and etoposide. Author(s): Shepherd JD, Reece DE, Barnett MJ, Klingemann HG, Nantel SH, Sutherland HJ, Phillips GL. Source: Leukemia & Lymphoma. 1993 February; 9(3): 211-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8471979

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Intensive sequential chemotherapy for children with acute myelogenous leukemia. Author(s): Grier HE, Gelber RD, Clavell LA, Camitta BM, Link MP, Garcea MJ, Weinstein HJ.


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Intensive sequential chemotherapy for children with acute myelogenous leukemia: VAPA, 80-035, and HI-C-Daze. Author(s): Grier HE, Gelber RD, Link MP, Camitta BP, Clavell LA, Weistein HJ. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992; 6 Suppl 2: 48-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1374493

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Intensive sequential chemotherapy with mitoxantrone and continuous infusion etoposide and cytarabine for previously treated acute myelogenous leukemia. Author(s): Archimbaud E, Leblond V, Michallet M, Cordonnier C, Fenaux P, Travade P, Dreyfus F, Jaubert J, Devaux Y, Fiere D. Source: Blood. 1991 May 1; 77(9): 1894-900. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2018832

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Intensive sequential post-induction therapy for adults with acute myelogenous leukemia in first remission: long-term follow-up and results. Author(s): Ino T, Kojima H, Miyazaki H, Maruyama F, Sobue R, Okamoto M, Matsui T, Shimizu K, Ezaki K, Hirano M. Source: Leukemia Research. 1992 June-July; 16(6-7): 577-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1635375

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Isolated IgA deficiency after chemotherapy for acute myelogenous leukemia in an infant. Author(s): Uram R, Rosoff PM. Source: Pediatric Hematology and Oncology. 2003 September; 20(6): 487-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14631625

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Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Author(s): Morrison FS, Kopecky KJ, Head DR, Athens JW, Balcerzak SP, Gumbart C, Dabich L, Costanzi JJ, Coltman CA, Saiki JH, et al. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 July; 6(7): 708-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1625490

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Long term follow-up of patients with acute myelogenous leukemia who received the daunorubicin, vincristine, and cytosine arabinoside regimen. Author(s): Beguin Y, Sautois B, Forget P, Bury J, Fillet G.

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Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia. Author(s): Schiller G, Gajewski J, Territo M, Nimer S, Lee M, Belin T, Champlin R. Source: Blood. 1992 December 15; 80(12): 2977-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1467513

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Mitoxantrone and etoposide: an effective regimen for refractory or relapsed acute myelogenous leukemia. Author(s): Lazzarino M, Morra E, Alessandrino EP, Orlandi E, Pagnucco G, Merante S, Bernasconi P, Inverardi D, Bonfichi M, Bernasconi C. Source: European Journal of Haematology. 1989 November; 43(5): 411-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2612614

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Mitoxantrone in the treatment of acute myelogenous leukemia: a review. Author(s): Thomas X, Archimbaud E. Source: Hematology and Cell Therapy. 1997 August; 39(4): 63-74. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9352324

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Oral Fusarium infection in a granulocytopenic patient with acute myelogenous leukemia: a case report. Author(s): Myoken Y, Sugata T, Kyo T, Fujihara M. Source: Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 1995 May; 24(5): 237-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7616464

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Overexpression of Bcl-2 or Bcl-xL inhibits Ara-C-induced CPP32/Yama protease activity and apoptosis of human acute myelogenous leukemia HL-60 cells. Author(s): Ibrado AM, Huang Y, Fang G, Liu L, Bhalla K. Source: Cancer Research. 1996 October 15; 56(20): 4743-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8840993

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Pharmacokinetics of mitoxantrone, etoposide and cytosine arabinoside in leukemic cells during treatment of acute myelogenous leukemia--relationship to treatment outcome and bone marrow toxicity. Author(s): Gruber A, Liliemark E, Tidefelt U, Paul C, Bjorkholm M, Peterson C, Liliemark J. Source: Leukemia Research. 1995 October; 19(10): 757-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7500654


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Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC833 in relapsed or refractory acute myelogenous leukemia. Author(s): Kornblau SM, Estey E, Madden T, Tran HT, Zhao S, Consoli U, Snell V, Sanchez-Williams G, Kantarjian H, Keating M, Newman RA, Andreeff M. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1997 May; 15(5): 1796-802. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9164187

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Phase I study of taxol in refractory acute myelogenous leukemias using a weekly schedule. Author(s): Munker R, Kantarjian H, O'Brien S, Keating M, Andreeff M, Estey EH. Source: Acta Haematologica. 1998; 99(2): 106-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9554461

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Phase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemia. Author(s): Kantarjian HM, Keating MJ, Walters RS, Koller CA, McCredie KB, Freireich EJ. Source: Cancer. 1989 March 1; 63(5): 813-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2914287

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Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia. Author(s): Schonbohn H, Schuler M, Kolbe K, Peschel C, Huber C, Bemb W, Aulitzky WE. Source: Annals of Hematology. 1995 October; 71(4): 161-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7578521

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Post-remission intensive consolidation with high-dose cytarabine-based chemotherapy and granulocyte colony-stimulatory factor in adults with acute myelogenous leukemia: a preliminary report. Author(s): Hsu HC, Chiu CF, Tan TD, Chau WK, Tseng CS, Ho CH. Source: Zhonghua Yi Xue Za Zhi (Taipei). 1995 November; 56(5): 305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8605644

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Prolonged administration of all-trans retinoic acid in combination with intensive chemotherapy and G-CSF for adult acute myelogenous leukemia: single-centre pilot study in different risk groups. Author(s): Bassan R, Chiodini B, Lerede T, Giussani U, Oldani E, Buelli M, Rossi A, Viero P, Rambaldi A, Barbui T. Source: The Hematology Journal : the Official Journal of the European Haematology Association / Eha. 2002; 3(4): 193-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189565

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Rapid engraftment after autologous transplantation utilizing marrow and recombinant granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in patients with acute myelogenous leukemia. Author(s): Demirer T, Buckner CD, Appelbaum FR, Petersen FB, Rowley S, Weaver CH, Lilleby K, Sanders J, Chauncey T, Storb R, et al. Source: Bone Marrow Transplantation. 1995 June; 15(6): 915-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7581091

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Reactive oxygen species-specific mechanisms of drug resistance in paraquat-resistant acute myelogenous leukemia sublines. Author(s): Choi CH, Kim HS, Kweon OS, Lee TB, You HJ, Rha HS, Jeong JH, Lim DY, Min YD, Kim MS, Chung MH. Source: Molecules and Cells. 2000 February 29; 10(1): 38-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10774745

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Remission induction and postremission therapy in acute myelogenous leukemia: British MRC Study. Author(s): Rees JK, Gray RG. Source: Haematol Blood Transfus. 1990; 33: 243-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1691131

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Remission induction therapy for adults with acute myelogenous leukemia: towards the ICE age? Author(s): Bassan R, Barbui T. Source: Haematologica. 1995 January-February; 80(1): 82-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7758997

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Resonance in periodic chemotherapy: a case study of acute myelogenous leukemia. Author(s): Andersen LK, Mackey MC. Source: Journal of Theoretical Biology. 2001 March 7; 209(1): 113-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11237575

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Reversal of acute myelogenous leukemia in humanized SCID mice using a novel adoptive transfer approach. Author(s): Cesano A, Visonneau S, Cioe L, Clark SC, Rovera G, Santoli D. Source: The Journal of Clinical Investigation. 1994 September; 94(3): 1076-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8083348

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Secondary acute myelogenous leukemia and myelodysplasia without abnormalities of chromosome 11q23 following treatment of acute leukemia with topoisomerase IIbased chemotherapy. Author(s): Seiter K, Feldman EJ, Sreekantaiah C, Pozzuoli M, Weisberger J, Liu D, Papageorgio C, Weiss M, Kancherla R, Ahmed T.


Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 June; 15(6): 963-70. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11417484 •

Secondary acute myelogenous leukemia following safe exposure to etoposide. Author(s): Stine KC, Saylors RL, Sawyer JR, Becton DL. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1997 April; 15(4): 1583-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9193356

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Secondary acute myelogenous leukemia following treatment with oral etoposide. Author(s): Katato K, Flaherty L, Varterasian M. Source: American Journal of Hematology. 1996 September; 53(1): 54-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8813107

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The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia. Author(s): Vey N, Giles FJ, Kantarjian H, Smith TL, Beran M, Jeha S. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 February; 6(2): 731-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10690560

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Therapy of acute myelogenous leukemia in adults. Author(s): Petti MC, Broccia G, Caronia F, Di Raimondo F, Fioritoni G, Ladogana S, Leone G, Liso V, Musso M, Neri A, et al. Source: Haematol Blood Transfus. 1990; 33: 249-53. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2182417

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Therapy-related acute myelogenous leukemia associated with 11q23 chromosomal abnormalities and topoisomerase II inhibitors: report of four additional cases and brief commentary. Author(s): Bredeson CN, Barnett MJ, Horsman DE, Dalal BI, Ragaz J, Phillips GL. Source: Leukemia & Lymphoma. 1993 September; 11(1-2): 141-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8220147

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Therapy-related myelodysplastic syndrome or acute myelogenous leukemia in patients with acute promyelocytic leukemia (APL). Author(s): Garcia-Manero G, Kantarjian HM, Kornblau S, Estey E. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 September; 16(9): 1888. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12200720

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Timed sequential chemotherapy with concomitant granulocyte colony-stimulating factor for high-risk acute myelogenous leukemia: a single arm clinical trial. Author(s): He XY, Elson P, Pohlman B, Lichtin A, Hussein M, Andresen S, Kalaycio M. Source: Bmc Cancer [electronic Resource]. 2002 May 9; 2(1): 12. Epub 2002 May 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12019034

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Timed sequential therapy of acute myelogenous leukemia in adults: a phase II study of retinoids in combination with the sequential administration of cytosine arabinoside, idarubicin and etoposide. Author(s): Bolanos-Meade J, Karp JE, Guo C, Sarkodee-Adoo CB, Rapoport AP, Tidwell ML, Buddharaju LN, Chen TT. Source: Leukemia Research. 2003 April; 27(4): 313-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12531222

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Timed-sequential chemotherapy with concomitant granulocyte colony-stimulating factor for newly diagnosed de novo acute myelogenous leukemia. Author(s): He XY, Pohlman B, Lichtin A, Rybicki L, Kalaycio M. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 June; 17(6): 1078-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12764371

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Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia. Author(s): Kaufmann SH, Karp JE, Jones RJ, Miller CB, Schneider E, Zwelling LA, Cowan K, Wendel K, Burke PJ. Source: Blood. 1994 January 15; 83(2): 517-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7904487

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Treatment of acute myelogenous leukemia in patients over 50 years of age with VTAD: a Southwest Oncology Group study. Author(s): Bigelow CL, Kopecky K, Files JC, Head D, Lipschitz DA, Grever M, Appelbaum FR. Source: American Journal of Hematology. 1995 April; 48(4): 228-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7717369

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Treatment of acute myelogenous leukemia. An EBMT-EORTC retrospective analysis of chemotherapy versus allogeneic or autologous bone marrow transplantation. Author(s): Hermans J, Suciu S, Stijnen T, Aegerter P, Gorin NC, Gratwohl A, Hayat M, Stryckmans P, Zittoun R, Zwaan FE. Source: Eur J Cancer Clin Oncol. 1989 March; 25(3): 545-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2649378

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Treatment of childhood acute myelogenous leukemia with allogeneic and autologous stem cell transplantation during the first remission: a report from the KyushuYamaguchi Children's Cancer Study group in Japan.


Author(s): Matsuzaki A, Eguchi H, Ikuno Y, Ayukawa H, Yanai F, Ishii E, Sugimoto T, Inada H, Anami K, Nibu K, Hara T, Miyazaki S, Okamura J. Source: Pediatric Hematology and Oncology. 2000 December; 17(8): 623-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11127394 •

Treatment of childhood acute myelogenous leukemia with an intensive regimen (AML-87) that individualizes etoposide and cytarabine dosages: short- and long-term effects. Author(s): Arnaout MK, Radomski KM, Srivastava DK, Tong X, Belt JR, Raimondi SC, Behm FG, Santana VM, Crom WR, Mirro J Jr, Ribeiro RC. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 October; 14(10): 1736-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11021748

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Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Author(s): Advani R, Saba HI, Tallman MS, Rowe JM, Wiernik PH, Ramek J, Dugan K, Lum B, Villena J, Davis E, Paietta E, Litchman M, Sikic BI, Greenberg PL. Source: Blood. 1999 February 1; 93(3): 787-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9920827

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

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

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

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

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

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

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

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

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

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

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

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

Dissertations on Acute Myelogenous Leukemia 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 acute myelogenous leukemia. 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: •

Characterization of a novel myeloid differentiation antigen associated with acute myelogenous leukemia by Askew, David Stephen; PhD from The University of British Columbia (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL35031

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Characterization of the hierarchy of proliferative capacity in acute myelogenous leukemia by Ichim, Christine Victoria; MSc from University of Toronto (Canada), 2003, 172 pages http://wwwlib.umi.com/dissertations/fullcit/MQ78214

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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. LEUKEMIA

PATENTS

ON

ACUTE

MYELOGENOUS

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

Patents on Acute Myelogenous Leukemia By performing a patent search focusing on acute myelogenous leukemia, 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 8Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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

Tumor cell suppression Inventor(s): Broitman; Selwyn A. (Newton Highlands, MA), Treon; Steven P. (W. Roxbury, MA) Assignee(s): Trustees of Boston University (boston, Ma) Patent Number: 5,230,886 Date filed: March 18, 1992 Abstract: A method for treating a cancer includes administration of an endotoxin to a patient at least a portion of whose neoplastic cells express the CD14 surface receptor. The endotoxin can be administered concurrently or sequentially with a binding protein capable of binding the endotoxin and, for example, where the endotoxin is a lipopolysaccharide or a nontoxic portion of a lipopolysaccharide, it may for example be administered concurrently with a lipopolysaccharide binding protein. Also, the method including a step of first determining whether a portion of the patient's neoplastic cells express the CD14 surface receptor and, if not, administering to the patient prior to or concurrently with the endotoxin a cytokine. Also, a composition for treating a cancer, that includes an endotoxin in combination with at least one cytokine. Administration of the composition can provide more effective treatment of cancers than administration of a composition containing one or more cytokines alone. The method of the invention, and administration of the composition according to the invention can induce autocrine and paracrine suppression of growth by leukemic cells, and thus can be particularly effective for treatment of acute myelogenous leukemia. Excerpt(s): This invention relates to the therapeutic treatment of cancers. In recent years investigators have begun treating cancers with cytokines. The cytokines, which include tumor necrosis factor, interferons, interleukins and various other factors, are a class of immunomodulatory proteins secreted by monocytes, macrophages, and lymphocytes in response to mitogens. Cytokines have demonstrated antiproliferative and cytotoxic effects on some malignant cell lines in vitro, necrosis of tumors in vivo in animal models, and therapeutic effects in some human clinical trials. Tumor necrosis factor alpha ("TNF.alpha.") has been described as inhibiting the proliferation in vitro of human melanoma cells, primary myeloid cells, and of some but not all myeloid leukemia cell lines when added to the culture media (Helson et al., 1975, Nature, Vol. 258, pp. 731-732; Peetre et al., 1986, Jour. Clin. Invest., Vol. 78, pp. 1694-1700; Munker et al., 1987, Blood, Vol. 69, pp. 1102-1108). Intravenous or intra-tumoral injection of murine TNF.alpha. has also been described as being toxic against both human and murine transplanted tumors in nude mice (Haranaka et al., 1984, Int. Jour. Cancer, Vol. 34, pp. 263-267). Web site: http://www.delphion.com/details?pn=US05230886__

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

BAALC expression as a diagnostic marker for acute leukemia Inventor(s): de la Chapelle, Albert; (Delaware, OH), Tanner, Stephan Markus; (Columbus, OH) Correspondence: Calfee Halter & Griswold, Llp; 800 Superior Avenue; Suite 1400; Cleveland; OH; 44114; US Patent Application Number: 20030119043 Date filed: November 12, 2002 Abstract: Overexpression of the gene, BAALC, in biological samples from a patient is prognostic for tumor aggressiveness and unfavorable patient outcome. The present invention provides polynucleotide primers and probes for assaying for overexpression of BAALC transcripts. Kits containing the primers and probes are also provided. Also provided are antibodies for assaying for overexpression of BAALC proteins as well as peptide immunogens for producing the anti-BAALC antibodies. The present invention also provides methods for characterizing acute myelogenous leukemia, chronic myelogenous leukemia and prostate cancer in a patient, base on detection of BAALC overexpression. Excerpt(s): This application claims priority to U.S. Provisional Application S/ No. 60/348,210, filed Nov. 9, 2001, which is incorporated herein in its entirety. Leukemias comprise approximately 2% of adult cancers and are a heterogeneous group. There are two broad categories of leukemias. Acute leukemias arise when there is a block in the normal differentiation of cells to mature blood cells that results in large accumulations of immature cells or blasts in the blood. Examples of such cancers are acute myelogenous leukemia (AML; other names are acute myeloid leukemia and acute nonlymphocytic leukemia) and acute lymphoblastic leukemia (ALL). In chronic leukemia, on the other hand, there is unregulated proliferation of cells that have differentiated to mature blood cells. Examples of such cancers are chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). CML has a chronic phase which then progresses to a phase called blast crisis where immature, blast cells are present in the blood. Both acute and chronic leukemias involve the myeloid cells of the bone marrow, including white cells, red cells, megakaryocytes and cells of the lymphoid lineage. The cytogenetics of many leukemias are characterized by balanced chromosomal translocations that give rise to gene rearrangements. In acute myeloid leukemia (AML) for example, about 55% of adult de novo cases have clonal cytogenetic abnormalities, many of which are specific translocations. However, in the remaining cases, no visible cytogenetic abnormalities are found, although genetic changes are detected methods other than cytogenetics. In adult acute lymphoblastic leukemia (ALL), the proportion of patients with no cytogenetic abnormality is about 31%. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

9

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

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Method for the rapid and ultra-sensitive detection of leukemic cells Inventor(s): Nisson, Paul E.; (Gaithersburg, MD), Sacchi, Nicoletta; (Gaithersburg, MD) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W.; Washington; DC; 20005; US Patent Application Number: 20030170715 Date filed: March 24, 2003 Abstract: An improved method is disclosed for diagnosing the presence of a chromosomal translocation characteristic of acute myelogenous leukemia. Nucleic acid molecules that may be used in this improved method are described. Excerpt(s): The invention relates to improved methods for diagnosing the presence or onset of acute myelogenous leukemia (AML) in an individual. The invention also pertains to nucleic acid probes that are capable of recognizing a chromosomal translocation that is characteristic of AML. Leukemia is a progressive, malignant disease of the blood-forming organs, characterized by the abnormal proliferation and development of leukocytes, and their precursors in the blood and bone marrow. The disease is classified clinically on the basis of (1) whether the condition is acute or chronic, (2) whether it involves myeloid (i.e. myelogenous), lymphoid (nonmyelogenous) or monocytic cells, and (3) whether it is associated with an increase in the concentration of abnormal cells in the blood. A characteristic of leukemia is the presence of specific chromosomal abnormalities which are considered to be involved in tumor development (Rabbitts, T., Cell 67:641-644 (1991); Cleary, M. L., Cell 66:619-622 (1991), both herein incorporated by reference). In acute leukemia, such chromosomal abnormalities frequently activate transcription factors. These factors are often important in differentiation. Thus, for example, the activation of the c-myc gene, is associated with T-cell acute leukemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method of identifying and/or isolating stem cells and prognosing responsiveness to leukemia treatment Inventor(s): Schuetz, John; (Memphis, TN), Sorrentino, Brian; (Memphis, TN) Correspondence: David A. Jackson, ESQ.; Klauber & Jackson; 411 Hackensack Avenue; Hackensack; NJ; 07601; US Patent Application Number: 20020102244 Date filed: May 29, 2001 Abstract: The present invention includes methods of identifying and/or isolating stem cells based on expression of BCRP. The present invention also describes methods of obtaining and/or using cell populations enriched for stem cells. In addition, methods are provided for diagnosing and/or prognosing leukemia, particularly human acute myelogenous leukemia (AML), through assaying for BCRP expression in leukemic cells. Excerpt(s): The present Application is a Continuation-In-Part of co-pending U.S. Ser. No. 09/584,586 filed May 31, 2000 which is a Continuation-In-Part of co-pending International Application PCT/US99/11825 filed May 27, 1999, which claims the priority of provisional U.S. Ser. No. 60/086,988 filed May 28, 1998, the disclosures of which are hereby incorporated by reference in their entireties. Applicants claim the

Patents 147

benefits of these Applications under 35 U.S.C.sctn.sctn. 120 and 119(e). The present invention provides a method of identifying and/or isolating stem cells. The present invention also provides methods of using cell populations enriched for stem cells. In addition, the present invention provides methods for diagnosing and/or prognosing human acute myelogenous leukemia (AML). All of the cells and cell types of an individual adult mammal are derived from a single cell, the zygote. However, as cells mature and differentiate they lose their ability to be converted into a different cell type. Thus, most adult cells are fully differentiated and normally cannot be converted into another cell type. One particular exception is the adult stem cell. Adult stem cells retain the ability to differentiate into other cell types, though this differentiation is generally limited to forming cells of a single tissue type. For example, hematopoietic stem cells (HSCs) are capable of differentiating into any cell type of the blood and immune system, whereas brain stem cells can differentiate into the different cell types of the brain. In recent years, therapies for treating degenerative diseases and/or cancer (such as leukemia) have been designed which employ stem cells. However, heretofore, isolating stem cells from the human donors has proved to be extremely difficult since stem cells are relatively rare. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treating leukemia Inventor(s): Giles, Francis J.; (Houston, TX), Gourdeau, Henriette; (Montreal, CA) Correspondence: Millen, White, Zelano & Branigan, PC; 2200 Clarendon Blvd; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20020107225 Date filed: January 16, 2002 Abstract: The present invention provides a novel method for treating leukemia and more particularly acute myelogenous leukemia (AML) in a host comprising administering to the host a therapeutically effective amount of a compound having the formula I: 1wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, and 2wherein each Rc is independenty selected from the group comprising H, C.sub.1-6 alkyl, C.sub.2-6 alkynyl and an hydroxy protecting group; andwherein said compound is substantially in the form of the (-) enantiomer. Excerpt(s): The present invention relates to methods for treating leukemia, and more particularly, to the use of nucleoside analogues as an effective treatment for acute or chronic myelogenous leukemia. Leukemia is a malignant cancer of the bone marrow and blood. It is characterized by the uncontrolled growth of blood cells. The common types of leukemia are divided into four categories: acute or chronic myelogenous, involving the myeloid elements of the bone marrow (white cells, red cells, megakaryocytes) and acute or chronic lymphocytic, involving the cells of the lymphoid lineage. Acute leukemia is a rapidly progressing disease that results in the massive accumulation of immature, functionless cells (blasts) in the marrow and blood. The marrow often can no longer produce enough normal red and white blood cells and platelets. Anemia, a deficiency of red cells, develops in virtually all leukemia patients. The lack of normal white cells impairs the body's ability to fight infections. A shortage of platelets results in bruising and easy bleeding. In contrast, chronic leukemia progresses more slowly and leads to unregulated proliferation and hence marked overexpansion of

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a spectrum of mature (differentiated) cells. In general, acute leukemia, unlike the chronic form, is potentially curable by elimination of the neoplastic clone. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods to impair hematologic cancer progenitor cells and compounds related thereto Inventor(s): Jordan, Craig; (Lexington, KY) Correspondence: Mcdermott, Will & Emery; 600 13th Street, N.W.; Washington; DC; 20005-3096; US Patent Application Number: 20030039611 Date filed: March 6, 2001 Abstract: Primitive or progenitor hematologic cancer cells have been implicated in the early stages and development of leukemia and malignant lymphoproliferative disorders, including acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and chronic lymphoid leukemia (CLL). Interleukin-3 receptor alpha chain (IL-3R.alpha. or CD123) is strongly expressed on progenitor hematologic cancer cells, but is virtually undetectable on normal bone marrow cells. The present invention provides methods of impairing progenitor hematologic cancer (e.g., leukemia and lymphomic) cells by selectively targeting cells expressing CD123. These methods are useful in the detection and treatment of leukemias and malignant lymphoproliferative disorders. Also provided are compounds useful for selectively binding to CD123 and impairing progenitor hematologic cancer cells. These compounds may include cytotoxic moieites such as, for example, radioisotopes or chemotherapeutics. Excerpt(s): The present application claims the benefit of priority to U.S. Provisional Patent Application Nos. 60/187,123, filed Mar. 6, 2000, and 60/227,295, filed Aug. 24, 2000, the disclosures of which are incorporated by reference herein in their entirety. The present invention is related to methods of impairing progenitor hematologic cancer cells or treating hematologic cancer by targeting a cell surface marker specific for progenitor hematologic cancer cells. The present invention is also related to a method for diagnosing hematologic cancer. Stem cells are commonly found in a variety of mammalian tissue systems. While the criteria by which such cells are defined vary depending upon the specific context, two properties are generally regarded as central features of stem cell populations: (1) stem cells must exhibit some capacity for selfreplication or self-renewal, and (2) stem cells must be capable of differentiating into appropriate lineages (Potten CS: Stem Cells. London, Academic Press, 1997). Cells of this nature have been described for a number of tissues including hematopoietic, embryonic, neural, muscle and hepatic systems (Lemischka I R. Clonal, in vivo behavior of the totipotent hematopoietic stem cell. Semin Immunol 1991, 3: 349-55; Morrison S J, et al., The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol. 1995, 11: 35-71; Robertson E J., Using embryonic stem cells to introduce mutations into the mouse germ line. Biol Reprod 1991, 44: 238-45; Gage F H., Mammalian neural stem cells. Science 2000, 287: 1433-8; and, Alison M, et al., Hepatic stem cells. J Hepatol 1998, 29: 676-82). Thus, it is perhaps not surprising that similar cells have recently been documented in the context of malignant populations (Bonnet D, et al., Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3: 730-737; Blair A, et al., Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71()/HLA-DR-. Blood 1998, 92: 4325-35; Cobaleda C, et al., A primitive hematopoietic cell is

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the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood 2000, 95: 1007-13). Indeed, a stem cell is in some respects the ideal target for malignant transformation in that relatively little biological change is required. Since stem cells already possess the genetic programming necessary to be highly proliferative and developmentally plastic, one can imagine that relatively subtle perturbations might be sufficient to induce disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

MLL translocations specify a distinct gene expression profile, distinguishing a unique leukemia Inventor(s): Armstrong, Scott A.; (Wayland, MA), Golub, Todd R.; (Newton, MA), Korsmeyer, Stanley J.; (Weston, MA) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20030134300 Date filed: July 17, 2002 Abstract: The present invention relates to the diagnosis of mixed lineage leukemia (MLL), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML) according to the gene expression profile of a sample from an individual, as well as to methods of therapy and screening that utilize the genes identified herein as targets. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/306,103 filed on Jul. 17, 2001. The entire teachings of the above application are incorporated herein by reference. A subset of human acute leukemias with a decidedly unfavorable prognosis possess a chromosomal translocation involving the Mixed Lineage Leukemia (MLL, HRX, AU-1) gene on chromosome segment 11q23. The leukemic cells, which typically have a lymphoblastic morphology, have been classified as Acute Lymphoblastic Leukemia (ALL). However, unlike the majority of childhood ALL, the presence of the MLL translocations often results in an early relapse after chemotherapy. As MLL translocations are typically found in leukemias of infants and chemotherapy-induced leukemia, it has remained uncertain whether host related factors or tumor-intrinsic biological differences are responsible for the poor survival in patients with the translocations. Lymphoblastic leukemias with either rearranged or germline MLL are similar with respect to most morphological and histochemical characteristics. Immunophenotypic differences associated with lymphoblasts bearing an MLL translocation include the lack of the early lymphocyte antigen CD 10, expression of the proteoglycan NG2, and the propensity to co-express the myeloid antigens CD15 and CD65. This prompted the corresponding disease to be called Mixed Lineage Leukemia and suggested models, largely unresolved, in which the leukemia reflects disordered cell fate decisions or the transformation of a more multi-potential progenitor. Generally, therapeutic treatment is more successful when tailored to the specific type of leukemia. Thus, a need exists for accurate and efficient methods for diagnosis of leukemia and identification of subclasses of leukemias. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Phospho-specific antibodies to Flt3 and uses thereof Inventor(s): Comb, Michael J.; (Manchester, MA), Crosby, Katherine; (Middleton, MA), Wetzel, Randall K.; (Stoneham, MA), Wu, Jiong; (Salem, MA) Correspondence: James Gregory Cullem, ESQ.; Intellectual Property Counsel; Cell Signaling Technology, INC.; 166b Cummings Center; Beverly; MA; 01915; US Patent Application Number: 20030219827 Date filed: February 18, 2003 Abstract: The invention discloses two newly-discovered Flt3 phosphorylation sites, tyrosine 589 (Tyr589) and tyrosine 591 (Tyr591) in the intracellular domain, and provides antibodies, both polyclonal and monoclonal, that selectively bind to Flt3 when phosphorylated at these novel sites. Also provided are assays utilizing these reagents, including methods for determining the phosphorylation of Flt3 in a biological sample, selecting a patient suitable for Flt3 inhibitor therapy, profiling Flt3 activation in a test tissue, and identifying a compound that modulates phosphorylation of Flt3 in a test tissue, by using a detectable reagent, such as the disclosed antibodies, that binds to Flt3 when phosphorylated at Tyr589 or Tyr591. The sample or test tissue may be taken from a subject suspected of having cancer, such as acute myelogenous leukemia (AML). Excerpt(s): This application claims priority to U.S. Ser. No. 60/358,153, filed Feb. 20, 2002, now abandoned. The invention relates generally to antibodies, and more particularly to activation state-specific antibodies to receptor tyrosine kinases and their uses. Many cancers are characterized by disruptions in cellular signaling pathways that lead to uncontrolled growth and proliferation of cancerous cells. Receptor tyrosine kinases (RTKs) play a pivotal role in these signaling pathways, transmitting extracellular molecular signals into the cytoplasm and/or nucleus of a cell. Cells of virtually all tissue types express transmembrane receptor molecules with intrinsic tyrosine kinase activity through which various growth and differentiation factors mediate a range of biological effects (reviewed in Aaronson, Science 254: 1146-52 (1991)). RTKs share a similar architecture, having an intracellular catalytic domain, a hydrophobic transmembrane domain, and an extracellular ligand-binding domain. The binding of ligand to the extracellular portion is believed to promote dimerization, resulting in transphosphorylation and activation of the intracellular tyrosine kinase domain (see Schlessinger et al., Neuron 9:383-391 (1992)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Treatment of acute myeloid leukemia with indolinone compounds Inventor(s): Cherrington, Julie; (San Francisco, CA), O'Farrell, Anne-Marie; (Menlo Park, CA) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20030130280 Date filed: October 28, 2002 Abstract: A method of treating acute myeloid leukemia in patient positive for FLT-3ITD is described. The treatment is accomplished by administration of a compound of Formula I or II as defined herein.

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Excerpt(s): This application claims priority to U.S. Provisional Patent Application Serial No. 60/330,623, which is hereby incorporated in its entirety by reference. The invention relates to a method of treating acute myeloid leukemia by administering an indolinone compound. Acute myeloid leukemia (AML) is a disease in which cancerous cells develop in the blood and bone marrow. Untreated AML is a fatal disease with median survival time of 3 months. Patients with AML that are FLT-3-ITD (internal tandem duplication) positive typically exhibit poor response to traditional chemotherapy. The present invention is directed to treating AML patients and preferably patients positive for FLT-3-ITD but not restricted to FLT-3-ITD by administering indolinone compounds of Formula I or II. The present invention also is directed to a method of inhibiting phosphorylation of FLT-3. Acute myeloid leukemia, also called acute non-lymphocytic leukemia, is a form of cancer in which too many immature white blood cells are found in the blood and bone marrow. These immature cells, also called blasts, have failed to develop into mature infection-fighting cells. 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 acute myelogenous leukemia, 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 “acute myelogenous leukemia” (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 acute myelogenous leukemia. You can also use this procedure to view pending patent applications concerning acute myelogenous leukemia. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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

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

Consultations Source: in Lockhart, P.B. Oral Medicine and Hospital Practice. Chicago, IL: Special Care Dentistry. 1997. p. 4.3-4.40. Contact: Available from Special Care Dentistry. 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2660. Fax (312) 440-2824. PRICE: $27.00 (member) or $30.00 (nonmember), plus shipping and handling; institutional prices and bulk orders available. ISBN: 0965719103. Summary: This chapter is from a manual designed to help dental residents, students and practitioners engaged in the care of patients in the hospital setting. This chapter discusses consultations in the hospital setting. The first section describes how to request consults from other services, how to answer consult requests from other services, and a recommended consult format. The remainder of the chapter provides examples of

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fourteen specific types of consults: poorly fitting denture on an atrophic ridge; acute myelogenous leukemia, stomatitis, and fungal infection; oral ulcerations of unknown etiology; endocarditis of possible dental origin; myeloproliferative disorder and facial swelling; aortic valve replacement and poor dentition; juvenile onset diabetes and poor dentition; dental trauma following motor vehicle accident (MVA), risk of aspiration; newborn infant with masses on alveolar ridge; acute lymphocytic leukemia and oral ulcers; AIDS with multiple oral problems; cerebral palsy and excessive drooling; malocclusion following old mandibular fracture; and ruling out a dental source of endocarditis. Most information is presented in outline format, for ease of access. •

Hepatitis C Virology: Antigen, Antibody, and Molecular Testing Source: in Gordon, S.C. Management of Chronic Viral Hepatitis. New York, NY: Marcel Dekker Inc. 2002. p. 33-64. Contact: Available from Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016. (212) 696-9000. Fax (212) 685-4540. Website: www.dekker.com. PRICE: $150.00 plus shipping and handling. ISBN: 0824705823. Summary: This chapter on hepatitis B virology is from a monograph on the management of chronic viral hepatitis (liver inflammation), bringing the advances of clinical and basic research into the doctor's office. This chapter uses a brief clinical case presentation in order to address the real life intricacies of managing patients who present with viral hepatitis. The authors focus on antigen, antibody, and molecular testing for hepatitis C virology. The case patient is a 54 year old male physician with a history of acute myelogenous leukemia who received multiple transfusions in August 1989 who developed abnormal liver chemistries in March 1990. Serological (blood) testing revealed that he was anti-HCV negative by the ELISA 1 assay; anti-HAV (total) was positive, but anti HAV IgM was negative. HBsAg and anti HBc were negative and anti HBs positive. Both the antinuclear antibodies (ANA) and the anti smooth muscle antibody tests were negative. This case illustrates a number of points that relate to the history of the hepatitis C virus and its associated serological assays. The first generation test for anti HCV was released in the United States in May 1990, although it was available in Europe as early as 1989. This patient had hepatitis C in 1990, but it was not until later with the development of more refined assays that his serological profile became defined. Later, as the patient underwent treatment with antiviral agents, the development of increasingly more sophisticated molecular based assays assisted in his clinical management. 11 figures. 2 tables. 53 references.

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CHAPTER 7. PERIODICALS AND NEWS ON ACUTE MYELOGENOUS LEUKEMIA Overview In this chapter, we suggest a number of news sources and present various periodicals that cover acute myelogenous leukemia.

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

Encouraging response seen with FLT3 inhibitor in acute myelogenous leukemia Source: Reuters Industry Breifing Date: June 05, 2003

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Targeted Radiation Therapy Improves Survival In Patients With Acute Myelogenous Leukemia Source: Reuters Medical News Date: December 09, 1996

•

New Regimen Improves Survival In Patients With Acute Myelogenous Leukemia Source: Reuters Medical News Date: March 14, 1995 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 “acute myelogenous leukemia” (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 “acute myelogenous leukemia” (or synonyms). If you know the name of a company that is relevant to acute myelogenous leukemia, 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/.

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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 “acute myelogenous leukemia” (or synonyms).

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

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

U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for acute myelogenous leukemia. 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 acute myelogenous leukemia 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 “acute myelogenous leukemia” (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

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approval.” If the orphan product about which you are seeking information is approved for marketing, information on side effects can be found on the product’s label. If the product is not approved, you may need to contact the sponsor. The following is a list of orphan drugs currently listed in the NORD Orphan Drug Designation Database for acute myelogenous leukemia: •

Gemtuzumab Zogamicin http://www.rarediseases.org/nord/search/nodd_full?code=1004

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Histamine (trade name: Maxamine) http://www.rarediseases.org/nord/search/nodd_full?code=1009

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clofarabine (trade name: Clofarex) http://www.rarediseases.org/nord/search/nodd_full?code=1239

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Mitoxantrone HCL (trade name: Novantrone) http://www.rarediseases.org/nord/search/nodd_full?code=115

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clofarabine (trade name: Clofarex) http://www.rarediseases.org/nord/search/nodd_full?code=1265

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Lintuzumab (trade name: Zamyl) http://www.rarediseases.org/nord/search/nodd_full?code=1305

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Monoclonal antibody PM-81 http://www.rarediseases.org/nord/search/nodd_full?code=137

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2-chlorodeoxyadenosine http://www.rarediseases.org/nord/search/nodd_full?code=2

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Sargramostim (trade name: Leukine) http://www.rarediseases.org/nord/search/nodd_full?code=35

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Ricin (blocked) conjugated murine MCA (anti-my9) http://www.rarediseases.org/nord/search/nodd_full?code=465

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Idarubicin HC1 for injection (trade name: Idamycin) http://www.rarediseases.org/nord/search/nodd_full?code=775

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2'-deoxycytidine http://www.rarediseases.org/nord/search/nodd_full?code=790

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Filgrastim (trade name: Neupogen) http://www.rarediseases.org/nord/search/nodd_full?code=800

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Cladribine (trade name: Laustatin) http://www.rarediseases.org/nord/search/nodd_full?code=881

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Ricin (blocked) conjugated murine MCA (anti-my9) http://www.rarediseases.org/nord/search/nodd_full?code=895

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Aldesleukin (trade name: Proleukin) http://www.rarediseases.org/nord/search/nodd_full?code=928

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

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APPENDICES

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

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

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

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

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

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

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

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

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

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

10

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

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•

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

•

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

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

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

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

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

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

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

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

11

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

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•

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

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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 “acute myelogenous leukemia” (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 18944 71 1093 21 81 20210

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 “acute myelogenous leukemia” (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/.

The Genome Project and Acute Myelogenous Leukemia In the following section, we will discuss databases and references which relate to the Genome Project and acute myelogenous leukemia. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).21 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 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. 21 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “acute myelogenous leukemia” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for acute myelogenous leukemia: •

Acute Myelogenous Leukemia Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602439

•

Acute Myelogenous Leukemia, Familial Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601626 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease,

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Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html •

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

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To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “acute myelogenous leukemia” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database22 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database23 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “acute myelogenous leukemia” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

22

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 23 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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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 acute myelogenous leukemia 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 acute myelogenous leukemia. 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 acute myelogenous leukemia. 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 “acute myelogenous leukemia”:

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Bone Marrow Diseases http://www.nlm.nih.gov/medlineplus/bonemarrowdiseases.html Bone Marrow Transplantation http://www.nlm.nih.gov/medlineplus/bonemarrowtransplantation.html Lymphoma http://www.nlm.nih.gov/medlineplus/lymphoma.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 acute myelogenous leukemia. 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: •


•

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

•

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

•

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

•

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

•

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

•

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

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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to acute myelogenous leukemia. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with acute myelogenous leukemia. 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 acute myelogenous leukemia. 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 “acute myelogenous leukemia” (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 “acute myelogenous leukemia”. 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 “acute myelogenous leukemia” (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 “acute myelogenous leukemia” (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.24

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

24

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)25: •

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/

25

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

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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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

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

•

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

•

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

•

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

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

Basic Guidelines for Acute Myelogenous Leukemia Acute myelogenous leukemia (AML)- Adult Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000542.htm

•

Signs & Symptoms for Acute Myelogenous Leukemia Anemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Bleeding from the nose Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003106.htm Bleeding into the skin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Bone pain or tenderness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003180.htm

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Bruising Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Ecchymoses Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Epistaxis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003106.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Gums, bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003062.htm Gums, swollen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003066.htm Leukemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001299.htm Menstrual periods, abnormal Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003263.htm Paleness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003244.htm Petechiae Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Pinpoint red spots Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003235.htm Shortness of breath Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Skin rash or lesion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Weight loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003107.htm •

Diagnostics and Tests for Acute Myelogenous Leukemia Bone marrow aspiration Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003658.htm

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CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm Platelets Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm WBC count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003643.htm •

Surgery and Procedures for Acute Myelogenous Leukemia Bone marrow transplant Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003009.htm

•

Background Topics for Acute Myelogenous Leukemia Aggravated by Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002227.htm Bleeding Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000045.htm Cancer - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002166.htm Chemotherapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002324.htm Exercise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001941.htm Incidence Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002387.htm Leukemia - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002151.htm Malignancy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002253.htm Physical examination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002274.htm Proliferation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002276.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.htm

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Toxins Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002331.htm

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

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

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

•

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

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ACUTE MYELOGENOUS LEUKEMIA DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Aberrant: Wandering or deviating from the usual or normal course. [EU] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Aclarubicin: An anthracycline antibiotic produced by Streptomyces galilaeus. It has potent antineoplastic activity, especially in the treatment of leukemias, with reduced cardiac toxicity in comparison to daunorubicin or doxorubicin. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]

Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [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] 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] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When

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transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] 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] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]

Aggressiveness: The quality of being aggressive (= characterized by aggression; militant; enterprising; spreading with vigour; chemically active; variable and adaptable). [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] 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] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [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

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herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveoli: Tiny air sacs at the end of the bronchioles in the lungs. [NIH] Amifostine: A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia. [NIH] Amino Acid Motifs: Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a conserved sequence which can be represented by a consensus sequence. [NIH]

Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino-terminal: The end of a protein or polypeptide chain that contains a free amino group (-NH2). [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amsacrine: N-(4-(9-Acridinylamino)-3-methoxyphenyl)methanesulfonamide. Aminoacridine derivative that is a potent intercalating antineoplastic agent. It is effective in the treatment of acute leukemias and malignant lymphomas, but has poor activity in the treatment of solid tumors. It is frequently used in combination with other antineoplastic agents in chemotherapy protocols. It produces consistent but acceptable myelosuppression and cardiotoxic effects. [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] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH]

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Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anergy: Absence of immune response to particular substances. [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] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [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]

Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]

Anterior chamber: The space in front of the iris and behind the cornea. [NIH] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [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] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] 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]

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Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antiproliferative: Counteracting a process of proliferation. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Antiviral Agents: Agents used in the prophylaxis or therapy of virus diseases. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aorta: The main trunk of the systemic arteries. [NIH] Aortic Valve: The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. [NIH] Aplasia: Lack of development of an organ or tissue, or of the cellular products from an organ or tissue. [EU] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]

Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the 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] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arsenic trioxide: An anticancer drug that induces programmed cell death (apoptosis) in certain cancer cells. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH]

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Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Aspergillosis: Infections with fungi of the genus Aspergillus. [NIH] Aspiration: The act of inhaling. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have highaffinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [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] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Bacteremia: The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. [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] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical

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manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] 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]

Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] 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] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Bladder: The organ that stores urine. [NIH]

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Blast Crisis: Rapid increase in the proportion of blast cells in the blood and bone marrow. [NIH]

Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blastomycosis: A fungal infection that may appear in two forms: 1) a primary lesion characterized by the formation of a small cutaneous nodule and small nodules along the lymphatics that may heal within several months; and 2) chronic granulomatous lesions characterized by thick crusts, warty growths, and unusual vascularity and infection in the middle or upper lobes of the lung. [NIH] Blasts: Immature blood cells. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [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-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 Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] 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] Breast Neoplasms: Tumors or cancer of the breast. [NIH]

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Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchial: Pertaining to one or more bronchi. [EU] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiolitis Obliterans: Inflammation of the bronchioles with obstruction by fibrous granulation tissue or bronchial exudate. It may follow inhalation of irritating gases or foreign bodies and it complicates pneumonia. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]

Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [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] Callus: A callosity or hard, thick skin; the bone-like reparative substance that is formed round the edges and fragments of broken bone. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]

Carbohydrates: The largest class of organic compounds, including starches, glycogens, cellulose, gums, and simple sugars. Carbohydrates are composed of carbon, hydrogen, and oxygen in a ratio of Cn(H2O)n. [NIH] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carboxy: Cannabinoid. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH]

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Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiological: Relating to the study of the heart. [EU] Cardiotoxic: Having a poisonous or deleterious effect upon the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] 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] 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 proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain

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functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Cellulitis: An acute, diffuse, and suppurative inflammation of loose connective tissue, particularly the deep subcutaneous tissues, and sometimes muscle, which is most commonly seen as a result of infection of a wound, ulcer, or other skin lesions. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [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 Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] 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] Cerebral Hemorrhage: Bleeding into a cerebral hemisphere of the brain, including lobar, subcortical white matter, and basal ganglia hemorrhages. Commonly associated conditions include hypertension; intracranial arteriosclerosis; intracranial aneurysm; craniocerebral trauma; intracranial arteriovenous malformations; cerebral amyloid angiopathy; and cerebral infarction. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] 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] 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] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH]

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Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]

Chemotherapy: Treatment with anticancer drugs. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chimeric Proteins: Proteins in individuals that are derived from genetically different zygotes. [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 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] Chondrocytes: Polymorphic cells that form cartilage. [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 Abnormalities: Defects in the structure or number of chromosomes resulting in structural aberrations or manifesting as disease. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic leukemia: A slowly progressing cancer of the blood-forming tissues. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [NIH] Chronic phase: Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary Body: A ring of tissue extending from the scleral spur to the ora serrata of the retina. It consists of the uveal portion and the epithelial portion. The ciliary muscle is in the uveal portion and the ciliary processes are in the epithelial portion. [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

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calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] C-kit receptor: A protein on the surface of some cells that binds to stem cell factor (a substance that causes certain types of cells to grow). Altered forms of this receptor may be associated with some types of cancer. [NIH] 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 trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colony-Stimulating Factors: Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GMCSF). [NIH] Combination chemotherapy: Treatment using more than one anticancer drug. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols

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C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of

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separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] 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] Consensus Sequence: A theoretical representative nucleotide or amino acid sequence in which each nucleotide or amino acid is the one which occurs most frequently at that site in the different sequences which occur in nature. The phrase also refers to an actual sequence which approximates the theoretical consensus. A known conserved sequence set is represented by a consensus sequence. Commonly observed supersecondary protein structures (amino acid motifs) are often formed by conserved sequences. [NIH] Conserved Sequence: A sequence of amino acids in a polypeptide or of nucleotides in DNA or RNA that is similar across multiple species. A known set of conserved sequences is represented by a consensus sequence. Amino acid motifs are often composed of conserved sequences. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Cooperative group: A group of physicians, hospitals, or both formed to treat a large number of persons in the same way so that new treatment can be evaluated quickly. Clinical trials of new cancer treatments often require many more people than a single physician or hospital can care for. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH]

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Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [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] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetic Analysis: Examination of chromosomes to diagnose, classify, screen for, or manage genetic diseases and abnormalities. Following preparation of the sample, karyotyping is performed and/or the specific chromosomes are analyzed. [NIH] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytopenia: A reduction in the number of blood cells. [NIH]

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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] Cytotoxic: Cell-killing. [NIH] Cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] 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] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Decitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Decontamination: The removal of contaminating material, such as radioactive materials, biological materials, or chemical warfare agents, from a person or object. [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] 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]

Dentition: The teeth in the dental arch; ordinarily used to designate the natural teeth in position in their alveoli. [EU] Deoxycytidine: A drug that protects healthy tissues from the toxic effects of anticancer drugs. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depsipeptide: Anticancer drugs obtained from microorganisms. [NIH] Developmental Biology: The field of biology which deals with the process of the growth and differentiation of an organism. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diethylcarbamazine: An anthelmintic used primarily as the citrate in the treatment of filariasis, particularly infestations with Wucheria bancrofti or Loa loa. [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

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throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Dipeptidases: Exopeptidases that specifically act on dipeptides. EC 3.4.13. [NIH] Dipeptides: Peptides composed of two amino acid units. [NIH] Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of Corynebacterium diphtheriae. It is characterized by the presence of a pseudomembrane at the site of infection. Diphtheria toxin, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. [NIH] Diphtheria Toxin: A 60 kD single chain protein elaborated by Corynebacterium diphtheriae that causes the sign and symptoms of diphtheria; it can be broken into two unequal fragments, the smaller (A fragment) inhibits protein synthesis and is the lethal moiety that needs the larger (B fragment) for entry into cells. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Drug 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

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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] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [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] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolytes: Substances that break up into ions (electrically charged particles) when they are dissolved in body fluids or water. Some examples are sodium, potassium, chloride, and calcium. Electrolytes are primarily responsible for the movement of nutrients into cells, and the movement of wastes out of cells. [NIH] Electromagnetic Fields: Fields representing the joint interplay of electric and magnetic forces. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryogenesis: The process of embryo or embryoid formation, whether by sexual (zygotic) or asexual means. In asexual embryogenesis embryoids arise directly from the explant or on intermediary callus tissue. In some cases they arise from individual cells (somatic cell embryoge). [NIH] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]

Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

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] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU]

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Endocardium: The innermost layer of the heart, comprised of endothelial cells. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endophthalmitis: Suppurative inflammation of the tissues of the internal structures of the eye; not all layers of the uvea are affected. Fungi, necrosis of intraocular tumors, and retained intraocular foreign bodies often cause a purulent endophthalmitis. [NIH] Endostatin: A drug that is being studied for its ability to prevent the growth of new blood vessels into a solid tumor. Endostatin belongs to the family of drugs called angiogenesis inhibitors. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [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] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroid Progenitor Cells: Committed, erythroid stem cells derived from myeloid stem cells. The progenitor cells develop in two phases: erythroid burst-forming units (BFU-E) followed by erythroid colony-forming units (CFU-E). BFU-E differentiate into CFU-E on stimulation by erythropoietin, and then further differentiate into erythroblasts when stimulated by other factors. [NIH] Erythropoiesis: The production of erythrocytes. [EU]

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Escalation: Progressive use of more harmful drugs. [NIH] Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Ethylnitrosourea: A nitrosourea compound with alkylating, carcinogenic, and mutagenic properties. [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] Evaluable patients: Patients whose response to a treatment can be measured because enough information has been collected. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excisional: The surgical procedure of removing a tumor by cutting it out. The biopsy is then examined under a microscope. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] 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]

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Eye socket: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Facial: Of or pertaining to the face. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] 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]

Febrile: Pertaining to or characterized by fever. [EU] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [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] Fibronectin: An adhesive glycoprotein. One form circulates in plasma, acting as an opsonin; another is a cell-surface protein which mediates cellular adhesive interactions. [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] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluconazole: Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in AIDS. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH]

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Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Fungemia: The presence of fungi circulating in the blood. Opportunistic fungal sepsis is seen most often in immunosuppressed patients with severe neutropenia or in postoperative patients with intravenous catheters and usually follows prolonged antibiotic therapy. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gametogenesis: The first phase of sexual reproduction which involves the transforming of certain cells in the parent into specialized reproductive cells. [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] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gastric: Having to do with the stomach. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal stromal tumor: GIST. A type of tumor that usually begins in cells in the wall of the gastrointestinal tract. It can be benign or malignant. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gemcitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Gemtuzumab ozogamicin: A type of monoclonal antibody used in cancer detection or therapy. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [NIH]

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Gene Rearrangement: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. [NIH] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [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 cell tumors: Tumors that begin in the cells that give rise to sperm or eggs. They can occur virtually anywhere in the body and can be either benign or malignant. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gingival Hyperplasia: A pathological increase in the depth of the gingival crevice surrounding a tooth at the gum margin. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] 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]

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Glossitis: Inflammation of the tongue. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycogen Storage Disease: A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycans: Heteropolysaccharides which contain an N-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1,4- and 1,3-linkages consisting of either N-acetylglucosamine or Nacetylgalactosamine. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Gonadal: Pertaining to a gonad. [EU] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

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] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Granulation Tissue: A vascular connective tissue formed on the surface of a healing wound, ulcer, or inflamed tissue. It consists of new capillaries and an infiltrate containing lymphoid cells, macrophages, and plasma cells. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of

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inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [NIH] Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]

Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [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] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Heat-Shock Proteins: Proteins which are synthesized in eukaryotic organisms and bacteria in response to hyperthermia and other environmental stresses. They increase thermal tolerance and perform functions essential to cell survival under these conditions. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hematopoietic tissue: Tissue in which new blood cells are formed. [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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH]

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Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemolysis: The destruction of erythrocytes by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] 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]

Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Hidradenitis: The inflammation of a sweat gland (usually of the apocrine type). The condition can be idiopathic or occur as a result of or in association with another underlying condition. Neutrophilic eccrine hidradenitis is a relatively rare variant that has been reported in patients undergoing chemotherapy, usually for non-Hodgkin lymphomas or leukemic conditions. [NIH] Histone Deacetylase: Hydrolyzes N-acetyl groups on histones. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeobox: Distinctive sequence of DNA bases. [NIH] Homeotic: Characterizes genes the mutations of which lead to inappropriate expressions of characteristics normally associated with another part of the organism (homeotic mutants). [NIH]

Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homoharringtonine: An anticancer drug that belongs to the plant alkaloid family of drugs. [NIH]

Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU]

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Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] 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] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypopyon: An accumulation of pus in the anterior chamber of the eye associated with infectious diseases of the cornea, the iris, and the ciliary body. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Idarubicin: An orally administered anthracycline antibiotic. The compound has shown activity against breast cancer, lymphomas and leukemias, together with potential for reduced cardiac toxicity. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

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

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(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] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunophenotyping: Process of classifying cells of the immune system based on structural and functional differences. The process is commonly used to analyze and sort Tlymphocytes into subsets based on CD antigens by the technique of flow cytometry. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Immunotoxin: An antibody linked to a toxic substance. Some immmunotoxins can bind to cancer cells and kill them. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] 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] Induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. [NIH] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH]

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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]

Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Insertional: A technique in which foreign DNA is cloned into a restriction site which occupies a position within the coding sequence of a gene in the cloning vector molecule. Insertion interrupts the gene's sequence such that its original function is no longer expressed. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] 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

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distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-12: A heterodimeric cytokine that stimulates the production of interferon gamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. It is an initiator of cell-mediated immunity. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-3: A multilineage cell growth factor secreted by lymphocytes, epithelial cells, and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Also called multi-CSF, it is considered one of the hematopoietic colony stimulating factors. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intracranial Aneurysm: A saclike dilatation of the walls of a blood vessel, usually an artery. [NIH]

Intracranial Arteriosclerosis: Vascular diseases characterized by thickening, hardening, and remodeling of the walls of intracranial arteries. There are three subtypes: (1) atherosclerosis, marked by fatty depositions in the innermost layer of the arterial walls, (2) Monckeberg's sclerosis, which features calcium deposition in the media and (3) arteriolosclerosis, which refers to sclerosis of small caliber arteries. Clinically, this process may be associated with transient ischemic attack, brain infarction, intracranial embolism and thrombosis, or intracranial aneurysm. [NIH] Intraocular: Within the eye. [EU] Intrathecal: Describes the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. Drugs can be injected into the fluid or a sample of the fluid can be removed for testing. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH]

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Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Itraconazole: An antifungal agent that has been used in the treatment of histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. [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] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [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] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most

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prominently involved. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Levamisole: An antiparasitic drug that is also being studied in cancer therapy with fluorouracil. [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligase: An enzyme that repairs single stranded discontinuities in double-stranded DNA molecules in the cell. Purified DNA ligase is used in gene cloning to join DNA molecules together. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH]

Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] 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]

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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] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH] Lymphocytic: Referring to lymphocytes, a type of white blood cell. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lymphoproliferative Disorders: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [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] Macrophage Colony-Stimulating Factor: A mononuclear phagocyte colony-stimulating factor synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (receptor, macrophage colony-stimulating factor). [NIH] Mafosfamide: A form of cyclophosphamide that can be administered as an intrathecal infusion. Mafosfamide is being studied as an anticancer drug; it belongs to the family of drugs called alkylating agents. [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] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mastocytosis: A group of diseases resulting from proliferation of mast cells. [NIH]

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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] Meatus: A canal running from the internal auditory foramen through the petrous portion of the temporal bone. It gives passage to the facial and auditory nerves together with the auditory branch of the basilar artery and the internal auditory veins. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Median survival time: The point in time from either diagnosis or treatment at which half of the patients with a given disease are found to be, or expected to be, still alive. In a clinical trial, median survival time is one way to measure how effective a treatment is. [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] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Megakaryocytes: Very large bone marrow cells which release mature blood platelets. [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] Melphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - melphalan, the racemic mixture - merphalan, and the dextro isomer medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meningeal: Refers to the meninges, the tissue covering the brain and spinal cord. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Meningoencephalitis: An inflammatory process involving the brain (encephalitis) and

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meninges (meningitis), most often produced by pathogenic organisms which invade the central nervous system, and occasionally by toxins, autoimmune disorders, and other conditions. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] 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] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] 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] 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] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitoxantrone: An anthracenedione-derived antineoplastic agent. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative

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procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [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] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] 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] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH]

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Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed). [NIH] Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplasia: Abnormal bone marrow cells that may lead to myelogenous leukemia. [NIH]

Myelodysplastic Syndromes: Conditions in which the bone marrow shows qualitative and quantitative changes suggestive of a preleukemic process, but having a chronic course that does not necessarily terminate as acute leukemia. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloid Progenitor Cells: One of the two stem cells derived from hematopoietic stem cells the other being the lymphoid progenitor cell. Derived from these myeloid progenitor cells are the erythroid progenitor cells and the myeloid cells (monocytes and granulocytes). [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [NIH] Myelosuppression: A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. [NIH] Myelotoxic: 1. Destructive to bone marrow. 2. Arising from diseased bone marrow. [EU] 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] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Nasal Cavity: The proximal portion of the respiratory passages on either side of the nasal septum, lined with ciliated mucosa, extending from the nares to the pharynx. [NIH] Natural killer cells: NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes (LGL). [NIH] 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]

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Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [NIH] 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] 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] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore

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complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleic Acid Probes: Nucleic acid which complements a specific mRNA or DNA molecule, or fragment thereof; used for hybridization studies in order to identify microorganisms and for genetic studies. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [NIH] Oligonucleotide Probes: Synthetic or natural oligonucleotides used in hybridization studies in order to identify and study specific nucleic acid fragments, e.g., DNA segments near or within a specific gene locus or gene. The probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the probe include the radioisotope labels 32P and 125I and the chemical label biotin. [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] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH]

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Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Orbit: One of the two cavities in the skull which contains an eyeball. Each eye is located in a bony socket or orbit. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Orderly: A male hospital attendant. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteonecrosis: Death of a bone or part of a bone, either atraumatic or posttraumatic. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH]

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Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancytopenia: Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. [NIH] Papilloma: A benign epithelial neoplasm which may arise from the skin, mucous membranes or glandular ducts. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [NIH]

Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] 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] 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] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Peer Review: An organized procedure carried out by a select committee of professionals in evaluating the performance of other professionals in meeting the standards of their specialty. Review by peers is used by editors in the evaluation of articles and other papers submitted for publication. Peer review is used also in the evaluation of grant applications. It is applied also in evaluating the quality of health care provided to patients. [NIH] Pelvic: Pertaining to the pelvis. [EU] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Pericarditis: Inflammation of the pericardium. [EU] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]

Periorbital: Situated around the orbit, or eye socket. [EU] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral stem cell transplantation: A method of replacing blood-forming cells destroyed by cancer treatment. Immature blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are given after treatment to help the bone marrow recover and continue producing healthy blood cells. Transplantation may be autologous (an individual's own blood cells saved earlier), allogeneic (blood cells donated by someone else),

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or syngeneic (blood cells donated by an identical twin). Also called peripheral stem cell support. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] P-Glycoprotein: A 170 kD transmembrane glycoprotein from the superfamily of ABC transporters. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many antineoplastic agents. Overexpression of this glycoprotein is associated with multidrug resistance. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] 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] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] 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 Projects: Small-scale tests of methods and procedures to be used on a larger scale if the

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pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [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 cells: A type of white blood cell that produces antibodies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Transfusion: The transfer of blood platelets from a donor to a recipient or reinfusion to the donor. [NIH] Platelet-Derived Growth Factor: Mitogenic peptide growth hormone carried in the alphagranules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [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

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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] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polyneuritis: Inflammation of several peripheral nerves at the same time. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] 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] 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] Postremission therapy: Anticancer drugs to kill cancer cells that survive after remission induction therapy. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] 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] Predictive factor: A situation or condition that may increase a person's risk of developing a certain disease or disorder. [NIH] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Premalignant: A term used to describe a condition that may (or is likely to) become cancer.

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Also called precancerous. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] 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] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Prognostic factor: A situation or condition, or a characteristic of a patient, that can be used to estimate the chance of recovery from a disease, or the chance of the disease recurring (coming back). [NIH] 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] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]

Prophylaxis: An attempt to prevent disease. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [NIH]

Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteoglycan: A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues.

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[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] Proteome: The protein complement of an organism coded for by its genome. [NIH] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Proviruses: Duplex DNA sequences in eukaryotic chromosomes, corresponding to the genome of a virus, that are transmitted from one cell generation to the next without causing lysis of the host. Proviruses are often associated with neoplastic cell transformation and are key features of retrovirus biology. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [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] 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]

Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Quality of Health Care: The levels of excellence which characterize the health service or health care provided based on accepted standards of quality. [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] 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]

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Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation 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] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU]

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Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] 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] Remission Induction: Therapeutic act or process that initiates a response to a complete or partial remission level. [NIH] Remission induction therapy: The initial chemotherapy a person receives to bring about a remission. [NIH] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH] Research Personnel: Those individuals engaged in research. [NIH] Research Support: Financial support of research activities. [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

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(= cell respiration). [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoblastoma Protein: Product of the retinoblastoma tumor suppressor gene. It is a nuclear phosphoprotein hypothesized to normally act as an inhibitor of cell proliferation. Rb protein is absent in retinoblastoma cell lines. It also has been shown to form complexes with the adenovirus E1A protein, the SV40 T antigen, and the human papilloma virus E7 protein. [NIH]

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] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [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] Salvage Therapy: A therapeutic approach, involving chemotherapy, radiation therapy, or surgery, after initial regimens have failed to lead to improvement in a patient's condition. Salvage therapy is most often used for neoplastic diseases. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] 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] 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] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] 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

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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] 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] Senescence: The bodily and mental state associated with advancing age. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] 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] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Single-agent: The use of a single drug or other therapy. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH]

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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] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [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] 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] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Sphenoid: An unpaired cranial bone with a body containing the sphenoid sinus and forming the posterior part of the medial walls of the orbits. [NIH] Sphenoid Sinus: One of the paired paranasal sinuses, located in the body of the sphenoid bone and communicating with the highest meatus of the nasal cavity on the same side. [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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [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] Stem Cell Factor: Hematopoietic growth factor and the ligand of the c-kit receptor CD117

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(proto-oncogene protein C-kit). It is expressed during embryogenesis and provides a key signal in multiple aspects of mast-cell differentiation and function. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stomatitis: Inflammation of the oral mucosa, due to local or systemic factors which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. [EU]

Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Stromal tumors: Tumors that arise in the supporting connective tissue of an organ. [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] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU]

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Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppurative: Consisting of, containing, associated with, or identified by the formation of pus. [NIH] Suramin: A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tachypnea: Rapid breathing. [NIH] Tegafur: 5-Fluoro-1-(tetrahydro-2-furanyl)-2,4-(1H,3H)-pyrimidinedione. Congener of fluorouracil with comparable antineoplastic action. It has been suggested especially for the treatment of breast neoplasms. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH]

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Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [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] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombocytosis: Increased numbers of platelets in the peripheral blood. [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] Thrush: A disease due to infection with species of fungi of the genus Candida. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidylate Synthase: An enzyme of the transferase class that catalyzes the reaction 5,10methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. [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] Tissue Banks: Centers for acquiring, characterizing, and storing organs or tissue for future use. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue

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culture includes both organ culture and cell culture. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tonicity: The normal state of muscular tension. [NIH] 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] Total-body irradiation: Radiation therapy to the entire body. Usually followed by bone marrow or peripheral stem cell transplantation. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH]

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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]

Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Trypanosomiasis: Infection with protozoa of the genus Trypanosoma. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] 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 and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; 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] Ubiquitin: A highly conserved 76 amino acid-protein found in all eukaryotic cells. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urokinase: A drug that dissolves blood clots or prevents them from forming. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the ciliary body and iris in the front of the eye. [NIH] Vaccination: Administration of vaccines to stimulate the host's immune response. This includes any preparation intended for active immunological prophylaxis. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also

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called the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] 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 Hepatitis: Hepatitis caused by a virus. Five different viruses (A, B, C, D, and E) most commonly cause this form of hepatitis. Other rare viruses may also cause hepatitis. [NIH] Viral Proteins: Proteins found in any species of virus. [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] Virus Diseases: A general term for diseases produced by viruses. [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] 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]

Wound Healing: Restoration of integrity to traumatized tissue. [NIH]

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Xenograft: The cells of one species transplanted to another species. [NIH] Xeroderma Pigmentosum: A rare, pigmentary, and atrophic autosomal recessive disease affecting all races. It is manifested as an extreme photosensitivity to ultraviolet light as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zebrafish: A species of North American fishes of the family Cyprinidae. They are used in embryological studies and to study the effects of certain chemicals on development. [NIH] Zoster: A virus infection of the Gasserian ganglion and its nerve branches, characterized by discrete areas of vesiculation of the epithelium of the forehead, the nose, the eyelids, and the cornea together with subepithelial infiltration. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

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INDEX A Aberrant, 6, 16, 18, 20, 23, 24, 30, 51, 56, 58, 62, 187 Acceptor, 28, 187, 227 Aclarubicin, 72, 99, 187 Acute leukemia, 6, 23, 27, 29, 36, 48, 54, 60, 80, 108, 136, 145, 146, 147, 149, 187, 189, 224 Acute lymphoblastic leukemia, 17, 35, 36, 53, 61, 64, 81, 145, 149, 187 Acute lymphocytic leukemia, 54, 89, 154, 187 Acute nonlymphocytic leukemia, 145, 187 Adaptability, 187, 196, 197 Adenine, 187 Adenocarcinoma, 100, 187 Adenosine, 10, 187, 229 Adenovirus, 52, 187, 236 Adolescence, 40, 187, 228 Adoptive Transfer, 136, 187 Adverse Effect, 188, 237 Aerobic, 188, 222, 227 Affinity, 9, 45, 54, 82, 90, 188, 192, 220 Agar, 188, 199, 202 Aggressiveness, 145, 188 Algorithms, 188, 193 Alkaloid, 188, 195, 199, 213 Alkylating Agents, 39, 188, 195, 220, 243 Alleles, 28, 188, 213 Allo, 22, 188 Allogeneic, 20, 31, 74, 77, 79, 81, 83, 93, 100, 107, 138, 188, 211, 212, 228 Allogeneic bone marrow transplantation, 20, 31, 77, 79, 93, 188 Alopecia, 188, 202 Alpha Particles, 188, 234 Alternative medicine, 156, 188 Alveoli, 189, 203 Amifostine, 94, 189 Amino Acid Motifs, 189, 201 Amino Acid Sequence, 189, 190, 201, 210 Amino Acids, 189, 201, 210, 228, 231, 232 Amino-terminal, 31, 50, 189 Amplification, 78, 189 Amsacrine, 118, 120, 127, 129, 189 Amyloid, 189, 197 Anaesthesia, 189, 215 Anal, 48, 189

Analog, 9, 94, 189, 208 Analogous, 189, 242 Anaphylatoxins, 189, 200 Anaplasia, 189 Anatomical, 190, 198, 215, 236 Anemia, 56, 59, 86, 91, 99, 147, 171, 183, 190, 209 Anergy, 96, 190 Angiogenesis inhibitor, 190, 206 Angiopathy, 190, 197 Animal model, 12, 21, 26, 32, 50, 56, 58, 144, 190 Annealing, 190, 230 Antecedent, 10, 190 Anterior chamber, 190, 214, 218 Anthracycline, 187, 190, 203, 214 Antibacterial, 190, 238 Antibiotic, 187, 190, 195, 203, 204, 209, 214, 238, 241 Antibodies, 48, 145, 150, 154, 190, 212, 213, 223, 230, 234 Anticoagulant, 190, 232 Antifungal, 111, 190, 208, 218 Antigen, 15, 30, 108, 141, 149, 154, 188, 190, 191, 200, 203, 213, 214, 215, 216, 221, 236 Antigen-Antibody Complex, 191, 200 Antigen-presenting cell, 191, 203 Anti-inflammatory, 191, 211 Antimetabolite, 191, 208, 222 Antineoplastic, 39, 187, 188, 189, 191, 195, 202, 204, 208, 221, 222, 229, 230, 240, 242, 244 Antineoplastic Agents, 39, 188, 189, 191, 229, 244 Antiproliferative, 69, 144, 191 Antiviral, 154, 191, 216, 228 Antiviral Agents, 154, 191 Anus, 189, 191, 199 Aorta, 191, 244 Aortic Valve, 154, 191 Aplasia, 51, 191 Aplastic anemia, 7, 51, 191 Apoptosis, 8, 9, 10, 12, 13, 15, 26, 30, 54, 72, 78, 79, 94, 102, 103, 105, 121, 129, 134, 191, 196 Applicability, 42, 191 Aqueous, 191, 193, 203

248

Acute myelogenous leukemia

Arachidonic Acid, 191, 219 Arsenic trioxide, 17, 191 Arterial, 191, 192, 197, 214, 217, 232 Arteries, 190, 191, 194, 201, 217, 219, 224 Arteriovenous, 192, 197 Aspergillosis, 104, 110, 111, 192, 218 Aspiration, 154, 184, 192 Assay, 11, 13, 17, 20, 24, 25, 154, 192 Astrocytes, 192, 217 Ataxia, 56, 170, 171, 192, 241 Atrophy, 170, 171, 192 Atypical, 4, 192 Autoimmune disease, 192, 223 Autologous bone marrow transplantation, 39, 72, 119, 120, 127, 128, 129, 138, 192, 212 B Bacteremia, 65, 115, 192 Bacteria, 190, 192, 193, 200, 206, 207, 212, 213, 222, 234, 237, 238, 242, 243 Bacterium, 192, 200 Barbiturate, 192, 241 Basal Ganglia, 192, 197, 209 Basal Ganglia Diseases, 192 Base, 39, 40, 145, 187, 193, 203, 210, 218, 230 Basophils, 193, 211 Benign, 193, 209, 210, 225, 228, 234 Bile, 73, 193, 214, 219, 239 Bile Acids, 193, 239 Bile Acids and Salts, 193 Bioavailability, 46, 193 Biochemical, 6, 18, 19, 30, 37, 49, 188, 191, 193, 208, 210 Biological response modifier, 39, 193, 216 Biological therapy, 193, 212 Biomarkers, 16, 193 Biopsy, 4, 193, 207 Biotechnology, 14, 62, 65, 156, 167, 169, 170, 171, 172, 193 Biotin, 193, 226 Bladder, 193, 200, 223, 232, 243 Blast Crisis, 145, 194 Blast phase, 70, 194, 198 Blastocyst, 194, 230 Blastomycosis, 194, 218 Blasts, 8, 54, 64, 70, 73, 78, 80, 82, 85, 90, 91, 96, 99, 106, 108, 113, 120, 129, 145, 147, 151, 194 Blood Platelets, 194, 221, 230, 241 Blood pressure, 194, 214, 223

Blood vessel, 190, 194, 196, 198, 201, 206, 207, 217, 218, 220, 222, 238, 240, 241, 244 Blood-Brain Barrier, 46, 194 Blot, 13, 108, 194, 226 Body Fluids, 193, 194, 195, 205, 243 Bone Marrow Cells, 53, 57, 86, 148, 194, 199, 212, 221, 224 Bowel, 110, 189, 194, 217, 239 Brachytherapy, 194, 217, 218, 234, 245 Brain Stem, 147, 194, 197 Breast Neoplasms, 194, 240 Broad-spectrum, 10, 195 Bronchial, 195 Bronchioles, 189, 195 Bronchiolitis, 83, 195 Bronchiolitis Obliterans, 83, 195 Buccal, 44, 195, 239 Busulfan, 39, 72, 89, 128, 130, 195 Bypass, 49, 195 C Calcitonin, 114, 195 Calcium, 195, 200, 205, 217, 221, 237, 244 Callus, 195, 205 Camptothecin, 132, 195, 218 Candidiasis, 78, 195, 208 Candidosis, 195 Carbohydrates, 195, 196, 227 Carbon Dioxide, 195, 230, 235 Carboplatin, 119, 126, 128, 195 Carboxy, 31, 195 Carcinogen, 195, 221, 224 Carcinogenesis, 12, 58, 195 Carcinogenic, 188, 196, 207, 216, 226, 232, 239 Cardiac, 38, 82, 187, 196, 205, 206, 211, 214, 224, 239 Cardiological, 114, 196 Cardiotoxic, 189, 196 Cardiovascular, 93, 196, 219 Case report, 3, 4, 67, 68, 73, 85, 88, 91, 104, 109, 134, 196 Caspase, 31, 196 Catabolism, 73, 196 Catalytic Domain, 150, 196 Catheters, 196, 209, 215, 217 Causal, 58, 196, 213 Cell Adhesion, 5, 196 Cell Count, 13, 73, 196 Cell Cycle, 11, 12, 26, 58, 102, 196, 199, 202, 207 Cell Death, 9, 30, 51, 54, 59, 191, 196, 207, 225

249

Cell Differentiation, 8, 13, 15, 196, 237, 239 Cell Division, 170, 192, 196, 202, 207, 212, 221, 222, 230, 236 Cell Lineage, 19, 196 Cell membrane, 61, 97, 196, 203 Cell proliferation, 5, 11, 18, 57, 196, 217, 236, 237 Cell Respiration, 196, 222, 227, 235 Cell Size, 196, 208 Cell Survival, 5, 10, 31, 53, 55, 196, 212 Cellulitis, 65, 82, 115, 122, 197 Central Nervous System, 34, 197, 209, 219, 222, 223, 231 Ceramide, 8, 197 Cerebellar, 109, 192, 197, 235 Cerebellum, 197, 231, 235 Cerebral, 72, 154, 192, 194, 197, 206, 207 Cerebral Cortex, 192, 197, 207 Cerebral hemispheres, 192, 194, 197 Cerebral Hemorrhage, 72, 197 Cerebral Infarction, 197 Cerebral Palsy, 154, 197 Cerebrum, 197, 243 Character, 197, 203 Chemical Warfare, 197, 203 Chemical Warfare Agents, 197, 203 Chemotactic Factors, 197, 200 Chemotherapeutic agent, 44, 86, 130, 198 Chemotherapeutics, 8, 148, 198 Chemotherapy, 3, 4, 17, 30, 35, 36, 39, 40, 44, 54, 57, 65, 66, 68, 70, 72, 73, 74, 78, 80, 81, 83, 84, 87, 88, 91, 92, 94, 95, 96, 97, 98, 102, 107, 109, 110, 112, 118, 120, 121, 123, 125, 126, 129, 130, 132, 133, 134, 135, 136, 138, 149, 151, 185, 189, 198, 213, 235, 236 Chimera, 30, 198 Chimeric Proteins, 31, 198 Chin, 198, 222 Cholesterol, 73, 193, 198, 219, 239 Chondrocytes, 198, 208 Chromatin, 19, 56, 191, 198, 220 Chromosome Abnormalities, 76, 198 Chronic Disease, 198, 218 Chronic granulocytic leukemia, 198 Chronic leukemia, 145, 147, 198 Chronic myelogenous leukemia, 40, 53, 118, 126, 145, 147, 148, 194, 198 Chronic phase, 145, 198 Chronic renal, 198, 230 Ciliary, 198, 214, 243 Ciliary Body, 198, 214, 243

CIS, 30, 56, 198 Cisplatin, 61, 199 C-kit receptor, 199, 238 Clinical Medicine, 199, 231 Clinical Protocols, 42, 43, 199 Cloning, 14, 21, 30, 46, 193, 199, 216, 219 Cofactor, 199, 232, 241 Colchicine, 199, 243 Colitis, 102, 199 Collagen, 199, 207, 208, 221 Colon, 73, 170, 199 Colony-Stimulating Factors, 199, 211 Combination chemotherapy, 123, 139, 199 Complement, 31, 47, 48, 189, 199, 200, 210, 218 Complementary and alternative medicine, 125, 140, 200 Complementary medicine, 125, 200 Complete remission, 16, 22, 69, 91, 98, 107, 109, 120, 127, 128, 132, 200, 235 Complete response, 200 Compliance, 35, 42, 200 Computational Biology, 167, 169, 200 Concomitant, 65, 112, 138, 200 Confounding, 7, 200 Conjugated, 161, 193, 200, 202, 226 Conjugation, 8, 200 Connective Tissue, 194, 197, 199, 201, 208, 209, 211, 222, 232, 236, 239 Consensus Sequence, 55, 189, 201 Conserved Sequence, 189, 201 Consolidation, 4, 70, 72, 83, 98, 105, 134, 135, 201 Constitutional, 44, 201 Continuous infusion, 61, 119, 133, 135, 201 Contraindications, ii, 201 Cooperative group, 32, 36, 39, 61, 201 Coordination, 34, 35, 43, 197, 201, 223 Cornea, 190, 201, 214, 245 Coronary, 201, 224 Coronary Thrombosis, 201, 224 Corticosteroids, 201, 211 Cranial, 197, 201, 228, 238 Crossing-over, 201, 235 Culture Media, 144, 188, 202 Curative, 20, 99, 202, 241 Cutaneous, 63, 75, 78, 96, 110, 194, 195, 202, 229 Cyclic, 118, 126, 202 Cyclin, 26, 30, 51, 56, 58, 63, 105, 202 Cyclin-Dependent Kinases, 26, 202

250


Cyclophosphamide, 39, 89, 119, 128, 130, 202, 214, 220 Cyclosporine, 10, 22, 38, 86, 102, 106, 202 Cysteine, 8, 202 Cystine, 202 Cytochrome, 10, 202 Cytogenetic Analysis, 74, 202 Cytogenetics, 7, 27, 42, 43, 48, 63, 65, 66, 72, 76, 77, 78, 86, 91, 93, 105, 107, 145, 202 Cytokine, 59, 75, 79, 80, 94, 120, 144, 202, 217, 241 Cytopenia, 80, 202 Cytoplasm, 150, 191, 193, 196, 203, 206, 220, 225 Cytotoxic, 10, 15, 54, 60, 77, 83, 132, 144, 148, 203, 234, 237 Cytotoxic chemotherapy, 83, 203 Cytotoxicity, 15, 82, 90, 93, 115, 199, 203 D Daunorubicin, 66, 91, 93, 97, 106, 133, 187, 203, 204 De novo, 10, 22, 74, 75, 91, 95, 98, 108, 112, 120, 131, 138, 145, 203 Decidua, 203, 230 Decitabine, 15, 203 Decontamination, 110, 203 Degenerative, 147, 203, 213 Deletion, 11, 28, 64, 76, 191, 203 Denaturation, 203, 230 Dendrites, 203 Dendritic, 61, 75, 76, 82, 96, 99, 203, 221 Dendritic cell, 61, 75, 76, 96, 99, 203 Dentition, 154, 203 Deoxycytidine, 161, 203 Depolarization, 203, 237 Depsipeptide, 15, 203 Developmental Biology, 58, 203 Diagnostic procedure, 143, 156, 203 Diethylcarbamazine, 203, 240 Diffusion, 203, 216 Digestion, 6, 193, 194, 204, 217, 219, 239 Dihydrotestosterone, 204, 235 Dimerization, 150, 204 Dipeptidases, 8, 204 Dipeptides, 204 Diphtheria, 90, 100, 115, 204 Diphtheria Toxin, 90, 100, 115, 204 Diploid, 204, 223, 230, 243 Direct, iii, 6, 9, 14, 16, 18, 19, 44, 49, 59, 199, 204, 235 Discrete, 204, 245

Disease-Free Survival, 8, 37, 204 Disposition, 46, 204 Dissection, 45, 204 Dissociation, 188, 204 Dominance, 19, 204 Doxorubicin, 79, 111, 187, 204 Drug Interactions, 160, 204 Drug Resistance, 8, 10, 22, 23, 24, 41, 42, 44, 60, 81, 95, 108, 136, 204, 205 Drug Tolerance, 204, 242 Duodenum, 193, 205, 239 Dysplasia, 72, 171, 205 Dystrophy, 170, 205 E Echocardiography, 82, 205 Effector, 199, 205 Efficacy, 9, 15, 29, 42, 73, 129, 205, 243 Elective, 110, 205 Electrolytes, 193, 205 Electromagnetic Fields, 68, 205 Electrons, 193, 205, 218, 227, 234 Embryo, 194, 196, 205, 215 Embryogenesis, 5, 50, 205, 239 Enalapril, 38, 205 Encapsulated, 205, 219 Encephalitis, 205, 221 Encephalopathy, 70, 205 Endocarditis, 154, 195, 205 Endocardium, 205, 206 Endogenous, 11, 23, 52, 106, 206, 242 Endophthalmitis, 100, 206 Endostatin, 110, 206 Endothelial cell, 194, 206, 208, 241 Endotoxin, 144, 206, 243 End-stage renal, 198, 206, 230 Enhancer, 50, 63, 206 Enkephalin, 52, 206 Environmental Exposure, 206, 226 Environmental Health, 166, 168, 206 Enzymatic, 15, 46, 195, 196, 200, 202, 206, 231 Eosinophil, 206, 212 Eosinophilia, 19, 206 Epinephrine, 206, 225, 243 Epithelial, 6, 187, 198, 203, 206, 213, 217, 228 Epithelial Cells, 6, 206, 213, 217 Epithelium, 206, 218, 245 Erythrocytes, 190, 194, 206, 213, 228, 235 Erythroid Progenitor Cells, 206, 224 Erythropoiesis, 59, 206 Escalation, 66, 78, 129, 207

251

Essential Tremor, 170, 207 Ethylnitrosourea, 21, 207 Eukaryotic Cells, 207, 215, 227, 243 Evaluable patients, 33, 207 Evoke, 207, 239 Excisional, 207, 245 Excitation, 207, 208, 225 Exogenous, 11, 23, 106, 206, 207 Extensor, 207, 233 External-beam radiation, 207, 218, 234, 245 Extracellular, 52, 150, 189, 192, 201, 207, 208, 221 Extracellular Matrix, 201, 207, 208, 221 Extracellular Matrix Proteins, 207, 221 Exudate, 195, 207 Eye Infections, 187, 207 Eye socket, 208, 228 F Facial, 82, 154, 208, 221 Family Planning, 167, 208 Fat, 190, 191, 193, 194, 197, 208, 219, 223, 238 Fatigue, 4, 184, 208 Febrile, 121, 135, 208 Fetus, 208, 230, 232 Fibroblast Growth Factor, 110, 208 Fibroblasts, 6, 97, 208 Fibronectin, 94, 208 Fibrosarcoma, 65, 208 Fibrosis, 171, 208, 236 Flow Cytometry, 42, 208, 215 Fluconazole, 97, 208 Fludarabine, 74, 84, 86, 102, 106, 114, 208 Fluorescence, 72, 74, 84, 88, 208 Fluorescent Dyes, 208 Fluorouracil, 208, 219, 240 Folate, 108, 111, 209 Fold, 46, 60, 209 Folic Acid, 209 Fungemia, 64, 109, 209 Fungus, 195, 209 G Gametogenesis, 5, 209 Gamma Rays, 209, 224, 234 Ganglia, 189, 192, 209, 225, 240 Ganglion, 209, 245 Gastric, 100, 209 Gastrointestinal, 5, 56, 206, 209, 219, 239, 243 Gastrointestinal stromal tumor, 5, 209 Gastrointestinal tract, 5, 209, 219, 243

Gemcitabine, 60, 101, 106, 209 Gemtuzumab ozogamicin, 105, 106, 209 Gene Expression, 12, 17, 22, 24, 26, 27, 47, 51, 52, 54, 62, 98, 101, 149, 171, 209, 210 Gene Expression Profiling, 22, 209 Gene Rearrangement, 100, 101, 110, 145, 210 Gene Silencing, 16, 210 Gene Therapy, 33, 97, 187, 210 Genetic Code, 210, 226 Genetic Engineering, 193, 199, 210 Genetic Screening, 21, 210 Genetic Techniques, 49, 210 Genetic testing, 210, 231 Genetics, 16, 19, 24, 30, 42, 66, 72, 76, 77, 78, 86, 93, 105, 200, 202, 204, 210 Genomics, 46, 47, 210 Genotype, 27, 44, 210, 229 Germ cell tumors, 5, 118, 126, 210 Germ Cells, 58, 210, 221, 227, 238 Gestation, 210, 230 Gingival Hyperplasia, 4, 210 Gingivitis, 67, 210 Gland, 210, 213, 227, 228, 230, 232, 236, 239, 241 Glossitis, 89, 211 Glucocorticoid, 52, 211 Glucose, 170, 211, 212, 236 Glycogen, 67, 211 Glycogen Storage Disease, 67, 211 Glycoprotein, 10, 24, 46, 48, 79, 81, 130, 208, 211, 220, 229, 241, 243 Glycosaminoglycans, 207, 211, 232 Glycosidic, 211 Gonadal, 211, 239 Governing Board, 211, 231 Gp120, 211, 228 Graft, 20, 79, 81, 83, 211, 215 Graft Rejection, 211, 215 Graft-versus-host disease, 79, 83, 211 Granulation Tissue, 195, 211 Granulocyte, 21, 65, 73, 79, 87, 88, 91, 93, 99, 109, 112, 114, 115, 119, 122, 128, 130, 132, 135, 136, 138, 199, 211 Granulocyte-Macrophage ColonyStimulating Factor, 73, 115, 199, 211 Granulocytopenia, 21, 212 Granuloma, 89, 212 Growth factors, 59, 212 Guanine, 5, 212 H Haploid, 212, 230

252


Haptens, 188, 212 Heat-Shock Proteins, 23, 212 Hematologic malignancies, 20, 212 Hematopoiesis, 5, 18, 30, 39, 50, 52, 56, 57, 58, 59, 79, 89, 212 Hematopoietic growth factors, 8, 44, 114, 212 Hematopoietic Stem Cell Transplantation, 21, 79, 212 Hematopoietic Stem Cells, 61, 147, 148, 212, 224 Hematopoietic tissue, 8, 194, 212 Hemoglobin, 190, 206, 212, 213 Hemoglobinopathies, 210, 212 Hemoglobinuria, 51, 92, 170, 213 Hemolysis, 51, 213 Hemorrhage, 111, 115, 213 Hepatic, 89, 148, 213 Hepatitis, 70, 83, 84, 97, 154, 213, 244 Hepatocytes, 213 Hereditary, 213, 229, 236 Heredity, 209, 210, 213 Heterogeneity, 12, 27, 48, 86, 90, 188, 213 Heterozygote, 56, 213 Hidradenitis, 102, 213 Histone Deacetylase, 15, 26, 55, 62, 213 Histones, 198, 213 Homeobox, 6, 23, 213 Homeotic, 6, 31, 213 Homogeneous, 7, 213 Homoharringtonine, 66, 118, 125, 126, 131, 135, 213 Homologous, 51, 99, 188, 201, 210, 213, 236, 240 Homozygotes, 56, 204, 213 Hormonal, 192, 213 Hormone, 188, 195, 201, 206, 213, 230, 232, 237, 240, 241 Humoral, 30, 211, 213 Humour, 213, 214 Hybrid, 13, 30, 45, 56, 58, 214, 226 Hybridization, 50, 74, 214, 226 Hydrogen, 187, 193, 195, 203, 207, 214, 223, 225, 226, 227, 233 Hydrolysis, 199, 214, 229, 231, 233 Hydrophobic, 150, 214, 219 Hypersensitivity, 206, 214, 219 Hypertension, 197, 205, 214 Hyperthermia, 212, 214 Hypnotic, 192, 214, 241 Hypopyon, 97, 214 Hypothalamus, 206, 214, 230

I Idarubicin, 39, 66, 81, 92, 102, 112, 120, 131, 138, 161, 214 Idiopathic, 213, 214 Ifosfamide, 61, 214 Immune response, 30, 190, 191, 192, 211, 212, 214, 215, 239, 243, 244 Immune system, 22, 50, 147, 191, 193, 214, 215, 219, 220, 223, 229, 243, 244 Immunity, 214, 217 Immunization, 187, 214, 215 Immunocompromised, 4, 110, 215 Immunodeficiency, 23, 170, 215 Immunologic, 31, 37, 187, 197, 214, 215, 234 Immunology, 16, 34, 36, 61, 188, 208, 215 Immunophenotyping, 36, 215 Immunosuppressant, 188, 208, 215, 222 Immunosuppression, 215, 226 Immunosuppressive, 202, 211, 214, 215 Immunosuppressive therapy, 215 Immunotherapy, 48, 188, 193, 215 Immunotoxin, 49, 71, 215 Impairment, 192, 207, 215, 222 Implant radiation, 215, 217, 218, 234, 245 In situ, 6, 8, 21, 43, 72, 74, 84, 88, 215 In Situ Hybridization, 6, 21, 72, 74, 84, 88, 215 Incision, 215, 217 Induction therapy, 91, 114, 118, 121, 127, 129, 132, 133, 215 Infancy, 40, 215 Infarction, 197, 216, 217 Infiltration, 82, 216, 245 Informed Consent, 35, 39, 216 Infusion, 31, 101, 106, 118, 127, 216, 220, 242 Inhalation, 195, 216 Initiation, 216, 242 Initiator, 216, 217 Inorganic, 199, 216 Insertional, 13, 19, 216 Insight, 7, 26, 48, 58, 60, 216 Insulator, 216, 223 Interferon, 70, 79, 94, 120, 216, 217, 220 Interferon-alpha, 216 Interleukin-1, 93, 216, 217 Interleukin-12, 93, 217 Interleukin-2, 83, 91, 217 Interleukin-3, 90, 148, 199, 217 Interleukins, 144, 217

253

Internal Medicine, 15, 53, 58, 103, 119, 120, 121, 212, 217 Internal radiation, 217, 218, 234, 245 Interstitial, 5, 194, 217, 218, 245 Intestinal, 5, 217, 220 Intestine, 193, 194, 205, 213, 217, 235 Intracellular, 48, 73, 150, 210, 216, 217, 237 Intracranial Aneurysm, 197, 217 Intracranial Arteriosclerosis, 197, 217 Intraocular, 94, 206, 217 Intrathecal, 96, 133, 217, 220 Intravascular, 51, 217 Intravenous, 95, 144, 209, 216, 217 Intrinsic, 149, 150, 188, 217 Invasive, 68, 97, 104, 111, 214, 217, 220 Involuntary, 192, 207, 217, 224 Ionizing, 188, 206, 218, 234 Ions, 193, 204, 205, 214, 218 Irinotecan, 60, 218 Iris, 190, 201, 214, 218, 243 Irradiation, 54, 99, 218, 245 Ischemia, 192, 218 Itraconazole, 95, 97, 218 K Karyotype, 7, 16, 96, 112, 218 Kb, 6, 46, 166, 218 Kidney Disease, 166, 171, 218 Kinetics, 11, 79, 218 L Labile, 85, 199, 218 Latency, 58, 218 Latent, 218, 231 Lesion, 184, 194, 212, 218, 219, 243 Lethal, 204, 218, 224 Leucocyte, 206, 218, 220 Leukaemia, 45, 218 Leukotrienes, 8, 191, 219 Levamisole, 96, 133, 219 Levo, 219, 221 Life Expectancy, 56, 219 Ligament, 219, 232 Ligase, 49, 219 Ligation, 82, 219 Linkage, 219 Lipid, 68, 219, 223 Lipopolysaccharide, 144, 219 Lipoprotein, 97, 219 Liposomal, 66, 91, 97, 106, 111, 219 Liver, 46, 64, 97, 154, 191, 193, 202, 209, 211, 212, 213, 219 Localization, 58, 219 Localized, 59, 204, 205, 216, 219, 230, 243

Low-density lipoprotein, 97, 219 Lymphatic, 216, 219, 220, 222, 238, 241 Lymphatic system, 220, 238, 241 Lymphoblastic, 6, 22, 27, 145, 149, 220 Lymphoblasts, 35, 44, 149, 187, 220 Lymphocytes, 15, 31, 80, 94, 144, 190, 203, 214, 215, 216, 217, 218, 220, 224, 241, 244 Lymphocytic, 15, 54, 59, 74, 114, 145, 147, 151, 198, 220 Lymphoid, 11, 27, 35, 40, 41, 61, 145, 146, 147, 148, 190, 201, 211, 218, 220, 224 Lymphoproliferative, 20, 37, 148, 220 Lymphoproliferative Disorders, 148, 220 Lysine, 15, 213, 220 M Macrophage, 72, 79, 87, 88, 130, 199, 212, 217, 220 Macrophage Colony-Stimulating Factor, 72, 87, 88, 130, 199, 220 Mafosfamide, 98, 220 Magnetic Resonance Imaging, 104, 220 Maintenance therapy, 38, 220 Malabsorption, 170, 220 Malignancy, 21, 37, 56, 185, 220 Malignant tumor, 220, 227, 236 Malnutrition, 192, 220, 223 Mastocytosis, 5, 220 Matrix metalloproteinase, 113, 221 Maximum Tolerated Dose, 39, 205, 221 Meatus, 221, 238 Medial, 111, 221, 238 Median survival time, 151, 221 Mediate, 31, 48, 55, 150, 221 Mediator, 217, 221 MEDLINE, 167, 169, 171, 221 Megakaryocytes, 145, 147, 194, 221 Meiosis, 58, 221, 240 Melanin, 218, 221, 229, 243 Melanocytes, 221 Melanoma, 31, 144, 170, 221 Melphalan, 39, 221 Membrane, 10, 46, 48, 55, 192, 196, 200, 203, 207, 211, 221, 223, 225, 227, 228, 237, 242 Memory, 23, 221 Meningeal, 73, 221 Meninges, 197, 221, 222 Meningitis, 208, 218, 221, 222 Meningoencephalitis, 83, 221 Mental, iv, 4, 52, 166, 168, 172, 197, 198, 204, 208, 221, 222, 233, 237 Mental Processes, 204, 222, 233

254


Mental Retardation, 52, 172, 222 Mercury, 208, 222 Mesenchymal, 212, 220, 222 Metabolic disorder, 211, 222 Metabolite, 7, 60, 73, 222, 232 Metastasis, 221, 222 Methotrexate, 35, 39, 41, 222 Microbe, 222, 242 Microbiology, 75, 109, 115, 121, 192, 222 Microorganism, 199, 222, 244 Migration, 5, 222 Mitochondria, 9, 222, 227 Mitochondrial Swelling, 222, 225 Mitosis, 191, 222 Mitotic, 207, 222, 244 Mobilization, 103, 222 Modification, 46, 56, 210, 223, 233 Modulator, 56, 123, 139, 223 Monitor, 4, 24, 114, 223, 225 Monoclonal, 15, 48, 127, 150, 161, 209, 218, 223, 234, 245 Monoclonal antibodies, 15, 48, 127, 209, 223 Monocyte, 220, 223 Mononuclear, 90, 212, 220, 223, 243 Monophosphate, 147, 223 Monosomy, 77, 105, 223 Morphological, 149, 205, 209, 221, 223 Morphology, 27, 149, 212, 223 Mucosa, 223, 224, 239 Mucositis, 223, 241 Multidrug resistance, 10, 24, 38, 46, 79, 81, 87, 108, 123, 130, 139, 223, 229 Multiple sclerosis, 67, 223 Muscle Fibers, 223 Muscular Atrophy, 170, 223 Mustard Gas, 224 Mutagen, 13, 224 Mutagenesis, 13, 19, 21, 30, 58, 224 Mutagenic, 188, 207, 224 Myelin, 223, 224 Myelodysplasia, 51, 59, 75, 76, 98, 136, 224 Myelodysplastic Syndromes, 10, 17, 66, 81, 86, 90, 107, 114, 224 Myelogenous, 3, 4, 5, 6, 7, 17, 19, 22, 23, 28, 30, 40, 47, 51, 52, 54, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 118, 119, 120, 121, 122, 123,

124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 141, 144, 145, 146, 147, 148, 149, 150, 154, 155, 156, 170, 183, 187, 224 Myeloid Cells, 6, 15, 30, 32, 57, 61, 144, 145, 224 Myeloid Progenitor Cells, 16, 57, 224 Myeloproliferative Disorders, 37, 224 Myelosuppression, 59, 189, 224 Myelotoxic, 17, 224 Myocardial infarction, 72, 201, 224 Myocarditis, 204, 224 Myocardium, 224 Myotonic Dystrophy, 170, 224 N Nasal Cavity, 224, 228, 238 Natural killer cells, 217, 224 NCI, 1, 27, 165, 199, 224 Necrosis, 3, 71, 144, 191, 197, 206, 216, 224, 225 Neoplasia, 5, 30, 42, 170, 225 Neoplasm, 225, 228, 236, 243 Nephropathy, 218, 225 Nephrosis, 225 Nephrotic, 67, 225 Nervous System, 170, 197, 221, 225, 239, 240 Networks, 5, 30, 56, 225 Neural, 148, 189, 213, 225 Neuroblastoma, 34, 36, 37, 39, 40, 44, 225 Neurology, 43, 61, 225 Neurosurgery, 41, 43, 61, 225 Neurotransmitter, 187, 225, 237, 239 Neutrons, 188, 218, 225, 234 Neutropenia, 76, 111, 121, 135, 209, 225 Neutrophil, 32, 225 Nitrogen, 188, 202, 207, 221, 225 Nuclear, 18, 31, 32, 58, 62, 104, 108, 192, 195, 200, 205, 207, 209, 225, 226, 236 Nuclear Envelope, 225 Nuclear Pore, 31, 225 Nuclear Proteins, 31, 226 Nuclei, 188, 201, 205, 210, 213, 220, 222, 225, 226, 233 Nucleic acid, 146, 203, 210, 214, 215, 225, 226 Nucleic Acid Hybridization, 214, 226 Nucleic Acid Probes, 146, 226 Nucleoproteins, 226 Nucleus, 150, 191, 192, 193, 198, 202, 203, 207, 209, 220, 221, 223, 225, 226, 233, 239, 241

255

Nurse Practitioners, 33, 226 O Occupational Exposure, 68, 226 Oligonucleotide Probes, 63, 226 Oncogene, 18, 58, 61, 170, 226, 239 Oncogenic, 5, 13, 19, 23, 58, 226 Oncologist, 121, 226 Operon, 226, 235 Opiate, 206, 226 Opportunistic Infections, 20, 226 Oral Health, 4, 227 Orbit, 208, 227, 228 Orbital, 70, 105, 227 Orderly, 27, 227 Organ Culture, 227, 242 Organelles, 203, 221, 227 Osteoclasts, 195, 227 Osteogenic sarcoma, 227 Osteonecrosis, 3, 227 Osteosarcoma, 33, 227 Ovary, 88, 227, 239 Overall survival, 57, 227 Overexpress, 50, 57, 227 Ovum, 203, 210, 227, 232, 245 Oxidation, 8, 187, 202, 227 Oxidative metabolism, 219, 227 P P53 gene, 35, 227 Palate, 227, 239 Palliative, 227, 241 Pancreas, 193, 227, 228, 243 Pancreatic, 170, 227, 228 Pancreatic cancer, 170, 228 Pancytopenia, 51, 59, 228 Papilloma, 228, 236 Paranasal Sinuses, 228, 238 Paroxysmal, 51, 92, 170, 228 Partial remission, 228, 235 Particle, 228, 242 Pathologic, 191, 193, 195, 201, 214, 228, 233, 244 Pathologic Processes, 191, 228 Pathophysiology, 14, 21, 228 Pediatrics, 21, 22, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 47, 57, 60, 122, 228 Peer Review, 59, 117, 228 Pelvic, 228, 232 Peptide, 45, 54, 55, 82, 145, 195, 208, 228, 230, 231, 232, 233 Peptide T, 55, 228 Pericarditis, 93, 228 Pericardium, 228

Periodontitis, 210, 228 Periorbital, 122, 228 Peripheral blood, 9, 19, 28, 39, 81, 83, 90, 98, 103, 119, 122, 127, 128, 136, 212, 216, 228, 241 Peripheral stem cell transplantation, 74, 83, 228, 242 Peripheral stem cells, 211, 229 Peroxidase, 8, 113, 229 Peroxide, 229 Petechiae, 4, 184, 229 P-Glycoprotein, 48, 229 Phagocyte, 220, 229 Pharmacodynamic, 15, 229 Pharmacokinetic, 7, 15, 229 Pharmacologic, 15, 31, 37, 41, 58, 229, 242 Phenotype, 10, 13, 15, 19, 23, 24, 29, 30, 50, 51, 53, 55, 57, 58, 75, 87, 112, 148, 229 Phenylalanine, 229, 243 Phospholipases, 229, 237 Phosphorus, 195, 229 Phosphorylated, 99, 150, 229 Phosphorylation, 26, 46, 150, 151, 202, 229 Photosensitivity, 229, 245 Physiologic, 229, 235 Physiology, 212, 229 Pigment, 221, 229 Pilot Projects, 41, 229 Pilot study, 44, 62, 106, 107, 135, 230 Pituitary Gland, 208, 230 Placenta, 46, 230, 232 Plants, 188, 195, 211, 223, 230, 236, 242 Plasma, 40, 121, 135, 190, 195, 196, 199, 208, 211, 212, 230, 237 Plasma cells, 190, 211, 230 Platelet Activation, 80, 230, 237 Platelet Transfusion, 71, 230 Platelet-Derived Growth Factor, 85, 230 Platelets, 147, 185, 224, 228, 230, 241 Ploidy, 43, 230 Pneumonia, 83, 195, 201, 230 Podophyllotoxin, 207, 230 Point Mutation, 11, 28, 47, 54, 61, 230 Polycystic, 171, 230 Polymerase, 63, 108, 114, 191, 230, 235 Polymerase Chain Reaction, 63, 108, 114, 230 Polymorphism, 25, 44, 46, 231 Polyneuritis, 204, 231 Polypeptide, 6, 189, 199, 201, 214, 231, 245 Polysaccharide, 190, 231, 232 Pons, 194, 231

256


Posterior, 189, 192, 197, 218, 227, 231, 238 Postnatal, 5, 231, 239 Postoperative, 209, 231 Postremission therapy, 122, 136, 231 Postsynaptic, 231, 237 Potentiates, 84, 216, 231 Potentiation, 231, 237 Practicability, 231, 243 Practice Guidelines, 102, 168, 231 Precancerous, 231, 232 Preclinical, 49, 60, 231 Precursor, 19, 58, 191, 202, 205, 206, 211, 229, 231, 232, 243 Predictive factor, 79, 231 Predisposition, 56, 93, 231 Premalignant, 21, 231 Prenatal, 205, 210, 232 Probe, 226, 232 Prodrug, 20, 232 Progeny, 200, 232 Progesterone, 232, 239 Prognostic factor, 7, 78, 101, 106, 121, 232 Progression, 11, 12, 18, 19, 26, 58, 76, 190, 202, 232 Progressive, 146, 196, 198, 204, 207, 224, 225, 230, 232, 243 Promoter, 11, 16, 18, 20, 26, 51, 52, 58, 232 Promyelocytic leukemia, 17, 26, 30, 49, 55, 56, 112, 123, 137, 232 Prophylaxis, 68, 79, 95, 97, 111, 191, 232, 243 Prospective study, 99, 121, 135, 232 Prostate, 145, 170, 193, 232, 243 Protease, 105, 134, 232 Protective Agents, 23, 232 Protein C, 6, 30, 144, 189, 219, 232, 233 Protein S, 5, 11, 51, 171, 191, 193, 201, 204, 210, 232, 241 Proteoglycan, 149, 232 Proteolytic, 200, 233 Proteome, 46, 233 Protocol, 10, 29, 35, 36, 38, 39, 41, 42, 59, 83, 123, 233 Protons, 188, 214, 218, 233, 234 Protozoa, 200, 222, 233, 243 Proviruses, 14, 233 Psoriasis, 96, 224, 233 Psychic, 222, 233, 237 Psychology, 43, 204, 233 Public Policy, 167, 233 Publishing, 62, 233 Pulmonary, 64, 194, 219, 233, 244

Pulse, 223, 233 Purulent, 206, 233, 244 Q Quality of Health Care, 228, 233, 242 Quality of Life, 111, 233, 240 R Race, 218, 221, 222, 233, 234 Racemic, 221, 234 Radiation oncologist, 39, 226, 234 Radiation therapy, 35, 43, 207, 217, 218, 234, 236, 242, 245 Radioactive, 203, 214, 215, 217, 218, 223, 225, 226, 234, 245 Radiobiology, 48, 234 Radioimmunotherapy, 110, 234 Radioisotope, 226, 234 Radiolabeled, 218, 234, 245 Radiology, 43, 70, 234 Radiotherapy, 34, 40, 194, 218, 234, 239, 245 Randomized, 38, 42, 60, 66, 98, 108, 110, 118, 126, 205, 234 Randomized clinical trial, 42, 234 Reactivation, 83, 234 Reactive Oxygen Species, 8, 234 Reagent, 150, 234 Recombinant, 48, 71, 91, 120, 122, 136, 235, 244 Recombination, 51, 200, 210, 235 Rectum, 191, 199, 232, 235 Recurrence, 22, 105, 109, 235 Red blood cells, 206, 224, 235, 236 Red Nucleus, 192, 235 Reductase, 9, 222, 235 Refer, 1, 195, 199, 219, 225, 234, 235, 242 Refraction, 235, 238 Regeneration, 208, 235 Remission Induction, 47, 96, 108, 131, 133, 231, 235 Remission induction therapy, 136, 231, 235 Repressor, 15, 30, 55, 226, 235 Reproductive cells, 209, 210, 235 Research Personnel, 33, 235 Research Support, 14, 235 Residual disease, 17, 27, 44, 47, 77, 94, 107, 118, 235 Respiration, 195, 223, 227, 235 Retinoblastoma, 99, 170, 236 Retinoblastoma Protein, 99, 236 Retinoid, 30, 49, 55, 56, 94, 236 Retinol, 120, 131, 236

257

Retrospective, 57, 111, 138, 236 Retroviral vector, 11, 210, 236 Retrovirus, 62, 233, 236 Reversion, 86, 236 Rhabdomyosarcoma, 41, 61, 236 Ribose, 187, 236 Risk factor, 57, 232, 236 S Salivary, 228, 236 Salvage Therapy, 101, 236 Saponins, 236, 239 Sarcoma, 33, 38, 61, 70, 72, 88, 95, 101, 104, 105, 236, 238 Sclerosis, 170, 217, 223, 236 Screening, 16, 21, 45, 50, 55, 149, 199, 210, 236 Secretion, 80, 214, 217, 236, 237 Secretory, 5, 236 Sedimentation, 236, 243 Segregation, 235, 236 Seizures, 228, 237 Semen, 232, 237 Semisynthetic, 195, 207, 237 Senescence, 56, 237 Sepsis, 209, 237 Sequence Homology, 228, 237 Sequencing, 16, 231, 237 Serum, 40, 110, 187, 189, 199, 219, 237, 243 Sex Characteristics, 187, 237, 240 Sex Determination, 171, 237 Shock, 237, 242 Side effect, 159, 161, 188, 193, 202, 224, 237, 240, 242 Signal Transduction, 18, 46, 53, 65, 80, 237 Signs and Symptoms, 4, 235, 237 Single-agent, 60, 237 Skeletal, 12, 237 Skeleton, 237, 238 Smooth muscle, 154, 189, 238, 239 Soft tissue, 61, 194, 208, 238 Soft tissue sarcoma, 61, 208, 238 Solid tumor, 15, 35, 39, 42, 60, 61, 189, 190, 204, 206, 238 Soma, 238 Somatic, 13, 47, 51, 187, 205, 213, 221, 222, 238 Somatic cells, 13, 221, 222, 238 Specialist, 175, 238 Specificity, 21, 45, 188, 238 Spectrum, 10, 148, 238 Sperm, 198, 210, 235, 238, 243 Sphenoid, 104, 228, 238

Sphenoid Sinus, 104, 238 Spinal cord, 192, 194, 197, 198, 209, 217, 221, 225, 238, 240 Sporadic, 236, 238 Stabilization, 85, 238 Standard therapy, 7, 83, 238 Statistically significant, 36, 238 Stem Cell Factor, 70, 199, 238 Stereotactic, 35, 38, 239 Sterility, 202, 239 Steroid, 4, 193, 236, 239 Stimulus, 59, 207, 218, 239 Stomach, 209, 213, 239 Stomatitis, 154, 239 Stool, 199, 239 Strand, 230, 239 Stress, 4, 34, 184, 231, 239 Stromal, 5, 12, 50, 59, 94, 97, 194, 239 Stromal Cells, 194, 239 Stromal tumors, 5, 239 Subacute, 216, 239 Subclinical, 216, 237, 239 Subcutaneous, 197, 239 Subspecies, 238, 239 Substance P, 222, 236, 239 Substrate, 26, 46, 196, 239 Support group, 185, 240 Supportive care, 41, 240 Suppression, 7, 26, 49, 79, 122, 144, 210, 240 Suppurative, 197, 206, 240 Suramin, 122, 240 Survival Rate, 227, 240 Sweat, 65, 115, 213, 240 Sympathetic Nervous System, 225, 240 Symphysis, 198, 232, 240 Symptomatic, 67, 103, 240 Synaptic, 225, 237, 240 Synergistic, 77, 240 Systemic, 4, 46, 94, 95, 111, 191, 194, 195, 204, 206, 216, 218, 234, 239, 240, 245 Systemic disease, 4, 240 T Tachycardia, 192, 240 Tachypnea, 192, 240 Tegafur, 101, 240 Telangiectasia, 56, 171, 240 Teratogenic, 188, 240 Testosterone, 235, 240 Tetracycline, 23, 51, 53, 241 Thalamic, 192, 241 Thalamic Diseases, 192, 241

258


Thalidomide, 66, 241 Therapeutics, 22, 33, 42, 160, 241 Thermal, 204, 212, 225, 230, 241 Threonine, 228, 241 Thrombin, 232, 241 Thrombocytes, 230, 241 Thrombocytopenia, 67, 241 Thrombocytosis, 67, 241 Thrombomodulin, 232, 241 Thrombosis, 217, 232, 241 Thrush, 195, 241 Thymidine, 13, 241 Thymidylate Synthase, 108, 241 Thymus, 23, 215, 219, 220, 241 Thyroid, 195, 241, 243 Tissue Banks, 44, 241 Tissue Culture, 60, 241 Tolerance, 187, 212, 242 Tonicity, 213, 242 Topoisomerase inhibitors, 218, 242 Topotecan, 60, 66, 92, 102, 121, 242 Total-body irradiation, 95, 242 Toxic, iv, 144, 188, 201, 203, 204, 206, 214, 215, 221, 230, 242 Toxicity, 9, 30, 34, 38, 44, 83, 121, 134, 187, 204, 214, 221, 222, 242 Toxicology, 7, 49, 168, 242 Toxin, 204, 206, 242 Transcriptase, 236, 242 Transcription Factors, 12, 18, 28, 31, 47, 50, 52, 55, 75, 146, 242 Transduction, 13, 20, 53, 55, 65, 237, 242 Transfection, 49, 193, 210, 242 Transfusion, 82, 242 Translational, 39, 210, 242 Translocation, 6, 19, 25, 49, 51, 63, 64, 65, 67, 68, 74, 85, 99, 113, 146, 149, 242 Transplantation, 13, 20, 29, 33, 34, 39, 41, 57, 58, 66, 69, 71, 72, 74, 79, 81, 83, 87, 89, 90, 95, 98, 99, 100, 103, 107, 110, 119, 120, 121, 122, 123, 125, 127, 128, 129, 130, 136, 138, 174, 194, 197, 198, 212, 214, 228, 242 Trauma, 154, 193, 197, 225, 241, 242 Treatment Failure, 10, 242 Treatment Outcome, 121, 134, 243 Trisomy, 63, 65, 243 Trypanosomiasis, 240, 243 Tuberous Sclerosis, 171, 243 Tubulin, 40, 243 Tumor marker, 193, 243

Tumor Necrosis Factor, 64, 70, 79, 85, 144, 241, 243 Tumor suppressor gene, 21, 104, 227, 236, 243 Tumour, 45, 209, 243 Tyrosine, 5, 20, 29, 46, 47, 53, 56, 61, 63, 150, 243 U Ubiquitin, 49, 243 Ulcer, 197, 211, 243 Ulceration, 4, 243 Uracil, 101, 243 Urethra, 232, 243 Urine, 193, 199, 213, 243 Urokinase, 100, 243 Uvea, 206, 243 V Vaccination, 30, 243 Vaccine, 31, 233, 243 Vagina, 195, 243, 244 Vaginitis, 195, 244 Vascular, 211, 216, 217, 230, 244 Vasodilation, 189, 244 Vector, 19, 46, 216, 242, 244 Vein, 192, 217, 225, 244 Venous, 192, 197, 232, 244 Ventricle, 191, 214, 233, 244 Verapamil, 120, 244 Veterinary Medicine, 167, 244 Vinblastine, 243, 244 Vinca Alkaloids, 244 Vincristine, 39, 97, 133, 243, 244 Viral, 52, 154, 191, 205, 226, 236, 242, 244 Viral Hepatitis, 154, 244 Viral Proteins, 52, 244 Virulence, 242, 244 Virus, 13, 83, 84, 97, 154, 191, 206, 210, 211, 216, 233, 236, 242, 244, 245 Virus Diseases, 191, 244 Viscera, 238, 244 Vitro, 9, 19, 20, 26, 28, 30, 37, 39, 49, 50, 52, 53, 54, 56, 60, 72, 76, 80, 93, 96, 103, 106, 120, 127, 144, 148, 210, 215, 230, 241, 244 Vivo, 7, 9, 11, 15, 18, 20, 23, 28, 30, 31, 37, 45, 46, 49, 50, 52, 53, 55, 56, 60, 81, 94, 96, 120, 132, 144, 148, 210, 215, 244 W White blood cell, 147, 151, 187, 190, 194, 198, 211, 212, 220, 223, 224, 225, 230, 244 Wound Healing, 208, 221, 244 X Xenograft, 190, 245

259

Xeroderma Pigmentosum, 56, 245 X-ray, 208, 209, 218, 224, 225, 234, 239, 245 X-ray therapy, 218, 245 Y Yeasts, 195, 209, 229, 245

Z Zebrafish, 21, 245 Zoster, 89, 245 Zygote, 147, 201, 245 Zymogen, 232, 245

260


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