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

CHILDHOOD CANCER 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., 1960Childhood Cancer: 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: 0-497-00228-0 1. Childhood Cancer-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 childhood cancer. 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 CHILDHOOD CANCER .............................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Childhood Cancer.......................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 55 The National Library of Medicine: PubMed ................................................................................ 56 CHAPTER 2. NUTRITION AND CHILDHOOD CANCER ..................................................................... 99 Overview...................................................................................................................................... 99 Finding Nutrition Studies on Childhood Cancer......................................................................... 99 Federal Resources on Nutrition ................................................................................................. 101 Additional Web Resources ......................................................................................................... 101 CHAPTER 3. ALTERNATIVE MEDICINE AND CHILDHOOD CANCER ............................................ 103 Overview.................................................................................................................................... 103 National Center for Complementary and Alternative Medicine................................................ 103 Additional Web Resources ......................................................................................................... 107 General References ..................................................................................................................... 107 CHAPTER 4. DISSERTATIONS ON CHILDHOOD CANCER .............................................................. 109 Overview.................................................................................................................................... 109 Dissertations on Childhood Cancer............................................................................................ 109 Keeping Current ........................................................................................................................ 110 CHAPTER 5. BOOKS ON CHILDHOOD CANCER ............................................................................. 111 Overview.................................................................................................................................... 111 Book Summaries: Federal Agencies............................................................................................ 111 Book Summaries: Online Booksellers......................................................................................... 112 Chapters on Childhood Cancer................................................................................................... 113 CHAPTER 6. PERIODICALS AND NEWS ON CHILDHOOD CANCER ............................................... 117 Overview.................................................................................................................................... 117 News Services and Press Releases.............................................................................................. 117 Newsletter Articles .................................................................................................................... 120 Academic Periodicals covering Childhood Cancer ..................................................................... 120 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 125 Overview.................................................................................................................................... 125 NIH Guidelines.......................................................................................................................... 125 NIH Databases........................................................................................................................... 127 Other Commercial Databases..................................................................................................... 129 APPENDIX B. PATIENT RESOURCES ............................................................................................... 131 Overview.................................................................................................................................... 131 Patient Guideline Sources.......................................................................................................... 131 Associations and Childhood Cancer........................................................................................... 133 Finding Associations.................................................................................................................. 134 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 137 Overview.................................................................................................................................... 137 Preparation................................................................................................................................. 137 Finding a Local Medical Library................................................................................................ 137 Medical Libraries in the U.S. and Canada ................................................................................. 137 ONLINE GLOSSARIES................................................................................................................ 143 Online Dictionary Directories ................................................................................................... 143 CHILDHOOD CANCER DICTIONARY .................................................................................. 145

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INDEX .............................................................................................................................................. 195

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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 childhood cancer 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 childhood cancer, 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 childhood cancer, 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 childhood cancer. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to childhood cancer, 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 childhood cancer. The Editors

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

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

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

Disturbances in Oral and Dental Structures in Patients with Pediatric Lymphoma After Chemotherapy: A Preliminary Report Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 87(3): 317-321. March 1999. Contact: Available from Mosby, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-3318. (800) 453-4351 or (314) 453-4351. Summary: This article reports on a study undertaken to evaluate the effects of chemotherapy on oral and dental structures and craniofacial growth in 30 survivors of childhood lymphoma (cancer). Eruption status, root malformations, premature apexification (closure of the tooth root), agenesis (lack of a tooth or teeth), crown anomalies, soft tissue abnormalities, gingival and periodontal status, enamel defects and

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Childhood Cancer

discolorations, and craniofacial growth status of the subjects were documented and compared with findings in 20 healthy children who served as controls. Statistically significant differences between the study and control groups were found for plaque index, enamel hypoplasia, discolorations, and agenesis. The authors conclude that antineoplastic therapy and or childhood cancer can result in a higher prevalence of various malformations in teeth. Children treated in the early years of their lives displayed the most severe dental defects, suggesting that immature teeth are at a greater risk of developmental disturbances than fully developed teeth. 1 figure. 3 tables. 22 references. (AA-M).

Federally Funded Research on Childhood Cancer The U.S. Government supports a variety of research studies relating to childhood cancer. 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 childhood cancer. 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 childhood cancer. The following is typical of the type of information found when searching the CRISP database for childhood cancer: •

Project Title: A MUTATIONAL MODEL FOR CHILDHOOD CANCER Principal Investigator & Institution: Strong, Louise C.; Professor; Pediatrics; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JUL-1984; Project End 30-APR-2004 Summary: Overall Description (Applicant's Description) We have developed a multidisciplinary program to investigate genetic susceptibility to childhood and associated cancer using genetic epidemiologic, cellular, and molecular techniques. The hypotheses are based on a multi-stage model for cancer, and are tested in two model familial syndromes of childhood and adolescent cancers, sarcomas and Li Fraumeni syndrome and its variants and Wilms' tumor of the kidney. or each tumor type, genetic loci have been identified that may be altered both as germline mutations and as tumor-specific mutations. There is also significant evidence for genetic heterogeneity, or involvement of additional cancer susceptibility loci. The underlying themes of the program include characterization of the underlying characterization of the underling cancer susceptibility, determination of the heritable contribution to each tumor, determination of the role and nature of genomic instability and genes that confer genomic instability in familial cancer syndromes, analysis of germline and somatic mutations by type and mechanism, development of animal models for human cancer susceptibility syndromes

2

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

Studies

5

to explore evidence for modifier genes and developmental effects, and determination of the implications of germline mutations for the patients and their families. The findings from this program should provide insights into the mechanisms of carcinogenesis as well as guidelines for clinical programs for patients at high risk of cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTICANCER DRUG EFFLUX TRANSPORTERS IN DEVELOPMENT Principal Investigator & Institution: Sartorelli, Alan C.; Professor; Pharmacology; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: Resistance of tumor cells to multiple chemotherapeutic agents (MDR) is a major obstacle to the treatment of most human cancers. The phenomenon of MDR confers upon malignant cells the ability to withstand exposure to lethal doses of many structurally unrelated antineoplastic agents. Multidrug resistance has been characterized by the overexpression of membrane-associated glycoproteins; the two most studied of these ATP-binding cassette (ABC) transporters which have a role in drug efflux are the P-glycoprotein (P-gly) and the multidrug resistance (-associated) protein (MRP1). Little is known about the expression of the ABC transporters during ontogeny and how their development impacts the host response to therapeutic agents in utero and in early postnatal life. Similarly, little information is available on their role in the toxicity of cancer chemotherapeutic agents to normal tissues and their importance to the treatment of malignant diseases during childhood. Accordingly, we plan to determine the murine development patterns of the P-gly (mdr1a/1b) and the multidrug resistance protein family (mrps 1-7) by examining the tissue distribution of these ABC transporters prenatally and postnatally at 1, 3, and 10-12 weeks of age, corresponding approximately to the fetal, newborn, childhood and adulthood developmental periods. As model systems we will employ wild-type and genetically deficient mrp1 (-/-); mdr1a/1b(-/-); and mrp1 (- /-), mdr1a/1b(-/-) mice and embryonic fibroblast cell lines derived therefrom (a) to evaluate the role of these ABC transporters in protecting normal tissue from several anticancer agents, particularly stressing their relationships to vincristine and methotrexate, including their impact on the metabolism and pharmacokinetic disposition of these drugs; (b) to determine the impact of the absence of one or more of the ABC transporters, as well as determine the presence of possible compensatory mechanisms; and (c) to ascertain the involvement of the P-gly and the MRP family of transporters (MRPs 1-6) in the prediction of response of childhood cancers to antineoplastic agents. Thus, we will obtain information on the utility of measurements of the ABC transporters in childhood cancers in selecting therapeutic agents with the greatest potential to induce response and on the use of knockout mice and cell lines as model systems to estimate the role of the ABC transporters on the toxicity to and disposition of anticancer agents in normal tissues. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MILLENNIUM

C.O.G.--NURSES

WORKING

TOGETHER

IN

THE

NEW

Principal Investigator & Institution: Ettinger, Alice G.; National Childhood Cancer Foundation Suite 402 Arcadia, Ca 91066 Timing: Fiscal Year 2003; Project Start 27-JUN-2001; Project End 31-MAR-2006 Summary: Pediatric oncology is a dynamic field with ever changing research protocols, chemotherapeutic regimens, radiation and surgical techniques, and ethical consideration

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for the professionals, families, and the patient. The pediatric oncology nurse is the consistent caregiver serving the patient and family in the inpatient arena, in the ambulatory setting, and in the patient's home. The nurse is called upon to answer questions, assist with procedures, administer therapies, and support the family and child throughout the treatment trajectory. The nurse must remain on the leading edge of knowledge in order to perform these functions. Therefore, continuing education is essential to the ongoing knowledge and expertise of these nurses. The Children's Cancer Group and the Pediatric Oncology Group have combined to form The Children's Oncology Group (C.O.G.). The Nursing Committee of the C.O.G. is sponsoring its first combined workshop to educate nurses caring for children on clinical trials. There has been a long-standing history of successful workshops sponsored by these groups and the C.O.G. Nursing Discipline believes that there should be a continuation of these efforts at least every 18 months. The planned workshop, to be held on April 20th and 21st, 2001 in Chicago, IL will bring together nurses from all over the United States and Canada in order to learn about new protocols, techniques, and research within the C.O.G. Recent improvements in survival after childhood cancer have been achieved with complex multimodal treatment protocols. Unless nurses understand these protocols and have the requisite skills, clinical trials cannot be performed safely and correctly. Achievement of clinical trials' competencies by nurses demands high quality organized and continuous educational effort using a variety of communication channels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER IN CHILDREN Principal Investigator & Institution: Whitlock, James A.; Pediatrics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JAN-1981; Project End 30-NOV-2002 Summary: The long-range objective of this proposal is further improvement in the treatment of cancer in children through the participation of investigators at the Vanderbilt University School of Medicine in Children Cancer Group (CCS). The multidisciplinary team of investigators from Vanderbilt are pooling resources with comparable teams from other institutions to investigate the biology, treatment, and epidemiology of the childhood cancers. Specific aims can be summarized in terms of Vanderbilt's contributions to the Group's scientific endeavors and administrative leadership. These include the following: 1. Through participation in disease-specific Strategy Groups, establish research priorities and develop new strategies for therapeutic studies of acute lymphocytic leukemia (ALL), Hodgkin's disease, neuroblastoma, bone sarcomas, and brain tumors. 2. Through Study Committee chairmanships, provide leadership in the development, conduct, analysis, and reporting of investigation dealing with the treatment of ALL, neuroblastoma, and brain tumors. 3. Through participation as Study Committee members, assist in the conduct of studies concerned with the treatment of ALL, Hodgkin's disease, astrocytoma, and brain stem tumors. 4. Provide leadership in the development and interpretation of studies that assess the developmental and neuropsychologic sequelae of curative therapy for ALL. 5. Through committee participation, contribute to the development and analyses of investigational drugs. 6. Provide administrative leadership through participation on the Executive Committee, the Officers Committee, and the Affiliate Activities Steering Committee. In addition, investigators will continue to enlist the participation of Vanderbilt patients in CCG research protocols so as to facilitate the expeditious conduct and timely conclusion of Group studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

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Project Title: CARDIAC RISK FACTORS IN PEDIATRIC CANCER SURVIVORS Principal Investigator & Institution: Lipshultz, Steven E.; Professor and Chairman of Pediatrics; Pediatrics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 02-SEP-1998; Project End 30-JUN-2004 Summary: (Applicant's Description) Although subclinical cardiac abnormalities are common and often progressive in long-term survivors of childhood cancer who have been treated with anthracycline chemotherapy or mediastinal irradiation, a comprehensive assessment of risk factor for premature symptomatic cardiovascular disease has never been performed. The relationship between emerging late effects of treatment (lipid abnormalities, obesity, and cardiomyopathy) warrants further study. In this application, the investigators will study and identify a comprehensive cardiac risk factor profile on all eligible long-term survivors of childhood cancer within the catchment area of upstate New York. The primary hypothesis is that these patients will have more risk factors for subsequent symptomatic cardiovascular disease than two control populations that will be studied. The first will be matched siblings of treated patients, and the second will be long-term survivors of childhood cancer who have not been treated with therapy known to be cardiotoxic. The investigators will be able to determine whether there are increased risk factors and whether these risk factors are related to prior oncologic therapy. The second hypothesis is that there are differences in the number of cardiac risk factors for three groups of long-term survivors: those treated with anthracyclines alone, those treated with radiation to the heart alone, and those treated with both. The applicants will specifically determine the presence of depressed left ventricular (LV) function, thin LV wall, elevated LV afterload, increased body fat, elevated blood pressure, abnormal endothelial function, and abnormal lipid profiles. These will be compared to the control populations. Other secondary risk factors will be determined. Longitudinal changes in study and control patients will be determined as well to chart the trajectory over time in risk factors in different populations. If the hypotheses are true, this should enable more rational recommendations for preventive cardiology in long-term survivors to be made and to standardize care and management for this population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIOVASCULAR IRRADIATION

RISK

50

YEARS

AFTER

THYMIC

Principal Investigator & Institution: Adams, Michael J.; Community and Prev Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: The purpose of this K-23 grant proposal is to develop a didactic training and research program that will enable Dr. Adams to become an independent investigator in the epidemiology of cardiovascular disease. Dr. Adams is particularly interested in the epidemiology of cardiovascular disease in survivors of childhood cancer and would like to expand his knowledge and skill in order to look at the precursors of cardiovascular disease in general. The specific aims of this proposal are: 1) To establish a comprehensive training program in field techniques of epidemiology, follow-up study design and advanced statistical techniques including mathematical model building and survival analysis; 2) To analyze data from an ongoing study at the University of Rochester evaluating cardiovascular functioning in childhood cancer survivors treated with high-dose mediastinal irradiation; 3) To design a non-concurrent prospective study to assess the association between chest irradiation during infancy and coronary artery

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Childhood Cancer

disease in adulthood; 4) To design and carry out a pilot study to assess the association between chest irradiation during infancy and subclinical cardiovascular disease. This program takes advantage of expertise in preventive cardiology, pediatrics, and radiation-associated heart disease found within the University of Rochester Medical Center. Additionally, a previously well followed cohort in the Rochester area of nearly 2800 individuals exposed to low-dose irradiation to the thymus as infants and 4800 of their siblings provides a unique opportunity to assess the potential association between low-dose chest irradiation during infancy and cardiovascular disease later in life. The major project of this proposal evaluating this cohort is in fact two studies: 1) the followup of the entire cohort evaluating the risk of clinical coronary artery disease events associated with radiotherapy and 2) a pilot study clinically evaluating CAD risk factors and cardiac function. At the end of the training program, Dr. Adams will be an independent investigator in the field of preventive cardiology with experience in several study designs. The clinical and public health significance of this proposal is based on the fact that much remains unknown about the epidemiology and pathophysiology of atherosclerosis in special subpopulations such as those exposed to irradiation during childhood. This group of individuals, if shown to be at high risk, constitutes a potentially huge number of persons who may benefit from additional preventive measures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZING THE OBESITY OF LONG-TERM CANCER SURVIVORS Principal Investigator & Institution: Nunez, Susan B.; Attending Physician; Children's Research Institute Washington, D.C., Dc 20010 Timing: Fiscal Year 2004; Project Start 25-JUN-2004; Project End 31-MAY-2006 Summary: (provided by applicant) We have more than 1000 long-term survivors of childhood cancer followed in our Late Effects and Neuro-Oncology Clinics. With improved treatment modalities, more patients diagnosed with childhood cancer are surviving into adulthood. Endocrine and cardiovascular late effects have been described by our group and others in long-term survivors of childhood cancer. This includes obesity and the Metabolic Syndrome (1-8). The atherosclerotic cardiovascular disease component of the Metabolic Syndrome continue to be one of the leading cause of death in the general population and may occur earlier and with increased frequency in survivors of childhood cancer. Obesity is major component of the Metabolic Syndrome. There is little information on the mechanism of obesity in long-term cancer survivors. This project is a pilot study to determine the role of neuropeptides in the development of obesity in cancer survivors treated with cranial irradiation with or without surgery. We plan to enroll obese cancer survivors and perform a 2-hr oral glucose tolerance test (OGTT) measuring glucose, insulin and obesity-related peptides levels. We hypothesize that childhood cancer survivors exposed to cranial irradiation and/or cranial surgery experience disruption in the hypothalamus that increases the risk for the development of hypothalamic obesity and insulin resistance, both components of the Metabolic Syndrome many years after completion of therapy. Obese survivors with these treatments will have abnormal levels of obesity-related peptides compared to obese survivors without those treatments. Among obese survivors, the proportion of insulin resistant patients is higher among those who had cranial irradiation and/or cranial surgery and who also have abnormal levels of the obesity-related peptides. A successful conclusion to this project will not only result in the development of preventive and intervention therapy to minimize the cardiovascular risks in these patients but also open

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9

the way to more focused studies of neuropeptide involvement in the pathogenesis of osteopenia/osteoporosis, a less well-described but recently recognized to have a higher incidence in long-term survivors of childhood cancers (22). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDHOOD CANCER GENE PROGRAM PROJECT GRANT Principal Investigator & Institution: Downing, James R.; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-MAY-2006 Summary: The long-range goal of this program project is to improve our understanding of the pathogenesis and pathophysiology of childhood cancers, and to capitalize on the insights gained from these basic studies to device new means of assessing prognosis and improving therapy. This broad objective is being pursued through four interactive projects whose goal is to define the mechanisms by which chimeric transcription factors and altered tumor suppressors contribute to the pathogenesis of childhood cancer. Specifically, this program will examine the translocation-encoded fusion oncoprotein AML1-ETO and Pax3-FKHR and the ARF/Mdm2/p53 tumor suppressor pathway. Together, these genetic abnormalities represent the underlying lesions in a variety of common pediatric malignancies, including leukemias, soft tissue sarcomas, and epithelial tumors. The focus of Project 1 (M. Roussel) is to understand how p16/INK4a and ARF mediate tumor suppressive functions in different physiologic contexts, by studying their regulation, downstream targets and genetic modifier. Project 2 (J. Downing) seeks to define the molecular pathway by which alterations of AML1 leads to leukemia, by defining the spectrum of mutations that cooperate with the t(8;21)encoded AML1-ETO oncoprotein to induce leukemia, and determine how point mutations in AML1 predispose hematopoietic stem cells to leukemic transformation. Project 3 (G. Grosveld) will use biochemical, cell biological and mouse experiments to determine how Pax3-FKHR acts as an activated oncogene in alveolar rhabdomyosarcoma, and to identify the secondary genetic alterations that are required to cooperate with Pax3-FKHR to induce a full tumor phenotype. In Project 4 (G. Zambetti) will directly examine the biochemical and biophysical properties of a novel germline p53 mutation (p53R337H) that has identified in a cluster of pediatric patients in Southern Brazil with adrenal cortical carcinoma (ACC). These patients lack features of Li-Fraumenia syndrome, suggesting that p53R337H is predisposing patients to ACC. To test this hypothesis, Dr. Zambetti will directly examine the biochemical and biophysical properties of this mutant p53 protein, and will develop mice that contain this mutation in the germline. The proposed research is supported by an Administrative Core and three scientific Core's that provide assistance in the generation of genetically modified mice and the subsequent analysis of these animals through a Pathology Core and a Microarray Gene Expression Laboratory. Through this coordinated program of research, we anticipate substantial progress toward the ultimate goal of improving the treatment of children with cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHILDHOOD CANCER SURVIVOR STUDY Principal Investigator & Institution: Robison, Leslie L.; Professor; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 20-JUL-1993; Project End 31-MAY-2005

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Childhood Cancer

Summary: The resource represented by the Childhood Cancer Survivor Study (CCSS) is the result of a multi-institutional collaborative project, which has established and followed a retrospectively ascertained cohort of over 14,000 five year survivors of childhood cancer diagnosed between 1970 and 1986 and over 6000 sibling controls. Members of the cohort, currently ranging in age from 11 to 48 years (median age 26 years) have provided information encompassing over 200,000 person-years of followup since diagnosis of the original cancer. This population represents a large and heterogenous group of childhood cancer survivors treated in a fashion that has direct relevance to most current heterogenous group of childhood cancer survivors treated in a fashion that has direct relevance to most current therapeutic strategies. This characteristic, in combination with the high rate of participation, the extensive characterization of participants' prior therapy, and attention to collection of high quality data, makes the CSS an outstanding and, indeed, unique national resource for the conduct of innovative research. The objectives of this competitive renewal application, which reflects a conversion from a U01 to U24, are to (1) expand the research questions posed in the original grant application by extending the length of follow-up of this unique population with questions posed in the original grant application by extending the length of follow-up of this unique population with approximately 65,000 additional person-years; (b) strengthen the resource by establishing repositories for biological specimens to facilitate future molecular biologic investigations; (c) maintain the current consortium of investigators from specimens to facilitate future molecular biologic investigations; (c) maintain the current consortium of investigations from the 25 participating centers in the United States and Canada, who provide scientific expertise and facilitate ongoing activities; (d) serve as a source of ongoing education for the survivor population; and (3) continue to be a resource for innovative investigatorinitiated studies of childhood cancer survivors. These objectives will be achieved through specific aims: (1) continued follow-up and interaction with members of the cohort to educate and ascertain key outcomes; (2) collection and storage of biologic specimens consisting of tumor specimens from subsequent neoplasms, buccal cells as a source of genomic DNA on all members of the cohort, a and peripheral blood for establishment of lymphoblastoid cell lines for survivors who develop a subsequent neoplasm or have a known genetic condition associated with cancer risk; and (3) facilitate the use of the CCSS resource to address important questions related to cancer survivorship including the development and testing of intervention strategies. The CCSS provides a dynamic framework and resource in which to investigate current and future questions regarding consequences of therapy, genetic associations, disease processes and causation, interventions, and quality of life among childhood cancer survivors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Stork, Linda C.; Children's Hospital (Denver) 1056 E 19Th Ave Denver, Co 80218 Timing: Fiscal Year 2002; Project Start 05-APR-1994; Project End 30-NOV-2002 Summary: The objectives of this application is to demonstrate the increasing contributions of The Children's Hospital, Denver and its network to the specific goals of Children's Cancer Group (CCG): continued increase in long-term survival of children and adolescents with cancer, improving the quality of life for these survivors, further understanding of the biology of these neoplastic processes, increased correlation of objective laboratory parameters of the malignant cells with response to treatment and

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outcome, and improved understanding of the epidemiology of childhood cancer which will hopefully ultimately lead to preventive measures. Our staff has become increasingly qualified and committed to contributing to these objectives. Our network has excellent balance with highly qualified pediatric specialists in every important aspect of pediatric oncology: Drs. Albano, Cullen, Greffe, Odom, and Stork in oncology, Drs. Foreman and Arenson in neuro-oncology, Dr. Wilkening in neuro-psychology, Drs. Giller and Quinonas in bone marrow transplantation, Dr. Haase and his colleagues in surgery, Dr. McGavran in cancer cytogenetics, and physician scientists Drs. Hunger and Garcea whose labs are committed to scientific advancement in this field through translational research in the molecular biology of leukemia and oncogenic viruses, Dr. Strain and colleagues in radiology, Dr. Tyson and colleagues in pathology, and Patricia McGuire-Cullen and Margi Morse and their colleagues in nursing. Significant contributions by our network to CCG goals during the next grant cycle will be accomplished through the recent appointments of Dr. Stork as chair of the standard risk ALL study, Dr. McGavran as cytogeneticist for AML studies, and Dr. Steve Hunger to the Biology Research and Young Investigator committees. Additionally, Dr. Haase remains group Vice Chair for multidisciplinary and intergroup affairs, Dr. Giller remains coordinator of Intergroup Germ Cell Tumor Studies, Dr. Arenson, chair of the protocol for high grade astrocytomas, and Mrs. McGuire-Cullen and Mrs. Morse continue to have major roles in CCG nursing activities. A sophisticated and specialized group of clinical research associates, pediatric oncology nurses, pharmacists, social workers, and nutritionists also provide important support for the clinical program and investigational research projects. This institutional network is in a strong position to make important contributions to the goals of the Children's Cancer Group during the forthcoming grant cycle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Fallon, Robert J.; Pediatrics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 11-MAR-1994; Project End 30-NOV-2002 Summary: This is a proposal for the continued support of Indiana University's participation in the Children's Cancer Group (CCG) activities. Indiana University has been a funded member of CCG since 1971. The Indiana University childhood cancer program has recruited substantial numbers of patients into CCG studies and consistently has ranked in the top 10 of 35 of CCG institutions. This should continue as this program remains the major referral center for the State of Indiana and is committed to CCG participation. This application supports the efforts of 41 Indiana University investigators and support staff. Additional strengths of the Indiana program which serve the interests of CCG include basic and translational research. Funding from the NIH/NCI for childhood cancer research at the Indiana University program was 2.9M dollars for 1995-1996. Areas of expertise are in basic hematopoiesis, DNA repair and gene therapy. Translational efforts include the use of peripheral blood progenitor cells for hematopoietic support, and gene therapy and DNA repair proteins to off-set hematopoietic toxicity of chemotherapy. These efforts have already lead to Drs. Jakacki and Kreissman acting as study chairs for novel translational studies within the CCG targetted for brain tumors and neuroblastoma. Similar efforts in gene therapy at the institutional level may be ready for limited institutional CCG trials in 3-5 years. The Indiana program can be expected to feed the CCG with pilot data for these novel translational studies. This should greatly aid efforts directed toward the development of

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Childhood Cancer

scientifically-based, hypothesis-driven research aims within the CCG. Indiana investigators chair 6 scientific committees, 7 serve on disease strategy groups, and have chaired 11 studies during the 1992-1997 period. Finally, multidisciplinary expertise is represented in the areas of cytogenetics (Heerema), local tumor control (Rescorla), and tumor imaging (Cohen). The Indiana group remains dedicated to the understanding and development of better treatment for children with cancer through its participation in the CCG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Geyer, J R.; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 30-NOV-2002 Summary: The specific research interests are: 1) To participate fully in the clinical studies of the CCG by enrolling as many eligible children with primary or recurrent malignant disorders on CCG studies as possible, including Phase I, II and III studies; 2) To continue to provide scientific and administrative expertise to CCG through active participation in Strategy groups, Scientific and Discipline Committees and study committees; 3) To enhance fundamental understanding of biology and treatment of childhood cancer, focusing particularly on the areas of bone marrow transplantation, AML, bone and soft tissue sarcomas, brain tumors, and new agent development; 4) To conduct pilot biologic and therapeutic studies in hematopoietic stem cell transplantation and peripheral blood stem cell support of intensive chemotherapy to provide preliminary data for consideration of these approaches by the CCG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Gaynon, Paul S.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 900276062 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 30-NOV-2002 Summary: The project proposes continuation of a comprehensive pediatric oncology program at Childrens Hospital Los Angeles (CHLA). This program is designed to improve the treatment of children with cancer by conducting clinical investigations as a member of the Childrens Cancer Group (CCG) and by independently conducting other research which is directly related to the mission of CCG. CHLA is a major pediatric referral center for the Pacific Southwest and has one of the largest pediatric oncology services in the nation. An interdepartmental program has developed which involves basic and clinical scientists and has evolved into a multidisciplinary model for the management of pediatric cancers. CHLA is one of the major contributors of patients to CCG studies and the multidisciplinary staff at this institution participate in all activities of CCG. Participation of CHLA investigators in CCG enables quantitative comparative clinical investigations aimed at establishing the best mode of any cancer therapy. The unique resources of CHLA permit development of new therapeutic approaches for Group-wide application. These include participation in the Leukemia/Lymphoma, Neuro-Oncology, Bone and Soft Tissue Tumor, and Long-Term Followup Programs; the evaluation of new dose schedules and combinations of established agents predicted by in vitro and in vivo pharmacological studies; investigation of mechanisms of drug resistance; bone marrow peripheral blood and umbilical cord stem cell transplantation; immunological characterization of selected neoplasms; effects of cancer and its

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treatment on hematopoiesis optimum nutritional support in childhood malignancies; approaches to psychosocial rehabilitation of the pediatric cancer patient and family; education of caregivers and patients/families; epidemiology of childhood malignancies; preclinical studies in molecular and cellular pharmacology; tumor cell biology; carcinogenesis and chemoprevention; cytogenetics; and in vitro and in vivo tumor model systems. A network of community physicians participate in the CCG under the sponsorship of CHLA which enables the use of optimal therapy in children who are not referred for initial cancer care. The project also provides continuation of entry of minority patients on CCG clinical trials. Through the proposed renewal, the comprehensive program at CHLA will seek as its ultimate goal an integrated and investigative approach to childhood cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Rausen, Aaron R.; Pediatrics; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 10-JUN-1999; Project End 30-NOV-2002 Summary: The objectives of this proposal are to support and enhance the current and future activities of New York University Medical Center (NYUMC) as a principal member of the Children's Cancer Group (CCG) by: (1) Improving the outcome for children with cancer through, a) continued patient entries at an increasing level to active CCG protocols, b) participation in leadership positions on CCG Strategy Groups and Discipline Committees so as to develop improved methods of treating childhood cancer, c) collaborating in the development of new studies by NYUMC investigators. 2) Developing new methodologies for the treatment of childhood cancer by, a) participation and leadership roles in Phase II studies and New Agent Phase I studies, b) piloting studies that have potential for incorporation into future CCG trials in selected disease entities such as brain tumors. 3) Improving the quality of life for survivors of childhood cancer and their families by, a) participating in CCG long-term effects studies, b) evaluating quality of life issues in children being treated for cancer, c) placing all eligible patients on open supportive care studies, d) continued participation in the cardiac intervention study conducted by the Children's Hospital of Philadelphia. 4) Active participation in biology studies by, a) timely and complete submission of biology samples and data, b) participation of NYUMC scientists and laboratories in studies involving cytogenetics, molecular biology and other laboratory disciplines. 5) Increasing the network of affiliated institutions relating to NYUMC so as to recruit patients for study who are currently not available for clinical trials. This includes the affiliation with Brooklyn Hospital and the recent affiliation with Maimonides Hospital- both caring for urban minority populations not otherwise participating in clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Dinndorf, Patricia A.; Principal Investigator; Children's Research Institute Washington, D.C., Dc 20010 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 30-NOV-2002 Summary: The objective of this proposal is to enable investigators at Children's National Medical Center (CNMC) to conduct investigations of the therapy, biology, and causes of malignant disease in infants, children and adolescents through participation in the Children's Cancer Group (CCG) and to provide scientific and administrative leadership

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Childhood Cancer

of such studies. We propose to enter all eligible patients on Groupwide studies of multimodality therapy of acute leukemia and solid tumors. We propose to develop and conduct limited institution pilot (toxicity and/or feasibility) studies incorporating novel treatment strategies for childhood ALL, and dose-intensified treatments incorporating hematopoietic growth factors and stem cell transplantation. We propose to develop and conduct limited institution pilot studies of new agents and novel therapeutic approaches for the management of brain tumors and will continue to design and conduct clinical trials which pose questions of CNS pharmacologic interest. CNMC will continue as the most active CCG institution in the evaluation of new agents, both cytotoxic and biologic. We will participate in correlative pharmacology and biology studies. We will comply with protocol-specified therapy as well as required evaluations and will submit complete and accurate data to the Operations Office in a timely fashion. CNMC will continue as a performance site of the CCG ALL Biology Reference Laboratory for the identification of appropriate patients for biotherapeutic studies incorporating monoclonal antibodies to leukemia cell associated antigens to identify specific immunotoxins for immunotherapeutic classes of disease. This laboratory will lead the effort to evaluate the efficacy of new classes of agents in acute lymphoblastic leukemia using a variety of preclinical models. Laboratory studies of the significance of the expression of the mdr-1 gene at diagnosis and correlation with functional assessment of multidrug resistance and clinical outcome will continue in homogeneously treated patient groups. We propose to continue investigation of the biological significance of shed tumor gangliosides in neuroblastoma, as well as the evaluation of differences in neuroblastoma membrane ganglioside patterns between patients identified through screening programs and patients with overt clinical disease. We propose to participate in case controlled epidemiologic studies of childhood cancer to investigate the possible relationship between genetic predisposition and pre- and post-natal environmental factors on the development of specific malignancies. We will participate in the formulation and conduct of quality of life evaluations to examine the long-term impact of successful anticancer therapy on all aspects of growth and development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Neglia, Joseph P.; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 30-NOV-2002 Summary: Dramatic gains have been made in childhood cancer including markedly more effective therapy, insights into the biology of these diseases, a clearer definition of etiologic factors, and a new focus on the outcomes of the survivors of these diseases. These gains have largely been facilitated by the cooperative clinical trials groups. This grant will facilitate the continued involvement of the investigators at the University of Minnesota in the multi-institutional cooperative therapeutic and non- therapeutic studies conducted by the Children's Cancer Group (CCG). Minnesota investigators have been at the forefront of all of these venues over the past grant cycle and are poised to continue this productive relationship into the future. In 1997, the Minnesota consortium registered 162 patients on therapeutic trials (phase I, II, and III) and, in addition, registered patients on almost 100 non-therapeutic (biology, epidemiology) studies. The combination of strong patient accrual, data management, group leadership, and authorship of CCG publications resulted in Minnesota being ranked first among all group institutions in 1995, 1996, and 1997. Minnesota investigators have continued strong leadership roles in Epidemiology and Cancer Control, Hematopoetic Stem Cell

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Transplantation, acute lymphoblastic and acute myeloid leukemia, biology, and experimental therapeutics. Over the past grant cycle, Minnesota investigators have chaired fourteen group therapeutic or scientific committees and served as vice-chairs on an additional twenty four. Minnesota has consistently led the group in first- authorship of group publications. Institutional research in stem cell transplantation, epidemiology and cancer control, experimental therapeutics, and biology has been applied to group studies and future investigations of all of these areas are under development. This grant requests support for the personnel critical to our future group activities. It will assure continued excellence in data management, allow travel by investigators and other key personnel to group meetings, and supply the funds needed for expenses generated by the accrual of patients to group studies. This funding will assure the continued leadership of Minnesota investigators in all aspects of the Children's Cancer Group over the coming five years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Arndt, Carola A.; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-JAN-1981; Project End 30-NOV-2002 Summary: The primary objective of this proposal is to continue to support and expand Mayo Clinic's participation in the activities of Children's Cancer Group through: 1.) Evaluating new cancer chemotherapeutic agents and developing new approaches to treatment of children with cancer by, a) maintaining a leadership role in CCG Phase II and New Agent Study Committees, b) performing pilot studies for potential incorporation into future randomized CCG trials, c) entering patients on new agent studies, d) utilizing the resources in Doctor Ames' pharmacology laboratory to evaluate the pharmacology and pharmacokinetics of cancer chemotherapy. 2.) Improving treatment and potential for cure of various childhood cancers and leukemias by, a) continuing to enter patients into CCG treatment protocols with the expectation that study entries will increase as new studies for various tumor systems are activated, b) playing a leadership role in CCG Strategy Groups in order to develop new approaches to the treatment of childhood cancer, c) participating in the development of new randomized trials for the treatment of specific diseases and maintaining active participation in CCG study committees by Mayo investigators currently assigned to study committees, d) studying long-term effects of treatment. 3.) Studying the biology and epidemiology of childhood cancer by, a) active participation in regional and CCG case-control epidemiology studies, b) making available to CCG the skills and resources of Mayo investigators in Pathology, Immunology, Molecular Biology, cytogenetics and other areas of basic and applied laboratory research. 4.) Improving supportive care of children with cancer by, a) continued participation in CCG supportive care studies, b) standardization of drug administration procedures for various chemotherapeutic agents, c) development and evaluation of methods for controlling cancer- related and procedure-related side-effects. 5.) Providing access for patients in outlying areas to these clinical research programs through affiliates in Des Moines, Iowa; Fargo, North Dakota; Duluth, Minnesota; Regina and Saskatoon, Sasketchewan; Sioux Falls, South Dakota; and Green Bay, Wisconsin. 6.) Active participation in CCG administrative activities by continuing to chair and participate in appropriate committees, including Membership, Data Monitoring, and Constitution and By-Laws. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHILDRENS CANCER GROUP Principal Investigator & Institution: Ruymann, Frederick B.; Children's Research Institute 700 Children's Dr Columbus, Oh 432052664 Timing: Fiscal Year 2002; Project Start 01-MAR-1994; Project End 30-NOV-2002 Summary: Columbus Children's Hospital (CCH) is a 313-bed fully capable children's hospital, which has been a funded Childrens Cancer Group (CCG) institution since 1958. Dr. Frederick B. Ruymann has been the Principal Investigator (PI) and CCG representative to the Intergroup Rhabdomyosarcoma Study (IRS) since November 1982. The Division of Hematology/Oncology is the pediatric component of the OSU-NCI funded Comprehensive Cancer Center and has an approved hematology/oncology fellowship with 60 residents in pediatrics. CCH serves as the CCG-Pathology Center, which is under the direction of Dr. Stephen Qualman (Co-Investigator), a member of the CCG Pathology Steering Committee. The CCH/CCG Network, which includes three other institutions in Ohio, The Medical College of Ohio (Toledo), the Children's Medical Center/Wright Patterson AFB (Dayton), and The Cleveland Clinic Foundation (Cleveland), saw 241 children and adolescents with newly diagnosed malignancy in 1996. In November 1997, the Cabell Huntington Hospital in Huntington, West Virginia became the fourth affiliate in the CCH/CCG network. From 1992 through 1996 an average of 87 patients were placed annually on CCG therapeutic (Phase I/II) studies; 56 cases per year were placed on non-therapeutic studies. From 1992-1996, there were 437 therapeutic and 282 non-therapeutic CCG entries by the CCH/CCG Network. CCH/CCG Network follows 561 long-term survivors of childhood cancer and an additional 213 survivors on Intergroup studies. CCH is an approved CCG Phase I/II (1990) and bone marrow transplant (1992) institution under the direction of Drs. Kathryn Klopfenstein and Alfred Grovas (Co-Investigators), respectively. CCH was approved by the National Marrow Donor Program for the performance of matched unrelated transplants in July 1997. CCH's resident scientist, M. Sue O'Dorisio, MD, PhD (Co-Investigator) is a world expert on the neuropeptide regulation of neuroblastoma and a member of the CCG Neuroblastoma Strategy Committee. Other Co-Investigators on this grant include Dr. Allan Yates (neuropathology), and Dr. Amanda Rauck (pediatric oncology) who both have major roles in CCG science and leadership. CCH has made major contributions in diagnosis, treatment, and biology of leukemia, rhabdomyosarcoma, brain tumors, and neuroblastoma, through CCG pilot and preclinical investigations. Current protocols or proposals include escalating cyclophosphamide in intermediate risk rhabdomyosarcoma, neuropeptide imaging in neuroblastoma and peripheal neural ectodermal tumors, high-dose rate brachytherapy in soft tissue sarcomas, and bone marrow transplant in brain tumors. The status of each of these protocols is discussed in the text of this competing renewal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHILDRENS CANCER GROUP (CCG) Principal Investigator & Institution: Rogers, Paul C.; University of British Columbia 2075 Wesbrook Pl Vancouver, Bc Timing: Fiscal Year 2002; Project Start 01-JUL-1981; Project End 30-NOV-2002 Summary: The Pediatric Oncology Division of the University of British Columbia, Department of Pediatrics, has a long established record of commitment to CCG. The Division has enjoyed full membership since 1974 and NCI funding support since 1980. The Division actively participates in CCG Trials as well as being involved in strategic planning, trial design, lab-based research, outcome analysis and administrative

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responsibilities within the CCG network. During the next 5 year grant cycle, the Division will continue to participate in all aspects of CCG activities. Specific aims: Commitment to continue to enter as many patients as possible into CCG Trials; Actively participate in new proposals specifically in the field of high risk acute lymphatic leukemia (Dr. K. Schultz), Hodgkin's Disease (Dr. C. Fryer), radionucleotide imaging studies- Thallium (Dr. H. Nadel), radiotherapy aspects of CCG (Dr. C. Fryer); Investigate prognostic markers specifically the significance of molecular abnormalities in sarcomas (Dr. P. Sorensen); Continue to develop new therapies for poor prognostic patients, specifically to continue Phase II Pilot work on marrow ablative therapy and PBSC rescue in patients presenting with metastatic disease utilizing molecular genetic techniques to detect minimal residual disease and contamination of PBSC; To continue our laboratory research into understanding mechanisms of graft-versus-host disease and graft-versus-leukemia effect to gain further understanding of the host response to malignant disease; To expand our molecular biology research into the genetic changes associated with childhood cancers; and to investigate the cytolytic T-cell therapy for Hodgkin's Disease directed against EB viral antigens (Dr. K. Schultz and Dr. Ru Tan). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDREN'S ONCOLOGY GROUP CHAIR'S GRANT Principal Investigator & Institution: Reaman, Gregory H.; Professor of Pediatrics/ Chairman; National Childhood Cancer Foundation Suite 402 Arcadia, Ca 91066 Timing: Fiscal Year 2003; Project Start 07-JUL-2003; Project End 28-FEB-2008 Summary: The Children's Oncology Group (COG) is a new multidisciplinary clinical trials group resulting from the unification of the four pediatric cooperative groups. It is the largest childhood cancer research organization in the world and encompasses approximately 238 pediatric cancer programs as clinical trial sites throughout all of North America, Australia, and several institutions in Europe. It is exclusively well poised to translate basic biology studies into clinical investigations and to develop translational approaches through human proof of principle, toxicity assessment, identification of efficacy, and ultimately, incorporation into established treatments to improve outcome and/or decrease toxicity. COG represents the legacy of four groups, the oldest of which existed for nearly 50 years. Currently, 48,259 patients accrued to clinical trials are in active follow-up; over 2,500,000 person years of life have been saved. Although childhood cancer mortality has decreased by 50% in the last two decades and by 25% inthe past decade, nearly 2,500 children and adolescents die from cancer annually inthe U.S. alone. The majority of these deaths can be attributed to specific pediatric cancers for which new therapeutic approaches must be devised. Improvement in the cure rates for these high-risk cancers is more likely to emerge as a result of the identification of biologic features which predict resistance and, more importantly, by the identification of new anti-cancer agents with novel mechanisms of action, whose efficacy might be predicted on the basis of specific unique molecular abnormalities detected in cancer cells. COG is also uniquely able to establish for the first time a North America-wide population-based registry of childhood cancer to investigate, utilizing case control studies, potential epidemiologic associations, including genetic alterations and ultimately interactions of genes with the environment. COG, through a series of hypothesis-driven research studies, seeks to maximize cure rates for children with cancer; to achieve an expanded understanding of tumor and host biology; to elucidate new therapeutic strategies and to build on the concept of risk-adjusted therapy; and to reduce treatment-related toxicity and morbidity, thereby optimize quality of life and survival.The proposed research is aimed at reducing deaths from childhood cancer by

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20% and increasing 5-year disease-free survival (cure) rates to >85% during the study period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SURVIVORS

COGNITIVE

REMEDIATION

FOR

CHILDHOOD

CANCER

Principal Investigator & Institution: Butler, Robert W.; Pediatrics; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 26-SEP-2000; Project End 31-AUG-2004 Summary: (adapted from investigator's abstract): As a result of central nervous system involvement or treatment, many survivors of childhood cancer suffer from significant attentional deficits. The proposed project will investigate the efficacy of a multi-modal Cognitive Remediation Program (CRP) specifically designed to improve survivors attentional deficits which occurred, presumably, as a consequence of cancer and its treatment. For this study, survivors are further defined as having been treated or prophylaxed for a central nervous system cancer (leukemia, brain tumor, non-Hodgkin's lymphoma). A randomized design will be used to evaluate the effectiveness of a 4-to-5 month CRP on attention and other cognitive skills in school-aged children/adolescents 6 to 17 years of age. The stability of achieved change will be evaluated six months later. Childhood cancer survivors who are at least one year off treatment will be screened for an attentional deficit and if it is detected, they will be randomized to receive CRP (n=112) or no treatment (n=56). CRP consists of 20 two-hour sessions of attention training. Subjects will be evaluated pre-treatment, post-treatment (or at a 5 month interval for the control subjects), and for the treatment group at six-month follow-up. Measures of focused attention, working memory, memory recall, learning, vigilance, academic achievement, school behavior, and self-esteem will be administered. Statistical analyses will assess individual and group changes in attention and other cognitive skills, and these changes will be related to changes in academic achievement, school behavior, and self-esteem. To evaluate the mothers' role in influencing the child's compliance with CRP, they will be evaluated pre-treatment with measures of problem-solving skills, parenting skills, and emotional stability. Secondary and exploratory analyses will examine the influences of maternal factors on CRP adherence and effectiveness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONDITIONAL RHABDOMYOSARCOMA

MOUSE

MODEL

OF

ALVEOLAR

Principal Investigator & Institution: Keller, Charles; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 07-SEP-2001; Project End 31-JUL-2006 Summary: Alveolar rhabdomyosarcoma is an aggressive childhood muscle cancer associated with significant morbidity and mortality. Eighty-five percent of alveolar rhabdomyosarcomas demonstrate a common genetic alteration, the translocationmediated fusion of a developmentally regulated Pax transcription factor (either Pax3 or Pax7) to the Forkhead transcription factor, Fkhr. An understanding of the molecular events underlying the development of alveolar rhabdomyosarcomas will improve our ability to stratify patients to risk-based therapies and to develop new therapies. The goals of this project are to investigate whether the postembryonic, translocationmediated fusion of Pax3 to Fkhr initiates an aberrant embryonic muscle development program which is involved in the genesis of alveolar rhabdomyosarcoma, and to

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investigate whether the early and intermediate steps in the activation of oncogenic properties contributing to the genesis of alveolar rhabdomyosarcoma occur in a predictable sequence. The specific aims of this proposal are (I) to examine whether a genomic single copy-number of Pax3:Fkhr is sufficient and necessary to cause both aberrant Pax3 pathway activation and the initiation of alveolar rhabdomyosarcoma, (II) to study whether genetic, transcriptional, or translational contributions to common oncogenic mechanisms (eg. insensitivity to antigrowth signals, evasion of apoptosis) occur in a predictable sequence in alveolar rhabdomyosarcomas, and (III) to determine whether Cre recombinase-mediated translocations between heterologous chromosomes can be induced somatically at a frequency sufficient for the initiation of alveolar rhabdomyosarcoma. For the first and second aims, a conditional, knock-in mouse model of alveolar rhabdomyosarcoma will be created which initially harbors two functionally normal Pax3 alleles. Conditional, somatic expression of the site-specific DNA recombinase Cre will mediate a genomic rearrangement converting a single Pax3 allele to a single Pax3:Fkhr allele in skeletal muscle only. Animals will be serially sacrificed to analyze the ensuing sequence of intracellular changes in cells harboring Pax3:Fkhr. Analysis will be performed at the genomic, mRNA, and protein level with an emphasis on known markers of tumor progression. For the final aim, a conditional, somatic translocation between the Pax3 and Fkhr loci will be attempted using Cre-mediated rearrangement of heterologous chromosomes. Dr. Keller's research training with Dr. Capecchi and the support of the NCI will prepare Dr. Keller for an independent research career investigating developmental aspects of pediatric cancer. Ultimately, a detailed knowledge of dysregulated developmental pathways in pediatric malignancies may improve our ability to treat childhood cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--HIGH RISK PATIENTS AND FAMILIES Principal Investigator & Institution: Li, Frederick P.; Chief; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: Women differ in their risk of developing breast cancer. Studies of individuals and families with exceptionally high risk have led to the identification of inherited breast cancer susceptibility genes, including BRCA1, BRCA2, p53, and recently, chk2. These and other cancer- predisposing genes were identified through studies of unusual patients with multiple primary cancers, early-onset cancers, precancerous lesions or cancers associated with malformation syndromes. Within this SPORE, the High Risk Core will identify patients at high risk of breast cancer who are likely to be informative in future cancer research. Our Core recruitment criteria include: families carrying one of the high penetrance breast cancer predisposing genes; early onset breast cancer particularly with a family history of either breast or ovarian cancer, family cluster of three or more first and second-degree relatives with either breast or ovarian cancer; breast cancer diagnosed before age 45 with family history of childhood cancers; breast cancer under 45, associated with major malformations or another primary cancer; or precancerous lesions (ADH, DCIS or LCIS) at any age. Our Core staff will consent eligible individuals and families to respond to a standard questionnaire and donate blood samples and their fresh or fixed tumor tissues for research. All tissue samples will be delivered to the Tissue and Pathology Core under Drs. Harris and Schnitt for processing, storage and future distribution. After replacing personal identifiers with codes, data on biospecimen availability and questionnaire information will be entered into a searchable database that can be accessed by approved SPORE investigators. Blood

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sample and tumor specimens will also be made available with approval. The High Risk Core will also facilitate re-contact of patients and families for additional collection of specimens and data, including mortality and the occurrences of new cancers on followup. Based on the proposed personnel, we will enroll at least 1,000 breast cancer cases over the next 5 years and at least 4,000 of their affected and at-risk relatives (total 5,000 family members). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--TRANSGENIC/GENE KNOCKOUT SHARED RESOURCE Principal Investigator & Institution: Grosveld, Gerard C.; Chair; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 24-JUN-2002; Project End 28-FEB-2007 Summary: (provided by applicant): The Transgenic/Gene Knockout Facility was established in 1993 and transitioned into the Cancer Center in 1995. Under the directorship of Gerard Grosveld, Ph.D., the facility provides genetically modified mice to the members of St. Jude Cancer Center. These animals are created by transgenic and gene targeting technology. The investigators provide the core facility with targeted ES cells or injectionready DNA constructs and in turn, the core provides the investigators with transgenic or chimeric offspring. During the past 4 years the core facility produced 84 different knockout and 83 different transgenic lines, respectively. To keep up with the increasing demand for genetically modified mice, due to our expanding research effort, our facility will move to the Integrated Research Center in the fall of 2001. This will increase the available space from the present 1,235 net sq. ft. (900 sq. ft. holding space; 335 sq. ft. laboratory space) to 5,100 net sq. ft. (4,500 sq. ft. holding space; 600 sq. ft. laboratory space). We will increase the number of injection stations from the present 3, manned by three Transgenic Research Specialists, to 5 in the first year of occupancy, adding a sixth in the second year. The increase in injection stations will lead to the hiring and training of three additional Transgenic Research Technologists. The projected total budget for this Shared Resource in year 25 of this grant is approximately $800,000, of which 26% ($207,969) is requested from the CCSG; the remainder of the budget ( 74%; $892,031) will be provided by SJCRH institutional funds, by chargeback to individual investigators and by funds from the Childhood Cancer Gene program project. More than 90% of the usage of this Shared Resource is by Cancer Center members for peerreviewed funded projects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYSTATHIONINE B SYNTHASE AND ARA C THERAPY FOR LEUKEMIA Principal Investigator & Institution: Taub, Jeffrey W.; Pediatrics; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: The goal of this project is to better understand the biology of acute myeloid leukemia (AML) in Down syndrome (DS) children related to the association of the chromosome 21-localized gene, cystathionine-beta- synthase (CBS) and response to cytosine arabinoside (ara-C)-based therapy. Childhood AML has the worst prognosis of all major childhood cancers with five year relative survival rates of approximately 37%. In contrast, DS children with AML represent an unique group of leukemia patients in view of having significantly higher event-free survival (EFS) rates (70-100% with relapse rates < 15%) compared to non-DS children when treated with ara-C-based protocols.

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Thus, identifying the biological basis for the extremely high cure rates of DS AML patients can have very important implications and potentially can lead to improvements in AML therapy for all patients. Our previous results have begun to shed light on the underlying mechanisms responsible for the striking increased EFS in DS AML patients. Our results demonstrating i) significantly increased CBS transcript levels in DS myeloblasts and a correlation with in vitro ara-C sensitivity and ara-CTP generation, ii) dramatic increased in ara-C metabolism to ara-CTP in vitro in leukemia cell lines transfected with the CBS cDNA, associated with increased in vitro and in vivo ara-C sensitivity, and iii) significant differences in frequency of the 844ins68 CBS gene polymorphism in DS myeloblasts, provide compelling evidence of an integral relationship between CBS gene expression and ara-C metabolism. This mechanisms is likely a major factor that accounts for the increased chemotherapy sensitivity and high cure rates of pediatric DS AML patients. This study will continue to examine over novel hypothesis and laboratory observations which bridge basic research (e.g., understanding the transcriptional regulation of CBS, determining the relation of CBS mutations/polymorphisms and ara-C metabolism) and apply this work to translational studies using clinical leukemia samples. These findings may ultimately be applied clinically to improve the treatment and cure of AML. The specific aims of the study are: 1) To characterize the transcriptional regulation of the CBS gene in leukemia cell lines and clinical leukemia samples; 2) To develop CBS-transfected AML cell models and to determine the mechanistic basis for the effects of CBS on ara-C metabolism and sensitivity; 3) To determine the relationships between CBS gene expression and ara-C sensitivities in patient myeloblasts with wild-type CBS and with the T833C, G919A, 844ins68 CBS gene variants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG METABOLISM, DNA REPAIR & SECOND CANCERS Principal Investigator & Institution: Friedman, Debra L.; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 29-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Candidate: Dr. Friedman is a pediatric oncologist with research training and interest in cancer epidemiology, prevention and long-term health-related outcomes of therapy. Environment: The Fred Hutchinson Cancer Research Center (FHCRC), University of Washington (UW) and Children's Hospital and Regional Medical Center (CHRMC) comprise the Seattle Cancer Care Alliance (SCCA), which facilitates sharing of research resources. This research will be performed in the FHCRC Cancer Prevention Research Program under the mentorship of Dr. John Potter. Research Plan: The hypothesis to be tested is that genetic differences in the metabolism of chemotherapeutic agents, in the provision of nucleotides for DNA synthesis, and in DNA repair modify risk of SMN development. To address this hypothesis, we will examine allelic variants of genes involved in these processes in two well-defined cohorts at high risk of SMN. These are patients treated for childhood cancer with conventional therapy, and patients treated with hematopoietic stem cell transplant. The genes chosen for study include methylenetetrahydrofolate reductase (MTHFR), Glutathione-Stransferase (GST), GSTT1, GSTM1, GSTM3, GSTP1, Cytochrome P-450 (CYP) CYP2C9, CYP2C19, CYP3A4, thiopurine methyltransferase, methylguanine DNA methyltransferase, ERCC1, XPD, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC5. Nested case-control methodology will be used, in each of the cohorts, to examine the association of specific allelic variants with SMN development. Career Plan and Development: Dr. Friedman's career goal is to be a translational researcher with a focus on cancer control,

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prevention, and long-term outcomes of therapy. This award will provide continued mentored training in molecular biology, cancer genetics and epidemiology and biostatistics. Educational opportunities will be provided to Dr. Friedman in the Division of Public Health Sciences at Fred Hutchinson Cancer Research center and in the School of Public Health at the University of Washington. The findings of this research can be applied to the development of preventive strategies of second malignant neoplasms and other adverse long-term health-related outcomes for cancer survivors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENVIRONMENTAL EXPOSURES, HOST FACTORS, AND HUMAN DISEASE Principal Investigator & Institution: Peters, John M.; Professor and Director; Preventive Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-APR-1996; Project End 03-MAR-2006 Summary: This application is to continue our Southern California Environmental Health Services Center whose main purposes are 1) to study the effects of environmental exposures on humans; 2) to determine host factors (genetic and other) influencing response to these exposures; and 3) to inform the public. To accomplish these goals we bring together an interdisciplinary team of investigators from 2 major Souther California universities: USC and UCLA. The research of our Center features interdisciplinary cornerstones: detained exposure assessment, including toxicokinetics and biomarkers; cutting edge study design, including the most powerful statistical and epidemiologic approaches; and the basic sciences, including physiology, molecular biology, genetics, chemistry and engineering. The foci of the Center cover a wide range of problems and address environmental exposures of public health importance including indoor and outdoor air pollution, pesticides, alflatoxins, radiation, passive smoking, bioaerosols and nitrites. The 5 Research Cores consist of: Respiratory Effects; Exposure Assessment; Childhood Cancer, Adult Cancer Study Design and Statistical Methodology. The 3 Facility Cores consist of: the Molecular Biology, Sample Processing and Storage Core; the Analytic Chemistry, Exposure Assessment and Aerosol Sciences Core; and the Biostatistics Core. The Center also features a separate core for Community Outreach and Education (COEP). The Center is structured to promote interdisciplinary research and linkage between the research and the COEP. Processes creating these interactions include the seminar series, pilot projects, research focus groups, workshops and retreats. The first 4 years of support for this Center have resulted in recruitment of new investigators, more investigators working on environmental health problems, doubling of funding support, more interaction between researchers from different disciplines and a greater production of research findings relevant to answering critical public health questions. The Center also developed research initiatives for the next 5 years that focus the interdisciplinary team of investigators on important environmental health problems involving genetic-environmental interactions as asthma and cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ESTROGEN IN THE ESTABLISHMENT OF PEAK BONE MASS Principal Investigator & Institution: Mulder, Jean E.; Medicine; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 15-SEP-1999; Project End 30-JUN-2004

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Summary: Advances in the treatment of childhood cancers have resulted in markedly improved survival rates for many patients. These advancements in therapy, however, have led to new problems, namely, long-term consequences of effective tretments such as the premature loss of gonadal function. Premature ovarian failure (POF) places women at great risk for osteoporosis. The issues raised in this research project, however, differ from usual considerations of age-related menopausal ovarian failure and the accelerated bone loss that ensues. This more typical clinical event follows well after the establishment of peak bone mass. The young women to be investigated in this research project have become estrogen deficient before achieving peak bone mass in this setting. The skeletal profile of young women cancer survivors with ovarian failure will be characterized first. Other potential contributing factors, such as androgen deficiency, growth hormone deficiency, chemotherapeutic agents, nutritional, and other metabolic parameters will be evaluated. The dosage of estrogen required to establish peak bone mass optimally will then be determined. In this prospective, longitudinal study, young cancer survivors with POF will be randomized to one of two estrogen replacement regimens (high dose versus conventional dose). Patients will be monitored every three months for 2 years. Evaluations will include peripheral and central measurements of bone density, indices of bone turnover, and endocrine studies. We anticipate that these studies will yield new information regarding the sufficiency of estrogen replacement therapy in establishing peak bone density in young amenorrheic women. My goal is to become an independent investigator in the field of metabolic bone disease. This award will enable me to obtain new skills in clinical research methods, as well as a greater understanding of the relationship between estrogen and bone modeling in young women. The proposal is particularly fitting for a research career award because it sets the groundwork for future studies, which are essential to my development as an independent investigator. My environment is ideally suited for achieving my goals. My sponsor, Dr. Bilezikian, is an internationally recognized investigator in the field of metabolic bone disease and is committed to providing me with the support I need to pursue my research plans as I make my transition to independent investigator. Through my collaboration with Dr. Sklar, I have access to a large number of young female cancer survivors with ovarian failure. Our Metabolic Bone Unit, with its distinguished tradition in metabolic bone research and education, is an excellent environment in which to develop my career as a clinical investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVOLUTION OF AXIAL SPECIFICATION IN CAENORHABDITIS Principal Investigator & Institution: Baird, Scott E.; Associate Professor; Biological Sciences; Wright State University Colonel Glenn Hwy Dayton, Oh 45435 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2005 Summary: (provided by applicant): Axial specification in bilateral organisms is regulated by the expression of homeotic cluster/homeobox-containing (HOM-C/Hox) genes. Changes in HOM-C/Hox expression patterns have been correlated with changes in vertebrate and invertebrate body plans. In humans and other mammals, altered cervical vertebrae specification due to defects in HOM-C/Hox gene expression patterns is associated with thoracic outlet syndrome and early childhood cancer. Despite the overwhelming evidence for the role of HOM-C/Hox genes in axial specification, little is known about the evolutionary mechanisms that lead to altered HOM-C/Hox gene expression patterns and hence to altered body plans. The research proposed in this application will address the evolution of axial specification in the nematode genus Caenorhabditis. In Caenorhabditis, the pattern of sensory rays in the male tail and the

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size of the vulval equivalence group are determined by positional information imparted from HOM-C/Hox genes. Both of these characters have changed during the evolution of C. briggsae. The overall goal of the research proposed in this application is to determine the genetic basis of these changes. Specific aims are: 1. to determine the number of genes involved in the evolution of these characters; 2. to determine if changes in ray pattern and in the vulval equivalence group have a common genetic basis; and 3. to map and identify those genes responsible for ray pattern and vulva equivalence group evolution. These aims will be achieved through genetic analyses of C. briggsae variant strains that exhibit ancestral phenotypes for ray pattern and for specification of cell fates in the vulval equivalence group. Gene number will be determined from the frequency with which parental strains are recovered following crosses between C. briggsae variants that express ancestral and derived characters. Cosegregation of ray pattern and vulval equivalence group phenotypes will be evidence of a common genetic basis. Genes will be mapped and identified using multifactor data from such crosses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXPOSURE INSIGHTS USING GIS IN A CASE-CONTROL STUDY Principal Investigator & Institution: Reynolds, Peggy; Cheif; Impact Assessment, Inc. 2166 Avenida De La Playa, Ste F La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2003 Summary: (provided by applicant): The proposed geographic information system-based study of the causes of childhood leukemia is not only designed to advance the state-ofthe-art in epidemiologic methods, but also to lead to greater understanding of the etiologic role of environmental pollutants. The study employs an innovative application of GIS analytic capability to address some of the fundamental shortcomings of traditional epidemiology. It will build on one of the first large-scale GIS studies of patterns of childhood cancer, and one of the most extensive case-control studies of childhood leukemia undertaken in the US. As such, it represents an important direction in the evolution of GIS as an analysis tool. A key objective is to solve the problem of characterizing the spectrum of exposure opportunity to individuals, especially for the range of chemical agents potentially encountered in residential settings from environmental sources. The proposed study is organized around the hypothesis that perinatal or early life exposures to environmental chemicals are associated with increased risk of developing childhood leukemia. Primary exposure sources of concern for this project include agricultural pesticides, motor vehicle emissions, and other sources of air toxicants. The project will create individualized geographically-based estimates of exposure constructed from residential and school history data collected in the first five years of an ongoing UC Berkeley/California Department of Health Services case-control study, calibrated by measured air monitoring data and validated by means of laboratory analyses of household dust and air samples. These exposure estimates will be applied to the full case-control study (an estimated total of 660 cases and 1052 controls accessioned by year-2 of this project) to assess risk relationships, with adjustment for important covariables. The study offers sufficient power to detect even modest changes in environmental risk factors associated with the chemical agents of concern. The proposed project presents an unusual opportunity to extend the capabilities of GIS tools to assist epidemiologists in attributing population exposures, to validate generated exposure attributes, and to integrate these estimates with individual measures for a more comprehensive assessment of the role of environmental risk factors in the etiology of these little understood diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GIS-BASED EXPOSURE FOR CHILDHOOD CANCER STUDIES Principal Investigator & Institution: Sussman, Nancy B.; Environ & Occupational Health; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): The overall objectives of the proposed research are (1) to refine models of potential exposures for use in environmental epidemiology that are derived from Geographical Information Systems (GIS) and (2) to assess the feasibility of application of the novel exposure indices to a case-control study of childhood cancers in the Southwestern Pennsylvania region. The proposed research will be accomplished under the following specific aims: (1) a GIS-based, index of potential exposure from hazardous sources will be refined for use in new and ongoing environmental epidemiology studies. The novel approach uses directionally-dependent wind rose frequencies and wind velocity in various combinations with toxic emission quantities, emission toxicities and frequencies to calculate an index of potential exposure from hazardous sources. (2) The potential exposure indices will be calculated for administrative regions (census tracts and blocks) in Southwestern Pennsylvania and compared with the indices calculated for iso-density population centers and randomly distributed regions. (3) Stand -alone algorithms will be created for use with GIS databases centered on other regions of interest identified using the GIS-based Atlas of Cancer. (4) A concurrent feasibility study for childhood cancer in a six-county region of Southwestern Pennsylvania will be performed. This portion of the study will determine the accessibility of relevant information for hospital-based cases and controls in the sixcounty region and develop the necessary mechanisms for mounting a full-scale casecontrol study using the novel potential exposure indices. The GIS-derived potential exposure indices derived in this research can be geographically referenced for use in GIS-based health studies in general and also directly linked with the coordinates of individual cases and controls in specific studies of disease. When the exposure estimates are coupled with geographically-reference health data, such as published in the Atlas of Cancer, this will crate an effective tool for (1) screening studies linking environmental exposures with disease and (2) providing a relative exposure measure for individuals in case-control studies of disease. Overall, the simplified potential exposure indices will improve both environmental epidemiological studies and the monitoring for purposes of disease control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEALTH BEHAVIORS IN ADOLESCENT CANCER SURVIVORS Principal Investigator & Institution: Ford, Jennifer S.; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2003; Project Start 27-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Healthy People 2010 (USDHHS, 2000), highlights critical health objectives for adolescents, including the importance of reducing tobacco use, reducing the proportion who are overweight or obese, increasing the proportion who engage in regular physical activity, and increasing the proportion who engage in sun protection. Given adolescent cancer survivors' increased risk for physical late-effects and their increased vulnerability to additional chronic conditions, these health behaviors are even more critical. Advances in pediatric cancer care have resulted in a growing population of childhood cancer survivors. However, little research to date has investigated the mechanisms that promote or hinder a healthy lifestyle among adolescent cancer survivors. Guided by the Theory of Planned Behavior, and

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empirically supported cancer-related variables, this study will identify the patterns and covariates of health-protective and health-damaging behavioral intentions and behaviors among adolescent cancer survivors. Specifically, we will investigate survivors' tobacco use, regular exercise, nutritional habits, and sun protection intentions. We will assess 200 adolescents (14-19 years of age), who were diagnosed with cancer during late childhood to early adolescence (8-14 years of age), have no evidence of disease (NED) and are at least 1 year post-treatment. No studies to date have examined theoreticallydriven covariates of adolescent survivors' health behavior intentions that may influence their future risk of disease. There is evidence to suggest that life-threatening illness may increase health behavior change among adults, however, the study of health risk behaviors among pediatric cancer survivors is an area that has received little attention. The proposed study will fill a research gap in a high priority area and the findings are likely to have both clinical and theoretical implications. The study findings will address a national priority and advance behavioral science by identifying theory-driven covariates that impact the health-protective and health-damaging behaviors of adolescent cancer survivors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEALTH PROMOTION IN CHILDHOOD CANCER SURVIVORS Principal Investigator & Institution: Cox, Cheryl L.; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 31-AUG-2005 Summary: (provided by applicant): The health and long-term survival of the growing population of childhood cancer survivors is threatened by late sequelae of therapy: cardiovascular complications, obesity, osteoporosis, and new malignancies. This application proposes a re-examination of a methodologically sophisticated clinical trial data set that has the potential to generate new hypotheses about the antecedents of health-risk behavior and health-promotion behavior in adolescent survivors of childhood cancer. The analysis will use a tested, broad-based, middle range theory of health behavior to identify potential new determinants of these behaviors in previously unexplored and/or reconfigured variables from the parent clinical trial. Unlike the parent trial, the proposed study will examine the health risk behaviors and health protective behaviors as 10 separate behaviors and as two multidimensional constructs, rather than as a single, unidimensional construct. This economical investigative approach maximizes the probability of identifying new targets for interventions aimed at reducing survivors' risk of late sequelae. Specifically, this study will: (1) define the relationships between selected demographic, social, psychological, and resource variables and the health risk behaviors and health promotion behaviors of adolescent survivors of childhood cancer; (2) specify two separate structural equation models (health risk behavior and health promotion behavior) in adolescent survivors of childhood cancer by using the Interaction Model of Client Health behavior (IMCHB); and (3) compare the explanatory power of the cognitive processing theory (Health Belief Model, which directed the parent clinical trial) with that of the IMCHB, which will direct the proposed study. This study will afford an established investigator (PI) an opportunity to enter a newly targeted high-priority area (health promotion and quality of life in people with chronic illness) with a self-contained research project that uses novel methods of analysis (reconceptualization of measures, logistic and multiple regression, item response theory, and structural equation model development). This study has the potential to make a major conceptual contribution to childhood cancer

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research and to provide the conceptual basis for prospective clinical trials of health promotion interventions for survivors of childhood cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATITIS C IN CHILDHOOD CANCER SURVIVORS Principal Investigator & Institution: Hudson, Melissa M.; Associate Professor of Pediatrics; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 15-SEP-1999; Project End 30-JUN-2004 Summary: The broad, long-term objective of this proposal is to conduct a prospective, longitudinal natural history study of hepatitis C (HCV) infection in a well-defined cohort of childhood cancer survivors. The specific aims of this proposal are (1) to assemble a cohort of survivors of childhood cancer who were infected with HCV by transfusion during childhood, and (2) to develop predictive models for the subsequent development of cirrhosis, chronic active hepatitis, fibrosis, liver decompensation, hepatoma, hepatocellular carcinoma, and other HCV-related hepatic sequelae. This cohort is unique in comparison with other groups with chronic HCV infection in that these patients acquired the infection when they were young and were receiving immunosuppressive or hepatotoxic therapy. Thus, studies of this cohort should advance the understanding of clinical risk factors that predispose patients to clinically significant liver disease. So far, 1,441 of 3,767 (38.3 percent) patients who received transfusions at St. Jude Children's Research Hospital between 1962 and July 1992 have been screened for HCV by enzyme immunoblot assay. Of these, 110 (7.6 percent) patients have detectable HCV antibodies; 59 of these patients have been enrolled, and the remaining 51 are potentially eligible for participation in a longitudinal study of the natural history of HCV. Based on the prevalence of HCV infection in our currently screened cohort, we estimate that 293 transfused, but untested patients will be HCV seropositive. After adjusting for the anticipated rates of survival and study participation, we estimate that we will enroll a total of 268 HCV seropositive cancer survivors in a prospective epidemiologic study. As the ultimate aims of this proposal are to define the risk of progression to clinically significant liver disease in this cohort and to elucidate the impact of age, immunosuppression, and hepatotoxic cancer therapy on the outcome of chronic HCV infection, the histologic findings of these study patients will be correlated with clinical, laboratory, and diagnostic imaging variables. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMPROVED DIAGNOSIS IN ALL Principal Investigator & Institution: Stephan, Dietrich A.; Assistant Professor; Children's Research Institute Washington, D.C., Dc 20010 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2003 Summary: (provided by applicant): Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and the second leading cause of deaths from childhood cancer in the United States: 1. Approximately 3000 cases a year, representing 75 percent of all pediatric leukemias, are diagnosed in children in the United States, and the incidence continues to increase steadily 2. Despite dramatic progress in treating this disease, the absolute number of patients who relapse (who are initially defined as 'standard' risk) is greater than the number of children diagnosed with AML, neuroblastoma, or Wilms tumor 2. These patients appear to have a different class of disease, which cannot be differentiated using available clinical/pathological approaches (such as white blood celI count) at the time of diagnosis. The goal of this proposal is to

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define a diagnostic system, derived from gene expression profiles, which would differentiate between tumors initially classified as 'standard risk' which are amenable to therapy (achieve long-term disease free survival (LTDFS)) and those which are not (relapse within 2 years). Salvage therapy for this poor outcome group is currently ineffectual (LTDFS in less than 10 percent of cases) but there is evidence that intensification of treatment at the time of diagnosis for these cases would be highly effective. Expression profiling and analysis, blinded to clinical data, has previously been shown to easily discriminate between different types of leukemia tumors (ALL vs. AML) 3. We hypothesize that similar techniques will enable us to identify tumor subtypes with increased propensity to rapidly relapse within the 'standard' risk group. Our team consists of the Chairman of the Children's Oncology Group (Dr. Reaman), CNMC (one of 11 sites in the country to receive a $14,000,000 NHLBI PGA grant for profiling clinical samples)(Dr. Stephan), and several of the most experienced groups in the field of expression array statistics and bioinformatics in the community (Drs. Butte, Golub, Trent). In the R21 portion of this proposal we will first develop, as a proof-of-principle, a cDNA array-based system that can, in a single step, provide prognostic fusion transcript information, which is currently obtained by cytogenetics. We have an in-house tissue bank of greater than 3000 leukemia bone marrow aspirates (extremely high tissue homogeneity) which have been flash frozen which will be used as the resource for the entire proposal. Secondly, we will expression profile 50 tumors of the 'standard' risk - no relapse and 50 closely matched tumors of 'standard' risk which relapse rapidly after therapy to define a set of predictor gene candidates using both supervised and unsupervised techniques. In the R33 phase, this set of predictor gene candidates will be validated by profiling an additional 100 ALL samples blinded to relapse status. These samples will simultaneously be genotyped for the known prognostic indicators using the cDNA array to validate our ability to detect translocation status (specificity and sensitivity determined by comparison with the COG database). Finally, both the oligos which are able to detect translocation status from tumor RNA, as well as the validated predictor gene set will be incorporated onto a custom Affymetrix array for use as a rapid, one-step, inexpensive molecular diagnostic tool. The future goal of this proposal is to prospectively diagnose relapse so that therapy can be intensified at the time of presentation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVING INFORMED CONSENT IN CHILDHOOD CANCER TRIALS Principal Investigator & Institution: Kodish, Eric D.; Director; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2003; Project Start 21-JAN-1999; Project End 28-FEB-2007 Summary: (provided by applicant): Informed consent requires further study, and pediatric oncology is the ideal context for the conduct of such research. The primary goal of this study is to improve the quality of informed consent for childhood cancer trials. The project will take place as a limited-institution study within the Children's Oncology Group, the single pediatric member of the NCI's Clinical Trials Cooperative Group Program. The long-term objective will be to capitalize on our understanding of consent to yield generalizable findings that can be implemented to improve consent in clinical trials across various diseases and all age groups. The research plan is based on the premise that specific outcome measures and rigorous scientific methodology are required to accurately study the complex interaction that is informed consent. The work accomplished to date has allowed us to refine this methodology, select key outcome

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measures, and develop rational intervention plans; it is the foundation upon which this competitive renewal proposal is based. The Specific Aims of the project are: 1) To utilize our scientific understanding of the informed consent process in childhood leukemia trials to further develop, test and implement two databased interventions to improve informed consent: a) a physician-directed intervention based on teaching improved management of the informed consent conference, and b) a parent-directed intervention based on the model of anticipatory guidance for informed consent; 2) To conduct a clinical trial to test the effect of each intervention on three specific outcomes: a) parental comprehension of choice and alternative to clinical trial participation, b) parental understanding of randomization, and c) parental participation during the informed consent process as measured by the number and quality of questions asked by parents, and; 3) To determine if either intervention is superior to a control group, and how the two interventions compare to one another. This clinical trial of two rational, data-driven interventions will allow us to act on what we have learned, to determine whether we can improve informed consent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRATHECAL CAMPTOTHECIN ANALOGS FOR NEOPLASTIC MENINGITIS Principal Investigator & Institution: Friedman, Henry S.; Professor; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002 Summary: Primary brain tumors, including malignant gliomas and ependymomas, are second only to leukemia as a cause of childhood cancer. Advances in chemotherapy and combined modality regimens, though dramatically successful in the treatment of other pediatric malignancies, have not been translated into effective therapy for most pediatric brain tumors. Although the role of chemotherapy in the treatment of malignant gliomas and ependymomas remains poorly defined, recent clinical and laboratory studies support the activity of the classical bifunctional alkylating agents against these tumors. Nevertheless, substantial increases in patient survival as a result of adjuvant use of these agents remain to be demonstrated, and an understanding of the mechanisms responsible for drug failure is critical for the design of optimal chemotherapeutic intervention. Successful establishment of cell line and xenograft models of childhood high grade glioma and ependymoma now provide the biological tools to facilitate an understanding of alkylator resistance in these tumors. Resistance to alkylating agents, including cyclophosphamide and melphalan, is multifactorial, with a diverse spectrum of mechanisms observed in murine and human neoplasia. Mechanisms of resistance to cyclophosphamide include increased aldehyde dehydrogenase activity., increased glutathione-S- transferase activity, elevated levels of glutathione, and a presently undefined mechanism in medulloblastoma. Similarly, mechanisms of resistance to malphalan include decreased cellular transport, increased intracellular glutathione levels protective of critical cellular targets, cellular detoxification and enhanced capacity to repair damaged DNA. These studies may not be relevant to the mechanisms of resistance operational in childhood malignant glioma and ependymoma. The hypothesis of this proposal is: definition and modulation/bypass of alkylator resistance in childhood high grade glioma and ependymoma will allow selection of alkylator regimens active in the treatment of these tumors and increase survival of children with these neoplasms. The specific aims of this proposal are: 1) To continue to establish childhood high grade glioma and ependymoma cell lines and transplantable xenografts in athymic mice with de novo clinical, acquired clinical and laboratory-generated

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cyclophosphamide and melphalan resistance. 2) To define the mechanisms of resistance to cyclophosphamide and melphalan of childhood high grade glioma and ependymoma cell lines and xenografts with de novo, acquired clinical, and laboratory-generated resistance. 3) To define modulation effective in bypassing/reversing cyclophosphamide and melphalan resistance in childhood high grade glioma and ependymoma cell lines and xenografts and 4) To define the role of L- amino acid oxidase-mediated depletion of plasma large neutral amino acids to enhance delivery and activity of melphalan in the treatment of subcutaneous and intracranial childhood high grade glioma and ependymoma xenografts in athymic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ISOLATION OF THE NEUROBLASTOMA PREDISPOSITION GENE Principal Investigator & Institution: Maris, John M.; Assistant Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2003; Project Start 14-AUG-1998; Project End 30-APR-2007 Summary: (provided by applicant): Neuroblastoma remains an important pediatric disease that results in 15% of overall childhood cancer mortality. Several chromosomal aberrations that contribute to the malignant phenotypes are known, but the genetic events essential to initiate neuroblastoma tumorigenesis have not been discovered. We have shown that hereditary predisposition to develop neuroblastoma is genetically linked to the distal short arm of chromosome 16. In addition, we have demonstrated that hemizygous deletions of the same locus are a common somatically acquired event in sporadic neuroblastomas. Thus, we hypothesize that hereditary neuroblastoma is due to mutations in a tumor suppressor gene (HNB1) located at 16p12-13. We also predict that functional inactivation of this gene is responsible for the initiation of many nonfamilial human neuroblastomas, and perhaps other cancers. Accordingly, we propose to first localize HNB1 to within a one megabase region at 16p12-13 and identify candidates for mutation analysis. This will be accomplished using a multifaceted approach including high-density SNP genotyping, array-based comparative genomic hybridization, and gene expression profiling using oligonucleotide arrays. Second, we will identify HNB1 and characterize the spectrum of germline and somatically acquired mutations in familial and sporadic neuroblastomas. We will also survey a large panel of sporadic neuroblastoma primary tumor samples, as well as other human cancers with particular emphasis on neural crest derived tumors, for HNB1 mutations and loss of functional protein expression. Third, we will characterize HNB1 as a tumor suppressor and reintroduce wild-type HNB1 into HNB1-null neuroblastoma cell lines to determine effect on proliferation in vitro and tumorigenicity in vivo. Fourth, we will describe the phenotype of mice harboring heterozygous inactivation of one allele of the murine HNB1 homologue, with particular attention to neural crest tumor formation. Successful completion of these experiments will determine if inactivation of HNB1 is the seminal initiating event for human neuroblastomas, or if genetic heterogeneity exists. Successful completion of this project should dramatically improve our understanding of the fundamental genetic basis of neuroblastoma, and perhaps other human cancers. We also expect that this project will result in a valuable mouse model of this enigmatic pediatric disease. Ultimately, these experiments should lead to the identification of a common pathway to neuroblastoma tumorigenesis that will be an outstanding target for rationally designed therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: KNOWLEDGE EMPOWERMENT FOR YOUTH WITH SOLID TUMORS Principal Investigator & Institution: Jones, Judith K.; President and Ceo; Degge Group, Ltd. 1616 N Fort Meyer Dr, Ste 1430 Arlington, Va 22209 Timing: Fiscal Year 2003; Project Start 01-AUG-2000; Project End 31-JAN-2005 Summary: (provided by investigator): Childhood cancer is the number one disease killer of children and adolescents in North America. For adolescents, a diagnosis of cancer comes at a particularly vulnerable developmental stage in their lives. Phase I focus group interviews indicated that these adolescents are adamant about wanting to know and learn about all aspects of their disease and how it will impact their lives. Unfortunately, few educational tools exist for these young cancer patients, particularly those with solid tumors, and none are in an interactive format. This application seeks funding to complete and evaluate a multimedia CD-ROM for 12-18 year-olds with solid tumors to teach them about their disease, treatment, and coping strategies. A combination of text, videos, animations/graphics, voice-overs, music, and games will creatively relay important information in an interactive and non-threatening manner. This innovative product is the first of its kind, focusing on solid tumors. It will be evaluated in a randomized pre-post design against a "usual care" print handbook to determine its effect on coping skills, feelings of control over health, knowledge about solid tumors and their treatment, satisfaction, and acceptability. Once developed, the CD-ROM will be marketed so that it will be available to all adolescents with solid tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LAB RESEARCH TRAINING IN HEMATOLOGY

PEDIATRIC

ONCOLOGY-

Principal Investigator & Institution: Civin, Curt I.; Professor of Cancer Research; Oncology Center; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 30-SEP-1993; Project End 31-MAY-2008 Summary: (provided by applicant): To continue to make progress in Pediatric OncologyHematology (POH), we need to perpetuate the pool of talented and trained POH physician-scientists and Ph.D. scientists who will make POH-relevant discoveries and provide investigative leadership. Nevertheless, in the field of POH, there continues to be a shortage of young investigators with extensive laboratory research expertise. In the current funding period (1998-2003), this grant has already supported superb laboratory research training for an outstanding group of 17 physician-scientists and 12 Ph.D. scientists who have demonstrated a high degree of productivity and commitment to careers in cancer research. Selection of the 2002-2003 trainees is in progress. In addition, these trainees have strengthened the laboratory research base in the POH in the Johns Hopkins Medical Institutions (JHMI). This application now seeks support for 10 interdisciplinary postdoctoral research fellowship positions per year to fund the research training that is the major ingredient of the recently combined Johns Hopkins University/National Cancer Institute (NCI) Subspecialty Fellowship Training Program in POH (JHU/NCISFTP). Two groups of postdoctoral fellows will be supported by the grant proposed herein. The major group of trainees will be composed of physicianscientists, since the laboratory research training of academic POH physician-scientists is the primary objective of this training program. These highly selected physician-scientists will have completed the clinical year of their fellowships in the JHU/NCISFTP. The second (smaller) group of trainees will be composed of Ph.D. postdoctoral scientists

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working at JHMI on projects highly relevant to the biology of childhood cancer and blood diseases. These strongly qualified postdoctoral trainees will be provided intensive 3-year research experiences that will prepare them for careers in cancer research. Trainees will work on projects relevant to the biology of childhood cancer and blood diseases, in the laboratories of leading scientists in the field. The trainees and their mentors will participate in an interactive, dynamic research environment bridging the JHMI and the National Institutes of Health (NIH), with an emphasis on translational research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LANGUAGE AND INFORMED CONSENT IN CHILDHOOD CANCER Principal Investigator & Institution: Simon, Christian M.; Cancer Center; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Communication is the fabric of medical care. Nevertheless, it has recently been estimated that more than 31 million people in the United States are unable to communicate in the same language as their health care providers. Pressure to recruit interpreters in order to facilitate communication between clinicians and patients has followed, a factor that introduces into health care communication such issues as interpreter inaccuracy, role conflict, and other complexities of language interpretation. This two-year study investigates language interpretation in the context of informed consent for cancer clinical trials, where effective communication is vital to the optimal disclosure and understanding of information, and the decision-making competency of patients and their families. It focuses on informed consent discussions involving parents with children who were newly diagnosed with leukemia. The study's objectives are to: 1. Examine how interpreters function during informed consent discussions for cancer clinical trials, and how their behaviors shape the consent process; 2. Assess the impact of interpreter behaviors on parental understanding of informed consent; and, 3. Tie the above findings to first-hand data on the concerns and needs of key stakeholders in interpreted informed consent. The study plans to meet the first two objectives through a structured, sentenceby-sentence analysis of the English and Spanish portions of a sample of audiotaped informed consent discussions. Structured questionnaires will be used to meet the third objective. These will be administered to a sample of interpreters, parents, and clinicians who have previously participated in multilingual informed consent discussions for cancer clinical trials. Little research exists on the use of interpreter services in informed consent for cancer trials, even though it is clear that informed consent obtained without competent language interpretation is unlikely to be truly informed. The proposed study will identify aspects of language interpretation that may require improvement, or that may serve as a model for enhanced communication and understanding in informed consent discussions for cancer trials, both within and beyond the pediatric setting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LATE TRANSPLANTATION

EFFECTS

IN

SURVIVORS

OF

STEM

CELL

Principal Investigator & Institution: Baker, Kevin S.; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006

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Summary: (Applicant's Description) K. Scott Baker, M.D. is a pediatric oncologist in the Blood and Marrow Transplant Program at the University of Minnesota, and holds an appointment as an Assistant Professor in the Department of Pediatrics. The candidates career goals are: 1) to develop clinical research expertise which has a solid foundation in clinical research methodology, epidemiology, and biostatistics, 2) to focus these activities on patient oriented research in the field of hematopoietic stem cell transplantation (SCT), specifically transplant related complications and late effects, 3) to utilize these newly acquired skills in order to achieve the status as an independent clinical investigator. The proposed career development plan will provide a comprehensive, multidisciplinary, closely mentored, patient oriented research experience. This will be accomplished in conjunction with formal didactic training in Clinical Research obtained by the candidate enrolling in the master's degree program in clinical research in the Division of Epidemiology. Under the mentorship of Dr. Leslie Robison and Dr. Norma Ramsay, the candidate will initiate investigations into the late effects seen in long-term survivors after SCT. The proposed research will establish prospective and retrospective, long-term follow-up studies of SCT survivors at the University of Minnesota for the systematic, protocol driven, evaluation of the incidence, risk factors, and characteristics of cardiopulmonary, renal, endocrine and reproductive late effects, quality of life outcomes, and second malignant neoplasms. Hypothesis driven investigations will also be undertaken in the current population of 1226 longterm survivors. These will include studies of the impact of different transplant conditioning regimens (total body irradiation, total lymphoid irradiation, and chemotherapy only) on subsequent late effects in children, an analysis of the spectrum and severity of treatment related sequelae which develop in the second decade of longterm follow-up, and an analysis of the impact that chronic graft-versus-host disease has on late effects and quality of life in SCT survivors. The candidate will also utilize data frorn the ongoing, multi-institutional, Childhood Cancer Survivor Study (Dr. Robison is Principal Investigator) for a comparative analysis of patients in that cohort receiving standard chemotherapy versus those who have undergone SCT as part of their therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEARNING IMPAIRMENTS AMONG SURVIVORS OF CHILDHOOD CANCER Principal Investigator & Institution: Mulhern, Raymond K.; Director of the Department of Behavioral; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 12-JUL-1999; Project End 30-APR-2004 Summary: (adapted from investigator's abstract): Children surviving some types of cancer, particularly acute lymphoblastic leukemia (ALL) and brain tumors, have an increased incidence of learning impairments compared to their healthy peers in the general population. These impairments, for which there is no known effective treatment, are of sufficient severity to inhibit normal academic achievement, vocational attainment, and quality of life. Previous investigations have suggested a model in which treatmentinduced lesions of the brain, especially in the white matter, are an underlying cause of learning difficulties that are frequently manifested as deficits in the ability to sustain attention. The goal of this research proposal is to test the validity of this model by defining the neuroanatomic substrates of problems with attention and learning and by assessing the behavioral response of these problems to pharmacological intervention. To accomplish this goal, quantitative magnetic resonance imaging (qMRI) of the brain and neuropsychological testing will be conducted on 625 participating children treated for ALL or malignant brain tumors at 3 pediatric cancer centers. It is hypothesized that

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Childhood Cancer

volumes of normal white matter in patients will be: a) significantly reduced compared to healthy peers, b) directly associated with the intensity of their central nervous system treatment, and c) positively correlated with their performance on measures of sustained attention and learning. A second study hypothesis is that methylphenidate will be effective in reducing their problems with attention and learning. This hypothesis will be tested with 200 children selected from the larger screened sample on the basis of objective problems with sustained attention and learning with regard to: (a) immediate (1-1/2 hr) behavioral benefits in our laboratory and (b) short-term (3 week) benefits at home and school in randomized, placebo-controlled, crossover designs, and then (c) long-term (12 month) maintenance benefits at home and school. The results of these studies will have a potentially important impact on childhood cancer by reducing the cognitive morbidities of cancer and cancer treatment and by furthering our knowledge of their biological basis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LONG-TERM COMPLICATIONS OF CHILDREN/ADOLESCENTS & CANCER Principal Investigator & Institution: Green, Daniel M.; Associate Chief; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): We propose to hold a two-day conference on June 28-29, 2002 at Queen's Landing Inn (Niagara-on-the-Lake, Ontario, Canada). The program will be of interest to pediatric hematologists/oncologists, pediatric nurse practitioners, pediatric psychologists, pediatric oncology social workers, medical oncologists, fellows, residents, interns, clinical research associates and other primary care providers. The topic of bone complications following treatment of children and adolescents for cancer will be addressed. The goals of the 7th International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer will be to: 1) Review the biology of the basic multicellular unit; 2) review the role of the kidney in the regulation of calcium metabolism; 3) review the effect of cis-platinum on renal function and calcium metabolism; 4) review the late effects of ifosfamide on the kidney; 5) review the issues involved in the measurement of bone density; 6) review the effects of radiation therapy effects on bone density; 7) review the effects of glucocorticoid hormones on bone density; 8) review the roles of androgen and estrogen in skeletal physiology; 9) review the issues involved in the management of osteoporosis due to ovarian failure; 10) review the role of growth hormone in the regulation of bone density; and 11) review the issues involved in the duration of treatment with growth hormone replacement therapy. The conference will include presentations by nationally and internationally recognized experts in these areas. The conference will facilitate subsequent discussions among the investigators of the Childhood Cancer Survivor Study, most of whom attend this conference, regarding future research on bone complications among participants in the Childhood Cancer Survivor Study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MATERNAL PROBLEM-SOLVING TRAINING IN CHILDHOOD CANCER Principal Investigator & Institution: Sahler, Olle Jane Z.; Pediatrics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-AUG-2007

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Summary: (provided by applicant): Research and experience document that caregivers, especially, mothers of children with cancer encounter extraordinary stresses during the child's illness. These stresses are particularly severe during diagnosis and induction therapy and can interfere significantly with caregivers' ability to make reasoned and timely decisions on their children's behalf. With increasing survivor rates, it has become evident that decisions made in the early stages of cancer management can have profound, long-term effects, adding to the distress caregivers feel trying to make the "right" decisions. To help mothers of newly diagnosed children cope more effectively with these challenges, we conducted two randomized trials as part of our previous work (R25-CA65520) to develop, field test, and evaluate the efficacy of problem-solving skills training (PSST), a cognitive behavioral therapy shown to decrease anxiety and depression --- two symptoms of post-traumatic stress commonly experienced among this group of mothers. We also pilot tested a multimedia, technology-based PSST enhancement, Carmen's Bright IDEAS. Our findings clearly show that PSST significantly increases problem-solving skills (primary effect) and decreases negative affectivity (secondary effect) in mothers from a variety of racial, ethnic, and socioeconomic backgrounds. Particularly powerful and long-lasting effects were noted in Spanishspeaking mothers, an especially underserved population. At this stage, it is essential that we investigate PSST as rigorously as possible by testing its clinical effectiveness against an active control and that we intensify the intervention to extend its duration of action among all users. These goals are the basis for the 4-5 aims of the proposed project. Aim 1" To develop a time-and-attention control condition to better assess the direct and mediational effects of PSST independent of social support (placebo). Aim 2: To develop a personal digital assistant hand-held supplement to standard PSST to provide real-time training, reinforcement, and on-the-spot documentation of PSST usage. Aim 3 A, B: To develop independent measures of the application of problem-solving strategies in everyday life. Aim 4: To measure utilization of and satisfaction with other resources accessed by mothers as independent indicators of the usefulness and cost-effectiveness of PSST. (Aim 5) To incorporate a maintenance phase into the PSST protocol to promote longer term change. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOLIC EFFECTS OF BRAIN RADIATION IN CHILDREN Principal Investigator & Institution: Horska, Alena; Radiology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Brain radiation therapy (RT) has contributed positively to long term disease-free survival from childhood cancer. Despite its therapeutic benefit, RT has been associated with a spectrum of acute, early-delayed, and late-delayed toxicities to the central nervous system. As a consequence, children treated with brain radiation often develop neurological and neurocognitive deficits manifesting as behavioral or learning disabilities. It is unclear whether the neurocognitive deficits are due mainly to damage to the white matter or if cortical areas are also involved. Are there markers that could be measured non-invasively that reflect the degree of brain injury? Could these markers predict early in the course of treatment if brain damage will occur? Could these markers be used to evaluate sensitivity of different brain regions to radiation? Can the temporal course of regional changes due to radiation be mapped in the brain, non-invasively? We intend to answer these questions using non-invasive methods based on magnetic resonance (MR): magnetic resonance spectroscopy, diffusion tensor imaging, and volumetric MRI. Methods using MR have been

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Childhood Cancer

demonstrated to be promising tools for detection of radiation damage. However, their ability to explain neuropsychological deficits in children remains to be evaluated. We plan to perform a longitudinal MR study with a 30 months follow-up to assess changes in brain metabolism, damage to tissue microstructure, and loss of brain tissue. Concurrent neuropsychological assessments will further enhance our understanding of the relationship between neuropsychological status and parameters measured by the proposed MR methods. The broad objectives of our research are to determine a) how brain function and integrity, as measured by MR techniques, can be correlated with total radiation dose delivered to the brain and b) whether changes in measured parameters (metabolite concentrations, water diffusion characteristics, and lobar gray and white volumes) can be used as surrogate markers to predict the neuropsychological outcome from RT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NORTHERN CALIFORNIA COOPERATIVE FAMILY REGISTRY Principal Investigator & Institution: John, Esther M.; Director; Northern California Cancer Center 32960 Alvarado Niles Rd, Ste 600 Union City, Ca 94587 Timing: Fiscal Year 2004; Project Start 30-SEP-1995; Project End 30-NOV-2005 Summary: This project proposes to establish a Family Registry for Breast Cancer (FRBC) as part of an NCl-funded cooperative registry. The FRBC will be population-based (in the Greater San Francisco Bay Area), include many racial/ethnic minorities, and use a cost-efficient design to: 1) collect pedigree information, epidemiologic data, and biologic specimens from breast cancer cases with a family history of breast, ovarian and/or childhood cancers; 2) identify a population at high- risk for breast cancer that could be examined for inherited BRCA1 and p53 mutations, and facilitate cloning and analysis of other susceptibility genes; and 3) identify and obtain biologic specimens from Greater Bay Area families with Li-Fraumeni syndrome and a select subset of Dr. Li's established Li-Fraumeni families to broaden the resource for characterizing genetic susceptibility to breast cancer. Data included in the FRBC will be available to approved investigators to further genetic and translational research for breast cancer. Cases included in the FRBC will be identified by the Northern California Cancer Center's (NCCC) population-based Greater Bay Area Cancer Registry (GBACR), which covers six million residents. During a 3-year ascertainment period, 8047 female cases (< age65) and 78 male cases (< age 80), diagnosed from 1/1/95 through 12/31/97, will be identified. Cases will be asked to complete a brief screening questionnaire about their family history of cancer. Based on the reported cancer patterns of breast, ovarian and childhood cancers in their families, we will classify cases as "exceptional," "ordinary," or "sporadic" probands. "Exceptional" and a sample of "ordinary" probands (n=875), the groups reporting positive family histories, will be sent a family pedigree and a brief risk-factor questionnaire. A racestratified sample of "exceptional" and "ordinary" probands who complete the questionnaires (N= 424) will be asked to provide a blood sample and access to archived tissue. Affected relatives of probands from these high-risk families whose diagnoses have been verified by review of pathology and medical records will be asked to complete a family pedigree, donate blood, and provide access to archived tissue (N=648). Blood collected as part of the FRBC will be processed and stored at NCCC. Archived tissue will be prepared for storage by a Co- Investigator at Stanford University. With the proposed sampling strategy, racial/ethnic minorities will comprise one-half of the high-risk probands and affected family members. Cases will be followed using GBACR methods to obtain survival and recurrence data. Genetic counseling will be provided as needed using trained oncology nurse/genetic counselor pairs and

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existing community resources. An Operations Core will track all aspects of the project, record pedigrees, and make FRBC data accessible electronically; this unit also will conduct quality-control measures at all steps of data collection. Four pilot studies using the FRBC are proposed. FRBC Investigators will serve on NCl's Steering Committee and develop common policies for quality and distribution of data from the FRBC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NUDR--A POTENTIAL TUMOR SUPPRESSOR OF CHILDHOOD CANCERS Principal Investigator & Institution: Huggenvik, Jodi I.; Physiology; Southern Illinois University Carbondale 900 S. Normal Carbondale, Il 629014709 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: NUDR is a mammalian transcription factor with homology to Drosophila DEAF-1, a developmental cofactor of Hox and homeodomain proteins. NUDR will regulate target genes in adults and during fetal development, and may influence the process of genomic imprinting. NUDR behaves as a transcriptional repressor by binding to CpG containing motifs found in target genes that include its own promoter and hnRNP A2/B1, an early biomarker of lung cancer. NUDR has sequence or structural homology to known and putative oncoproteins (c-myc, AML1/MTG8, SP100). NUDR is cell-cycle regulated and may recruit the corepressor N-CoR to produce chromatin remodeling. Mutations in NUDR cDNAs from tumor tissues have been identified that will produce truncated and altered proteins. Human ovarian and breast tumors show variable expression of a NUDR anti-sense gene, Nopps, which is encoded on the opposite strand as NUDR and may affect the expression of NUDR. Mutations in NUDR result in transformed cell phenotypes that produce tumors in athymic nude mice, thus mutated NUDR acts as an oncogene. Normal NUDR and Nopps produce strong tumor suppression of the childhood cancer cell line, RD. NUDR maps to the precise chromosomal region (11 p15.5) harboring multiple tumor suppressors for lung, liver, Wilms', and possibly many other cancers. Loss of imprinting at 11 p15.5 is likely to be an underlying mechanism for a number of pediatric and adult cancers, and based upon its profile, NUDR is the most likely candidate for the WT2 tumor suppressor. To investigate the normal physiological role of NUDR and Nopps, and to determine the role that NUDR functional domains may contribute to childhood cancers, we propose the following: 1) Establish stable cell lines expressing Nopps or NUDR functional domains. 2) Determine if the functional domains promote or inhibit tumor formation. 3) Eliminate the NUDR gene by homologous recombination in mouse and determine the physiological phenotypes. and 4) Determine if the Nopps tumor suppressor is expressed in mice and assess the feasibility for gene targeting. These studies will provide an understanding of how NUDR and Nopps act as tumor suppressors, how mutations in NUDR contribute to the development of childhood malignancies and adult cancers, and how global changes in chromosome function may affect oncogenic processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OPTIMIZING IMMUNOTHERAPY FOR NEUROBLASTOMA AFTER BMT Principal Investigator & Institution: Johnson, Bryon D.; Associate Professor; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 31-MAY-2009

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Childhood Cancer

Summary: (provided by applicant): Neuroblastoma remains a serious childhood malignancy, accounting for 8-10% of all childhood cancers. Prognosis for patients with advanced disease remains poor, with a 2-year disease-free survival of only 10-30%. Recent clinical research has shown that for patients with advanced disease, bone marrow transplantation (BMT) with purged autologous marrow improves event-free survival. However, the majority of patients still relapse within 2 years after transplant. Immune intervention early after transplant might improve survival of these patients. Our preliminary data in an experimental model indicates that T cells capable of responding to a neuroblastoma tumor vaccine are required for induction of anti-tumor immunity after BMT. Immune regulatory T cells (CD4+CD25+) have been found to play a key role in regulating self-non-self recognition by the immune system, and it appears that these cells can be recruited or induced by tumors to prevent immune activation and tumor elimination. The presence of these regulatory cells in the diseased host may in part explain the low degree of success with tumor vaccines. The time period early after BMT, before regulatory T cells have reestablished dominant peripheral tolerance, offers a unique setting to induce effective anti-tumor immunity by combining T cell add-back and tumor vaccination with the inhibition of CD4+25+ T cell-mediated tolerance. Utilizing a mouse model for neuroblastoma, Neuro-2a, we hypothesize that: (1) Using a novel technology, nucleofection, neuroblastoma can be genetically engineered with DNA plasmid vectors to rapidly and efficiently express costimulatory/accessory molecules (CDS0, CD86, ICAM-1, and/or 4-1BBL), and that these engineered cells can serve as a potent tumor vaccine; (2) CD25+ cells suppress anti-neuroblastoma immunity, and depletion of these regulatory T cells augments immunity during tumor vaccination by increasing the contribution of multiple immune effector populations; and (3) Optimal T cell immunity to neuroblastoma can be induced early post-BMT by combining T cell addback with novel tumor vaccines in a setting where cellular mediators of tolerance induction (to tumor) have been removed. The goal of these studies is to provide preclinical data that will lead to the testing of novel immunotherapeutic strategies to prevent neuroblastoma relapse after BMT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEDIATRIC ONCOLOGY CLINICAL RESEARCH TRAINING PROGRAM Principal Investigator & Institution: Poplack, David G.; Director, Texas Children's Cancer Center; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant): The development of pediatric oncologists and pediatric oncology nurses who are highly trained in clinical research is essential for continued progress to be made in the treatment of childhood cancer. This proposal describes a Pediatric Oncology Clinical Research Training Program, developed by Baylor College of Medicine's Texas Children's Cancer Center, that is structured to provide a formal, comprehensive, multidisciplinary clinical research educational program that will train board eligible pediatric oncologists who have completed a three year fellowship and Ph.D.-prepared ontology nurses in the design, implementation and analysis of all phases of clinical research trials. Trainees will spend a portion of their first year participating in a core curriculum in clinical research and spend the remainder of that and subsequent year(s) receiving further clinical research training in their choice of one of five specialized training tracks (clinical pharmacology, neuro-oncology cell and gene therapy, leukemia or solid tumors). This carefully mentored training program will take advantage of BCM's funded (NIH-K30 award) Clinical Scientist Training Program

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to provide a comprehensive, didactic clinical research core curriculum that will serve as a foundation for further training within one of the five specialized areas of research. The research experience within each of these areas will be tailored to meet the individual trainee's long-term research goals. It will provide mentorship by both a laboratory and clinical mentor' while providing in depth exposure to the most important facets of the clinical research process. Trainees will be instructed in clinical trial design, statistical analysis, research ethics and regulatory requirements and guidelines. In addition, under the tutelage of experienced mentors, trainees will design and conduct clinical trials in their respective areas of focus and will learn by mentor modeling the uniquely interactive, collaborative skills necessary to successfully develop effective clinical trials. Because trainees who complete this program will be well-grounded in both in the basic biology of their particular specialty areas and translational research skills, they will be well suited to become future leaders in pediatric oncology clinical research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: PEDIATRIC ONCOLOGY GROUP 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,

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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 •

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

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

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Project Title: PEDIATRIC ONCOLOGY GROUP 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

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is an active affiliate of our institution. With the limited numbers of children admitted with any single oncologic diagnosis to an individual institution, it is clear that cooperative clinical research is required if significant advances are to be made. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: 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

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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: PESTICIDE DISPERSION IN TEXAS WATERSHEDS IN CHILD CANCER Principal Investigator & Institution: Thompson, James A.; None; Texas A&M University System College Station, Tx 778433578 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 29-SEP-2005 Summary: (provided by applicant): Cancer is the second leading cause of fatalities among U.S. children under the age of fifteen. Exposure to pesticides is potentially an important cause of childhood cancer. Contaminated drinking water is suspected as a source of such exposure. However, there is no direct evidence that implicates pesticidecontaminated water as a risk factor. The objective of this application is to estimate the risk of specific childhood cancers with each watershed in Texas and the role that 'local' cropping practices have in contaminating water supplies. The central hypothesis is that childhood cancers have incidence patterns that correspond to the agricultural use of pesticides and that a proportion of the risk is attributable to watershed-mediated exposure to agricultural pesticides. This hypothesis will be tested by three specific aims, which are strongly supported by preliminary analysis of the Texas Cancer Database. 1) Estimate the cancer risks attributable to cropping practices. The product of this aim will be a GIS layer of cancer risk based on county-level crop production. 2) Estimate the risk for specific childhood cancers in each watershed in Texas. The GIS layer of cancer risk produced here will be based on risk estimates for discrete watersheds. 3) Estimate the extent that the risk surfaces for watersheds and cropping practice are correlated. This aim will utilize formal Bayesian analysis of homology of the two GIS layers. The approach is innovative, because it capitalizes on recently developed Bayesian mapping and analytical techniques. The proposed research is significant, because we expect to estimate the potential for contaminated watersheds to mediate childhood exposure to pesticide agricultural carcinogens. Data acquired will be useful in further study design to select sampling sites that will optimize environmental and biomarker testing. It is anticipated that the results produced will provide the preliminary data needed to continue definitive investigations under the auspices of subsequent R01 funding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Childhood Cancer

Project Title: PILOT--CANCER GENETICS AND VIROLOGY Principal Investigator & Institution: Fearon, Eric R.; Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: Established in 1998, the Cancer Genetics and Virology Program is an interdisciplinary group of 34 scientists pursuing basic and translational research to advance understanding of the nature and role of mutations, gene expression changes, and viruses in the development and behavior of cancer. This research is supported by over $6.4 million in annual direct support. The Cancer Genetics Group focuses on studies of germline and somatic mutations in oncogenes and tumor suppressor genes in cancer cells as well as efforts to define critical gene expression changes in the cancer cell and the specific epigenetic mechanisms that underlie the changes. The Virology Group is focused on the investigation of mechanisms which regulate DNA and RNA tumor virus replication and gene expression, as well as the effects of such viruses on infected host cells, including the role of viruses in cancer pathogenesis. Due to the complementary nature of the research, and the overlapping research interests and goals of the two groups, investigators in the two groups work together in a single program. Program members have primary and joint appointments in more than 12 departments at the School of Medicine and Public Health. Investigators in other programs in the Basic Science, Clinical Science, and Prevention Divisions of the Cancer Center, including the Programs in Cancer Cell Biology, Tumor Immunology, Experimental Therapeutics, Breast Oncology, Childhood Cancer, Cutaneous Oncology, Gastrointestinal Oncology, Prostate Cancer/Urological Oncology, and Cancer Prevention/Biomedical Research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT--CHILDHOOD CANCER Principal Investigator & Institution: Boxer, Laurence A.; Professor of Pediatrics; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: The Program in Childhood Cancer has three goals: to develop a better understanding of the biology and molecular defects responsible for pediatric cancer, train postdoctoral level physicians for independent research in the field of pediatric oncology; and to develop new approaches to the treatment of pediatric cancers. The Program is based on the clinical and research interests and expertise of twenty members from eight departments. The Program has 19 members with a total of $2.3 million in annual direct funding. The areas of scientific investigation include: Molecular Studies in Pediatric Solid Tumors; Biology and Therapeutics of Pediatric Solid Tumors; and the Biology of Hematopoiesis. The members of the Childhood Cancer Program (CCP) utilize all of the Cancer Center cores to accomplish their research mission. The members of the CCP have established extensive collaborations with members of the Basic Science, Clinical Science, and the Cancer Prevention and Control Programs. The members of the CCP participate in the Children's Cancer Group (CCG) and serve as the principal site for CCG and our five affiliate institutions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PILOT--TUMOR IMMUNOLOGY Principal Investigator & Institution: Mule, James J.; Associate Center Director; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: The main objective of the Tumor Immunology Program is to investigate the immunologic interactions between the host and tumor and to translate these findings into novel clinical trials in patients with cancer. The Program's membership includes basic and clinical investigators from the Departments pf Surgery, Internal Medicine, Pediatrics, Radiology, Pathology, and Microbiology. In addition, the Program has established formal scientific and clinical interactions with the Breast Oncology, Leukemia/Lymphoma, Gastrointestinal Oncology, Childhood Cancers, Head and Neck, and Urological/Prostate Programs to investigate the elicitation of immune responses to these tumors and the use of immune- based therapies in these settings. The Tumor Immunology Program relies heavily on the functions of several Cores, including Biostatistics, Flow Cytometry, Molecular Biology and Protein Chemistry, Experimental Irradiation, Vector, Animal, and the Clinical Trials Office. The Program has also played a key organizational role in the new Immunological Monitoring Core and has initiated studies involving the new Microarray Core. The research component of the Program focuses on efforts to improve tumor immunotherapy by developing novel vaccine adoptive T cell, and gene therapy tumor immunotherapy by developing novel vaccine adoptive T cell, and gene therapy approaches through the use of well-defined in vivo animal models, in vitro tissue culture systems, and state-of-the-art immunologic assays. In addition, the Program's investigators are actively involved in studies of the induction and breaking of immune tolerance as well as actively involved in studies of the induction and breaking of immune tolerance as well as immune reconstitution following hematopoietic stem cell transplantation as critical areas in tumor immunology. By doing so, the basic research component of the Program focuses on efforts to improve cancer immunotherapy. The clinical research component actively enrolls advanced to improve cancer immunotherapy. The clinical research component actively enrolls advanced cancer patients in novel clinical trials as a direct outcome of Program. Current and planned future clinical trials include: the use of tumor-pulsed dendritic cells, recombinant vaccinia viruses, and gene-modified tumor cells in vaccine strategies; the adoptive transfer of immune effector T cells and gene-modified hematopoietic stem cells; and the systemic delivery of recombinant cytokines. In the area of education, the Program has spearheaded the formal establishment of a new Ph.D. degree granting Graduate Program in Immunology administered through the University of Michigan's Rackham Graduate School and the Medical School. This new graduate program is directed by the Tumor Immunology Program's current director (J. Mule) with additional oversight by an operating committee in which the majority of seats are currently held by members of the Tumor Immunology Program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREMATURE MENOPAUSE IN SURVIVORS OF CHILDHOOD CANCER Principal Investigator & Institution: Sklar, Charles A.; Attending Pediatrician; SloanKettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 05-SEP-1998; Project End 31-JUL-2003

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Childhood Cancer

Summary: (Applicant's Description) Advances in the treatment of childhood cancer have resulted in markedly improved survival rates. However, with these advancements, cancer survivors now face the long-term consequences of treatment with intensive, multimodality therapies. While the majority of prepubertal girls and adolescent females retain or recover ovarian function during or immediately after completing cancer therapy, preliminary data indicate that many of these young women are at risk for premature menopause in the future. We propose to study, in a cohort of young adult survivors of cancer diagnosed during childhood/adolescence, the prevalence of early menopause, risk factors for the development of early menopause, the impact of an early menopause on quality of life and psychosexual functioning. The study cohort will consist of 5,500 young adult female survivors of cancer diagnosed during childhood and adolescence, selected from a larger population of survivors of childhood cancer, the Childhood Cancer Survivor Study (CCSS), and 3,000 sibling controls. Data will be collected using a self-administered questionnaire and will include the following topics: menstrual history and menopause status, covariates of menopause, health-related outcomes associated with premature menopause, and standardized instruments which measure quality of life and psychosexual functioning. Detailed information concerning cancer diagnosis and treatment, including cumulative drug dosages and radiation fields/doses, will be known for all study participants, facilitating the study of endpoints of interest. The large size of the study population, the heterogeneity of diagnoses and exposures, combined with the extensive treatment data, will allow assessment of interaction between the major risk factors of interest. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SURVIVORS

PSYCHOSOCIAL

OUTCOMES

IN

CHILDHOOD

CANCER

Principal Investigator & Institution: Zebrack, Bradley J.; Assistant Professor; Pediatrics; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 08-FEB-2002 Summary: The purpose of this proposal is to further understanding of the prevalence, characteristics and predictors of the psychosocial health status, health risk behaviors and neurological sequelae of long-term survivors of childhood cancer. The research proposed in this application will make use of the Childhood Cancer Survivor Study, a multi-institutional collaborative project that has established and followed a retrospectively-ascertained cohort of long-term survivors of childhood cancer and 6,000 sibling controls. This is the largest sample of well-characterized childhood cancer survivors and sibling controls known to date. Previous work suggests that certain subsets of childhood cancer survivors are vulnerable to a variety of physical and psychosocial problems, but the generalizability of these findings are limited by small sample sizes, data derived from single institutions, and lack of a control group. Furthermore, study in this field has yet to identify critical variables that influence (1) long-term survivors' psychosocial problems, but the generalizability of these findings are limited by small sample sizes, data derived from single institutions, and lack of a control group. Furthermore, study in this field has yet to identify critical variables that influence (1) long-term survivors' psychosocial status/quality of life, including their experiences with pain, and (2) behaviors that place them at risk for future health problems. The work to be conducted during the period of this functioning, and health behaviors. Physical, psychological, social and neurological factors that potentially influence these outcomes will be investigated. Specific hypotheses related to these

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outcomes are proposed and potentially moderating and mediating factors will be investigated. Psychosocial support interventions throughout a continuum of care- from diagnosis through treatment and into long-term survivorship-will be suggested. Plans for intervention research will be forthcoming. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QUANTITATIVE MR MEASURE OF MTX NEUROTOXICITY IN CHILDREN Principal Investigator & Institution: Reddick, Wilburn E.; Assistant Member; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant): Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer with approximately 3,500 new cases each year in the United States. When cancer treatment specifically targets the immature brain, as is the case for children with ALL, treatment efficacy must be balanced against the potential for chronic neurotoxicity. With estimated three-year event-free survival for children with ALL now at approximately 90 percent, increasing attention is directed toward minimizing late neurotoxicity in this particularly vulnerable population. The most common method of CNS prophylaxis for pediatric ALL includes high-dose methotrexate (HDMTX). However, several studies have shown a significant association between HDMTX and neurotoxicity. Thus, treatment-induced neurotoxicity is an important and clinically relevant problem in pediatric oncology. Our own studies have confirmed that leukoencephalopathy can be observed in as many as 75 percent of patients during treatment with HDMTX, even those without seizures or other symptoms of acute neurotoxicity. Our research builds on the hypothesis that leukoencephalopathy resulting from HDMTX spans a continuum of severity that can be probed reliably using noninvasive MR technology. More than 300 children will be treated for ALL on a five-year protocol at our institution with therapy that includes five courses of either 2.5 or 5.0 g/m2 of HDMTX during the induction and consolidation phases. The proposed project will be the first to use quantitative imaging-based measures (hybrid neural network segmentation; T1 and T2 relaxation times) to investigate treatment-induced leukoencephalopathy during therapy in a group of subjects sufficiently large to adequately test the following hypotheses: 1) that leukoencephalopathy early in therapy is predictive of later white matter changes; 2) that leukoencephalopathy during therapy is proportionate to exposure to HDMTX; and 3) that leukoencephalopathy during therapy is predictive of treatment-induced neurocognitive outcome will have a direct impact on the design of future clinical trials for pediatric ALL. The ultimate goal is to use these quantitative MR imaging measures to detect early therapy-induced neurotoxicity, which is potentially reversible through therapy adjustments of other neurobehavioral and pharmacological interventions for individual children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RISK AGRICULTURAL *

OF

CHILDHOOD

CANCERS

ASSOCIATED

WITH

Principal Investigator & Institution: Carozza, Susan E.; Assistant Professor; Epidemiology and Biostatistics; Texas A&M University Health Science Ctr College Station, Tx 778433578 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2006

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Childhood Cancer

Summary: The overall goal of the proposed case-control study is to estimate the risk of specific childhood cancers associated with in utero exposure to pesticides (fungicides, herbicides and insecticides) used in agricultural settings, with particular emphasis on differential risk by race/ethnicity. In the process of addressing the study goal, we will be developing two tools which will have wider applications for public health research in Texas populations: 1) a geographic information system (GIS) capable of producing historical agricultural land use maps for a majority of Texas counties; and 2) a cropspecific Pesticide Exposure Index (PEI) for use in evaluating exposure to agricultural pesticides based on cropping and pesticide use patterns. These data applications will be of particular use in evaluating public health outcomes in rural populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEP, FATIGUE, AND DEXAMETHOSONE IN CHILDHOOD CANCER Principal Investigator & Institution: Hinds, Pamela S.; Director of Nursing Research; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 30-JUN-2004 Summary: Mounting evidence indicates that adding dexamethasone to the therapy for children and adolescents diagnosed with lymphoblastic leukernia contributes to more positive long-term outcomes such as lower rates of meningeal leukemia. The significant positive contributions of dexamethasone have not occurred without adverse effects including avascular necrosis. mania and psychosis, and aberrant sleep and fatigue. These adverse effects could be related to inter-individual variability in the systemic exposure to dexamethasone and if so, the adverse effects could serve as behavioral indicators of patient sensitivity to the dosing schedule. To determine whether dexamethasone dosing schedules need to be individualized to minimize adverse effects while maintaining antileukernic effects, the relationship between inter-individual variability and adverse effects must be established. The overall purpose of this two-site study is to determine the relationship between systemic exposure to dexamethasone and patients' sleep and fatigue by comparing multiple indicators of patient sleep and fatigue in two consecutive 5-day periods during Continuation therapy off and on dexatnethasone. Approximately 134 children and adolescents with low or standard fisk ALL will wear a wnist actigraph for the two consecutive 5-day study periods and will complete a self-report fatigue questionnaire during a telephone interview on Days 2 and 5 of both study periods. Their parents will complete a sleep diary and a fatigue questionnaire on Days 2 and 5 of both study periods regarding their child's sleep and fatigue patterns. In addition, on Day I of the on dexamethasone 5-day study period, patients will-have sequential blood samples collected pre- and post- the morning dose of dexamethasone. These samples will be analyzed for dexamethasone pharmacokinetics and genetic polymorphism. Using these data, we will test the hypothesis that dexamethasone contributes to aberrant sleep and increased fatigue in children and adolescents with ALL, and that the altered sleep and fatigue are related to the pharmacokinetics of the drug. Our study findings will explicate the relationship between sleep efficiency and fatigue, and between sleep, fatigue, and systemic exposure to dexamethasone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SURVIVORS

SMOKING

CESSATION

AMONG

CHILDHOOD

49

CANCER

Principal Investigator & Institution: Emmons, Karen M.; Deputy Director; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1998; Project End 31-JUL-2003 Summary: Childhood cancer survivors represent a large and rapidly increasing group due to successes in cancer therapy over the last several decades. However, the treatments for childhood cancers tend to damage vital organs, and there is an increased risk of second cancers in childhood cancer survivors who may already have an innate susceptibility to neoplasia. Therefore, it is extremely important that preventable risk factors of cardiac, pulmonary, neoplastic, and other major diseases be minimized among this high-risk population. Interventions to reduce smoking prevalence among childhood cancer survivors are a critical component of efforts to reduce their preventable cancer morbidity and mortality. We recently completed Partnership for Health (PFH), the first large-scale smoking cessation intervention study to be conducted with childhood cancer survivors. The PFH intervention yielded a doubling of quit rates in the intervention group, compared to a self-help control group. PFH was conducted in the context of the Childhood Cancer Survivor Study (CCSS), a large epidemiologic cohort study of the late effects of treatment for childhood cancers. CCSS is a consortium of 22 cancer centers that enrolled over 14,000 patients into this surveillance program. The CCSS institutions are all members of the Children's Oncology Group (COG), which is our partner in this dissemination effort. As a result of the success of PFH, we plan to disseminate the intervention directly to the 235 COG institutions that provide on-going follow-up to the majority of childhood cancer survivors in the US and Canada. Our initial discussions with several COG members suggest that few of its member institutions currently offer smoking cessation services. The 235 COG institutions provide care to over 95% of North American children with cancer. The focus of this supplement will be on the process of dissemination of the PFH intervention to COG institutions, and the evaluation of the effectiveness of our dissemination efforts guided by a well-delineated theoretical framework. In addition to evaluating the relationship of organizational characteristics to program adoption, we will conduct a randomized control trial to determine whether providing assistance with the more labor-intensive aspects of implementation increases adoption and effective implementation. Outcomes include: intervention adoption (percent of cancer centers that adopt the program), quality of implementation (number of components implemented and level of implementation of each), and delivery of the intervention to survivors (number of survivors enrolled in the dissemination effort). COG's infrastructures and clinical trials network has resulted in dramatic improvements in cure rates for pediatric cancers. The proposed project will begin an effort to build on this success related to clinical therapeutic outcomes, and transfer it to cancer prevention outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOUTH TEXAS PEDIATRIC MINORITY BASED CCOP Principal Investigator & Institution: Infante, Anthony J.; Professor; Pediatrics; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-SEP-1990; Project End 31-MAY-2004 Summary: The overall goal of the South Texas Pediatric Minority-Based Community Clinical Oncology Program (STP-MB-CCOP) is to reduce the incidence, morbidity and mortality of cancer among Mexican- American children and adolescents residing in the

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South Texas service area. The three specific aims of the STP-MB-CCOP are: 1) provide data management services to all pediatric oncology providers serving the region, 2) provide travel support for pediatric oncologists and support personnel to outreach clinics within the medically underserved areas along the Texas-Mexico border, and 3) increase awareness of cancer- related issues and available resources through a continuing medical education program aimed at primary care providers. The research plan involves the operation of a Clinical Research Office in San Antonio that coordinates the data management activities of the component institutions, including primary data collection and submission, IRB approval, Spanish translation, research base audits and sample collection. In addition, each site has an assigned clinical research associate (CRA). Each institution operates outreach clinics in the border counties to provide access to pediatric oncology services. The headquarters institution provides a CME program to promote the awareness of childhood cancer issues and resources. The program has an ongoing evaluation program, involving weekly meetings of the component institutions and quarterly meetings of the entire STP-MB-CCOP. The quarterly meetings specifically are directed at finding ways to implement and improve mechanisms for meeting MBCCOP accural target. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRESS, SUPPORT AND SURVIVAL--CHILDREN AT MEDICAL RISK Principal Investigator & Institution: Kazak, Anne E.; Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2002; Project Start 30-SEP-1993; Project End 30-JUN-2003 Summary: Our previous research on psychological sequelae of childhood cancer treatment indicates that symptoms of post traumatic stress are significant for many survivors and their mothers and fathers. Indeed, there are many aspects of cancer and its treatment which are potential traumatic stressors, including invasive medical procedures, life threat, and disruption of family relationships. These prior data support the importance of anxiety, beliefs about cancer and its treatment, social support and family functioning as both direct and indirect contributions to posttraumatic stress symptoms. This proposal expands research on child and family adjustment to long-term survival of childhood cancer by developing and examining an intervention for posttraumatic stress in childhood cancer survivors and their families. The intervention integrates cognitive behavioral and family intervention approaches for 11-18 year old adolescent survivors, at least one year from the completion of their cancer treatment, and their mothers and fathers, at The Children's Hospital of Philadelphia. Home-based pre (Time 1) and six-month post (Time 2) evaluations will be conducted. Families will be randomized to the intervention or wait list condition after Time 1. The wait list group will receive the intervention after Time 2. The intervention consists of two half-day weekend sessions, eight weeks apart, with the first half-day session focused individually on the recognition of the long-term psychological effects of cancer and its treatment and use of cognitive-behavioral strategies for reducing cancer-related distress, for survivors, mothers and fathers separately. The second half-day session is a family-oriented intervention directed towards helping families communicate more effectively about the impact of cancer and reframe the experiences for themselves as families. Eight families will participate in each intervention, for a total n of 128 families. Data analysis strategies address change in post traumatic stress symptoms with particular attention to anxiety, perceptions of life threat and perceived intensity of treatment, social support and family factors. To our knowledge, this project is unique in providing an empirical evaluation of

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an intervention combining cognitive behavioral and family intervention techniques to alleviate and prevent ongoing psychological distress in children who have survived cancer and their parents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDIES OF CHILDHOOD SOLID TUMORS Principal Investigator & Institution: Houghton, Peter J.; Member and Chairman; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 01-AUG-1978; Project End 30-JUN-2007 Summary: (provided by applicant): Our long-term goal is to advance cure rates for children with malignant solid tumors. The restructured program has an increased focus on developmental therapeutics, testing laboratory driven hypotheses developed from non-mammalian and mammalian experimental systems, in unique xenograft models of childhood cancers, with subsequent design of clinical trials that simulate schedules and systemic exposures found optimal in these models. This approach has been validated through our clinical project, where camptothecins, drugs that target DNA topoisomerase I, have demonstrated very significant activity in Phase I/II trials in pediatric patients. In this application we propose studies that will lead to a greater understanding of sensitivity or resistance to topoisomerase inhibitors, and will start of integrate cytotoxic agents with inhibitors of signal transduction pathways. Project 23 continues studies of mTOR signaling in growth, and survival of tumor cells. Studies will explore the therapeutic strategy of combining the mTOR inhibitor CCI-779, a rapamycin ester, in combination with IGF-I receptor antagonists and cytotoxic agents. Project 24 builds on the finding that hypomorphic alleles of genes that regulate cell cycle checkpoints in yeast confer dramatic hypersensitivity to camptothecin and rapamycin. Human homologues will be cloned, their function defined and their role in determining drug sensitivity in mammalian cells determined. Project 25 will focus on how know DNA damage response pathways determine cellular fate to camptothecins, and how hypoxia induced stress influences p53-directed cell fate. Project 26 will focus on how hypoxia or nutritional stress influences cellular sensitivity to topoisomerase II-targeted drugs and DNA cross-linking drugs through the unfolded protein response pathway. Project 27 builds on results showing that ZD1839 (an ErbB1 inhibitor) potently inhibits ABC transporters (BCRP/MRP4) that confer resistance to camptothecin drugs. The role of ZD1839 in reversing drug resistance, and altering the pharmacology of clinically used camptothecins will be explored. Project 10 comprises Phase I and II clinical trials with topotecan and irinotecan each of which is based on our laboratory and preclinical data. These protocols are supported by pharmacokinetic, and pharmacogenomic studies that ensure optimal systemic exposure, and biological studies designed to increase our understanding of parameters that determine therapeutic efficacy of camptothecin-based topoisomerase I inhibitors used alone or in combination. We will also evaluate the rapamycin ester, CCI-779, alone or in combination with vincristine, to test whether mTOR-targeted therapy will have therapeutic significance in children with solid malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: T-ALL STROMAL CELL INTERACTION AND PATIENT OUTCOME Principal Investigator & Institution: Larson, Richard S.; Pathology; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2005

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Summary: (provided by applicant): T-lineage acute lymphoblastic leukemia (T-ALL) accounts for 10-15% of childhood ALL, the most common form of childhood cancer. Prognostic indicators of patient outcome in T-ALL are few, and those currently identified are too weak or inappropriate for risk stratification. Since good biologic predictors of patient outcome in T-ALL do not exist, the utility of risk stratification strategies based on biologic predictors, a common and successful strategy for improving patient outcome in other types of leukemia, is not useful in T-ALL. In this R21 proposal, we hypothesize that ex vivo survival of T-ALL cells (T-lineage lymphoblasts) on bone marrow (BM) stromal cells is a discriminating predictor of patient outcome. Furthermore, we postulate that adhesion receptor defects alter survival of T-ALL cells on BM stroma and, when measured in a novel flow cytometry based assay, may also correlate with disease characteristics or patient outcome. In the first aim, we will test the hypothesis that ex vivo survival of T-lineage lymphoblasts predicts treatment outcome. We will use a novel cellular assay that we have recently established in our laboratory to examine ex vivo T-lineage lymphoblast survival. Ex vivo survival of T-lineage lymphoblasts will be correlated with event free survival (EFS, the primary endpoint) and slow early response (secondary endpoint, i.e. disappearance of blasts from the bone marrow during the first 14 days of therapy). In the second aim, we will test the hypothesis that adhesion receptor defects may correlate with T-ALL biology or patient outcome. The second aim is to employ a novel assay for detecting adhesion receptor activity on the surface of cells. This assay uses fluorescein-labeled small molecules that bind to the binding site of integrins LFA-1 or VLA-4. By using these compounds at a concentration equivalent to their affinity constant, we can detect the affinity state of the receptor as well as detect the affinity state conversion in real time, The affinity state of the receptor will be correlated with ex vivo survival, disease characteristics, and patient outcome as in Aim 1. Accomplishment of Aim 2 will provide an additional prognostic tool as well as provide novel insights into the biology of leukemia that can be pursued in future studies. Although aim 2 involves more risk than aim 1, its completion is likely to produce insightful and novel data about the importance of adhesion receptors in leukemia biology and cell survival. In addition, this novel assay format may be potentially valuable in a wide array of biologic and clinical studies. Identification of a strong predictor of patient outcome is important to improving therapy, since having good prognostic indicators will allow for risk-based treatment stratification. 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

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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 •

Project Title: PREDICTORS

THERAPY-RELATED

LEUKEMIA--CLINICAL/BIOLOGIC

Principal Investigator & Institution: Davies, Stella; Professor and Jacob G. Schmidlapp Endowe; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 20-SEP-2002 Summary: (Applicant's Abstract) Over the last 20 years marked improvements in survival from childhood cancer have been achieved, at least in part by significant increases in the dose intensity of chemotherapy administered. While this has improved survival from the primary malignancy, increases in dose intensity have been associated with a marked increase in the frequency of therapy-related acute myeloid leukemia or myelodysplasia (t-MDS/AML), with frequencies as high as 22% in a Children's Cancer Group (CCG) treatment protocol for children with Ewing's sarcoma. The applicant hypothesizes that it is possible to identify genetic markers of alkylator damage to predict risk of t-MDS/AML in children receiving high dose-alkylating agent chemotherapy for sarcoma. Additionally, she hypothesizes that host genetic polymorphisms in drug metabolizing enzymes will influence genetic susceptibility to tMDS/AML and could be used in the future to guide therapy. In this study she will investigate markers of genetic susceptibility and increased risk of t-MDS/AML in 321 children enrolled on CCG sarcoma treatment protocols. She will ask whether genetic susceptibility to alkylating agent damage can be measured prospectively (using analysis of glutathione-S-transferase genotype and glycophorin A mutation frequency). She will look for early signs of development of myeloid malignancy (clonal hematopoiesis), and for acquisition of later genetic events associated with myeloid malignancy (presence of ras gene mutations in peripheral blood leukocytes) in patients who have completed intensive chemotherapy. The identification of markers of genetic susceptibility to tMDS/AML will allow future modification of therapy for individual patients. The identification of markers of early progression to t-MDS/AML during or after therapy

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will also allow modification of therapy and/or the development of treatment with chemopreventive agents such as retinoids. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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

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Project Title: UNIV. MICHIGAN COMPREHENSIVE CANCER CENTER SUPPORT GRANT Principal Investigator & Institution: Wicha, Max S.; Director; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 30-SEP-1988; Project End 31-MAY-2006 Summary: The University of Michigan Comprehensive Cancer Center (UWCCC) requests renewal of its core grant in support of senior leadership, programs and shared core facilities. A core grant to support the UMCCC was initially awarded by NCI in 1988

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and renewed for five years in 1991 and 1995. The Cancer Center received comprehensive designation in 1991. The Center provides an organizational framework to promote interdisciplinary research through the development of defined clinical, basic and prevention programs in cancer research, and the development and support of shared resources. The Cancer Center has experienced considerable growth over the current grant period with a 76% increase in NCI funding and a doubling of patient accruals to clinical therapeutic trials. In 1997 the Center moved to a new $88 million facility which houses the Center's outpatient clinics and four and one half floors of research laboratories. The Cancer Center's four basic research programs are: Cancer Genetics/Virology, Cancer Cell Biology, Tumor Immunology and, Experimental Therapeutics. The eight clinical research programs investigating the biology and therapeutics of disease sites are: Cancer Genetics/Virology, Cancer Cell Biology, Tumor Immunology, and Experimental Therapeutics. The eight clinical research programs investigating the biology and therapeutics of disease sites are: Breast, Prostrate, Leukemia/Lymphoma, GI, Cutaneous, Childhood Cancers, Head & Neck, and Connective Tissue. The two prevention programs are Biomedical and Socio-Behavioral. Support is requested for a total of 13 shared core facilities: 11 9ongoing in Clinical Trials, Biostatistics, Tissue Procurement, Tumor Imaging, DNA and Protein Analysis, Morphology Flow Cytometry, Experimental Radiation, Animal Facility, Transgenic Mouse and Vector cores, as well as two new cores in DNA Array Analysis and Immune Monitoring. The Cancer Center senior leadership is composed of the director and five associate directors. Funds are also requested for Development, Planning and Evaluation, and Administration to support Center goals. Over the past 10 years the University and Medical Center have made substantial commitments to the Cancer Center, totaling over $130 million. The UMCCC members receive nearly $66 million in research funding, including over $20 million in annual direct NCI support. 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 “childhood cancer” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for childhood cancer in the PubMed Central database: •

3 4

Inosiplex for Localized Herpes Zoster in Childhood Cancer Patients: Preliminary Controlled Study. by Feldman S, Hayes FA, Chaudhary S, Ossi M.; 1978 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=352489

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

A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. Author(s): Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF. Source: Cancer Research. 1999 August 15; 59(16): 4095-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10463613

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A psychometric analysis of the Quality of Life-Cancer Survivors (QOL-CS) in survivors of childhood cancer. Author(s): Zebrack BJ, Chesler MA. Source: Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. 2001; 10(4): 319-29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11763245

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A reexamination of a childhood cancer stereotype. Author(s): Wiens BA, Gilbert BO. Source: Journal of Pediatric Psychology. 2000 April-May; 25(3): 151-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10780142

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Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. Author(s): Sklar C, Whitton J, Mertens A, Stovall M, Green D, Marina N, Greffe B, Wolden S, Robison L. Source: The Journal of Clinical Endocrinology and Metabolism. 2000 September; 85(9): 3227-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10999813

6

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

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Adjustment of siblings to childhood cancer: a literature review. Author(s): Houtzager BA, Grootenhuis MA, Last BF. Source: Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. 1999 September; 7(5): 302-20. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10483815

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Adult height and age at menarche in childhood cancer survivors. Author(s): Noorda EM, Somers R, van Leeuwen FE, Vulsma T, Behrendt H; Dutch Late Effects Study Group. Source: European Journal of Cancer (Oxford, England : 1990). 2001 March; 37(5): 605-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11290436

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Adult psychosocial functioning following childhood cancer: the different roles of sons' and daughters' relationships with their fathers and mothers. Author(s): Hill J, Kondryn H, Mackie E, McNally R, Eden T. Source: Journal of Child Psychology and Psychiatry, and Allied Disciplines. 2003 July; 44(5): 752-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831119

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After the cure. Long-term effects of childhood cancer. Author(s): Ruble K. Source: Adv Nurse Pract. 1999 September; 7(9): 48-51, 56. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10763613

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Agricultural pesticide use in California: pesticide prioritization, use densities, and population distributions for a childhood cancer study. Author(s): Gunier RB, Harnly ME, Reynolds P, Hertz A, Von Behren J. Source: Environmental Health Perspectives. 2001 October; 109(10): 1071-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11689348

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Alexithymia in long-term survivors of childhood cancer. Author(s): van Dijk M, Grootenhuis MA, de Boer M, Bermond B, Last BF. Source: Pediatric Rehabilitation. 2002 October-December; 5(4): 203-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12745899

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An evaluation of a psychosocial intervention for survivors of childhood cancer: paradoxical effects of response shift over time. Author(s): Schwartz CE, Feinberg RG, Jilinskaia E, Applegate JC. Source: Psycho-Oncology. 1999 July-August; 8(4): 344-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10474852

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An examination of the dental utilization practices of adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Author(s): Yeazel MW, Gurney JG, Oeffinger KC, Mitby PA, Mertens AC, Hudson MM, Robison LL. Source: J Public Health Dent. 2004 Winter; 64(1): 50-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078062

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Analysis of incidence of childhood cancer in the West Midlands of the United Kingdom in relation to proximity to main roads and petrol stations. Author(s): Harrison RM, Leung PL, Somervaille L, Smith R, Gilman E. Source: Occupational and Environmental Medicine. 1999 November; 56(11): 774-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10658564

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Antenatal irradiation and childhood cancer: causation or coincidence? Author(s): Mole RH. Source: British Journal of Cancer. 1974 September; 30(3): 199-208. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4476218

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Aspects of childhood cancer during the Byzantine period. Author(s): Ramoutsaki IA, Dimitriou H, Galanakis E, Stiakaki E, Kalmanti M. Source: Pediatric Hematology and Oncology. 2001 April-May; 18(3): 161-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11293282

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Association of childhood cancer with factors related to pregnancy and birth. Author(s): Schuz J, Kaatsch P, Kaletsch U, Meinert R, Michaelis J. Source: International Journal of Epidemiology. 1999 August; 28(4): 631-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10480689

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Associations between childhood cancer and ionizing radiation: results of a population-based case-control study in Germany. Author(s): Meinert R, Kaletsch U, Kaatsch P, Schuz J, Michaelis J. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 1999 September; 8(9): 793-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10498398

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Atonic seizures in survivors of childhood cancer. Author(s): Khan RB, Marshman KC, Mulhern RK. Source: Journal of Child Neurology. 2003 June; 18(6): 397-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12886974

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Attitudes and impressions of participants in a study of the causes of childhood cancer. Author(s): Jenkinson CM, Muir KM, Hawtin PG, Chilvers CE. Source: British Journal of Cancer. 2001 February 2; 84(3): 413-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11161409

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Bacteremia in childhood cancer. Author(s): Celkan T, Ozkan A, Apak H, Diren S, Can G, Yuksel L, Yildiz I. Source: Journal of Tropical Pediatrics. 2002 December; 48(6): 373-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521283

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Behavioral responses of healthy Chinese siblings to the stress of childhood cancer in the family: a longitudinal study. Author(s): Wang RH, Martinson IM. Source: Journal of Pediatric Nursing. 1996 December; 11(6): 383-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8991339

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Bias in studies of parental self-reported occupational exposure and childhood cancer. Author(s): Schuz J, Spector LG, Ross JA. Source: American Journal of Epidemiology. 2003 October 1; 158(7): 710-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14507608

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Binomial cokriging for estimating and mapping the risk of childhood cancer. Author(s): Oliver MA, Webster R, Lajaunie C, Muir KR, Parkes SE, Cameron AH, Stevens MC, Mann JR. Source: Ima Journal of Mathematics Applied in Medicine and Biology. 1998 September; 15(3): 279-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9773520

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Birth characteristics of childhood cancer cases, controls, and their siblings. Author(s): Savitz DA, Ananth CV. Source: Pediatric Hematology and Oncology. 1994 November-December; 11(6): 587-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7857782

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Birth defects and childhood cancer in offspring of survivors of childhood cancer. Author(s): Green DM, Fiorello A, Zevon MA, Hall B, Seigelstein N. Source: Archives of Pediatrics & Adolescent Medicine. 1997 April; 151(4): 379-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9111437

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Birthweight and the risk of early childhood cancer among Chinese in Singapore. Author(s): Lee J, Chia KS, Cheung KH, Chia SE, Lee HP. Source: International Journal of Cancer. Journal International Du Cancer. 2004 June 20; 110(3): 465-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15095317

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Bleomycin and cyclophosphamide toxicity simulating metastatic nodules to the lungs in childhood cancer. Author(s): Ben Arush MW, Roguin A, Zamir E, el-Hassid R, Pries D, Gaitini D, Dale A, Postovsky S. Source: Pediatric Hematology and Oncology. 1997 July-August; 14(4): 381-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9211543

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Bone mass and body composition after cessation of therapy for childhood cancer. Author(s): Nysom K, Molgaard C, Holm K, Hertz H, Michaelsen KF. Source: Int J Cancer Suppl. 1998; 11: 40-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9876476

•

Bone mineral density in long-term survivors of childhood cancer. Author(s): Arikoski P, Voutilainen R, Kroger H. Source: J Pediatr Endocrinol Metab. 2003 March; 16 Suppl 2: 343-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12729414

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Bone mineral density in long-term survivors of childhood cancer. Author(s): Hesseling PB, Hough SF, Nel ED, van Riet FA, Beneke T, Wessels G. Source: Int J Cancer Suppl. 1998; 11: 44-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9876477

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Bone mineral density in young adult survivors of childhood cancer. Author(s): Aisenberg J, Hsieh K, Kalaitzoglou G, Whittam E, Heller G, Schneider R, Sklar C. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 1998 May-June; 20(3): 241-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9628436

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Bone mineral status during and after therapy of childhood cancer: an increasing population with multiple risk factors for impaired bone health. Author(s): Kaste SC, Chesney RW, Hudson MM, Lustig RH, Rose SR, Carbone LD. Source: Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research. 1999 December; 14(12): 2010-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10620059

Studies

61

•

Breast cancer screening in childhood cancer survivors. Author(s): Powers A, Cox C, Reintgen DS. Source: Medical and Pediatric Oncology. 2000 March; 34(3): 210-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10696129

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Breast masses in women treated for childhood cancer: incidence and screening guidelines. Author(s): Kaste SC, Hudson MM, Jones DJ, Fryrear R, Greenwald CA, Fleming ID, Pratt CB. Source: Cancer. 1998 February 15; 82(4): 784-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9477113

•

Breastfeeding and childhood cancer risks: OSCC data. Author(s): Lancashire RJ, Sorahan T; OSCC. Source: British Journal of Cancer. 2003 April 7; 88(7): 1035-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12671700

•

Breastfeeding and childhood cancer. Author(s): UK Childhood Cancer Study Investigators. Source: British Journal of Cancer. 2001 November 30; 85(11): 1685-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11742489

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Brief report: assessment of body image in survivors of childhood cancer. Author(s): Kopel SJ, Eiser C, Cool P, Grimer RJ, Carter SR. Source: Journal of Pediatric Psychology. 1998 April; 23(2): 141-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9585640

•

Brief report: does posttraumatic stress apply to siblings of childhood cancer survivors? Author(s): Alderfer MA, Labay LE, Kazak AE. Source: Journal of Pediatric Psychology. 2003 June; 28(4): 281-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730285

•

Cardiovascular trials in long-term survivors of childhood cancer. Author(s): Lipshultz SE, Colan SD. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2004 March 1; 22(5): 769-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14990630

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Childhood Cancer

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Childhood cancer among Alaska Natives. Author(s): Lanier AP, Holck P, Ehrsam Day G, Key C. Source: Pediatrics. 2003 November; 112(5): E396. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14595083

•

Childhood cancer and residential radon exposure - results of a population-based casecontrol study in Lower Saxony (Germany). Author(s): Kaletsch U, Kaatsch P, Meinert R, Schuz J, Czarwinski R, Michaelis J. Source: Radiation and Environmental Biophysics. 1999 September; 38(3): 211-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10525959

•

Childhood cancer in relation to cured meat intake: review of the epidemiological evidence. Author(s): Blot WJ, Henderson BE, Boice JD Jr. Source: Nutrition and Cancer. 1999; 34(1): 111-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10453449

•

Childhood cancer in relation to infections in the community during pregnancy and around the time of birth. Author(s): Nyari TA, Dickinson HO, Parker L. Source: International Journal of Cancer. Journal International Du Cancer. 2003 May 10; 104(6): 772-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12640686

•

Childhood cancer in Seascale. Author(s): Wakeford R. Source: Journal of Public Health Medicine. 2002 December; 24(4): 343-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12546218

•

Childhood cancer in Thailand: 1995-1997. Author(s): Wiangnon S, Kamsa-Ard S, Jetsrisuparb A, Sriplung H, Sontipong S, Sumitsawan Y, Martin N. Source: Asian Pac J Cancer Prev. 2003 August-December; 4(4): 337-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14728593

•

Childhood cancer in the classroom. Author(s): VanDenburgh K. Source: School Nurse News. 2003 March; 20(2): 28-33. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12683314

Studies

63

•

Childhood cancer incidence and arsenic exposure in drinking water in Nevada. Author(s): Moore LE, Lu M, Smith AH. Source: Archives of Environmental Health. 2002 May-June; 57(3): 201-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12507173

•

Childhood cancer incidence rates and hazardous air pollutants in California: an exploratory analysis. Author(s): Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Hertz A, Smith DF. Source: Environmental Health Perspectives. 2003 April; 111(4): 663-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12676632

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Childhood cancer patients' access to cooperative group cancer programs: a population-based study. Author(s): Liu L, Krailo M, Reaman GH, Bernstein L; Surveillance, Epidemiology and End Results Childhood Cancer Linkage Group. Source: Cancer. 2003 March 1; 97(5): 1339-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12599243

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Childhood cancer registries in Ontario, Canada: lessons learned from a comparison of two registries. Author(s): Greenberg ML, Barr RD, DiMonte B, McLaughlin E, Greenberg C. Source: International Journal of Cancer. Journal International Du Cancer. 2003 May 20; 105(1): 88-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12672035

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Childhood cancer survival: the good news and the not-so-good news. Author(s): Schulmeister L. Source: Clinical Journal of Oncology Nursing. 2004 February; 8(1): 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14983756

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Childhood cancer survivors face long-term complications. Author(s): Nelson R. Source: Lancet. 2003 September 13; 362(9387): 884. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14506811

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Childhood cancer survivors--living beyond cure. Author(s): Kurkure P, Achrekar S, Dalvi N, Goswami S. Source: Indian J Pediatr. 2003 October; 70(10): 825-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14649480

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Childhood cancer. Rapid changes in the last 40 years. Author(s): Wilkinson RW. Source: Hawaii Med J. 2003 April; 62(4): 84-5. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12774677

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Childhood cancer--a mother's story. Author(s): Pfeifer R. Source: European Journal of Cancer (Oxford, England : 1990). 2003 November; 39(17): 2427-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14602128

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Childhood cancer--challenges and opportunities. Author(s): Arya LS. Source: Indian J Pediatr. 2003 February; 70(2): 159-62. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12661812

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Clusters and clustering of childhood cancer: a review. Author(s): Alexander FE. Source: European Journal of Epidemiology. 1999 October; 15(9): 847-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10608365

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Continued parental attendance at a clinic for adult survivors of childhood cancer. Author(s): Ressler IB, Cash J, McNeill D, Joy S, Rosoff PM. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 November; 25(11): 868-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14608196

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Daunorubicin cardiotoxicity in childhood cancer. Author(s): Samuel L, Cummings J, Shaw P. Source: Lancet. 1998 October 3; 352(9134): 1150. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9798620

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Deaths from childhood cancer in sibs. Author(s): Miller RW. Source: The New England Journal of Medicine. 1968 July 18; 279(3): 122-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5655197

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Dental parameters in the long-term survivors of childhood cancer compared with siblings. Author(s): Duggal MS, Curzon ME, Bailey CC, Lewis IJ, Prendergast M. Source: Oral Oncology. 1997 September; 33(5): 348-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9415335

Studies

65

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Description of a new computer wire coding method and its application to evaluate potential control selection bias in the Savitz et al. childhood cancer study. Author(s): Ebi KL, Kheifets LI, Pearson RL, Wachtel H. Source: Bioelectromagnetics. 2000 July; 21(5): 346-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10899770

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Detection of early anthracycline-induced cardiotoxicity in childhood cancer with dobutamine stress echocardiography. Author(s): Lenk MK, Zeybek C, Okutan V, Ozcan O, Gokcay E. Source: Turk J Pediatr. 1998 July-September; 40(3): 373-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9763901

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Determinants of parental decisions on 'drop out' from cancer treatment for childhood cancer patients. Author(s): Yeh CH, Lin CF, Tsai JL, Lai YM, Ku HC. Source: Journal of Advanced Nursing. 1999 July; 30(1): 193-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10403996

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Determinants of symptom interval in childhood cancer. Author(s): Saha V, Love S, Eden T, Micallef-Eynaud P, MacKinlay G. Source: Archives of Disease in Childhood. 1993 June; 68(6): 771-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8333770

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Developing a measure of health outcomes in survivors of childhood cancer: a review of the issues. Author(s): Jenney ME, Kane RL, Lurie N. Source: Medical and Pediatric Oncology. 1995 March; 24(3): 145-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7838035

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Developing strategies for long term follow up of survivors of childhood cancer. Author(s): Wallace WH, Blacklay A, Eiser C, Davies H, Hawkins M, Levitt GA, Jenney ME; Late Effects Committee of the United Kingdom Children's Cancer Study Group (UKCCSG). Source: Bmj (Clinical Research Ed.). 2001 August 4; 323(7307): 271-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11485960

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Diagnosing childhood cancer in primary care--a realistic expectation? Author(s): Feltbower RG, Lewis IJ, Picton S, Richards M, Glaser AW, Kinsey SE, McKinney PA. Source: British Journal of Cancer. 2004 May 17; 90(10): 1882-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138465

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Diagnosis and treatment of childhood cancer. A statewide attack. Author(s): Talbert JL. Source: J Fla Med Assoc. 1971 November; 58(11): 21-3. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5117652

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Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. Author(s): Rose SR, Lustig RH, Pitukcheewanont P, Broome DC, Burghen GA, Li H, Hudson MM, Kun LE, Heideman RL. Source: The Journal of Clinical Endocrinology and Metabolism. 1999 December; 84(12): 4472-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10599705

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Diagnostic X-ray and ultrasound exposure and risk of childhood cancer. Author(s): Shu XO, Jin F, Linet MS, Zheng W, Clemens J, Mills J, Gao YT. Source: British Journal of Cancer. 1994 September; 70(3): 531-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8080742

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Diminished ovarian reserve in female childhood cancer survivors with regular menstrual cycles and basal FSH