The Official Parent's Sourcebook on Childhood Rhabdomyosarcoma: A Revised and Updated Directory for the Internet Age

THE OFFICIAL PARENT’S SOURCEBOOK on CHILDHOOD RHABDOMYOSARCOMA J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H...

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THE OFFICIAL PARENT’S SOURCEBOOK

on

CHILDHOOD

RHABDOMYOSARCOMA

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

ii

ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright Ó2002 by ICON Group International, Inc. Copyright Ó2002 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: Tiffany LaRochelle 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 as a substitute for consultation with your child’s physician. All matters regarding your child’s health require medical supervision. 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, in close consultation with a qualified physician. The reader is advised to always check product information (package inserts) for changes and new information regarding dose and contraindications before administering 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., 1960The Official Parent’s Sourcebook on Childhood Rhabdomyosarcoma: A Revised and Updated Directory for the Internet Age/James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary and index. ISBN: 0-597-83449-0 1. Childhood Rhabdomyosarcoma-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 or as a substitute for consultation with licensed medical professionals. 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, or the authors are not responsible for the content of any Web pages nor publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this sourcebook for parent use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications are copyrighted. 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 sourcebook.

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Dedication To the healthcare professionals dedicating their time and efforts to the study of childhood rhabdomyosarcoma.

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this sourcebook which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which directly or indirectly are dedicated to childhood rhabdomyosarcoma. All of the Official Parent’s Sourcebooks 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 sourcebook. 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 LaRochelle 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 the Official Parent’s Sourcebook series published 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 the Official Parent’s Sourcebook series published by ICON Health Publications.

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About ICON Health Publications In addition to childhood rhabdomyosarcoma, Official Parent’s Sourcebooks are available for the following related topics: ·

The Official Patient's Sourcebook on Childhood Acute Lymphoblastic Leukemia

·

The Official Patient's Sourcebook on Childhood Acute Myeloid Leukemia - Other Myeloid Malignancies

·

The Official Patient's Sourcebook on Childhood Hodgkin's Disease

·

The Official Patient's Sourcebook on Childhood Liver Cancer

·

The Official Patient's Sourcebook on Childhood Non-hodgkin's Lymphoma

·

The Official Patient's Sourcebook on Childhood Rhabdomyosarcoma

·

The Official Patient's Sourcebook on Childhood Soft Tissue Sarcoma

·

The Official Patient's Sourcebook on Neuroblastoma

·

The Official Patient's Sourcebook on Unusual Childhood Cancers

·

The Official Patient's Sourcebook on Wilm's Tumor and Other Childhood Kidney Tumors

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

Contents vii

Table of Contents INTRODUCTION...................................................................................... 1

Overview............................................................................................................... 1 Organization......................................................................................................... 3 Scope ..................................................................................................................... 4 Moving Forward................................................................................................... 4

PART I: THE ESSENTIALS ................................................. 7 CHAPTER 1. THE ESSENTIALS ON CHILDHOOD RHABDOMYOSARCOMA: GUIDELINES................................................... 9

Overview............................................................................................................... 9 What Is Childhood Rhabdomyosarcoma? ........................................................... 11 Stages of Childhood Rhabdomyosarcoma ........................................................... 12 How Childhood Rhabdomyosarcoma Is Treated ................................................. 13 Treatment by Stage............................................................................................. 14 To Learn More .................................................................................................... 15 About PDQ......................................................................................................... 16 More Guideline Sources ..................................................................................... 18 Vocabulary Builder............................................................................................. 20

CHAPTER 2. SEEKING GUIDANCE ....................................................... 23

Overview............................................................................................................. 23 Associations and Childhood Rhabdomyosarcoma............................................... 23 Finding More Associations................................................................................. 26 Cancer Support Groups...................................................................................... 28 The Cancer Information Service ......................................................................... 30 Finding Cancer Resources in Your Community................................................ 32 Finding Doctors Who Specialize in Cancer Care ............................................... 36 Selecting Your Child’s Doctor............................................................................ 38 Working with Your Child’s Doctor.................................................................... 39 Getting a Second Opinion .................................................................................. 40 Finding a Cancer Treatment Facility ................................................................. 41 Questions and Answers about Children’s Cancer Centers ................................ 42 Additional Cancer Support Information ............................................................ 45 Vocabulary Builder............................................................................................. 45

CHAPTER 3. CLINICAL TRIALS AND CHILDHOOD RHABDOMYOSARCOMA ....................................................................... 47

Overview............................................................................................................. 47 Recent Trials on Childhood Rhabdomyosarcoma ............................................... 50 Benefits and Risks............................................................................................... 52 Clinical Trials and Insurance Coverage ............................................................. 55 Increasing the Likelihood of Insurance Coverage for Trials ............................... 58 If Your Insurance Claim Is Denied after the Trial Has Begun .......................... 59

viii Contents

Government Initiatives to Expand Insurance Coverage for Trials .................... 62 Keeping Current on Clinical Trials.................................................................... 63 General References.............................................................................................. 65 Vocabulary Builder............................................................................................. 66

PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL.................................................. 67 CHAPTER 4. STUDIES ON CHILDHOOD RHABDOMYOSARCOMA ........ 69

Overview............................................................................................................. 69 The Combined Health Information Database ..................................................... 69 Federally-Funded Research on Childhood Rhabdomyosarcoma ......................... 72 E-Journals: PubMed Central .............................................................................. 86 The National Library of Medicine: PubMed .................................................... 100 Vocabulary Builder........................................................................................... 118

CHAPTER 5. PATENTS ON CHILDHOOD RHABDOMYOSARCOMA ..... 127

Overview........................................................................................................... 127 Patents on Childhood Rhabdomyosarcoma....................................................... 128 Patent Applications on Childhood Rhabdomyosarcoma................................... 144 Keeping Current ............................................................................................... 145 Vocabulary Builder........................................................................................... 146

CHAPTER 6. BOOKS ON CHILDHOOD RHABDOMYOSARCOMA ........ 149

Overview........................................................................................................... 149 The National Library of Medicine Book Index ................................................. 149 Chapters on Childhood Rhabdomyosarcoma .................................................... 151 General Home References ................................................................................. 152 Vocabulary Builder........................................................................................... 153

CHAPTER 7. MULTIMEDIA ON CHILDHOOD RHABDOMYOSARCOMA ........................................................................................................... 155

Overview........................................................................................................... 155 Bibliography: Multimedia on Childhood Rhabdomyosarcoma ......................... 155

CHAPTER 8. PHYSICIAN GUIDELINES AND DATABASES ................... 157

Overview........................................................................................................... 157 NIH Guidelines................................................................................................. 157 What Is Childhood Rhabdomyosarcoma? ......................................................... 158 Prognosis .......................................................................................................... 160 Cellular Classification ...................................................................................... 162 Stage Information ............................................................................................. 165 Treatment Option Overview ............................................................................ 167 Surgical Management Treatment Options for Previously Untreated (Stages IIV) Childhood Rhabdomyosarcoma .................................................................. 167 Chemotherapy Treatment Options for Previously Untreated (Stages I-IV) Childhood Rhabdomyosarcoma......................................................................... 175 Radiation Therapy Management Treatment Options ...................................... 179

Contents

ix

Recurrent Childhood Rhabdomyosarcoma........................................................ 183 NIH Databases.................................................................................................. 185 Other Commercial Databases ........................................................................... 190 The Genome Project and Childhood Rhabdomyosarcoma ................................ 190 Specialized References....................................................................................... 195 Vocabulary Builder........................................................................................... 196

CHAPTER 9. DISSERTATIONS ON CHILDHOOD RHABDOMYOSARCOMA ........................................................................................................... 201

Overview........................................................................................................... 201 Dissertations on Childhood Rhabdomyosarcoma ............................................. 201 Keeping Current ............................................................................................... 203

PART III. APPENDICES .................................................. 205 APPENDIX A. RESEARCHING YOUR CHILD’S MEDICATIONS ........... 207

Overview........................................................................................................... 207 Your Child’s Medications: The Basics.............................................................. 208 Learning More about Your Child’s Medications ............................................. 209 Commercial Databases...................................................................................... 211 Drug Development and Approval .................................................................... 212 Understanding the Approval Process for New Cancer Drugs......................... 213 The Role of the Federal Drug Administration (FDA)...................................... 214 Getting Drugs to Patients Who Need Them .................................................... 218 Contraindications and Interactions (Hidden Dangers) ................................... 220 A Final Warning .............................................................................................. 221 General References............................................................................................ 221 Vocabulary Builder........................................................................................... 222

APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE ................... 223

Overview........................................................................................................... 223 What Is CAM? ................................................................................................. 224 What Are the Domains of Alternative Medicine?............................................ 225 Finding CAM References on Childhood Rhabdomyosarcoma.......................... 230 Additional Web Resources................................................................................ 239 General References............................................................................................ 240 Vocabulary Builder........................................................................................... 241

APPENDIX C. RESEARCHING NUTRITION ......................................... 243

Overview........................................................................................................... 243 Food and Nutrition: General Principles........................................................... 244 Finding Studies on Childhood Rhabdomyosarcoma ......................................... 248 Federal Resources on Nutrition........................................................................ 252 Additional Web Resources................................................................................ 253 Vocabulary Builder........................................................................................... 253

APPENDIX D. FINDING MEDICAL LIBRARIES.................................... 257

Overview........................................................................................................... 257

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Contents

Preparation ....................................................................................................... 257 Finding a Local Medical Library ...................................................................... 258 Medical Libraries Open to the Public............................................................... 258

APPENDIX E. YOUR CHILD’S RIGHTS AND INSURANCE ................... 265

Overview........................................................................................................... 265 Your Child’s Rights as a Patient ...................................................................... 265 Parent Responsibilities ..................................................................................... 269 Choosing an Insurance Plan............................................................................. 270 Medicaid ........................................................................................................... 272 Financial Assistance for Cancer Care............................................................... 273 NORD’s Medication Assistance Programs ..................................................... 276 Additional Resources ........................................................................................ 276

APPENDIX F. TALKING WITH YOUR CHILD ABOUT CANCER ........... 279

Overview........................................................................................................... 279 Why Should I Tell My Child? .......................................................................... 280 Parent’s Questions ........................................................................................... 280 What Should My Child Be Told? ..................................................................... 281 Questions Children May Ask ........................................................................... 283 Talking to Your Child with Late-Stage Cancer................................................ 284

ONLINE GLOSSARIES.................................................... 287 Online Dictionary Directories.......................................................................... 289

CHILDHOOD RHABDOMYOSARCOMA GLOSSARY ................................................................................................ 291 General Dictionaries and Glossaries ................................................................ 308

INDEX................................................................................... 310

Introduction

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INTRODUCTION Overview Dr. C. Everett Koop, former U.S. Surgeon General, once said, “The best prescription is knowledge.”1 The Agency for Healthcare Research and Quality (AHRQ) of the National Institutes of Health (NIH) echoes this view and recommends that all parents incorporate education into the treatment process. According to the AHRQ: Finding out more about your [child’s] condition is a good place to start. By contacting groups that support your [child’s] condition, visiting your local library, and searching on the Internet, you can find good information to help guide your decisions for your [child’s] treatment. Some information may be hard to find—especially if you don’t know where to look.2 As the AHRQ mentions, finding the right information is not an obvious task. Though many physicians and public officials had thought that the emergence of the Internet would do much to assist parents in obtaining reliable information, 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.3 Quotation from http://www.drkoop.com. The Agency for Healthcare Research and Quality (AHRQ): http://www.ahcpr.gov/consumer/diaginfo.htm. 3 Adapted from the NIH, National Cancer Institute (NCI): http://cancertrials.nci.nih.gov/beyond/evaluating.html. 1 2

2

Childhood Rhabdomyosarcoma

Since the late 1990s, physicians have seen a general increase in parent Internet usage rates. Parents frequently enter their children’s doctor’s offices with printed Web pages of home remedies in the guise of latest medical research. This scenario is so common that doctors often spend more time dispelling misleading information than guiding children through sound therapies. The Official Parent’s Sourcebook on Childhood Rhabdomyosarcoma has been created for parents who have decided to make education and research an integral part of the treatment process. The pages that follow will tell you where and how to look for information covering virtually all topics related to childhood rhabdomyosarcoma, from the essentials to the most advanced areas of research. The title of this book includes the word “official.” This reflects the fact that the sourcebook draws from public, academic, government, and peerreviewed research. Selected readings from various agencies are reproduced to give you some of the latest official information available to date on childhood rhabdomyosarcoma. Given parents’ increasing sophistication in using the Internet, abundant references to reliable Internet-based resources are provided throughout this sourcebook. Where possible, guidance is provided on how to obtain free-ofcharge, primary research results as well as more detailed information via the Internet. E-book and electronic versions of this sourcebook are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). Hard copy users of this sourcebook can type cited Web addresses directly into their browsers to obtain access to the corresponding sites. Since we are working with ICON Health Publications, hard copy Sourcebooks are frequently updated and printed on demand to ensure that the information provided is current. In addition to extensive references accessible via the Internet, every chapter presents a “Vocabulary Builder.” Many health guides offer glossaries of technical or uncommon terms in an appendix. In editing this sourcebook, we have decided to place a smaller glossary within each chapter that covers terms used in that chapter. Given the technical nature of some chapters, you may need to revisit many sections. Building one’s vocabulary of medical terms in such a gradual manner has been shown to improve the learning process. We must emphasize that no sourcebook on childhood rhabdomyosarcoma should affirm that a specific diagnostic procedure or treatment discussed in a research study, patent, or doctoral dissertation is “correct” or your child’s best option. This sourcebook is no exception. Each child is unique. Deciding

Introduction

3

on appropriate options is always up to parents in consultation with their children’s physicians and healthcare providers.

Organization This sourcebook is organized into three parts. Part I explores basic techniques to researching childhood rhabdomyosarcoma (e.g. finding guidelines on diagnosis, treatments, and prognosis), followed by a number of topics, including information on how to get in touch with organizations, associations, or other parent networks dedicated to childhood rhabdomyosarcoma. It also gives you sources of information that can help you find a doctor in your local area specializing in treating childhood rhabdomyosarcoma. Collectively, the material presented in Part I is a complete primer on basic research topics for childhood rhabdomyosarcoma. Part II moves on to advanced research dedicated to childhood rhabdomyosarcoma. Part II is intended for those willing to invest many hours of hard work and study. It is here that we direct you to the latest scientific and applied research on childhood rhabdomyosarcoma. When possible, contact names, links via the Internet, and summaries are provided. It is in Part II where the vocabulary process becomes important as authors publishing advanced research frequently use highly specialized language. In general, every attempt is made to recommend “free-to-use” options. Part III provides appendices of useful background reading covering childhood rhabdomyosarcoma or related disorders. The appendices are dedicated to more pragmatic issues facing parents. Accessing materials via medical libraries may be the only option for some parents, so a guide is provided for finding local medical libraries which are open to the public. Part III, therefore, focuses on advice that goes beyond the biological and scientific issues facing children with childhood rhabdomyosarcoma and their families.

4

Childhood Rhabdomyosarcoma

Scope While this sourcebook covers childhood rhabdomyosarcoma, doctors, research publications, and specialists may refer to your child’s condition using a variety of terms. Therefore, you should understand that childhood rhabdomyosarcoma is often considered a synonym or a condition closely related to the following: ·

Cancer Retina

·

Glioma Retina

·

Glioma Retina Child

·

Retina Glioma

·

Tumor Retina Child

In addition to synonyms and related conditions, physicians may refer to childhood rhabdomyosarcoma using certain coding systems. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) is the most commonly used system of classification for the world’s illnesses. Your physician may use this coding system as an administrative or tracking tool. The following classification is commonly used for childhood rhabdomyosarcoma:4 ·

190.5 malignant neoplasm of the retina

·

190.5 retinoblastoma, malignant neoplasm of eyes, retina

For the purposes of this sourcebook, we have attempted to be as inclusive as possible, looking for official information for all of the synonyms relevant to childhood rhabdomyosarcoma. You may find it useful to refer to synonyms when accessing databases or interacting with healthcare professionals and medical librarians.

Moving Forward Since the 1980s, the world has seen a proliferation of healthcare guides covering most illnesses. Some are written by parents, patients, or their family 4 This list is based on the official version of the World Health Organization’s 9th Revision, International Classification of Diseases (ICD-9). According to the National Technical Information Service, “ICD-9CM extensions, interpretations, modifications, addenda, or errata other than those approved by the U.S. Public Health Service and the Health Care Financing Administration are not to be considered official and should not be utilized. Continuous maintenance of the ICD-9-CM is the responsibility of the federal government.”

Introduction

5

members. These generally take a layperson’s approach to understanding and coping with an illness or disorder. They can be uplifting, encouraging, and highly supportive. Other guides are authored by physicians or other healthcare providers who have a more clinical outlook. Each of these two styles of guide has its purpose and can be quite useful. As editors, we have chosen a third route. We have chosen to expose you to as many sources of official and peer-reviewed information as practical, for the purpose of educating you about basic and advanced knowledge as recognized by medical science today. You can think of this sourcebook as your personal Internet age reference librarian. Why “Internet age”? When their child has been diagnosed with childhood rhabdomyosarcoma, parents will often log on to the Internet, type words into a search engine, and receive several Web site listings which are mostly irrelevant or redundant. Parents are left to wonder where the relevant information is, and how to obtain it. Since only the smallest fraction of information dealing with childhood rhabdomyosarcoma is even indexed in search engines, a non-systematic approach often leads to frustration and disappointment. With this sourcebook, we hope to direct you to the information you need that you would not likely find using popular Web directories. Beyond Web listings, in many cases we will reproduce brief summaries or abstracts of available reference materials. These abstracts often contain distilled information on topics of discussion. While we focus on the more scientific aspects of childhood rhabdomyosarcoma, there is, of course, the emotional side to consider. Later in the sourcebook, we provide a chapter dedicated to helping you find parent groups and associations that can provide additional support beyond research produced by medical science. We hope that the choices we have made give you and your child the most options in moving forward. In this way, we wish you the best in your efforts to incorporate this educational approach into your child’s treatment plan. The Editors

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PART I: THE ESSENTIALS

ABOUT PART I Part I has been edited to give you access to what we feel are “the essentials” on childhood rhabdomyosarcoma. The essentials typically include a definition or description of the condition, a discussion of who it affects, the signs or symptoms, tests or diagnostic procedures, and treatments for the disease. Your child’s doctor or healthcare provider may have already explained the essentials of childhood rhabdomyosarcoma to you or even given you a pamphlet or brochure describing the condition. Now you are searching for more in-depth information. As editors, we have decided, nevertheless, to include a discussion on where to find essential information that can complement what the doctor has already told you. In this section we recommend a process, not a particular Web site or reference book. The process ensures that, as you search the Web, you gain background information in such a way as to maximize your understanding.

Guidelines

CHAPTER 1. THE ESSENTIALS RHABDOMYOSARCOMA: GUIDELINES

ON

9

CHILDHOOD

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

The National Institutes of Health (NIH)5 The National Institutes of Health (NIH) is the first place to search for relatively current guidelines and fact sheets on childhood rhabdomyosarcoma. Originally founded in 1887, the NIH is one of the world’s foremost medical research centers and the federal focal point for medical research in the United States. At any given time, the NIH supports some 35,000 research grants at universities, medical schools, and other research and training institutions, both nationally and internationally. The rosters of those who have conducted research or who have received NIH support over the years include the world’s most illustrious scientists and

5

Adapted from the NIH: http://www.nih.gov/about/NIHoverview.html.

10 Childhood Rhabdomyosarcoma

physicians. Among them are 97 scientists who have won the Nobel Prize for achievement in medicine. There is no guarantee that any one Institute will have a guideline on a specific medical condition, though the National Institutes of Health collectively publish over 600 guidelines for both common and rare disorders. The best way to access NIH guidelines is via the Internet. Although the NIH is organized into many different Institutes and Offices, the following is a list of key Web sites where you are most likely to find NIH clinical guidelines and publications dealing with childhood rhabdomyosarcoma and associated conditions: ·

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

·

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

·

National Cancer Institute (NCI); guidelines available at http://cancernet.nci.nih.gov/pdq/pdq_treatment.shtml

Among the above, the National Cancer Institute (NCI) is particularly noteworthy. The NCI coordinates the National Cancer Program, which conducts and supports research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and the continuing care of cancer patients and the families of cancer patients.6 Specifically, the Institute: ·

Supports and coordinates research projects conducted by universities, hospitals, research foundations, and businesses throughout this country and abroad through research grants and cooperative agreements.

·

Conducts research in its own laboratories and clinics.

·

Supports education and training in fundamental sciences and clinical disciplines for participation in basic and clinical research programs and treatment programs relating to cancer through career awards, training grants, and fellowships.

·

Supports research projects in cancer control.

·

Supports a national network of cancer centers.

·

Collaborates with voluntary organizations and other national and foreign institutions engaged in cancer research and training activities.

This paragraph has been adapted from the NCI: http://www.nci.nih.gov/. “Adapted” signifies that a passage has been reproduced exactly or slightly edited for this book. 6

Guidelines 11

·

Encourages and coordinates cancer research by industrial concerns where such concerns evidence a particular capability for programmatic research.

·

Collects and disseminates information on cancer.

·

Supports construction of laboratories, clinics, and related facilities necessary for cancer research through the award of construction grants.

The NCI, established under the National Cancer Act of 1937, is the Federal Government’s principal agency for cancer research and training. The National Cancer Act of 1971 broadened the scope and responsibilities of the NCI and created the National Cancer Program. Over the years, legislative amendments have maintained the NCI authorities and responsibilities and added new information dissemination mandates as well as a requirement to assess the incorporation of state-of-the-art cancer treatments into clinical practice. Information dissemination is made possible through the NCI Online at www.cancer.gov. Cancer.gov offers to the public and physicians up-to-date information on the latest cancer research, current and upcoming clinical trials, statistics, research programs, and research funding. The following guideline was recently published by the NCI on childhood rhabdomyosarcoma.

What Is Childhood Rhabdomyosarcoma?7 Rhabdomyosarcoma is a disease in which cancer (malignant) cells begin growing in muscle tissue. Rhabdomyosarcoma is a type of a sarcoma, which means a cancer of the bone, soft tissues, or connective tissue (e.g., tendon or cartilage). Rhabdomyosarcoma begins in the soft tissues in a type of muscle called striated muscle. It can occur anywhere in the body. There are several types of sarcoma that are found in children and young adults. The cancer cells must be looked at under a microscope to tell which type of sarcoma it is. Rhabdomyosarcoma is the most common type of sarcoma found in the soft tissues of children. (Refer to the PDQ summaries on Adult Soft Tissue Sarcoma Treatment; Childhood Soft Tissue Sarcoma Treatment; and Ewing’s Family of Tumors Treatment for more information.) If your child has symptoms of a sarcoma, your child’s doctor may order xrays and other tests. Your child’s doctor may also cut out a small piece of The following guidelines appeared on the NCI website on Aug. 26, 2002. The text was last modified in August 2002. The text has been adapted for this sourcebook. 7


tissue and have it looked at under the microscope to see if there are any cancer cells. This is called a biopsy. Your child’s chance of recovery (prognosis) and choice of treatment depend on where the cancer is located, how far it has spread, how the cells look under the microscope (histology), the type of therapy administered, and how much of the cancer can be removed by surgery.

Stages of Childhood Rhabdomyosarcoma Once childhood rhabdomyosarcoma is found, more tests will be done to find out if the cancer cells have spread to other parts of the body. This is called staging. Your doctor needs to know how far the cancer has spread to plan treatment. There are several staging systems for childhood rhabdomyosarcoma. The treatment options in this summary are based on size, location, and how far and where the cancer has spread. Stage 1 Cancer is found in the eye, head and/or neck, or near the sex organs and bladder.

Stage 2 Cancer is located in only 1 area (but in none of the areas in Stage 1), is smaller than 2 inches (5 cm) in size, and has not spread to the lymph nodes. Stage 3 Cancer is located in only 1 area (but in none of the areas in Stage 1), is greater than 2 inches (5 cm) in size, and may have spread to the lymph nodes found near the cancer.

Stage 4 Cancer has spread and is found in more than 1 place at the time of diagnosis.

Guidelines 13

Recurrent Recurrent disease means that the cancer has come back (recurred) after it has been treated. It may come back in the area where it started or in another part of the body.

How Childhood Rhabdomyosarcoma Is Treated There are treatments for all patients with childhood rhabdomyosarcoma. Three types of treatment are used, most often in combination with each other: ·

Surgery

·

Chemotherapy (using drugs to kill cancer cells)

·

Radiation therapy (using high-energy x-rays or other high-energy rays to kill cancer cells)

Surgery is a common treatment for rhabdomyosarcoma. Depending on where the cancer is, your child’s doctor will take out as much of the cancer as possible, along with some of the normal tissue around it. If the cancer is in a place where it cannot be removed, surgery may be limited to taking out only a small piece of the cancer (biopsy). Surgery is usually followed by chemotherapy and radiation therapy. Chemotherapy uses drugs to kill cancer cells. Chemotherapy may be taken by mouth in the form of a pill, or it may be put into the body by a needle in a vein or muscle. Chemotherapy is called a systemic treatment because the drugs enter the bloodstream, travel through the body, and can kill cancer cells throughout the body. Radiation therapy uses high-energy x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external radiation therapy) or from putting materials that produce radiation (radioisotopes) through thin plastic tubes in the area where the cancer cells are found (internal radiation therapy). Clinical trials are testing radiation given in several small doses per day (hyperfractionated radiation therapy). Bone marrow transplantation is a treatment being studied for recurrent rhabdomyosarcoma. Sometimes rhabdomyosarcoma becomes resistant to treatment with standard doses of radiation therapy or chemotherapy. Very high doses of chemotherapy may then be used to treat the cancer. Because the high doses of chemotherapy can destroy the bone marrow, marrow is


taken from the bones before treatment. The marrow is then frozen and highdose chemotherapy with or without radiation therapy is given to treat the cancer. The marrow that was taken out is then thawed and given back through a needle in a vein to replace the marrow that was destroyed. This type of transplant is called an autologous transplant.

Treatment by Stage Treatment for childhood rhabdomyosarcoma depends on where the cancer is, how far it has spread, and what the cancer cells look like under a microscope. Your child may receive treatment that is considered standard based on its effectiveness in a number of patients in past studies, or you may choose to have your child go into a clinical trial. Not all patients are cured with standard therapy and some standard treatments may have more side effects than are desired. For these reasons, clinical trials are designed to test new treatments and to find better ways to treat cancer patients. A large cooperative group clinical trial comparing new treatments with standard treatments is ongoing in most parts of the country for all stages of rhabdomyosarcoma. If you want more information, call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237); TTY at 1-800-3328615. Previously Untreated (Stages 1-4) Childhood Rhabdomyosarcoma If the cancer can be removed, your child’s treatment will probably be surgery followed by chemotherapy. Radiation therapy may also be given if there is cancer left following surgery. If the cancer cannot be removed with surgery, your child’s treatment will probably be chemotherapy plus radiation therapy, followed, if needed, by surgery. Clinical trials are testing new chemotherapy drugs, new ways of giving radiation therapy, and autologous bone marrow transplantation following high-dose chemotherapy (for patients whose cancer has spread to other parts of the body).

Recurrent Childhood Rhabdomyosarcoma Your child’s treatment depends on how much of the cancer can be removed by surgery, where the cancer came back, and the treatment your child received before. Your child’s treatment may be chemotherapy. Clinical trials

Guidelines 15

are testing new chemotherapy agents followed by autologous bone marrow transplantation.

To Learn More Call For more information, U.S. residents may call the National Cancer Institute’s (NCI’s) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-4226237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-ofhearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

Web Sites and Organizations The NCI’s Cancer.gov Web site (http://cancer.gov) provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. There are also many other places where people can get materials and information about cancer treatment and services. Local hospitals may have information on local and regional agencies that offer information about finances, getting to and from treatment, receiving care at home, and dealing with problems associated with cancer treatment. Publications The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator (https://cissecure.nci.nih.gov/ncipubs). These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-8004-CANCER (1-800-422-6237), TTY at 1-800-332-8615.


LiveHelp The NCI’s LiveHelp service, a program available on several of the Institute’s Web sites, provides Internet users with the ability to chat online with an Information Specialist. The service is available from Monday - Friday 9:00 AM - 10:00 PM Eastern Time. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer. Write For more information from the NCI, please write to this address: National Cancer Institute Office of Communications 31 Center Drive, MSC 2580 Bethesda, MD 20892-2580

About PDQ PDQ Is a Comprehensive Cancer Database Available on Cancer.gov PDQ is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. Most of the information contained in PDQ is available online at Cancer.gov, the NCI’s Web site. PDQ is provided as a service of the NCI. The NCI is part of the National Institutes of Health, the federal government’s focal point for biomedical research. PDQ Contains Cancer Information Summaries The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries are available in two versions. The health professional versions provide detailed information written in technical language. The patient versions are written in easy-tounderstand, non-technical language. Both versions provide current and accurate cancer information. The PDQ cancer information summaries are developed by cancer experts and reviewed regularly. Editorial Boards made up of experts in oncology and related specialties are responsible for writing and maintaining the cancer information summaries. The summaries are reviewed regularly and changes

Guidelines 17

are made as new information becomes available. The date on each summary (“Date Last Modified”) indicates the time of the most recent change.

PDQ Contains Information on Clinical Trials In the United States, about two-thirds of children with cancer are treated in a clinical trial at some point in their illness. A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about new treatments, the risks involved, and how well they do or do not work. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Listings of clinical trials are included in PDQ and are available online at Cancer.gov. Descriptions of the trials are available in health professional and patient versions. For additional help in locating a childhood cancer clinical trial, call the Cancer Information Service at 1-800-4-CANCER (1-800-4226237), TTY at 1-800-332-8615.

The PDQ Database Contains Listings of Groups Specializing in Clinical Trials The Children’s Oncology Group (COG) is the major group that organizes clinical trials for childhood cancers in the United States. Information about contacting COG is available on Cancer.gov or from the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615. The PDQ Database Contains Listings of Cancer Professionals and Hospitals with Cancer Programs

Health

Because cancer in children and adolescents is rare, the majority of children with cancer are treated by health professionals specializing in childhood cancers, at hospitals or cancer centers with special facilities to treat them. The PDQ database contains listings of health professionals who specialize in childhood cancer and listings of hospitals with cancer programs. For help locating childhood cancer health professionals or a hospital with cancer programs, call the Cancer Information Service at 1-800-4-CANCER (1-800422-6237), TTY at 1-800-332-8615.


More Guideline Sources The previous guideline on childhood rhabdomyosarcoma is only one example of the kind of material that you can find online and free of charge. The remainder of this chapter will direct you to other sources which either publish or can help you find additional guidelines on topics related to childhood rhabdomyosarcoma. Many of the guidelines listed below address topics that may be of particular relevance to your child’s specific situation, while certain guidelines will apply to only some children with childhood rhabdomyosarcoma. Due to space limitations these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. Topic Pages: MEDLINEplus For parents wishing to go beyond guidelines published by specific Institutes of the NIH, the National Library of Medicine has created a vast and parentoriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages.” You can think of a health topic page as a guide to patient guides. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. If you do not find topics of interest when browsing health topic pages, then you can choose to use the advanced search utility of MEDLINEplus at http://www.nlm.nih.gov/medlineplus/advancedsearch.html. This utility is similar to the NIH Search Utility, with the exception that it only includes material linked within the MEDLINEplus system (mostly parent-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search.

Guidelines 19

The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search their site located at http://www.guideline.gov by using the keyword “childhood rhabdomyosarcoma” or synonyms. The following was recently posted: Healthfinder™ Healthfinder™ is an additional source sponsored by the U.S. Department of Health and Human Services which offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: ·

Retinoblastoma (PDQ®): Treatment Summary: This treatment information for patients is based on information in the PDQ® summary for health professionals on the cancer type -- retinoblastoma. Source: National Cancer Institute, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=5069

The NIH Search Utility After browsing the references listed at the beginning of this chapter, you may want to explore the NIH Search Utility. This allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEBSPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to childhood rhabdomyosarcoma. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and parents. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html.


NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing, for a nominal fee, short yet comprehensive guidelines on over 1,000 medical conditions. NORD primarily focuses on rare medical conditions that might not be covered by the previously listed sources. NORD’s Web address is www.rarediseases.org. To see if a recent fact sheet has been published on childhood rhabdomyosarcoma, simply go to the following hyperlink: http://www.rarediseases.org/cgi-bin/nord/alphalist. A complete guide on childhood rhabdomyosarcoma can be purchased from NORD for a nominal fee.

Additional Web Sources A number of Web sites that often link to government sites are available to the public. These can also point you in the direction of essential information. The following is a representative sample: ·

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

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drkoop.comÒ: http://www.drkoop.com/conditions/ency/index.html

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

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

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

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

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

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WebMDÒHealth: http://my.webmd.com/health_topics

Vocabulary Builder The material in this chapter may have contained a number of unfamiliar words. The following Vocabulary Builder introduces you to terms used in this chapter that have not been covered in the previous chapter: Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Biopsy: The removal of cells or tissues for examination under a microscope. When only a sample of tissue is removed, the procedure is called an incisional biopsy or core biopsy. When an entire tumor or lesion is removed,

Guidelines 21

the procedure is called an excisional biopsy. When a sample of tissue or fluid is removed with a needle, the procedure is called a needle biopsy or fineneedle aspiration. [NIH] Bladder: The organ that stores urine. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Histology: The study of tissues and cells under a microscope. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Oncology: The study of cancer. [NIH] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiology: The use of radiation (such as x-rays) or other imaging technologies (such as ultrasound and magnetic resonance imaging) to diagnose or treat disease. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH] Systemic: Affecting the entire body. [NIH] Transplantation: person. [NIH]

The replacement of an organ with one from another

Seeking Guidance 23

CHAPTER 2. SEEKING GUIDANCE Overview Some parents are comforted by the knowledge that a number of organizations dedicate their resources to helping people with childhood rhabdomyosarcoma. These associations can become invaluable sources of information and advice. Many associations offer parent support, financial assistance, and other important services. Furthermore, healthcare research has shown that support groups often help people to better cope with their conditions.8 In addition to support groups, your child’s physician can be a valuable source of guidance and support. In this chapter, we direct you to resources that can help you find parent organizations and medical specialists. We begin by describing how to find associations and parent groups that can help you better understand and cope with your child’s condition. The chapter ends with a discussion on how to find a doctor that is right for your child.

Associations and Childhood Rhabdomyosarcoma In addition to associations or groups that your child’s doctor might recommend, we suggest that you consider the following list (if there is a fee for an association, you may want to check with your child’s insurance provider to find out if the cost will be covered):

Churches, synagogues, and other houses of worship might also have groups that can offer you the social support you need. 8


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Children's Blood Foundation Address: Children's Blood Foundation 333 East 38th Street, Room 830, New York, NY 10016-2745 Telephone: (212) 297-4336 Toll-free: (800) 562-6265 Fax: (212) 297-4340 Email: [email protected] Background: The Children's Blood Foundation (CBF) is a nonprofit organization dedicated to promoting and/or supporting research, medical training of physicians, and care of children with leukemia, thalassemia, hemophilia, anemia, cancer, immune disorders, and AIDS. Established in 1952, the CBF has the largest hemophilia center in the New York area and the largest thalassemia center in North America, receiving more than 5,000 patient visits every year. All affected children are served, regardless of the family's ability to pay. Educational materials include a self-titled brochure, a regular newsletter entitled 'The Key to Life for a Child,' and a booklet entitled 'What's It Called Again? - Answers to the Most Commonly Asked Questions About Idiopathic Thrombocytopenic Purpura (ITP) In Children.' CBF has support groups, offers networking services, and engages in educational activities. Relevant area(s) of interest: Neuroblastoma, Retinoblastoma

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Institute for Families of Blind Children Address: Institute for Families of Blind Children P.O. Box 54700, Mailstop Number 111, Los Angeles, CA 90054-0700 Telephone: (323) 669-4649 Toll-free: (800) 562-6265 Fax: (323) 665-7869 Background: The Institute for Families of Blind Children is a not-forprofit voluntary organization dedicated to providing support, information, and understanding to families affected by blindness. All services are provided at no cost to families and professionals. Funding is provided by private donations. Established in 1987, the Institute provides consultation and therapy for parents, siblings, and extended family members and refers parents and physicians to organizations specializing in meeting the needs of children with visual impairment. Educational materials include regularly published journal articles, booklets, a regular newsletter, and videotapes that offer practical suggestions and coping strategies for individuals who are blind. The Institute also provides nationwide 'in service training' for physicians, residents, medical students, nurses, and other health care workers to enhance their understanding of issues facing affected families.

Seeking Guidance 25

Relevant area(s) of interest: Retinoblastoma ·

March of Dimes Birth Defects Foundation Address: March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue, White Plains, NY 10605 Telephone: (914) 428-7100 Toll-free: (888) 663-4637 Fax: (914) 997-4763 Email: [email protected] Web Site: http://www.modimes.org Background: The March of Dimes Birth Defects Foundation is a national not-forprofit organization that was established in 1938. The mission of the Foundation is to improve the health of babies by preventing birth defects and infant mortality. Through the Campaign for Healthier Babies, the March of Dimes funds programs of research, community services, education, and advocacy. Educational programs that seek to prevent birth defects are important to the Foundation and to that end it produces a wide variety of printed informational materials and videos. The March of Dimes public health educational materials provide information encouraging health- enhancing behaviors that lead to a healthy pregnancy and a healthy baby. Relevant area(s) of interest: Retinoblastoma

·

National Retinoblastoma Parent Group Address: National Retinoblastoma Parent Group PO Box 317, Watertown, MA 02471 Telephone: (914) 428-7100 Toll-free: (800) 562-6265 Fax: (617) 972-7444 Email: [email protected] Background: The National Retinoblastoma Parent Group is a not-forprofit self-help organization dedicated to providing information and support to parents of children with Retinoblastoma, a malignant tumor appearing in one or both eyes. Established in the late 1980s, the National Retinoblastoma Parent Group provides a variety of educational and support materials including a regular newsletter and medical journal article reprints concerning Retinoblastoma. Relevant area(s) of interest: Retinoblastoma


·

OncoLink: The University of Pennsylvania Cancer Center Resource Address: The University of Pennsylvania Cancer Center Resource Web Site on the Internet, Telephone: (212) 297-4336 Toll-free: (800) 562-6265 Email: [email protected] Web Site: http://www.oncolin.upenn.edu Background: OncoLink is a multimedia oncology information resource on the World Wide Web on the Internet. OncoLink's mission 'is consistent with that of the University of Pennsylvania Medical Center and the University of Pennsylvania Cancer Center, which have sanctioned the site's use and development. OncoLink is accessible worldwide to anyone with Internet access, and there is no charge for its use. Oncolink has been established with the following objectives: (1) dissemination of information relevant to the field of oncology; (2) education of health care personnel; (3) education of affected individuals, families, and other interested parties; and (4) rapid collection of information pertinent to the specialty. OncoLink's home page includes the following headings: Disease Oriented Headings (i.e., specific types of cancer); Medical Specialty Oriented Menus (i.e., medical specialities that deal with cancer, chemotherapy information, etc.); Psychosocial Support and Personal Experiences; Cancer Causes, Screening, and Prevention; Clinical Trials; Global Resources for Cancer Information; Cancer FAQs (frequently asked questions); Medical Supportive Care for the Cancer Patient; Conferences and Meetings; and Financial Issues for Cancer Patients. Relevant area(s) of interest: Neuroblastoma, Retinoblastoma

Finding More Associations There are a number of directories that list additional medical associations that you may find useful. While not all of these directories will provide different information than what is listed above, by consulting all of them, you will have nearly exhausted all sources for parent associations. The National Cancer Institute (NCI) The National Cancer Institute (NCI) has complied a list of national organizations that offer services to people with cancer and their families. To view the list, see the NCI fact sheet online at the following Web address: http://cis.nci.nih.gov/fact/8_1.htm. The name of each organization is

Seeking Guidance 27

accompanied by its contact information and a brief explanation of its services. Information on a number of organizations specializing in children’s issues is also available. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about childhood rhabdomyosarcoma. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.

DIRLINE A comprehensive source of information on associations is the DIRLINE database maintained by the National Library of Medicine. The database comprises some 10,000 records of organizations, research centers, and government institutes and associations which primarily focus on health and biomedicine. DIRLINE is available via the Internet at the following Web site: http://dirline.nlm.nih.gov. Simply type in “childhood rhabdomyosarcoma” (or a synonym) or the name of a topic, and the site will list information contained in the database on all relevant organizations.

The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “childhood rhabdomyosarcoma”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” By making these selections and typing in “childhood rhabdomyosarcoma” (or synonyms) into the “For these words:” box, you will only receive results on organizations dealing with childhood rhabdomyosarcoma. You should check back periodically with this database since it is updated every 3 months.


The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by specific medical conditions. You can access this database at the following Web site: http://www.rarediseases.org/cgi-bin/nord/searchpage. Select the option called “Organizational Database (ODB)” and type “childhood rhabdomyosarcoma” (or a synonym) in the search box.

Cancer Support Groups9 People diagnosed with cancer and their families face many challenges that may leave them feeling overwhelmed, afraid, and alone. It can be difficult to cope with these challenges or to talk to even the most supportive family members and friends. Often, support groups can help people affected by cancer feel less alone and can improve their ability to deal with the uncertainties and challenges that cancer brings. Support groups give people who are affected by similar diseases an opportunity to meet and discuss ways to cope with the illness. How Can Support Groups Help? People who have been diagnosed with cancer sometimes find they need assistance coping with the emotional as well as the practical aspects of their disease. In fact, attention to the emotional burden of cancer is sometimes part of a patient’s treatment plan. Cancer support groups are designed to provide a confidential atmosphere where cancer patients or cancer survivors can discuss the challenges that accompany the illness with others who may have experienced the same challenges. For example, people gather to discuss the emotional needs created by cancer, to exchange information about their disease—including practical problems such as managing side effects or returning to work after treatment—and to share their feelings. Support groups have helped thousands of people cope with these and similar situations.

9

This section has been adapted from the NCI: http://cis.nci.nih.gov/fact/8_8.htm.

Seeking Guidance 29

Can Family Members and Friends Participate in Support Groups? Family and friends are affected when cancer touches someone they love, and they may need help in dealing with stresses such as family disruptions, financial worries, and changing roles within relationships. To help meet these needs, some support groups are designed just for family members of people diagnosed with cancer; other groups encourage families and friends to participate along with the cancer patient or cancer survivor. How Can People Find Support Groups? Many organizations offer support groups for people diagnosed with cancer and their family members or friends. The NCI fact sheet National Organizations That Offer Services to People With Cancer and Their Families lists many cancer-concerned organizations that can provide information about support groups. This fact sheet is available at http://cis.nci.nih.gov/fact/8_1.htm on the Internet, or can be ordered from the Cancer Information Service at 1–800–4–CANCER (1–800–422–6237). Some of these organizations provide information on their Web sites about contacting support groups. Doctors, nurses, or hospital social workers who work with cancer patients may also have information about support groups, such as their location, size, type, and how often they meet. Most hospitals have social services departments that provide information about cancer support programs. Additionally, many newspapers carry a special health supplement containing information about where to find support groups.

What Types of Support Groups Are Available? Several kinds of support groups are available to meet the individual needs of people at all stages of cancer treatment, from diagnosis through follow-up care. Some groups are general cancer support groups, while more specialized groups may be for teens or young adults, for family members, or for people affected by a particular disease. Support groups may be led by a professional, such as a psychiatrist, psychologist, or social worker, or by cancer patients or survivors. In addition, support groups can vary in approach, size, and how often they meet. Many groups are free, but some require a fee (people can contact their health insurance company to find out whether their plan will cover the cost). It is important for people to find an atmosphere that is comfortable and meets their individual needs.


Online Support Groups In addition to support groups, commercial Internet service providers offer forums and chat rooms to discuss different illnesses and conditions. WebMDÒ, for example, offers such a service at their Web site: http://boards.webmd.com/roundtable. These online communities can help you connect with a network of people whose concerns are similar to yours. Online support groups are places where people can talk informally. If you read about a novel approach, consult with your child’s doctor or other healthcare providers, as the treatments or discoveries you hear about may not be scientifically proven to be safe and effective.

The Cancer Information Service10 The Cancer Information Service (CIS) is a program of the National Cancer Institute (NCI), the Nation’s lead agency for cancer research. As a resource for information and education about cancer, the CIS is a leader in helping people become active participants in their own health care by providing the latest information on cancer in understandable language. Through its network of regional offices, the CIS serves the United States, Puerto Rico, the U.S. Virgin Islands, and the Pacific Islands. For 25 years, the Cancer Information Service has provided the latest and most accurate cancer information to patients and families, the public, and health professionals by: ·

Interacting with people one-on-one through its Information Service,

·

Working with organizations through its Partnership Program,

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Participating in research efforts to find the best ways to help people adopt healthier behaviors,

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Providing access to NCI information over the Internet. How Does the CIS Assist the Public?

Through the CIS toll-free telephone service (1–800–4–CANCER), callers speak with knowledgeable, caring staff who are experienced at explaining medical information in easy-to-understand terms. CIS information specialists answer calls in English and Spanish. They also provide cancer information to deaf and hard of hearing callers through the toll-free TTY number (1–800– 10


Seeking Guidance 31

332–8615). CIS staff have access to comprehensive, accurate information from the NCI on a range of cancer topics, including the most recent advances in cancer treatment. They take as much time as each caller needs, provide thorough and personalized attention, and keep all calls confidential. The CIS also provides live, online assistance to users of NCI Web sites through LiveHelp, an instant messaging service that is available from 9:00 a.m. to 7:30 p.m. Eastern time, Monday through Friday. Through LiveHelp, information specialists provide answers to questions about cancer and help in navigating Cancer.gov, the NCI’s Web site. Through the telephone numbers or LiveHelp service, CIS users receive: ·

Answers to their questions about cancer, including ways to prevent cancer, symptoms and risks, diagnosis, current treatments, and research studies;

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Written materials from the NCI;

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Referrals to clinical trials and cancer-related services, such as treatment centers, mammography facilities, or other cancer organizations;

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Assistance in quitting smoking from information specialists trained in smoking cessation counseling. What Kind of Assistance Does the CIS Partnership Program Offer?

Through its Partnership Program, the CIS collaborates with established national, state, and regional organizations to reach minority and medically underserved audiences with cancer information. Partnership Program staff provide assistance to organizations developing programs that focus on breast and cervical cancer, clinical trials, tobacco control, and cancer awareness for special populations. To reach those in need, the CIS: ·

Helps bring cancer information to people who do not traditionally seek health information or who may have difficulties doing so because of educational, financial, cultural, or language barriers;

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Provides expertise to organizations to help strengthen their ability to inform people they serve about cancer; and

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Links organizations with similar goals and helps them plan and evaluate programs, develop coalitions, conduct training on cancer-related topics, and use NCI resources.


How Do CIS Research Efforts Assist the Public? The CIS plays an important role in research by studying the most effective ways to communicate with people about healthy lifestyles; health risks; and options for preventing, diagnosing, and treating cancer. The ability to conduct health communications research is a unique aspect of the CIS. Results from these research studies can be applied to improving the way the CIS communicates about cancer and can help other programs communicate more effectively. How Do People Reach the Cancer Information Service? ·

To speak with a CIS information specialist call 1–800–4–CANCER (1–800– 422–6237), 9:00 a.m. to 4:30 p.m. local time, Monday through Friday. Deaf or hard of hearing callers with TTY equipment may call 1–800–332–8615.

·

To obtain online assistance visit the NCI’s Cancer Information Web site at http://cancer.gov/cancer_information and click on the LiveHelp link between 9:00 a.m. and 7:30 p.m. Eastern time, Monday through Friday.

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For information 24 hours a day, 7 days a week call 1–800–4–CANCER and select option 4 to hear recorded information at any time.

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Visit NCI’s Web site at http://cancer.gov on the Internet.

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Visit the CIS Web site at http://cancer.gov/cis on the Internet.

Finding Cancer Resources in Your Community11 When your child has cancer or is undergoing cancer treatment, there are places in your community to turn to for help. There are many local organizations throughout the country that offer a variety of practical and support services to children with cancer and their families. However, parents often don’t know about these services or are unable to find them. National cancer organizations can assist you in finding these resources, and there are a number of things you can do for yourself. Whether you are looking for a support group, counseling, advice, financial assistance, transportation for your child to and from treatment, or information about cancer, most neighborhood organizations, local health care providers, or area hospitals are a good place to start. Often, the hardest part of looking for help is knowing the right questions to ask. 11

Adapted from the NCI: http://cis.nci.nih.gov/fact/8_9.htm.

Seeking Guidance 33

What Kind of Help Can I Get? Until now, you probably never thought about the many issues and difficulties that arise with a diagnosis of cancer. There are support services to help you deal with almost any type of problem that might occur. The first step in finding the help you need is knowing what types of services are available. The following pages describe some of these services and how to find them. ·

Information on Cancer. Most national cancer organizations provide a range of information services, including materials on different types of cancer, treatments, and treatment-related issues.

·

Counseling. While some parents are reluctant to seek counseling, studies show that having someone to talk to reduces stress. Counseling can also provide emotional support to children with cancer and help them better understand their illness. Different types of counseling include individual, group, family, self-help (sometimes called peer counseling), bereavement, patient-to-patient, and sexuality.

·

Medical Treatment Decisions. Often, parents need to make complicated medical decisions. Many organizations provide hospital and physician referrals for second opinions and information on clinical trials, which may expand treatment options.

·

Home Health Care. Home health care assists patients who no longer need to stay in a hospital, but still require professional medical help. Skilled nursing care, physical therapy, social work services, and nutrition counseling are all available at home.

·

Hospice Care. Hospice is care focused on the special needs of terminally ill cancer patients. Sometimes called palliative care, it centers around providing comfort, controlling physical symptoms, and giving emotional support to patients who can no longer benefit from curative treatment. Hospice programs provide services in various settings, including the patient’s home, hospice centers, hospitals, or skilled nursing facilities. Your child’s doctor or social worker can provide a referral for these services.

·

Rehabilitation. Rehabilitation services help people adjust to the effects of cancer and its treatment. Physical rehabilitation focuses on recovery from the physical effects of surgery or the side effects associated with chemotherapy.

·

Advocacy. Advocacy is a general term that refers to promoting or protecting the rights and interests of a certain group, such as cancer patients. Advocacy groups may offer services to assist with legal, ethical,


medical, employment, legislative, or insurance issues, among others. For instance, if you feel your insurance company has not handled your child’s claim fairly, you may want to advocate for a review of its decision. ·

Financial. Treating cancer can be a tremendous financial burden. There are programs sponsored by the government and nonprofit organizations to help parents of cancer patients with problems related to medical billing, insurance coverage, and reimbursement issues. There are also sources for financial assistance.

·

Housing/Lodging. Some organizations provide lodging for the family of a patient undergoing treatment, especially if it is a child who is ill and the parents are required to accompany the child to treatment.

·

Children’s Services. A number of organizations provide services for children with cancer, including summer camps, make-a-wish programs, and help for parents seeking child care. How to Find These Services

Often, the services that people with cancer are looking for are right in their own neighborhood or city. The following is a list of places where you can begin your search for help. ·

Your child’s hospital, clinic, or medical center should be able to give you information. The doctor or nurse may be able to tell you about your child’s specific medical condition, pain management, rehabilitation services, home nursing, or hospice care.

·

Most hospitals also have a social work, home care, or discharge planning department. This department may be able to help you find a support group or a nonprofit agency that helps people who have cancer and their families. While your child is undergoing treatment, be sure to ask the hospital about transportation, practical assistance, or even temporary child care. Talk to a hospital financial counselor in the business office about developing a monthly payment plan if you need help with hospital expenses.

·

The public library is an excellent source of information, as are patient libraries at many cancer centers. A librarian can help you find books and articles through a literature search.

·

A local church, synagogue, YMCA or YWCA, or fraternal order may provide financial assistance, or may have volunteers who can help with transportation and home care. Catholic Charities, the United Way, or the American Red Cross may also operate local offices. Some of these

Seeking Guidance 35

organizations may provide home care, and the United Way’s information and referral service can refer you to an agency that provides financial help. To find the United Way serving your community, visit their online directory at http://www.unitedway.org on the Internet or look in the White Pages of your local telephone book. ·

Local or county government agencies may offer low-cost transportation (sometimes called para-transit) to individuals unable to use public transportation. The Federal government runs the Hill-Burton program (1–800–638–0742), which funds certain medical facilities and hospitals to provide children with cancer with free or low-cost care if their families are in financial need. Getting the Most From a Service: What To Ask

No matter what type of help you are looking for, the only way to find resources to fit your needs is to ask the right questions. When you are calling an organization for information, it is important to think about what questions you are going to ask before you call. Many people find it helpful to write out their questions in advance, and to take notes during the call. Another good tip is to ask the name of the person with whom you are speaking in case you have follow-up questions. Below are some of the questions you may want to consider if you are calling or visiting a new agency and want to learn about how they can help: ·

How do I apply [for this service]?

·

Are there eligibility requirements? What are they?

·

Is there an application process? How long will it take? What information will I need to complete the application process? Will I need anything else to get the service?

·

Do you have any other suggestions or ideas about where I can find help?

The most important thing to remember is that you will rarely receive help unless you ask for it. In fact, asking can be the hardest part of getting help. Don’t be afraid or ashamed to ask for assistance. Cancer is a very difficult disease, but there are people and services that can ease your burdens and help you focus on your child’s treatment and recovery.


Finding Doctors Who Specialize in Cancer Care12 A common way to find a doctor who specializes in cancer care is to ask for a referral from your child’s primary care physician. Sometimes, you may know a specialist yourself, or through the experience of a family member, coworker, or friend. The following resources may also be able to provide you with names of doctors who specialize in treating specific diseases or conditions. However, these resources may not have information about the quality of care that the doctors provide. ·

Your local hospital or its patient referral service may be able to provide you with a list of specialists who practice at that hospital.

·

Your nearest National Cancer Institute (NCI)-designated cancer center can provide information about doctors who practice at that center. The NCI fact sheet The National Cancer Institute Cancer Centers Program describes and gives contact information, including Web sites, for NCIdesignated cancer treatment centers around the country. Many of the cancer centers’ Web sites have searchable directories of physicians who practice at each facility. The NCI’s fact sheet is available at http://cis.nci.nih.gov/fact/1_2.htm on the Internet, or by calling the Cancer Information Service (CIS) at 1–800–4–CANCER (1–800–422–6237).

·

The American Board of Medical Specialties (ABMS) publishes a list of board-certified physicians. The Official ABMS Directory of Board Certified Medical Specialists lists doctors’ names along with their specialty and their educational background. This resource is available in most public libraries. The ABMS also has a Web site that can be used to verify whether a specific physician is board-certified. This free service is located at http://www.abms.org/newsearch.asp on the Internet. Verification of a physician’s board certification can also be obtained by calling the ABMS at 1–866–275–2267 (1–866–ASK–ABMS).

·

The American Medical Association (AMA) provides an online service called AMA Physician Select that offers basic professional information on virtually every licensed physician in the United States and its possessions. The database can be searched by doctor’s name or by medical specialty. The AMA Physician Select service is located at http://www.ama-assn.org/aps/amahg.htm on the Internet.

·

The American Society of Clinical Oncologists (ASCO) provides an online list of doctors who are members of ASCO. The member database has the

12


Seeking Guidance 37

names and affiliations of over 15,000 oncologists worldwide. It can be searched by doctor’s name, institution’s name, location, and/or type of board certification. This service is located at http://www.asco.org/people/db/html/m_db.htm on the Internet. ·

The American College of Surgeons (ACOS) Fellowship Database is an online list of surgeons who are Fellows of the ACOS. The list can be searched by doctor’s name, geographic location, or medical specialty. This service is located at http://web.facs.org/acsdir/default.htm on the Internet. The ACOS can be contacted at 633 North Saint Clair Street, Chicago, IL 60611–3211; or by telephone at 312–202–5000.

·

Local medical societies may maintain lists of doctors in each specialty.

·

Public and medical libraries may have print directories of doctors’ names, listed geographically by specialty.

·

Your local Yellow Pages may have doctors listed by specialty under “Physicians.”

The Agency for Healthcare Research and Quality (AHRQ) offers Your Guide to Choosing Quality Health Care, which has information for consumers on choosing a health plan, a doctor, a hospital, or a long-term care provider. The Guide includes suggestions and checklists that you can use to determine which doctor or hospital is best for you. This resource is available at http://www.ahrq.gov/consumer/qntool.htm on the Internet. You can also order the Guide by calling the AHRQ Publications Clearinghouse at 1–800– 358–9295. If you are a member of a health insurance plan, your choice may be limited to doctors who participate in your plan. Your insurance company can provide you with a list of participating primary care doctors and specialists. It is important to ask your insurance company if the doctor you choose is accepting new patients through your health plan. You also have the option of seeing a doctor outside your health plan and paying the costs yourself. If you have a choice of health insurance plans, you may first wish to consider which doctor or doctors you would like to use, then choose a plan that includes your chosen physician(s). The National Comprehensive Cancer Network (NCCN) Physician Directory lists specialists who practice in the NCCN’s 19 member institutions across the U.S. To access the directory, go to http://www.nccn.org/ and click on “Physician Directory“. To use this service, you will be required to scroll to the bottom of the page and select “I agree.” Enter your search criteria and select “Find” at the bottom of the page. To obtain more information on a


physician or institution, contact the institution’s Physician Referral Department or the NCCN Patient Information and Referral Service at 1-888909-NCCN or [email protected]. If the previous sources did not meet your needs, you may want to log on to the Web site of the National Organization for Rare Disorders (NORD) at http://www.rarediseases.org/. NORD maintains a database of doctors with expertise in various rare diseases. The Metabolic Information Network (MIN), 800-945-2188, also maintains a database of physicians with expertise in various metabolic diseases.

Selecting Your Child’s Doctor13 There are many factors to consider when choosing a doctor. To make the most informed decision, you may wish to speak with several doctors before choosing one. When you meet with each doctor, you might want to consider the following: ·

Does the doctor have the education and training to meet my child’s needs?

·

Does the doctor use the hospital that I have chosen?

·

Does the doctor explain things clearly and encourage me to ask questions?

·

What are the doctor’s office hours?

·

Who covers for the doctor when he or she is unavailable? Will that person have access to my medical records?

·

How long does it take to get an appointment with the doctor?

If you are choosing a surgeon, you may wish to ask additional questions about the surgeon’s background and experience with specific procedures. These questions may include: ·

Is the surgeon board-certified?14

·

Has the surgeon been evaluated by a national professional association of surgeons, such as the American College of Surgeons (ACOS)?

·

At which treatment facility or facilities does the surgeon practice?

13 This

section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm. 14 While board certification is a good measure of a doctor’s knowledge, it is possible to receive quality care from doctors who are not board certified.

Seeking Guidance 39

·

How often does the surgeon perform the type of surgery that my child needs?

·

How many of these procedures has the surgeon performed? What was the success rate?

It is important for you and your child to feel comfortable with the specialist that you choose, because you will be working closely with that person to make decisions about your child’s cancer treatment. Trust your own observations and feelings when deciding on a doctor for your child’s medical care. Other health professionals and support services may also be important during cancer treatment. The National Cancer Institute fact sheet Your Health Care Team: Your Doctor Is Only the Beginning has information about these providers and services, and how to locate them. This fact sheet is located at http://cis.nci.nih.gov/fact/8_10.htm on the Internet, or can be obtained by calling the CIS at 1–800–4–CANCER (1–800–422–6237).

Working with Your Child’s Doctor15 Research has shown that parents who have good relationships with their children’s doctors tend to be more satisfied with their children’s care. Here are some tips to help you and your child’s doctor become partners: ·

You know important things about your child’s symptoms and health history. Tell the doctor what you think he or she needs to know.

·

Always bring any medications your child is currently taking with you to the appointment, or you can bring a list of your child’s medications including dosage and frequency information. Talk about any allergies or reactions your child has had to medications.

·

Tell your doctor about any natural or alternative medicines your child is taking.

·

Bring other medical information, such as x-ray films, test results, and medical records.

·

Ask questions. If you don’t, the doctor will assume that you understood everything that was said.

·

Write down your questions before the doctor’s visit. List the most important ones first to make sure that they are addressed.

This section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm.

15


·

Ask the doctor to draw pictures if you think that this will help you and your child understand.

·

Take notes. Some doctors do not mind if you bring a tape recorder to help you remember things, but always ask first.

·

Take information home. Ask for written instructions. Your child’s doctor may also have brochures and audio and videotapes on childhood rhabdomyosarcoma.

By following these steps, you will enhance the relationship you and your child have with the physician.

Getting a Second Opinion16 Once you have chosen a doctor and discussed a diagnosis and treatment plan, but before treatment has started, you may want to get a second opinion - that is, you may want to ask a different doctor to review the diagnosis and plan. Some insurance companies require a second opinion; some may pay for it if you ask. A second opinion may also be obtained during the course of treatment if it is not working as hoped. Most doctors support a parent’s decision to get a second opinion and many even suggest you do so. To find specialists to get a second opinion, you might: ·

Ask your child’s doctor to suggest a specialist for a second opinion.

·

Get the names of doctors who specialize in treating childhood cancer from the local medical society, a nearby hospital, or a medical school. You can find the telephone numbers for these organizations in your telephone directory or the Yellow Pages.

·

Contact an NCI Comprehensive Cancer Center for a second opinion and possible treatment. Considered “Centers of Excellence,” these cancer centers’ programs have been reviewed and selected by NCI. They offer the most up-todate diagnosis and treatment of cancer and are devoted to both basic and clinical research. To obtain information about the location of the different cancer centers, call the CIS at 1-800-4-CANCER (1-800422-6237) or TTY at 1-800-332-8615.

·

Contact the Pediatric Oncology Branch, NCI, located in Bethesda, Maryland, to ask for a second opinion appointment. They can be reached at 1-877-624-4878.

This section was adapted from the NCI: http://www.cancer.gov/CancerInformation/youngpeople.

16

Seeking Guidance 41

Finding a Cancer Treatment Facility17 Choosing a treatment facility is another important consideration for getting the best medical care possible. Although you may not be able to choose which hospital treats your child in an emergency, you can choose a facility for scheduled and ongoing care. If you have already found a doctor for your child’s cancer treatment, you may need to choose a facility based on where the doctor practices. The doctor may be able to recommend a facility that provides quality care. You may wish to ask the following questions when considering a treatment facility: ·

Has the facility had experience and success in treating my child’s condition?

·

Has the facility been rated by state, consumer, or other groups for its quality of care?

·

How does the facility check and work to improve its quality of care?

·

Has the facility been approved by a nationally recognized accrediting body, such as the American College of Surgeons (ACOS) and/or the Joint Commission on Accredited Healthcare Organizations (JCAHO)?

·

Does the facility explain patients’ rights and responsibilities? Are copies of this information available to patients?

·

Does the treatment facility offer support services, such as social workers and resources to help me find financial assistance if I need it?

·

Is the facility conveniently located?

If you are a member of a health insurance plan, your choice of treatment facilities may be limited to those that participate in your plan. Your insurance company can provide you with a list of approved facilities. Although the costs of cancer treatment can be very high, you have the option of paying out-of-pocket if you want to use a treatment facility that is not covered by your insurance plan. If you are considering paying for treatment yourself, you may wish to discuss the potential costs with your child’s doctor beforehand. You may also want to speak with the person who does the billing for the treatment facility. In some instances, nurses and social workers can provide you with more information about coverage, eligibility, and insurance issues.

Adapted from the NCI: http://cis.nci.nih.gov/fact/7_47.htm. At this Web site, information on how to find treatment facilities is also available for patients living outside the U.S. 17


The following resources may help you find a treatment facility for your child’s care: ·

The NCI fact sheet The National Cancer Institute Cancer Centers Program describes and gives contact information for NCI-designated cancer treatment centers around the country.

·

The ACOS accredits cancer programs at hospitals and other treatment facilities. More than 1,400 programs in the United States have been designated by the ACOS as Approved Cancer Programs. The ACOS Web site offers a searchable database of these programs at http://web.facs.org/cpm/default.htm on the Internet. The ACOS can be contacted at 633 North Saint Clair Street, Chicago, IL 60611–3211; or by telephone at 312–202–5000.

·

The JCAHO is an independent, not-for-profit organization that evaluates and accredits health care organizations and programs in the United States. It also offers information for the general public about choosing a treatment facility. The JCAHO Web site is located at http://www.jcaho.org on the Internet. The JCAHO is located at One Renaissance Boulevard, Oakbrook Terrace, IL 60181–4294. The telephone number is 630–792–5800.

·

The JCAHO offers an online Quality Check service that parents can use to determine whether a specific facility has been accredited by the JCAHO and view the organization’s performance reports. This service is located at http://www.jcaho.org/qualitycheck/directry/directry.asp on the Internet.

·

The AHRQ publication Your Guide To Choosing Quality Health Care has suggestions and checklists for choosing the treatment facility that is right for you.

Questions and Answers about Children’s Cancer Centers 18 Survival rates for childhood cancer have risen sharply over the past 20 years. In the United States, more than 75 percent of children with cancer are now alive 5 years after diagnosis, compared with about 60 percent in the mid1970s. Much of this dramatic improvement is due to the development of improved therapies at children’s cancer centers, where the majority of children with cancer have their treatment.

18


Seeking Guidance 43

What Are Children’s Cancer Centers? Children’s cancer centers are hospitals or units in hospitals that specialize in the diagnosis and treatment of cancer in children and adolescents. Most children’s, or pediatric, cancer centers treat patients up to the age of 20. Are There Standards for Children’s Cancer Centers? The following groups have established standards for children’s cancer centers or programs: ·

The National Cancer Institute (NCI)-sponsored Children’s Oncology Group (COG), formerly known as the Children’s Cancer Group (CCG) and the Pediatric Oncology Group (POG), is a network of children’s cancer centers that meet strict quality assurance standards.

·

The American Academy of Pediatrics (AAP) published Guidelines for the Pediatric Cancer Center and Role of such Centers in Diagnosis and Treatment in 1986 and 1997.

·

The American Society of Pediatric Hematology/Oncology (ASPH/O) established standard requirements for programs treating children with cancer and blood disorders.

These groups agree that a childhood cancer center should be staffed by trained pediatric oncologists (doctors who specialize in childhood cancer) and other specialists who work as a team. Other members of the health professional team usually include pediatric surgeons, specialist surgeons (for instance neurosurgeons and urologic surgeons), radiation oncologists, pathologists, nurses, consulting pediatric specialists, psychiatrists, oncology social workers, nutritionists, and home health care professionals—all with expertise in treating children and adolescents with cancer. Together, these professionals offer comprehensive care. What Are the Advantages of a Specialized Children’s Cancer Center? Because childhood cancer is relatively rare, it is important to seek treatment in centers that specialize in the treatment of children with cancer. Specialized cancer programs at comprehensive, multidisciplinary cancer centers follow established protocols (step-by-step guidelines for treatment). These protocols are carried out using a team approach. The team of health professionals is involved in designing the appropriate treatment and support program for


the child and the child’s family. In addition, these centers participate in specially designed and monitored research studies that help develop more effective treatments and address issues of long-term childhood cancer survival.

Can Children with Cancer Be Treated at the National Cancer Institute? The Pediatric Oncology Branch (POB) of the National Cancer Institute conducts clinical trials for a wide variety of childhood cancers at the Warren Grant Magnuson Clinical Center, which is located at the National Institutes of Health in Bethesda, Maryland. There is no charge to patients for services provided at the Clinical Center. Children, teenagers, and young adults with newly diagnosed or recurrent cancer (cancer that has come back) may be referred to the POB. To refer a patient with cancer, the patient’s doctor should call the POB’s toll-free number at 1–877–624–4878 between the hours of 8:30 a.m. and 5:00 p.m. and ask for the attending physician. The attending physician will discuss the case with the patient’s doctor, determine whether the patient is eligibile for treatment at NCI, and help arrange the referral. The POB can also be reached at http://www-dcs.nci.nih.gov/branches/pedonc/index.html on the Internet. POB attending physicians also are available to provide a second opinion about a patient. The patient, family, or physician can contact the POB to arrange for a second opinion. POB staff can offer assistance in cases where a diagnosis is difficult and also can aid in developing an appropriate treatment plan. Finding a Children’s Cancer Center A family’s pediatrician or family doctor often can provide a referral to a comprehensive children’s cancer center. Families and health professionals also can call the NCI’s Cancer Information Service (CIS) at 1–800–4– CANCER to learn about children’s cancer centers that belong to the Children’s Cancer Study Group and the Pediatric Oncology Group. All of the cancer centers that participate in these Groups have met strict standards of excellence for childhood cancer care.

Seeking Guidance 45

Additional Cancer Support Information In addition to the references above, the NCI has set up guidance Web sites that offers information on issues relating to cancer. These include: ·

Facing Forward - A Guide for Cancer Survivors: http://www.cancer.gov/cancer_information/doc_img.aspx?viewid=cc93a 843-6fc0-409e-8798-5c65afc172fe

·

Taking Time: Support for People With Cancer and the People Who Care About Them: http://www.cancer.gov/cancer_information/doc_img.aspx?viewid=21a4 6445-a5c8-4fee-95a3-d9d0d665077a

·

When Cancer Recurs: Meeting the Challenge: http://www.cancer.gov/cancer_information/doc_img.aspx?viewid=9e13 d0d2-b7de-4bd6-87da-5750300a0dab

·

Your Health Care Team: Your Doctor Is Only the Beginning: http://cis.nci.nih.gov/fact/8_10.htm

·

When Someone in Your Family Has Cancer: http://www.cancer.gov/CancerInformation/whensomeoneinyourfamily

Vocabulary Builder The following vocabulary builder provides definitions of words used in this chapter that have not been defined in previous chapters: Anemia: A condition in which the number of red blood cells is below normal. [NIH] Bereavement: Refers to the whole process of grieving and mourning and is associated with a deep sense of loss and sadness. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood


clots. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Mammography: The use of x-rays to create a picture of the breast. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurosurgeon: A doctor who specializes in surgery on the brain, spine, and other parts of the nervous system. [NIH] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [NIH] Palliative: 1. affording relief, but not cure. 2. an alleviating medicine. [EU] Pathologist: A doctor who identifies diseases by studying cells and tissues under a microscope. [NIH] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH]

Clinical Trials 47

CHAPTER 3. CLINICAL RHABDOMYOSARCOMA

TRIALS

AND

CHILDHOOD

Overview Very few medical conditions have a single treatment. The basic treatment guidelines that your child’s physician has discussed with you, or those that you have found using the techniques discussed in Chapter 1, may provide you with all that you will require. For some patients, current treatments can be enhanced with new or innovative techniques currently under investigation. In this chapter, we will describe how clinical trials work and show you how to keep informed of trials concerning childhood rhabdomyosarcoma.

What Is a Clinical Trial?19 Clinical trials involve the participation of people in medical research. Most medical research begins with studies in test tubes and on animals. Treatments that show promise in these early studies may then be tried with people. The only sure way to find out whether a new treatment is safe, effective, and better than other treatments for childhood rhabdomyosarcoma is to try it on patients in a clinical trial.

The discussion in this chapter has been adapted from the NIH and the NEI: www.nei.nih.gov/netrials/ctivr.htm.

19


What Kinds of Clinical Trials Are There? Clinical trials are carried out in three phases: ·

Phase I. Researchers first conduct Phase I trials with small numbers of patients and healthy volunteers. If the new treatment is a medication, researchers also try to determine how much of it can be given safely.

·

Phase II. Researchers conduct Phase II trials in small numbers of patients to find out the effect of a new treatment on childhood rhabdomyosarcoma.

·

Phase III. Finally, researchers conduct Phase III trials to find out how new treatments for childhood rhabdomyosarcoma compare with standard treatments already being used. Phase III trials also help to determine if new treatments have any side effects. These trials--which may involve hundreds, perhaps thousands, of people--can also compare new treatments with no treatment.

How Is a Clinical Trial Conducted? Various organizations support clinical trials at medical centers, hospitals, universities, and doctors’ offices across the United States. The “principal investigator” is the researcher in charge of the study at each facility participating in the clinical trial. Most clinical trial researchers are medical doctors, academic researchers, and specialists. The “clinic coordinator” knows all about how the study works and makes all the arrangements for your child’s visits. All doctors and researchers who take part in the study on childhood rhabdomyosarcoma carefully follow a detailed treatment plan called a protocol. This plan fully explains how the doctors will treat your child in the study. The “protocol” ensures that all patients are treated in the same way, no matter where they receive care. Clinical trials are controlled. This means that researchers compare the effects of the new treatment with those of the standard treatment. In some cases, when no standard treatment exists, the new treatment is compared with no treatment. Patients who receive the new treatment are in the treatment group. Patients who receive a standard treatment or no treatment are in the “control” group. In some clinical trials, patients in the treatment group get a new medication while those in the control group get a placebo. A placebo is a harmless substance, a “dummy” pill, that has no effect on childhood rhabdomyosarcoma. In other clinical trials, where a new surgery or device

Clinical Trials 49

(not a medicine) is being tested, patients in the control group may receive a “sham treatment.” This treatment, like a placebo, has no effect on childhood rhabdomyosarcoma and will not harm your child. Researchers assign patients “randomly” to the treatment or control group. This is like flipping a coin to decide which patients are in each group. If you choose to have your child participate in a clinical trial, you will not know which group he or she will be appointed to. The chance of any patient getting the new treatment is about 50 percent. You cannot request that your child receive the new treatment instead of the placebo or “sham” treatment. Often, you will not know until the study is over whether your child has been in the treatment group or the control group. This is called a “masked” study. In some trials, neither doctors nor patients know who is getting which treatment. This is called a “double masked” study. These types of trials help to ensure that the perceptions of the participants or doctors will not affect the study results. Natural History Studies Unlike clinical trials in which patient volunteers may receive new treatments, natural history studies provide important information to researchers on how childhood rhabdomyosarcoma develops over time. A natural history study follows patient volunteers to see how factors such as age, sex, race, or family history might make some people more or less at risk for childhood rhabdomyosarcoma. A natural history study may also tell researchers if diet, lifestyle, or occupation affects how a medical condition develops and progresses. Results from these studies provide information that helps answer questions such as: How fast will a medical condition usually progress? How bad will the condition become? Will treatment be needed? What Is Expected of Your Child in a Clinical Trial? Not everyone can take part in a clinical trial for a specific medical condition. Each study enrolls patients with certain features or eligibility criteria. These criteria may include the type and stage of the condition, as well as, the age and previous treatment history of the patient. You or your child’s doctor can contact the sponsoring organization to find out more about specific clinical trials and their eligibility criteria. If you would like your child to participate in a clinical trial, your child’s doctor must contact one of the trial’s


investigators and provide details about his or her diagnosis and medical history. When participating in a clinical trial, your child may be required to have a number of medical tests. Your child may also need to take medications and/or undergo surgery. Depending upon the treatment and the examination procedure, your child may be required to receive inpatient hospital care. He or she may have to return to the medical facility for followup examinations. These exams help find out how well the treatment is working. Follow-up studies can take months or years. However, the success of the clinical trial often depends on learning what happens to patients over a long period of time. Only patients who continue to return for follow-up examinations can provide this important long-term information.

Recent Trials on Childhood Rhabdomyosarcoma The National Institutes of Health and other organizations sponsor trials on various medical conditions. Because funding for research goes to the medical areas that show promising research opportunities, it is not possible for the NIH or others to sponsor clinical trials for every medical condition at all times. The following lists recent trials dedicated to childhood rhabdomyosarcoma.20 If the trial listed by the NIH is still recruiting, your child may be eligible. If it is no longer recruiting or has been completed, then you can contact the sponsors to learn more about the study and, if published, the results. Further information on the trial is available at the Web site indicated. Please note that some trials may no longer be recruiting patients or are otherwise closed. Before contacting sponsors of a clinical trial, consult with your child’s physician who can help you determine if your child might benefit from participation. ·

Chemotherapy Followed by Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Brain Tumor Condition(s): extraocular retinoblastoma; childhood choroid plexus tumor; disseminated neuroblastoma; childhood supratentorial ependymoma; previously untreated childhood rhabdomyosarcoma; localized unresectable neuroblastoma; untreated childhood supratentorial primitive neuroectodermal tumors; stage 4S neuroblastoma; untreated childhood medulloblastoma; childhood infratentorial ependymoma; regional neuroblastoma; localized resectable neuroblastoma; newly diagnosed childhood ependymoma

20

These are listed at www.ClinicalTrials.gov.

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Study Status: This study is currently recruiting patients. Sponsor(s): Kaplan Cancer Center Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of different regimens of combination chemotherapy followed by peripheral stem cell transplantation in treating children who have newly diagnosed brain tumor. Phase(s): Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003273;jsessionid=0ABF5E F0F931D2A87DEEA72AB8967092 ·

Combination Chemotherapy, Radiation Therapy, and Bone Marrow Transplantation in Treating Patients With Retinoblastoma Condition(s): extraocular retinoblastoma; recurrent retinoblastoma; intraocular retinoblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); St. Jude Children's Research Hospital Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy plus radiation therapy followed by bone marrow transplantation in treating patients who have retinoblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): Tennessee; Saint Jude Children's Research Hospital, Memphis, Tennessee, 38105-2794, United States; Recruiting; Carlos RodriguezGalindo 901-495-3300. Study chairs or principal investigators: Carlos Rodriguez-Galindo, Study Chair; St. Jude Children's Research Hospital


Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00004006;jsessionid=0ABF5E F0F931D2A87DEEA72AB8967092

Benefits and Risks21 What Are the Benefits of Participating in a Clinical Trial? If you are considering a clinical trial, it is important to realize that your child’s participation can bring many benefits: ·

A new treatment could be more effective than the current treatment for childhood rhabdomyosarcoma. Although only half of the participants in a clinical trial receive the experimental treatment, if the new treatment is proved to be more effective and safer than the current treatment, then those patients who did not receive the new treatment during the clinical trial may be among the first to benefit from it when the study is over.

·

If the treatment is effective, then it may improve your child’s health.

·

Clinical trial patients receive the highest quality of medical care. Experts watch them closely during the study and may continue to follow them after the study is over.

·

People who take part in trials contribute to scientific discoveries that may help others with childhood rhabdomyosarcoma. In cases where certain medical conditions run in families, your child’s participation may lead to better care or prevention for you and other family members. The Informed Consent

Once you agree to have your child take part in a clinical trial, you will be asked to sign an “informed consent.” This document explains a clinical trial’s risks and benefits, the researcher’s expectations of you and your child, and your child’s rights as a patient.

This section has been adapted from ClinicalTrials.gov, a service of the National Institutes of Health: http://www.clinicaltrials.gov/ct/gui/c/a1r/info/whatis?JServSessionIdzone_ct=9jmun6f291. 21

Clinical Trials 53

What Are the Risks? Clinical trials may involve risks as well as benefits. Whether or not a new treatment will work cannot be known ahead of time. There is always a chance that a new treatment may not work better than a standard treatment. There is also the possibility that it may be harmful. The treatment your child receives may cause side effects that are serious enough to require medical attention.

How Is Your Child’s Safety Protected? Clinical trials can raise fears of the unknown. Understanding the safeguards that protect your child can ease some of these fears. Before a clinical trial begins, researchers must get approval from their hospital’s Institutional Review Board (IRB), an advisory group that makes sure a clinical trial is designed to protect your child’s safety. During a clinical trial, doctors will closely watch your child to see if the treatment is working and if he or she is experiencing any side effects. All the results are carefully recorded and reviewed. In many cases, experts from the Data and Safety Monitoring Committee carefully monitor each clinical trial and can recommend that a study be stopped at any time. Your child will only be asked to participate in a clinical trial as a volunteer with your informed consent.

What Are Your Child’s Rights in a Clinical Trial? If your child is eligible for a clinical trial, you will be given information to help you decide whether or not you want him or her to participate. You and your child have the right to: ·

Information on all known risks and benefits of the treatments in the study.

·

Know how the researchers plan to carry out the study, for how long, and where.

·

Know what is expected of your child.

·

Know any costs involved for you or your child’s insurance provider.

·

Know before any of your child’s medical or personal information is shared with other researchers involved in the clinical trial.

·

Talk openly with doctors and ask any questions.


After your child joins a clinical trial, you and your child have the right to: ·

Leave the study at any time. Participation is strictly voluntary.

·

Receive any new information about the new treatment.

·

Continue to ask questions and get answers.

·

Maintain your child’s privacy. Your child’s name will not appear in any reports based on the study.

·

Know whether your child participated in the treatment group or the control group (once the study has been completed).

What Questions Should You Ask before Your Child Participates in a Clinical Trial? Questions you should ask when deciding whether or not to enroll your child in a clinical trial include the following: ·

What is the purpose of the clinical trial?

·

What are the standard treatments for childhood rhabdomyosarcoma? Why do researchers think the new treatment may be better? What is likely to happen to my child with or without the new treatment?

·

What tests and treatments will my child need? Will my child need surgery? Medication? Hospitalization?

·

How long will the treatment last? How often will my child have to come back for follow-up exams?

·

What are the treatment’s possible benefits to my child’s condition? What are the short- and long-term risks? What are the possible side effects?

·

Will the treatment be uncomfortable? Will it make my child sick? If so, for how long?

·

How will my child’s health be monitored?

·

Where will my child need to go for the clinical trial?

·

How much will it cost to participate in the study? What costs are covered by the study? How much will my child’s health insurance cover?

·

Who will be in charge of my child’s care?

·

Will taking part in the study affect my child’s daily life?

·

How does my child feel about taking part in a clinical trial? Will other family members benefit from my child’s contributions to new medical knowledge?

Clinical Trials 55

Clinical Trials and Insurance Coverage22 As you consider enrolling your child in a clinical trial, you will face the critical issue of how to cover the costs of care. Even if you have health insurance, your coverage may not include some or all of the patient care costs associated with a clinical trial. This is because some health plans define clinical trials as “experimental” or “investigational” procedures. Because lack of coverage for these costs can keep prospective participants from enrolling in trials, the National Cancer Institute is working with major health plans and managed care groups to find solutions. In the meantime, there are strategies that may help you deal with cost and coverage barriers. This section answers frequently asked questions about insurance coverage for clinical trial participation and directs you to additional information resources. The material here is mainly concerned with treatment clinical trials, since other types of trials (prevention, screening, etc.) are newer and generally not covered by health insurance at all. However, this guide may become more relevant for prevention and other types of trials as these trials grow more common. If you do not have any health insurance, you may find this section helpful for understanding some of the costs that trials involve.

What Costs Do Trials Involve? Who Is Usually Responsible for Paying Them? There are two types of costs associated with a trial: patient care costs and research costs. Patient care costs fall into two categories: ·

Usual care costs, such as doctor visits, hospital stays, clinical laboratory tests, x-rays, etc., which occur whether you are participating in a trial or receiving standard treatment. These costs have usually been covered by a third-party health plan, such as Medicare or private insurance.

·

Extra care costs associated with clinical trial participation, such as the additional tests that may or may not be fully covered by the clinical trial sponsor and/or research institution.

Adapted from the NCI: http://www.cancer.gov/clinical_trials/doc_header.aspx?viewid=1d92be79-8748-4bda-80052a56d332463b.

22


The sponsor and the participant’s health plan need to resolve coverage of these costs for particular trials. Research costs are those associated with conducting the trial, such as data collection and management, research physician and nurse time, analysis of results, and tests purely performed for research purposes. Such costs are usually covered by the sponsoring organization, such as NCI or a pharmaceutical company.

Criteria Used by Health Plans to Make Reimbursement Decisions about Trials Health insurance companies and managed care companies decide which health care services they will pay for by developing coverage policy regarding the specific services. In general, the most important factor determining whether something is covered is a health plan’s judgment as to whether the service is established or investigational. Health plans usually designate a service as established if there is a certain amount of scientific data to show that it is safe and effective. If the health plan does not think that such data exist in sufficient quantity, the plan may label the service as investigational. Health care services delivered within the setting of a clinical trial are very often categorized as investigational and not covered. This is because the health plan thinks that the major reason to perform the clinical trial is that there is not enough data to establish the safety and effectiveness of the service being studied. Thus, for some health plans, any mention of the fact that your child is involved in a clinical trial results in a denial of payment. Your health plan may define specific criteria that a trial must meet before extending coverage, such as the following:

Sponsorship Some plans may only cover costs of trials sponsored by organizations whose review and oversight of the trial is careful and scientifically rigorous, according to standards set by the health plan.

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Trial Phase and Type Some plans may cover patient care costs only for the clinical trials they judge to be “medically necessary” on a case-by-case basis. Trial phase may also affect coverage; for example, while a plan may be willing to cover costs associated with Phase III trials, which include treatments that have already been successful with a certain number of people, the plan may require some documentation of effectiveness before covering a Phase I or II trial. While health plans are interested in efforts to improve prevention and screening, they currently seem less likely to have a review process in place for these trials. Therefore, it may be more difficult to get coverage for the care costs associated with them. Some plans, especially smaller ones, will not cover any costs associated with a clinical trial. Policies vary widely, but in most cases your best bet is to have your child’s doctor initiate discussions with the health plan. Cost “Neutrality” Some health plans may limit coverage to trials they consider cost-neutral (i.e., not significantly more expensive than the treatments considered standard). Lack of Standard Therapy Some plans limit coverage of trials to situations in which no standard therapy is available. Facility and Personnel Qualifications A health plan may require that the facility and medical staff meet specific qualifications to conduct a trial involving unique services, especially intensive therapy such as a bone marrow transplant (high-dose chemotherapy with bone marrow/ stem cell rescue).


Increasing the Likelihood of Insurance Coverage for Trials23 There are several steps you can follow to deal with coverage issues up front when deciding to enroll your child in a clinical trial. Along the way, enlist the help of family members and your child’s doctor or other health professionals. You may find the following checklist useful:

Understand the Costs Associated with the Trial Ask your child’s doctor or the trial’s contact person about the costs that must be covered by you or your health plan. Are these costs significantly higher than those associated with standard care? Also, inquire about the experience of other patients in the trial. Have their plans paid for their care? Have there been any persistent problems with coverage? How often have the trial’s administrators been successful in getting plans to cover patient care costs? Understand Your Health Plan Be sure you know what’s in your policy; request and carefully review the actual contract language. If there’s a specific exclusion for “experimental treatment,” look closely at the policy to see how the plan defines such treatment and under what conditions it might be covered. If it is not clearly defined, call the plan’s customer service line, consult their Web site, and/or write to them. Ask for specific information about clinical trials coverage. Work Closely with Your Child’s Doctor Talk with the doctor about the paperwork he or she submits to your health plan. If there have been problems with coverage in the past, you might ask the doctor or the hospital to send an information package to the plan that includes studies supporting the procedure’s safety, benefits, and medical appropriateness. This package might include: ·

Publications from peer-reviewed literature about the proposed therapy that demonstrate patient benefits;

This section has been adapted from the NCI: http://www.cancer.gov/clinical_trials/doc_header.aspx?viewid=1d92be79-8748-4bda-80052a56d332463b&docid=0df4397a-eccb-465f-bd33-a89e7a708c46.

23

Clinical Trials 59

·

A letter that uses the insurance contract’s own language to explain why the treatment, screening method, or preventive measure should be covered;

·

Letters from researchers that explain the clinical trial;

·

Support letters from patient advocacy groups.

Be sure to keep your own copy of any materials that the doctor sends to your health plan for future reference.

Work Closely with Your Company’s Benefits Manager This person may be helpful in enlisting the support of your employer to request coverage for your child by the health plan. Give Your Health Plan a Deadline Ask the hospital or cancer center to set a target date for the therapy. This will help to ensure that coverage decisions are made promptly.

Know Your Child’s Rights24 A number of state governments are addressing the question of whether insurance companies ought to cover the costs associated with patients’ participation in clinical trials. Lack of such coverage is a significant barrier to many patients who might otherwise benefit from enrolling in a trial. Lack of coverage also makes it harder for researchers to successfully conduct trials that could improve prevention and treatment options. Information on State initiatives and legislation concerning cancer-related clinical trials is available at http://www.cancer.gov/ClinicalTrials/insurancelaws. By conducting your own research and learning about your child’s rights, you may increase the likelihood that your insurance company will cover the costs of a trial.

If Your Insurance Claim Is Denied after the Trial Has Begun If a claim is denied, read your policy to find out what steps you can follow to make an appeal. In “What Cancer Survivors Need to Know about Health 24

Adapted from Cancer.gov: http://www.cancer.gov/ClinicalTrials/insurancelaws.


Insurance”, the National Coalition for Cancer Survivorship suggests that you and your doctor demonstrate to the health plan that: ·

The therapy in the trial is not just a research study, but also a valid procedure that benefits patients;

·

Your child’s situation is similar to that of other patients who are participating in clinical trials as part of a covered benefit;

·

Possible complications have been anticipated and can be handled effectively.

You also may wish to contact your state insurance counseling hotline or insurance department for more help, or write your state insurance commissioner describing the problem. Where Else Can I Turn for Assistance? It’s never easy to deal with financial issues when a loved one faces cancer. Unfortunately, costs can present a significant barrier to clinical trials participation. The range of insurance issues and health plan contracts makes it impossible to deal with all of them here. You may wish to consult this partial list of publications, organizations, and Web sites for more information: Publications What Cancer Survivors Need to Know about Health Insurance National Coalition of Cancer Survivorship 1010 Wayne Avenue, 5th floor Silver Spring, MD 20910 (301) 650-8868 http://www.cansearch.org/ Cancer Treatments Your Insurance Should Cover The Association of Community Cancer Centers 11600 Nebel Street, Suite 201 Rockville, MD 20852 (301) 984-9496 http://www.accc-cancer.org/main2001.shtml The Managed Care Answer Guide Patient Advocate Foundation

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739 Thimble Shoals Boulevard, Suite 704 Newport News, VA 23606 (757) 873-6668 E-mail: [email protected] 1998 Guide to Health Insurance for People with Medicare, The Medicare Handbook Medicare Helpline: 1-800-444-4606 Health Care Financing Administration: http://www.hcfa.gov/ New Medicare site: http://www.medicare.gov/ Assistance Programs Candlelighters Childhood Cancer Foundation Ombudsman Program 910 Woodmont Avenue, #4607 Bethesda, MD 20814 (301) 657-8401; 1-800-366-2223 (toll-free) E-mail: [email protected] http://www.candlelighters.org The Ombudsman Program helps families of children with cancer and survivors of childhood cancer resolve a range of problems, including insurance coverage difficulties. Local groups appoint a Parent Advocate who works with the treatment center on behalf of families. Medical Care Management Corporation 5272 River Road, Suite 650 Bethesda, MD 20816-1405 (301) 652-1818 email: [email protected] http://www.mcman.com/ Working for a range of clients, including health plans, employers, and patients, MCMC conducts independent, objective reviews of hightechnology medical care cases to assist in decision-making. While it does charge for its services, MCMC also offers a volunteer program for those who cannot afford to pay.


More Information Resources OncoLink A service of the University of Pennsylvania Cancer Center. http://www.oncolink.com/ In addition to general cancer information, this web site features a section on financial information for patients. Among the topics: viatical settlements, life insurance, a glossary of financial and medical terms, and news about billing and insurance. American Association of Health Plans 1129 20th Street, NW, Suite 600 Washington, DC 20036-3421 (202) 778-3200 http://www.aahp.org/ The Web site section “For Consumers” includes a fact sheet on clinical research that describes various health plans’ efforts to support research initiatives and collaborate with academic health centers and universities. Health Insurance Association of America 555 13th Street, NW Washington, DC 20004 (202) 824-1600 ·

Home page: http://www.hiaa.org/

·

Consumer Information: http://www.hiaa.org/consumer/

·

Insurance Counseling Hotlines by State: http://www.hiaa.org/consumer/insurance_counsel.cfm

·

State Insurance Departments: http://www.hiaa.org/consumer/state_insurance.cfm

Government Initiatives to Expand Insurance Coverage for Trials25 The good news is that there has been a recent effort in the U.S. to assure clinical trials coverage, with NCI involved in several new initiatives as described below:

Adapted from the NCI: http://www.cancer.gov/clinical_trials/doc_header.aspx?viewid=1d92be79-8748-4bda-80052a56d332463b&docid=d8092601-daf9-4794-8536-3be2712eb6b9.

25

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NCI-Department of Defense Agreement An innovative 1996 agreement between NCI and the Department of Defense (DoD) has given thousands of DoD cancer patients more options for care and greater access to state-of-the-art treatments. Patients who are beneficiaries of TRICARE/CHAMPUS, the DoD’s health program, are covered for NCIsponsored Phase II and Phase III clinical treatment trials. NCI and DoD are refining a system that allows physicians and patients to determine quickly what current trials meet their needs and where they are taking place. NCI-Department of Veterans Affairs Agreement A 1997 agreement with the Department of Veterans Affairs provides coverage for eligible veterans of the armed services to participate in NCIsponsored prevention, diagnosis, and treatment studies nationwide. For additional information, see the VA/DoD Beneficiaries Digest Page at http://www.va.gov/cancer.htm.

Midwest Health Plans Agreement Some NCI Cooperative Groups have reached agreements with several insurers in Wisconsin and Minnesota to provide more than 200,000 people with coverage. The coverage is designated for patient care costs if they participate in a cooperative group-sponsored trial.

Pediatric Cancer Care Network This network, a cooperative agreement among the Children’s Cancer Group, the Pediatric Oncology Group, and the Blue Cross Blue Shield System Association (BCBS) nationwide, will ensure that children of BCBS subscribers receive care at designated centers of cancer care excellence and may promote the enrollment of children in Cooperative Group clinical trials.

Keeping Current on Clinical Trials Various government agencies maintain databases on trials. The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide the public and physicians with


current information about clinical research across the broadest number of medical conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to their Web site (www.clinicaltrials.gov) and search by “childhood rhabdomyosarcoma” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: ·

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

·

For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

·

For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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General References The following references describe clinical trials and experimental medical research. They have been selected to ensure that they are likely to be available from your local or online bookseller or university medical library. These references are usually written for healthcare professionals, so you may consider consulting with a librarian or bookseller who might recommend a particular reference. The following includes some of the most readily available references (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·

A Guide to Patient Recruitment: Today’s Best Practices & Proven Strategies by Diana L. Anderson; Paperback - 350 pages (2001), CenterWatch, Inc.; ISBN: 1930624115; http://www.amazon.com/exec/obidos/ASIN/1930624115/icongroupinterna

·

A Step-By-Step Guide to Clinical Trials by Marilyn Mulay, R.N., M.S., OCN; Spiral-bound - 143 pages Spiral edition (2001), Jones & Bartlett Pub; ISBN: 0763715697; http://www.amazon.com/exec/obidos/ASIN/0763715697/icongroupinterna

·

The CenterWatch Directory of Drugs in Clinical Trials by CenterWatch; Paperback - 656 pages (2000), CenterWatch, Inc.; ISBN: 0967302935; http://www.amazon.com/exec/obidos/ASIN/0967302935/icongroupinterna

·

The Complete Guide to Informed Consent in Clinical Trials by Terry Hartnett (Editor); Paperback - 164 pages (2000), PharmSource Information Services, Inc.; ISBN: 0970153309; http://www.amazon.com/exec/obidos/ASIN/0970153309/icongroupinterna

·

Dictionary for Clinical Trials by Simon Day; Paperback - 228 pages (1999), John Wiley & Sons; ISBN: 0471985961; http://www.amazon.com/exec/obidos/ASIN/0471985961/icongroupinterna

·

Extending Medicare Reimbursement in Clinical Trials by Institute of Medicine Staff (Editor), et al; Paperback 1st edition (2000), National Academy Press; ISBN: 0309068886; http://www.amazon.com/exec/obidos/ASIN/0309068886/icongroupinterna

·

Handbook of Clinical Trials by Marcus Flather (Editor); Paperback (2001), Remedica Pub Ltd; ISBN: 1901346293; http://www.amazon.com/exec/obidos/ASIN/1901346293/icongroupinterna


Vocabulary Builder The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Intraocular: Within the eye. [EU] Medulloblastoma: A malignant brain tumor that begins in the lower part of the brain and can spread to the spine or to other parts of the body. Medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Supratentorial: Located in the upper part of the brain. [NIH] Unresectable: Unable to be surgically removed. [NIH]

67

PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL

ABOUT PART II In Part II, we introduce you to additional resources and advanced research on childhood rhabdomyosarcoma. All too often, parents who conduct their own research are overwhelmed by the difficulty in finding and organizing information. The purpose of the following chapters is to provide you an organized and structured format to help you find additional information resources on childhood rhabdomyosarcoma. In Part II, as in Part I, our objective is not to interpret the latest advances on childhood rhabdomyosarcoma or render an opinion. Rather, our goal is to give you access to original research and to increase your awareness of sources you may not have already considered. In this way, you will come across the advanced materials often referred to in pamphlets, books, or other general works. Once again, some of this material is technical in nature, so consultation with a professional familiar with childhood rhabdomyosarcoma is suggested.

Studies 69

CHAPTER 4. STUDIES RHABDOMYOSARCOMA

ON

CHILDHOOD

Overview Every year, academic studies are published on childhood rhabdomyosarcoma or related conditions. Broadly speaking, there are two types of studies. The first are peer reviewed. Generally, the content of these studies has been reviewed by scientists or physicians. Peer-reviewed studies are typically published in scientific journals and are usually available at medical libraries. The second type of studies is non-peer reviewed. These works include summary articles that do not use or report scientific results. These often appear in the popular press, newsletters, or similar periodicals. In this chapter, we will show you how to locate peer-reviewed references and studies on childhood rhabdomyosarcoma. We will begin by discussing research that has been summarized and is free to view by the public via the Internet. We then show you how to generate a bibliography on childhood rhabdomyosarcoma and teach you how to keep current on new studies as they are published or undertaken by the scientific community.

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 rhabdomyosarcoma, 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 in “childhood rhabdomyosarcoma” (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 a sample of what you can expect from this type of search: ·

Factors for Improved Genetic Counseling for Retinoblastoma Based on a Survey of 55 Families Source: American Journal of Ophthalmology. 87(4):449-459, April 1979. Summary: A survey is presented that reveals inheritance patterns and other characteristics of families in which one or more members were treated after 1960 for retinoblastoma at the University of Minnesota Medical Center. Of 55 families treated, 5 involved more than 1 patient. Two of the five family cases involved collateral inheritance and three involved direct inheritance. Factors important for genetic counseling include the time of onset of first symptoms, the father's age, the occurrence of a second primary tumor, unilateral versus bilateral involvement, and the cytogenic analysis of the patient's chromosomes. Additionally, mutational mosaicism was considered as a cause for sporadic cases. Five genetic counseling categories for retinoblastoma are summarized, and pertinent risk figures are provided. 22 references.

·

Prenatal Epidemiology of Pediatric Tumors Source: Current Oncology Reports. 2(3):234-241, May 2000. Summary: The authors present an overview of epidemiologic studies of childhood cancer. The review focuses on studies investigating the prenatal period, specifically those examining ecologic hypotheses related to prenatal exposure. The studies are categorized as descriptive studies that examine trends in childhood cancer incidence worldwide and in the United States, ecologic studies, and analytical studies. Nearly 12,000 children under the age of 19 years are diagnosed with cancer each year. The most frequently diagnosed childhood malignancies include (1) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), (2) central nervous system tumors, (3) neuroblastoma, (4) Hodgkin's disease, (5) non-Hodgkin's lymphoma, (6) Wilms' tumor, (7) retinoblastoma, (8) soft tissue sarcoma, and (9) germ cell tumors. Recent analytic studies have focused on the following prenatal exposures and their association with

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childhood cancers: (1) Personal habits and physical characteristics; (2) occupation and occupational exposures; (3) environmental exposures, such as to electromagnetic fields; and (4) medical exposures, such as medications. With the exception of a small percentage of cases attributable to genetic syndromes such as familial retinoblastoma or Down's syndrome that predispose to childhood malignancies, the etiology of most childhood cancers is unknown. Four recent studies that investigated parental smoking and childhood malignancies produced inconsistent results. One study found a positive association between paternal smoking and elevated risks of childhood acute leukemia, lymphoma, and brain tumors. The second study found a significant positive association between paternal smoking and lymphoma and neuroblastoma and between maternal smoking and childhood ALL. The third study found no association with maternal smoking but a slightly increased risk between paternal smoking and infant ALL. The fourth study that examined paternal smoking and childhood AML and ALL found no association with either paternal or maternal smoking. 1 figure, 2 tables, 37 references. ·

From In Utero and Childhood Exposure to Parental Smoking to Childhood Cancer: A Possible Link and the Need for Action Source: Human and Experimental Toxicology. 18(4):192-201, 1999. Summary: Researchers critically summarize published studies in an effort to reassess the current state of knowledge regarding the potential association between prenatal exposure to environmental tobacco smoke (ETS), as well as maternal active smoking during pregnancy and postnatal exposure to ETS and enhanced incidence of childhood cancer. Elements to be considered include (1) the substantial reporting of pregnant women who remain smokers; (2) the widespread nature of exposure to environmental tobacco smoke during pregnancy as well as during childhood; (3) the known toxicology of tobacco smoke, and in particular, sidestream smoke, which is characterized by a rich carcinogen content; (4) the specific metabolism of fetuses and newborns; and (5) the amoun t of epidemiologic data already available. A thorough review of the literature identified studies that either exclusively dealt with the effect of passive smoking on the occurrence of childhood cancers, or more general etiologic studies of cancer. The researchers identified close to 50 publications presenting pertinent results from epidemiological investigations, and approximately 50 more on (1) mechanisms and metabolism, (2) smoking in pregnancy, and (3) exposure to environmental tobacco smoke, as well as selected reviews and commentaries. The vast majority were case-control studies dealing with


(1) all cancers, (2) leukemia and lymphomas, (3) central nervous system tumors, (4) Wilms' tumor, (5) retinoblastoma, (6) neuroblastoma, (7) hepatoblastoma, (8) rhabdomyosarcoma, (9) bone and soft tissues tumors, (10) germ cell tumors, and (11) specific histological types of leukemias, lymphomas or central nervous system tumors. No strong association between maternal smoking in pregnancy and/or exposure to environmental tobacco smoke and childhood cancer was found. However, several studies found slightly increased relative risks, generally smaller than 1.5. Tumors most often found associated with maternal smoking in pregnancy or environmental tobacco exposure are childhood brain tumors and leukemia-lymphoma, with risks up to two or greater in selected studies. In a few studies, risks associated with paternal smoking are higher than the maternal ones. This evidence from human studies, coupled with the demonstration of genotoxic effects on the fetus of exposure to metabolites of tobacco smoke and demonstrable presence of adducts, should lead to strong recommendations that aim to fully protect fetuses, newborns, and infants from tobacco smoke. 115 references.

Federally-Funded Research on Childhood Rhabdomyosarcoma The U.S. Government supports a variety of research studies relating to childhood rhabdomyosarcoma and associated conditions. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.26 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. Visit the site at http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket. You can perform targeted searches by various criteria including geography, date, as well as topics related to childhood rhabdomyosarcoma and related conditions. 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 rhabdomyosarcoma and related conditions. In some cases, 26 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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therefore, it may be difficult to understand how some basic or fundamental research could eventually translate into medical practice. The following sample is typical of the type of information found when searching the CRISP database for childhood rhabdomyosarcoma: ·

Project Title: DNA Damage Retinoblastoma and Cell Survival Principal Investigator & Institution: Fotedar, Arun; Associate Member and Head; Sidney Kimmel Cancer Center 10835 Altman Row San Diego, Ca 92121 Timing: Fiscal Year 2002; Project Start 1-MAR-2002; Project End 8-FEB2007 Summary: (provided by applicant) The Retinoblastoma (Rb) gene is functionally inactivated in many forms of cancer, like breast carcinoma and small cell lung carcinoma, and represents the prototypical tumor suppressor. In addition to its tumor suppressor activity Rb inhibits cell cycle progression, is essential for induction of cell cycle arrest after DNA damage and inhibits cell death. The complexity of biological effects of Rb is matched by the diversity of: proteins which bind Rb. Rb binds a number of proteins, including E2F-1, oncoviral proteins like the SV4O large T antigen, c-Abl, MDM2 and histone deacetylases. Although the observation that Rb inhibits cell death is almost nine years old, our understanding of the underlying molecular mechanisms remain obscure. We have found Rb mutants which retain the ability to inhibit cell cycle progression but do not promote cell survival after DNA damage. These studies have led us to propose a model of the anti-apoptotic activity of Rb in which the ability of Rb to promote cell survival after DNA damage is mediated by the LxCxE binding site of Rb. In this proposal we will further develop our hypothesis that the Rb-LxCxE interaction plays an essential role in cell survival after DNA damage. We will examine the generality of Rb-LxCxE interaction in cell survival after DNA damage and establish its biological significance by generating Rb -I- mice which express a mutant Rb transgene that is unable to bind LxCxE motif containing proteins. We will characterize the apoptosis signaling pathways engaged by Rb (Rb-LxCxE interaction) to promote cell survival. The relationship between the Rb-LxCxE interaction and other Rb binding proteins in the Rb survival pathway will also be clarified. These studies will impact our understanding of Rb in its cell biological functions and in human cancer. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket


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Project Title: Function of the Retinoblastoma Protein Principal Investigator & Institution: Harlow, Edward E.; Professor and Chairman; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2000; Project Start 5-AUG-1993; Project End 1-MAR2003 Summary: The retinoblastoma gene is the prototype of a class of cancer genes known as tumor suppressor genes. Tumor suppressor genes are defined by two key characteristics: (1) mutation of these genes promotes tumorigenesis (2) the selective advantage conferred by mutation of these genes is due to the loss of gene function. We are investigating the function of the retinoblastoma gene product (pRB). The best understood function of pRB is as a regulator of transcription factors. During the last grant cycle we characterized the ability of pRB and related proteins to regulate the E2F transcription factor and to control the expression E2Ftarget genes. The activation of E2F promotes cell cycle progression and, in normal cells, pRB acts to repress of E2F-dependent transcription. A great deal is known about the biochemistry of protein complexes formed between E2F and pRB-family proteins but the in vivo functions of this regulatory system are poorly understood. In the last two years we have established two experimental systems to examine the functions of these proteins. First, using homologous recombination we generated mutant alleles of E2F-1 in the mouse and studied the effects of eliminating E2F-1 function. Previous work had shown that E2F-1 behaved as an oncogene when over-expressed in tissue culture. However mice lacking E2F-1 developed a broad range of tumors revealing that E2F-1 acts to suppress tumor formation in vivo. In the next grant cycle we propose to continue this investigation of E2F function. We will concentrate on the characterization of the phenotype of E2F-1 null cells, on the phenotype of cells lacking DP-1 (the heterodimeric partner of E2F-1), and on the phenotype of cells lacking multiple pRB-regulated E2F s. To test role of the pRB/E2F-1 complex in pRB and E2F-1 functions we will characterize mouse strains carrying specific mutant alleles of E2F-1 that eliminate this interaction. A second area of functional studies that we initiated in the last grant cycle has also given unexpected findings. pRB is one member of a family of proteins, including p107 and p130, which share strong structual homologies. During the characterization of 3T3 cell lines prepared from pRB, p107 or p30 nullizygous mouse embryos, we observed that pRB, and p107 or p130 have specific and opposite effects on adipocyte differentiation. Whereas pRB promotes differentiation, p107 and p130 block adipocyte differentiation. We have finished the initial characterization of these differences and in the next round of this grant

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will investigate the functional differences between pRB p107 and p130 in adipogenesis and in other defined differentiation systems. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Gene Therapy for Retinoblastoma Principal Investigator & Institution: Hurwitz, Richard L.; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 2-JUL-2002; Project End 0-JUN2004 Summary: (provided by applicant): Current therapy for retinoblastoma utilizes surgical enucleation with resulting blindness and facial deformities or radiotherapy and chemotherapy that result in both local and systemic toxicity including an increase in the occurrence of second malignancies. Small tumors or large tumors that have been reduced in size by radiotherapy or chemotherapy can be treated successfully with laser photocoagulation or cryotherapy. Numerous preclinical and clinical trials have shown that adenoviral vectors used to deliver the Herpes thymidine kinase gene followed by ganciclovir can be safely administered. However, this approach has not been shown to be efficacious to cure large, aggressive malignancies such as brain tumors and prostate cancer. This phase I study is designed to show that this gene therapy approach can be used as an adjuvant treatment for children with retinoblastoma, a unique confined small tumor with relatively low malignant potential. The ultimate goal of this gene therapy is to salvage the affected eye by reducing the tumor burden sufficiently to allow for local control of the disease. Based on demonstrated potential for efficacy in preclinical laboratory studies, and in a preliminary clinical pilot study conducted at this institution, patients with nonmetastatic retinoblastoma are treated with a direct injection of an adenoviral vector that delivers the Herpes simplex thymidine kinase gene. Vector is delivered using cryotherapy before and after injection to minimize the chance of seeding the tumor. Ganciclovir is then administered intravenously at a dose of 10 mg/kg/day for 7 days. Up to a total of 4 injections of the viral vector will be considered depending on patient response. The objective of this phase I study is to determine whether this treatment is associated with significant toxicity. A secondary goal is to assess the efficacy of the therapy. If clinical efficacy is achieved before toxicity, the trial will be terminated at that dose of viral vector. The trial is designed as an intrapatient dose escalation study. The dose of the vector will begin at 1 x 1010 viral particles and, for the second dose, will increase by one-log increment in the absence of toxicity and progressive disease. Three patients will be treated using this treatment strategy and if no toxicity is


found the dose will be increased by one log increment and begin at 1 x 1011 viral particles. This research is the first step towards our ultimate goal, which is to develop a new generation of more effective, less toxic therapies for patients with ocular diseases Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Improved Ophthalmic Care for Retinoblastoma Patients Principal Investigator & Institution: O'brien, Joan M.; Director; Ophthalmology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2002; Project Start 1-AUG-2002; Project End 0-JUN2007 Summary: (provided by applicant): The long-term objective of this proposal is to improve ophthalmic care for patients with a pediatric ocular tumor, retinoblastoma (RB). We propose to provide rapid diagnosis and improved prognosis for patients with heritable ocular RB through improved genetic testing, and to innovate more effective and less toxic therapies for this ophthalmic disease.In pursuit of these objectives, two specific aims are proposed. These are: I. To develop and validate a protein truncation test (PTT) for detection of germline retinoblastoma gene (RB1) mutations and to determine whether mutation analysis can be used to predict ocular disease expression.This aim will be accomplished in 3 stages. We propose to: A. Develop PTT. B. Perform focused DNA sequencing to characterize RB1 mutations detected by PTT. C. Determine whether mutation analysis can be used to predict ocular disease expression .II. To determine the potential clinical utility of selected new pharmacologic agents in RB. These are: A. Cyclosporin A, and two potential alternatives, PSC-833 and FK506. B. Retinoids, including all-trans retinoic acid, ALRT1550, AM80, fenretinide, Targretin, 9-cis retinoic acid, and 13-cis retinoic acid.C. The alkylating agent, temozolomide. D. The blood-brain barrier permeabilizer, RMP-7 (Cereport).E. The tumor-specific viral agents, ONYX-015 and ONYXRB1.These agents are chosen for their relatively low toxicity and potential efficacy in the management of this ocular tumor. These agents also have potential utility in the management of other ophthalmic disorders. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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Project Title: Molecular Basis of Retinoblastoma Formation Principal Investigator & Institution: Lee, Wen-Hwa; Director; Inst of Biotechnology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229

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Timing: Fiscal Year 2000; Project Start 1-JUL-1991; Project End 8-FEB-2002 Summary: (adapted from the investigator's abstract) Retinoblastoma, the most common intraocular tumor in children, is a prototype for studying the mechanism of tumor suppression. The identification of the RB gene and the substantiation of its role in cancer suppression marked a new era of cancer research. Based on these important discoveries, we propose three interrelated projects to further explore the biochemical and cellular functions of the Rb protein. The major aims are as follows: I) T o systematically analyze the structure/function relationship of Rb protein. Informative single point mutations in the C-terminal A and B domains of Rb will be identified by their ability to bind interacting proteins using reverse yeast two-hybrid method. Rb carrying these mutations will be characterized by assaying their ability to function in cell growth regulation and in mediating terminal differentiation. The biological function of the N-terminal domain of Rb will also be addressed using a transgenic approach to rescue the Rb-/- developmentally lethal phenotype, and to suppress pituitary tumor development. Key factors that interact with the N-terminal domain of Rb will also be identified. II) To determine if Rb plays a role in chromosome segregation during M phase progression by specifically marking the chromosomes and testing their behavior in embryonic fibroblasts with RB +/+, +/- or -/- genotype. Establishment of this novel function of Rb will be useful for understanding its role in cancer suppression. III) To elucidate the biological significance of three RB associated proteins, C5, C15, and C11. C5 is a co-activator of the thyroid hormone receptor, C15 is a novel leucine heptad repeats-rich protein with a critical role in M phase progression, and C11 is a novel LXCXE containing protein with transactivation activity. The biological consequence of Rb interacting with these proteins will be explored. Results of these studies will contribute significantly to a basic understanding of the genesis of retinoblastoma in particular and human oncogenesis in general. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Molecular Biology of Retinoblastoma and Uveal Melanoma Principal Investigator & Institution: Albert, Daniel M.; Associate Surgeon in Ophthalmology; Ophthalmology and Visual Sci; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2000; Project Start 1-JUL-1976; Project End 0-NOV2000 Summary: This laboratory proposes to continue its studies into the molecular basis and treatment of retinoblastoma and uveal melanoma


utilizing new molecular genetic techniques, immunohistochemical staining, and classic morphologic techniques. Specifically, we plan the following studies: 1. We wish to identify each of the genetic lesions involved in the initiation and progression of retinoblastoma. We first will determine what the cellular genes responsible for retinoblastoma developing in transgenic mice carrying the human papillomaviral (HPV) transgene E6 and E7 are, and how these differ from the genetic alterations responsible for human retinoblastoma 2. We will assess the role of N-myc in retinoblastoma transgenic mice by producing and characterizing IRBPN-myc transgenic mice and opsin-N- myc mice 3. We will continue our study of 1,25 dihydroxy-16ene-23yneD3(16,23- vitaminD3) in transgenic mouse models and athymic nude mouse models to evaluate its efficacy in treatment of human retinoblastoma, hopefully in preparation of a human clinical trial. 4. We will evaluate the effectiveness of recombinant Herpes simplex virus (HSV) attenuated for neurovirulence in transgenic retinoblastoma mice. We will determine the effect of the mutants on the normal retina and on tumor parameters in transgenic retinoblastoma mice. 5. We will characterize pigmented tumors developing in the eyes of mice expressing SV40-T antigen (SV40-Tag) under the control of the mouse tyrosinase gene, and establish the relevance of these mice as a model for human uveal melanoma. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Paternal Exposure and Sporadic Bilateral Retinoblastoma Principal Investigator & Institution: Bunin, Greta R.; Research Associate Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 6-APR-2001; Project End 1-MAR2006 Summary: We propose to conduct a molecular epidemiologic study of sporadic heritable retinoblastoma (RBL), a cancer of the embryonal retina that occurs in infants and young children. Our knowledge of the molecular events leading to sporadic heritable RBL and certain features of the disease together provide a unique opportunity for this study. In the proposed study, we will investigate sporadic heritable RBL in its own right and as a model for new germline mutation. Sporadic heritable RBL results from a new germline mutation in the RBL gene, which occurs on the father's gene in over 90 percent of cases. The study's major objectives are to investigate the role of paternal occupational, dietary, x-ray and tobacco exposures before the child's conception. Since the RBL gene is well characterized, we will do molecular genetic analyses to identify the mutation in all of the cases. The mutation data will be used with the

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exposure data to test hypotheses that ionizing radiation and older paternal age are risk factors for specific types of mutation. The study will use a matched case-control design with 250pairs. Cases will be ascertained through seven centers that treat most of the RBL patients in the U.S. and Canada. Controls will be identified by random-digit dialing and matched to cases on birth date, race, and geographic area. Telephone interviews will be conducted with parents of cases and controls. Blood samples will be obtained from cases and case parents, so that DNA can be isolated for mutation analysis. The proposed molecular epidemiologic study will provide new information about the etiology of sporadic heritable retinoblastoma. The study will also contribute to our knowledge of new germline mutation generally, about which very little is known. Sporadic heritable RBL is a childhood cancer worth studying in its own right and an ideal model for the investigation of new germline mutation. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Regulation of Adipogenesis by Retinoblastoma Proteins Principal Investigator & Institution: Mcgehee, Robert E.; Director of Basic Science; Pediatrics; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, Ar 72205 Timing: Fiscal Year 2000; Project Start 1-JUL-1998; Project End 0-APR2002 Summary: The focus of this application is on adipocyte differentiation. Adipocyte differentiation requires the coordinated expression of numerous gene involved in growth. Early during the differentiation process, adipocyte precursors along with many other cell types, are required to re-enter the cell cycle and undergo a clonal expansion phase prior to growth arrest and terminal differentiation. The pathways involved in regulation of these early cell cycle events are largely unknown. Studies in tumor cells as well as non-malignant cells suggest that members of the retinoblastoma family of proteins play important roles in regulating cell cycle progression, particularly through their interaction with the E2F family of transcription factors. The PI has identified a regulation in p130 and p107 expression in differentiating 3T3L1 cells (a model of adipocyte differentiation). This "p130:p107 switch" correlates with early mitotic clonal expansion. They also present data suggesting that disruption of the p130:p107 switch by TNF alpha may explain the well described TNF alpha-induced inhibition of adipogenesis. They also present data that pRb is involved in transcriptional control of adipocyte genes. Based on these findings, they hypothesize that the retinoblastoma family of proteins is involved in adipocyte differentiation.


The application proposes experiments designed to examine mechanisms through which these interactions occur. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Signal Transduction by the Retinoblastoma Protein Principal Investigator & Institution: Kaelin, William G.; Associate Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2000; Project Start 1-AUG-1998; Project End 1-MAY2003 Summary: (adapted from the investigator's abstract) Many, and possibly all, human cancers contain mutations that lead to the loss of the wildtype retinoblastoma tumor suppressor protein (pRB) or to the untimely phosphorylation, and hence functional inactivation, of pRB by cyclin dependent kinases (cdk). How cdks recognize substrates in general, and pRB in particular, is poorly understood and will form the basis of specific aim 1. In this regard, they recently identified a short, colinear, motif which will target cyclin A/cdk2 complexes to potential substrates such as E2F1 and p107. Their preliminary biochemical data suggest that the Cterminus of pRB contains a sequence, or sequences, which, at least at the level of secondary structure, resembles this motif. The ability of pRB to regulate cell growth in vitro and to suppress tumor formation in vivo appears to be due, at least in part, to its ability to form pRB/E2F complexes which actively repress transcription from E2F responsive promoters. Using a panel of pRB mutants, we have recently found that the ability of pRB to bind to E2F can be dissociated from its ability to cooperate with certain non-E2F transcription factors to promote differentiation. Two naturally occurring, partially penetrant, pRB mutants were unable to bind to E2F but were wild-type for the ability to promote differentiation in vitro In contrast, classical null pRB mutants were defective for both of these functions. The lower risk of retinoblastoma associated with the partially penetrant alleles (~1/10 of a null allele) suggests that this differentiation promotion of pRB contributes to tumor suppression in vivo. Testing this hypothesis in a mouse model, as well as determining the biochemical basis for this activity, will form the basis of specific aim 2. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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Project Title: Transcriptional Repression by the Retinoblastoma Protein Principal Investigator & Institution: Gregory, Richard C.; Molecular and Cellular Biology; Harvard University 1350 Massachusetts Ave, Rm 458 Cambridge, Ma 02138

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Timing: Fiscal Year 2000; Project Start 1-AUG-2000 Summary: The main goal of the research presented within this proposal is to further our understanding of the molecular mechanisms of how the tumor suppressor retinoblastoma (Rb), regulates transcription via interactions with E2F family members. Several genes important for cell cycle progression and DNA synthesis have been identified as E2F targets. However, few experiments have been performed using natural promoters, and studies of E2F transcriptional regulation have focused primarily on synthetic promoter constructs as naked DNA templates. Therefore, using primer extension, and footprinting assays, the mechanisms of E2F transcriptional regulation will be investigated both on naked DNA and on reconstituted chromatin templates using several natural promoters as models. These will include the cyclin E (c-myc and B-myb) promoters each of which is suspected to be under the control of E2F and Rb family members. These experiments should help to address the molecular mechanisms used by Rb to regulate transcription from a natural promoter and in the context of a chromatin environment. Also proposed are studies to identify chromatin-remodeling factors recruited to the cyclin E promoter. Such experiments are based upon a recent link between Rb and histone deacetylases. These studies will add to our understanding of Rb's normal function which when perturbed can contribute to retinoblastoma and other human cancers. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: AHR Modulation of Androgen Dependent Prostate Growth Principal Investigator & Institution: Gragg, Richard D.; Florida Agricultural and Mechanical Univ Tallahassee, Fl 32307 Timing: Fiscal Year 2001; Project Start 1-JUL-2001; Project End 0-JUN2006 Summary: (provided by applicant): The objective of this pilot project is to examine whether arylhydrocarbon receptor (AhR) activation inhibits androgen-dependent prostate cell growth by regulating retinoblastoma tumor suppressor protein (pRb) activity. Recent evidence suggests that AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related polycyclic aromatic hydrocarbons, can suppress androgen (AR) activation and prostate cancer cell growth. pRb is a transcriptional coactivator for both the AhR and AR. Androgen signaling leads to up regulation of the cyclin-dependent kinases 2 and 4 responsible for cell cycle progression. TCDD signaling is known to increase the level of the cyclin-dependent kinase inhibitor, p27kip1, triggering cell cycle arrest. Both pathways affect pRb activity and identify pRb as a molecular target


for crosstalk between AhR and AR signaling. The investigators hypothesize that the arylhydrocarbon receptor (AhR) inhibits androgendependent cellular proliferation by regulating retinoblastoma tumor suppressor protein activity in the LNCAP human prostate cell line. 1. To determine whether the AhR can inhibit androgen dependent prostate cell proliferation by regulating G1 cell cycle progression. Recent evidence suggests that AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related polycyclic aromatic hydrocarbons, can suppress AR activation and prostate cancer cell growth. The effect of AhR agonists on the growth of the androgen-dependent LNCaP human prostate cancer cell line will be examined. LNCaP cell growth will be analyzed using flow cytometry, and p27kipl, cyclins D and E, and the cyclin dependent kinases 2 and 4. 2. To determine whether androgen-dependent cell growth in LNCaP cells can be regulated by controlling AhR function and the pRb protein level. Retinoblastoma tumor suppressor protein is a transcriptional coactivator for both the AhR and AR. Androgen signaling leads to up regulation of the cyclin dependent kinases 2 and 4 responsible for cell cycle progression. TCDD signaling is known to increase the level of the cyclin-dependent kinase inhibitor, p27kip1, triggering cell cycle arrest. Both pathways affect pRb activity and identify pRb as a molecular target for crosstalk between AhR and AR signaling. AhR activity will be regulated using dominant negative and antisense RNA strategies or by using AhR antagonists, and the effect on androgen-dependent LNCaP cell growth assessed. Crosstalk between the AhR and AR will be analyzed in LNCaP cells as a function of the pRb protein level by inducing ectopic pRb expression in LNCaP cells. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Function of Jumonji in Cardiovascular Development Principal Investigator & Institution: Lee, Youngsook; Anatomy; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 1-APR-2002; Project End 1-MAR2007 Summary: The long term gal of this project is to advance our understanding of the genetic controls that guide cardiac development. Identifying and characterizing the transcription factors cascade that control cardiac development is an important step in understanding the genesis of congenital heart defects and important clinical disorders such as cardiac hypertrophy and heart failure. The specific aim of this proposal is to identify the role of the jumonji gene (jmj) in the developing cardiovascular system. Neither the role of jmj in the cardiovascular development nor the molecular function of the jmj protein (JMJ) has been

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characterized. We generated the mutant mice that carry a homozygous mutation in jmj. Our analyses on jmj mutant mice revealed that jmj mutant embryos showed cardiac malformations including ventricular septal defect, double outlet right ventricle and non- compaction of the ventricular wall (thin ventricular wall), recapitulating human congenital heart disease. All mutants died soon after birth. Therefore, the underlying mechanisms of these cardiac defects will be examined in this proposal. JMJ is a novel protein whose molecular function remains unknown. JMJ contains the putative DNA binding domain that is homologous to the DNA binding transcription factor family, ARID. JMJ also contains the homologous region to the retinoblastoma binding protein (RBP) that binds to the retinoblastoma gene product (Rb). Rb is a key regulator of cell growth and differentiation. Our preliminary studies that JMJ is a DNA-binding nuclear protein that contains a transcriptional repressor domain. JMJ mediates cell growth and interacts with Rb. Based on these observations. my hypothesis is that JMJ is a DNA-binding transcription factor and regulate the myocardial cell growth by interacting with cofactors such as Rb. Therefore, the DNA-binding consensus motif of JMJ will be determined and its transcriptional function will be examined by a reporter gene assay. Molecular mechanisms by which JMJ mediates cell growth will be examined using cell lines and primary cultures from the wild type and jmj mutants. JMJ is a novel protein whose molecular function remains unknown. JMJ contains the putative DNA binding domain that is homologous to the DNA binding transcription factor family, ARID. JMJ also contains the homologous region to the retinoblastoma binding protein (RBP) that binds to the retinoblastoma gene product (Rb). Rb is a key regulator of cell growth and differentiation. Our preliminary studies indicate that JMJ is a DNA-binding nuclear protein that contains a transcriptional repressor domain. JMJ mediates cell growth and interacts with Rb. Based on these observations, my hypothesis is that JMJ is a DNA- binding transcription factor and regulate the myocardial cell growth by interacting with cofactors such as Rb. Therefore, the DNA-binding consensus motif of JMJ will be determined and its transcriptional function will be examined by a reporter gene assay. Molecular mechanisms by which JMJ mediates cell growth will be examined using cell lines and primary cultur4es from the wild type and jmj mutants. JMJ may play a role in molecular events leading to cardiac hypertrophy and failure, since jmj continues to be expressed in the adult heart. Therefore, the outcome of this research will lead us to develop new therapies for both congenital and adult heart diseases. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket


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Project Title: Requirements for Normal RB Function in Vivo Principal Investigator & Institution: Goodrich, David W.; Roswell Park Cancer Institute Corp Elm & Carlton Sts Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 1-JUN-1996; Project End 0-JUN2007 Summary: (provided by applicant): Mutational inactivation of the retinoblastoma tumor suppressor gene (Rb) causes retinoblastoma and contributes to most human cancers. Rb is also required for normal embryonic development in the mouse. The long-term goals of our lab are to characterize the mechanisms utilized to effect normal Rb function, to ascertain how these mechanisms are regulated, and to determine the contribution these mechanisms make to normal function in vivo. In vitro, Rb can regulate several major cellular processes, including the cell cycle, differentiation, and apoptosis. Since naturally occurring and synthetic mutations have been discovered that affect one of these Rb-dependent functions but not others, they are likely mediated by independent mechanisms. Mutational analysis also points out that these Rb-mediated molecular mechanisms can be regulated independently by phosphorylation at different subsets of serine or threonine residues. These observations suggest that normal Rb function in vivo may require the execution and proper coordination of distinct molecular mechanisms. It is currently unclear what contribution each of these molecular mechanisms, or their proper coordination by site-specific phosphorylation, make to normal embryonic development or Rb dependent tumor suppression. We hypothesize that normal Rb function in vivo will be partially compromised by mutations that affect a single Rb-mediated mechanism, or by mutations that affect normal site-specific phosphorylation. Through phenotypic analysis of such mutant alleles in vivo, the contribution of distinct Rbmediated molecular mechanisms to embryonic development and tumor suppression can be ascertained. We propose the following aims to test the hypothesis: 1) Identify mutant alleles specifically deficient in regulation of E2F 1-dependent transcription or normal site-specific phosphorylation; 2) Characterize the molecular defect in selected Rb mutant alleles; 3) Create and characterize mouse Rb mutant alleles analogous to selected human mutant alleles identified in aims 1-2; 4) Generate mice containing selected mutant Rb alleles; 5) Confirm the molecular deficiency of select mutant alleles in vivo; 6) Characterize the phenotype of mice containing mutant Rb alleles. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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Project Title: Role of O-Glcnac On the RB Family of Tumor Suppressors Principal Investigator & Institution: Wells, Robert L.; Biological Chemistry; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2000; Project Start 0-SEP-2000 Summary: The retinoblastoma family of proteins is a key regulator of cell cycle progression, differentiation, and apoptosis. These tumor suppressors that play a key role in oncogenesis are "active" when in a hypo-phosphorylated state. O-linked N-acetylglucosamine (O- GlcNAc) is an abundant and dynamic post-translational modification of cytoplasmic proteins. This modification that occurs on serine/threonine residues appears to be reciprocal in many ways to phosphorylation. Since preliminary data has identified O-GlcNAc on some members of the retinoblastoma family of proteins, this grant seeks to determine the functional consequences of O-GlcNAc modification of the retinoblastoma family of tumor suppressors. The following hypotheses will be tested: (1) that O-GlcNAcylation and serine/threonine phosphorylation of the retinoblastoma family of proteins occur in a reciprocal cell cycledependent manner; (2) that O-GlcNAc plays a critical role in proteinprotein interaction; and (3) that O- GlcNAc protects the retinoblastoma family of proteins from degradation via the apoptotic caspase pathway. These hypotheses will be tested by the completion of the following specific aims: (1) to characterize the O-GlcNAc modification of Rb, RBL1 (p107), and RBL2 (p130, RB2); and (2) to elucidate the role of O-GlcNAc in retinoblastoma family of protein-protein interactions. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket


E-Journals: PubMed Central27 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).28 Access to this growing archive of e-journals is free and unrestricted.29 To search, go to http://www.pubmedcentral.nih.gov/index.html#search, and type “childhood rhabdomyosarcoma” (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 rhabdomyosarcoma in the PubMed Central database: ·

A Maize cDNA Encoding a Member of the Retinoblastoma Protein Family: Involvement in Endoreduplication by G Grafi, RJ Burnett, T Helentjaris, BA Larkins, JA DeCaprio, WR Sellers, and WG Kaelin; 1996 August 20 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=38577

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A Pentamer Transcriptional Complex Including tal-1 and Retinoblastoma Protein Downmodulates c-kit Expression in Normal Erythroblasts by Luigi Vitelli, Gianluigi Condorelli, Valentina Lulli, Trang Hoang, Luisella Luchetti, Carlo M. Croce, and Cesare Peschle; 2000 July 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=85982

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A Potent Transrepression Domain in the Retinoblastoma Protein Induces a Cell Cycle Arrest when Bound to E2F Sites by WR Sellers, JW Rodgers, and WG Kaelin, Jr; 1995 December 5 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=40438

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A Single Amino Acid Substitution Results in a Retinoblastoma Protein Defective in Phosphorylation and Oncoprotein Binding by FJ Kaye, RA Kratzke, JL Gerster, and JM Horowitz; 1990 September 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=54650

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html. 28 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. 29 The value of PubMed Central, in addition to its role as an archive, lies 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. 27

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A thyroid hormone receptor coactivator negatively regulated by the retinoblastoma protein by Kai-Hsuan Chang, Yumay Chen, Tung-Ti Chen, Wen-Hai Chou, Phang-Lang Chen, Yen-Ying Ma, Teresa L. YangFeng, Xiaohua Leng, Ming-Jer Tsai, Bert W. O'Malley, and Wen-Hwa Lee; 1997 August 19 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=23019

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Adenovirus E1A, Simian Virus 40 Tumor Antigen, and Human Papillomavirus E7 Protein Share the Capacity to Disrupt the Interaction Between Transcription Factor E2F and the Retinoblastoma Gene Product by S Chellappan, VB Kraus, B Kroger, K Munger, PM Howley, and JR Nevins; 1992 May 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=49120

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Altered Expression of the Cyclin D1 and Retinoblastoma Genes in Human Esophageal Cancer by W Jiang, Y Zhang, SM Kahn, MC Hollstein, RM Santella, S Lu, CC Harris, R Montesano, and IB Weinstein; 1993 October 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=47494

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Amplification of a DEAD Box Protein Gene in Retinoblastoma Cell Lines by R Godbout and J Squire; 1993 August 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=47185

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Cell Cycle Arrest during Measles Virus Infection: a G0-Like Block Leads to Suppression of Retinoblastoma Protein Expression by Denise Naniche, Steven I. Reed, and Michael B. A. Oldstone; 1999 March http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=104430

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Characterization of protein kinase C [beta] isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization by Kiyoshi Suzuma, Noriko Takahara, Izumi Suzuma, Keiji Isshiki, Kohjiro Ueki, Michael Leitges, Lloyd Paul Aiello, and George L. King; 2002 January 22 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=117372

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Control of retinoblastoma protein-independent hematopoietic cell cycle by the pRB-related p130 by Yutaka Hoshikawa, Akio Mori, Keiko Amimoto, Koji Iwabe, and Masanori Hatakeyama; 1998 July 21 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=21117

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Correlation Between Retinoblastoma Gene Expression and Differentiation in Human Testicular Tumors by T Strohmeyer, P


Reissmann, C Cordon-Cardo, M Hartmann, R Ackermann, and D Slamon; 1991 August 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=52148 ·

C-Terminal Truncation of the Retinoblastoma Gene Product Leads to Functional Inactivation by J Shew, BT Lin, P Chen, BY Tseng, TL YangFeng, and W Lee; 1990 January 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=53188

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Cyclin D1 Expression is Regulated by the Retinoblastoma Protein by H Muller, J Lukas, A Schneider, P Warthoe, J Bartek, M Eilers, and M Strauss; 1994 April 12 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=43491

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Cyclin D1 Overexpression vs. Retinoblastoma Inactivation: Implications for Growth Control Evasion in Non-Small Cell and Small Cell Lung Cancer by IE Schauer, S Siriwardana, TA Langan, and RA Sclafani; 1994 August 2 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=44495

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Deficiency of Retinoblastoma Protein Leads to Inappropriate S-Phase Entry, Activation of E2F-Responsive Genes, and Apoptosis by A Almasan, Y Yin, RE Kelly, EYP Lee, A Bradley, W Li, JR Bertino, and GM Wahl; 1995 June 6 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41709

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Deficient Induction of Human hsp70 Heat Shock Gene Transcription in Y79 Retinoblastoma Cells Despite Activation of Heat Shock Factor 1 by SK Mathur, L Sistonen, IR Brown, SP Murphy, KD Sarge, and RI Morimoto; 1994 August 30 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=44673

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Degradation of the Retinoblastoma Tumor Suppressor by the Human Papillomavirus Type 16 E7 Oncoprotein Is Important for Functional Inactivation and Is Separable from Proteasomal Degradation of E7 by Sonia L. Gonzalez, Matt Stremlau, Xi He, John R. Basile, and Karl Munger; 2001 August 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=114993

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Destabilization of the Retinoblastoma Tumor Suppressor by Human Papillomavirus Type 16 E7 Is Not Sufficient To Overcome Cell Cycle

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Arrest in Human Keratinocytes by Anna-Marija Helt and Denise A. Galloway; 2001 August 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=114400 ·

Differential Regulation of Retinoblastoma Tumor Suppressor Protein by G1 Cyclin-Dependent Kinase Complexes In Vivo by Sergei A. Ezhevsky, Alan Ho, Michelle Becker-Hapak, Penny K. Davis, and Steven F. Dowdy; 2001 July 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=87164

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Disruption of Retinoblastoma Protein Family Function by Human Papillomavirus Type 16 E7 Oncoprotein Inhibits Lens Development in Part through E2F-1 by Jennifer McCaffrey, Lili Yamasaki, Nicholas J. Dyson, Ed Harlow, and Anne E. Griep; 1999 September http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=84615

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E1A Blocks Hyperphosphorylation of p130 and p107 without Affecting the Phosphorylation Status of the Retinoblastoma Protein by Matilde Parreno, Judit Garriga, Ana Limon, Xavier Mayol, George R. Beck, Jr., Elizabeth Moran, and Xavier Grana; 2000 April 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=111817

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E2F-1-Mediated Transactivation is Inhibited by Complex Formation with the Retinoblastoma Susceptibility Gene Product by EK Flemington, SH Speck, and WG Kaelin, Jr; 1993 August 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=47045

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EBNA-5, an Epstein-Barr Virus-Encoded Nuclear Antigen, Binds to the Retinoblastoma and p53 Proteins by L Szekely, G Selivanova, KP Magnusson, G Klein, and KG Wiman; 1993 June 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=46739

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Efficiency of Binding the Retinoblastoma Protein Correlates with the Transforming Capacity of the E7 Oncoproteins of the Human Papillomaviruses by DV Heck, CL Yee, PM Howley, and K Munger; 1992 May 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=49098

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Elevated Cyclin E Levels, Inactive Retinoblastoma Protein, and Suppression of the p27KIP1 Inhibitor Characterize Early Development of Promyeloid Cells into Macrophages by Qiang Liu, Roger W. VanHoy, J. H. Zhou, Robert Dantzer, Gregory G. Freund, and Keith W. Kelley; 1999 September http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=84572


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Enhanced Tumor Cell Growth Suppression by an N-Terminal Truncated Retinoblastoma Protein by H Xu, K Xu, Y Zhou, J Li, WF Benedict, and S Hu; 1994 October 11 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=44912

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Expression and State of Phosphorylation of the Retinoblastoma Susceptibility Gene Product in Cycling and Noncycling Human Hematopoietic Cells by Y Furukawa, JA DeCaprio, A Freedman, Y Kanakura, M Nakamura, TJ Ernest, DM Livingston, and JD Griffin; 1990 April 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=53772

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Factor-Binding Element in the Human c-myc Promoter Involved in Transcriptional Regulation by Transforming Growth Factor [beta]1 and by the Retinoblastoma Gene Product by JA Pietenpol, K Munger, PM Howley, RW Stein, and HL Moses; 1991 November 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=52901

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Frequent Inactivation of the Retinoblastoma Anti-Oncogene is Restricted to a Subset of Human Tumor Cells by JM Horowitz, S Park, E Bogenmann, J Cheng, DW Yandell, FJ Kaye, JD Minna, TP Dryja, and RA Weinberg; 1990 April 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=53773

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Functional Inactivation of the Retinoblastoma Protein Requires Sequential Modification by at Least Two Distinct Cyclin-cdk Complexes by Ante S. Lundberg and Robert A. Weinberg; 1998 February http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=108786

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Functional interaction between human topoisomerase II[alpha] and retinoblastoma protein by Uppoor G. Bhat, Pradip Raychaudhuri, and William T. Beck; 1999 July 6 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=22152

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Functional Interactions Between the Retinoblastoma (Rb) Protein and Sp-Family Members: Superactivation by Rb Requires Amino Acids Necessary for Growth Suppression by AJ Udvadia, DJ Templeton, and JM Horowitz; 1995 April 25 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=42080

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Further Characterization of Retinoblastoma Gene-Mediated Cell Growth and Tumor Suppression in Human Cancer Cells by Y Zhou, J Li, K Xu, S Hu, and WF Benedict; 1994 May 10 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=43745

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G1 Arrest and Down-Regulation of Cyclin E/Cyclin-Dependent Kinase 2 by the Protein Kinase Inhibitor Staurosporine are Dependent on the Retinoblastoma Protein in the Bladder Carcinoma Cell Line 5637 by JB Schnier, K Nishi, DW Goodrich, and EM Bradbury; 1996 June 11 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=39167

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Genomic Structure of the Human Retinoblastoma-Related Rb2/p130 Gene by A Baldi, V Boccia, PP Claudio, AD Luca, and A Giordano; 1996 May 14 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=39329

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Growth Suppression by an E2F-Binding-Defective Retinoblastoma Protein (RB): Contribution from the RB C Pocket by Laura L. Whitaker, Heyun Su, Rajasekaran Baskaran, Erik S. Knudsen, and Jean Y. J. Wang; 1998 July http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=108988

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Growth Suppression by P16ink4 Requires Functional Retinoblastoma Protein by RH Medema, RE Herrera, F Lam, and RA Weinberg; 1995 July 3 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41503

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Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4 /6 complexes results in active pRb by Sergei A. Ezhevsky, Hikaru Nagahara, Adita M. Vocero-Akbani, David R. Gius, Michael C. Wei, and Steven F. Dowdy; 1997 September 30 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=23451

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Identification of a substrate-targeting domain in cyclin E necessary for phosphorylation of the retinoblastoma protein by Beth L. Kelly, Karen G. Wolfe, and James M. Roberts; 1998 March 3 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=19404

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Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function by Gregory A. Otterson, Wei-dong Chen, Amy B. Coxon, Samir N. Khleif, and Frederic J. Kaye; 1997 October 28 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=23695


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Induction of a Retinoblastoma Phosphatase Activity by Anticancer Drugs Accompanies p53-Independent G1 Arrest and Apoptosis by QP Dou, B An, and PL Will; 1995 September 26 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=40915

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Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after [gamma]-irradiation by James Brugarolas, Ken Moberg, Scott D. Boyd, Yoichi Taya, Tyler Jacks, and Jacqueline A. Lees; 1999 February 2 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=15340

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Interferon [alpha] Induces the Expression of Retinoblastoma Gene Product in Human Burkitt Lymphoma Daudi Cells: Role in Growth Regulation by R Kumar and I Atlas; 1992 July 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=49549

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Interferons and Interleukin 6 Suppress Phosphorylation of the Retinoblastoma Protein in Growth-Sensitive Hematopoietic Cells by D Resnitzky, N Tiefenbrun, H Berissi, and A Kimchi; 1992 January 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=48245

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Involvement of Retinoblastoma Protein and HBP1 in Histone H10 Gene Expression by Claudie Lemercier, Kym Duncliffe, Isabelle Boibessot, Hui Zhang, Andre Verdel, Dimitar Angelov, and Saadi Khochbin; 2000 September 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=86159

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Lack of Functional Retinoblastoma Protein Mediates Increased Resistance to Antimetabolites in Human Sarcoma Cell Lines by W Li, J Fan, D Hochhauser, D Banerjee, Z Zielinski, A Almasan, Y Yin, R Kelly, GM Wahl, and JR Bertino; 1995 October 24 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=40812

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Laminin-Induced Retinoblastoma Cell Differentiation: Possible Involvement of a 100-kDa Cell-Surface Laminin-Binding Protein by A Albini, DM Noonan, A Melchiori, GF Fassina, M Percario, S Gentleman, J Toffenetti, and GJ Chader; 1992 March 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=48636

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Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma by Kristian Helin, Karin Holm, Anita Niebuhr, Hans

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Eiberg, Niels Tommerup, Susanne Hougaard, Hans Skovgaard Poulsen, Mogens Spang-Thomsen, and Peter Norgaard; 1997 June 24 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=21262 ·

Mitotic recombination map of 13cen --13q14 derived from an investigation of loss of heterozygosity in retinoblastomas by Stephanie A. Hagstrom and Thaddeus P. Dryja; 1999 March 16 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=15876

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Modulation of Retinoblastoma Gene in Normal Adult Hematopoiesis: Peak Expression and Functional Role in Advanced Erythroid Differentiation by GL Condorelli, U Testa, M Valtieri, L Vitelli, AD Luca, T Barberi, E Montesoro, S Campisi, A Giordano, and C Peschile; 1995 May 23 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41796

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Molecular Mechanisms of Oncogenic Mutations in Tumors from Patients with Bilateral and Unilateral Retinoblastoma by A Hogg, B Bia, Z Onadim, and JK Cowell; 1993 August 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=47135

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Mutational Analysis of the Conserved Region 2 Site of Adenovirus E1A and its Effect on Binding to the Retinoblastoma Gene Product: Use of the "Double-Tagging" Assay by ZX Wang and FJ Germino; 1995 May 9 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41998

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Negative Regulation of DNA Replication by the Retinoblastoma Protein Is Mediated by Its Association with MCM7 by Jacqueline M. Sterner, Susan Dew-Knight, Christine Musahl, Sally Kornbluth, and Jonathan M. Horowitz; 1998 May http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=110654

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Nonfunctional Mutants of the Retinoblastoma Protein are Characterized by Defects in Phosphorylation, Viral Oncoprotein Association, and Nuclear Tethering by DJ Templeton, SH Park, L Lanier, and RA Weinberg; 1991 April 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=51378


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Okadaic Acid Regulation of the Retinoblastoma Gene Product is Correlated with the Inhibition of Growth Factor-Induced Cell Proliferation in Mouse Fibroblasts by T Kim, BR Velasquez, and CE Wenner; 1993 June 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=46740

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Oncogenic Point Mutations in Exon 20 of the RB1 Gene in Families Showing Incomplete Penetrance and Mild Expression of the Retinoblastoma Phenotype by Z Onadim, A Hogg, PN Baird, and JK Cowell; 1992 July 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=49461

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Opposing Early and Late Effects of Insulin-Like Growth Factor I on Differentiation and the Cell Cycle Regulatory Retinoblastoma Protein in Skeletal Myoblasts by SM Rosenthal and Z Cheng; 1995 October 24 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=40785

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p53 Down-Regulates CHK1 through p21 and the Retinoblastoma Protein by Vanesa Gottifredi, Orit Karni-Schmidt, Sheau-Yann Shieh, and Carol Prives; 2001 February 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=99561

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p53 Regulation of G2 Checkpoint Is Retinoblastoma Protein Dependent by Patricia M. Flatt, Luo Jia Tang, Caroline D. Scatena, Suzanne T. Szak, and Jennifer A. Pietenpol; 2000 June 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=85790

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Phosphorylation of the Retinoblastoma Protein by cdk2 by T Akiyama, T Ohuchi, S Sumida, K Matsumoto, and K Toyoshima; 1992 September 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=49822

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PITALRE, a Nuclear CDC2-Related Protein Kinase that Phosphorylates the Retinoblastoma Protein in vitro by X Grana, AD Luca, N Sang, Y Fu, PP Claudio, J Rosenblatt, DO Morgan, and A Giordano; 1994 April 26 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=43676

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Polyomavirus Small t Antigen Prevents Retinoic Acid-Induced Retinoblastoma Protein Hypophosphorylation and Redirects Retinoic Acid-Induced G0 Arrest and Differentiation to Apoptosis by Andrew Yen, Lisa Placanica, Stephen Bloom, and Susi Varvayanis; 2001 June 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=114935

Studies 95

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Promoter Deletion and Loss of Retinoblastoma Gene Expression in Human Prostate Carcinoma by R Bookstein, P Rio, SA Madreperla, F Hong, C Allred, WE Grizzle, and W Lee; 1990 October 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=54828

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RBP1 Recruits Both Histone Deacetylase-Dependent and -Independent Repression Activities to Retinoblastoma Family Proteins by Albert Lai, Joseph M. Lee, Wen-Ming Yang, James A. DeCaprio, William G. Kaelin, Jr., Edward Seto, and Philip E. Branton; 1999 October http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=84642

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RBP1 Recruits the mSIN3-Histone Deacetylase Complex to the Pocket of Retinoblastoma Tumor Suppressor Family Proteins Found in Limited Discrete Regions of the Nucleus at Growth Arrest by Albert Lai, Brian K. Kennedy, David A. Barbie, Nicholas R. Bertos, Xiang Jiao Yang, Marie-Christine Theberge, Shih-Chang Tsai, Edward Seto, Yi Zhang, Andrei Kuzmichev, William S. Lane, Danny Reinberg, Ed Harlow, and Philip E. Branton; 2001 April 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=86920

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Regulation of Cell Cycle Progression and Nuclear Affinity of the Retinoblastoma Protein by Protein Phosphatases by AS Alberts, AM Thorburn, S Shenolikar, MC Mumby, and JR Feramisco; 1993 January 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=45667

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Regulation of Cellular Genes in a Chromosomal Context by the Retinoblastoma Tumor Suppressor Protein by Ann Marie Buchmann, Sathyamangalam Swaminathan, and Bayar Thimmapaya; 1998 August http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=109042

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Regulation of Differentiation by HBP1, a Target of the Retinoblastoma Protein by Heather H. Shih, Sergei G. Tevosian, and Amy S. Yee; 1998 August http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=109059

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Regulation of endogenous E2F1 stability by the retinoblastoma family proteins by Fabio Martelli and David M. Livingston; 1999 March 16 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=15859

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Regulation of the Retinoblastoma Protein-Related Protein p107 by G1 Cyclin-Associated Kinases by Z Xiao, D Ginsberg, M Ewen, and DM Livingston; 1996 May 14 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=39330


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Regulation of Transforming Growth Factor [beta]1 Gene Expression by the Product of the Retinoblastoma-Susceptibility Gene by S Kim, H Lee, PD Robbins, K Busam, MB Sporn, and AB Roberts; 1991 April 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=51382

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Repression of the Interleukin 6 Gene Promoter by p53 and the Retinoblastoma Susceptibility Gene Product by U Santhanam, A Ray, and PB Sehgal; 1991 September 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=52350

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Requirement for p27KIP1 in Retinoblastoma Protein-Mediated Senescence by Kamilah Alexander and Philip W. Hinds; 2001 June 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=86983

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Retinoblastoma Gene Product as a Downstream Target for a CeramideDependent Pathway of Growth Arrest by GS Dbaibo, MY Pushkareva, S Jayadev, JK Schwarz, JM Horowitz, LM Obeid, and YA Hannun; 1995 February 28 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=42516

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Retinoblastoma Growth Suppressor and a 300-kDa Protein Appear to Regulate Cellular DNA Synthesis by JA Howe, JS Mymryk, C Egan, PE Branton, and ST Bayley; 1990 August 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=54433

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Retinoblastoma Protein Contains a C-terminal Motif That Targets It for Phosphorylation by Cyclin-cdk Complexes by Peter D. Adams, Xiaotong Li, William R. Sellers, Kayla B. Baker, Xiaohong Leng, J. Wade Harper, Yoichi Taya, and William G. Kaelin, Jr.; 1999 February http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=116037

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Retinoblastoma Protein Directly Interacts with and Activates the Transcription Factor NF-IL6 by P Chen, DJ Riley, S Chen-Kiang, and W Lee; 1996 January 9 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=40259

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Retinoblastoma Protein Disrupts Interactions Required for RNA Polymerase III Transcription by Josephine E. Sutcliffe, Timothy R. P. Brown, Simon J. Allison, Pamela H. Scott, and Robert J. White; 2000 December 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=102177

Studies 97

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Retinoblastoma Protein Enhances the Fidelity of Chromosome Segregation Mediated by hsHec1p by Lei Zheng, Yumay Chen, Daniel J. Riley, Phang-Lang Chen, and Wen-Hwa Lee; 2000 May 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=85645

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Retinoblastoma Tumor Suppressor Protein Signals through Inhibition of Cyclin-Dependent Kinase 2 Activity To Disrupt PCNA Function in S Phase by Zvjezdana Sever-Chroneos, Steven P. Angus, Anne F. Fribourg, Huajing Wan, Ivan Todorov, Karen E. Knudsen, and Erik S. Knudsen; 2001 June 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=87065

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Rod Photoreceptor-Specific Gene Expression in Human Retinoblastoma Cells by AD Polo and DB Farber; 1995 April 25 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=42093

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Selection of a Dominant Negative Retinoblastoma Protein (RB) Inhibiting Satellite Myoblast Differentiation Implies an Indirect Interaction between MyoD and RB by Feng-Qian Li, Archie Coonrod, and Marshall Horwitz; 2000 July 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=85962

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Study of the Role of Retinoblastoma Protein in Terminal Differentiation of Murine Erythroleukemia Cells by S Zhuo, S Fan, S Huang, and S Kaufman; 1995 May 9 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41918

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TATA-Binding Protein and the Retinoblastoma Gene Product Bind to Overlapping Epitopes on c-Myc and Adenovirus E1A Protein by G Hateboer, HTM Timmers, AK Rustgi, M Billaud, Veer LJv', and R Bernards; 1993 September 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=47382

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The Activation Domain of Transcription Factor PU.1 Binds the Retinoblastoma (RB) Protein and the Transcription Factor TFIID in vitro: RB Shows Sequence Similarity to TFIID and TFIIB by C Hagemeier, AJ Bannister, A Cook, and T Kouzarides; 1993 February 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=45918

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The Epstein-Barr Virus Immediate-Early Gene Product, BRLF1, Interacts with the Retinoblastoma Protein during the Viral Lytic Cycle by Valerie L. Zacny, Julie Wilson, and Joseph S. Pagano; 1998 October http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=110141


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The histone deacetylase HDAC3 targets RbAp48 to the retinoblastoma protein by Estelle Nicolas, Slimane Ait-Si-Ali, and Didier Trouche; 2001 August 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=55834

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The Promyelocytic Leukemia Gene Product (PML) Forms Stable Complexes with the Retinoblastoma Protein by Myriam Alcalay, Lucia Tomassoni, Emanuela Colombo, Stephan Stoldt, Francesco Grignani, Marta Fagioli, Laszlo Szekely, Kristian Helin, and Pier Giuseppe Pelicci; 1998 February http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=108821

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The Retinoblastoma Gene Functions as a Growth and Tumor Suppressor in Human Bladder Carcinoma Cells by R Takahashi, T Hashimoto, H Xu, S Hu, and T Matsui; 1991 June 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=51851

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The Retinoblastoma Gene Product is a Cell Cycle-Dependent, Nuclear Matrix- Associated Protein by MA Mancini, B Shan, JA Nickerson, S Penman, and W Lee; 1994 January 4 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=42959

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The Retinoblastoma Protein Alters the Phosphorylation State of Polyomavirus Large T Antigen in Murine Cell Extracts and Inhibits Polyomavirus Origin DNA Replication by Inga Reynisdottir, Subarna Bhattacharyya, Dong Zhang, and Carol Prives; 1999 April http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=104060

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The Retinoblastoma Protein Binds to RIZ, a Zinc-Finger Protein that Shares an Epitope with the Adenovirus E1A Protein by IM Buyse, G Shao, and S Huang; 1995 May 9 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41965

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The Retinoblastoma Protein Is Linked to the Activation of Ras by Kwang Youl Lee, Mohamed H. Ladha, Christine McMahon, and Mark E. Ewen; 1999 November http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=84819

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The Retinoblastoma Tumor Suppressor Protein Targets Distinct General Transcription Factors To Regulate RNA Polymerase III Gene Expression by Heather A. Hirsch, Liping Gu, and R. William Henry; 2000 December 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=102176

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The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action by Ciro Abbondanza, Nicola Medici, Vincenzo Nigro, Valentina Rossi, Luigi Gallo, Giulio Piluso, Angela Belsito, Annarita Roscigno, Paola Bontempo, Annibale A. Puca, Anna Maria Molinari, Bruno Moncharmont, and Giovanni A. Puca; 2000 March 28 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=16204

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The Retinoblastoma-Susceptibility Gene Product Becomes Phosphorylated in Multiple Stages During Cell Cycle Entry and Progression by JA DeCaprio, Y Furukawa, F Ajchenbaum, JD Griffin, and DM Livingston; 1992 March 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=48539

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The Retinoblastoma-Susceptibility Gene Product Binds Directly to the Human TATA-Binding Protein-Associated Factor TAFII250 by Z Shao, S Ruppert, and PD Robbins; 1995 April 11 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=42115

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The State of the p53 and Retinoblastoma Genes in Human Cervical Carcinoma Cell Lines by M Scheffner, K Munger, JC Byrne, and PM Howley; 1991 July 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=51909

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Thymidine Kinase Transcription is Regulated at G1/S Phase by a Complex That Contains Retinoblastoma-Like Protein and a cdc2 Kinase by Q Dou, PJ Markell, and AB Pardee; 1992 April 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=48845

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Transcriptional Repression by the Retinoblastoma Protein through the Recruitment of a Histone Methyltransferase by Laurence Vandel, Estelle Nicolas, Olivier Vaute, Roger Ferreira, Slimane Ait-Si-Ali, and Didier Trouche; 2001 October 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=99795

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v-Jun Overrides the Mitogen Dependence of S-Phase Entry by Deregulating Retinoblastoma Protein Phosphorylation and E2F-Pocket Protein Interactions as a Consequence of Enhanced Cyclin E-cdk2 Catalytic Activity by W. Clark, E. J. Black, A. MacLaren, U. Kruse, N. LaThangue, P. K. Vogt, and D. A. F. Gillespie; 2000 April 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=85463


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. 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 the public.30 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 rhabdomyosarcoma, simply go to the PubMed Web site at www.ncbi.nlm.nih.gov/pubmed. Type “childhood rhabdomyosarcoma” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for “childhood rhabdomyosarcoma” (hyperlinks lead to article summaries): ·

Hyperfractionated external beam radiation therapy in the treatment of murine transgenic retinoblastoma. Author(s): Hayden BC, Murray TG, Cicciarelli N, Scott IU, Alexandridou A, Hernandez E, Wu X, Markoe AM, Feuer W, Fulton L, O'Brien JM. Source: Archives of Ophthalmology. 2002 March; 120(3): 353-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11879140&dopt=Abstract

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Hyperphosphorylation of the retinoblastoma gene product and altered subcellular distribution of E2F-1 during Alzheimer's disease and amyotrophic lateral sclerosis. Author(s): Ranganathan S, Scudiere S, Bowser R. Source: Journal of Alzheimer's Disease : Jad. 2001 August; 3(4): 377-385. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12214040&dopt=Abstract

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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Studies 101

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Immunoglobulin superfamily expression in primary retinoblastoma and retinoblastoma cell lines. Author(s): Madigan MC, Penfold PL, King NJ, Billson FA, Conway RM. Source: Oncol Res. 2002; 13(2): 103-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12392158&dopt=Abstract

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Immunohistochemical Analysis of the Cell Cycle-Associated Antigens Ki-67 and Retinoblastoma Protein in Parathyroid Carcinomas and Adenomas. Author(s): Lloyd RV, Carney JA, Ferreiro JA, Jin L, Thompson GB, Van Heerden JA, Grant CS, Wollan PC. Source: Endocr Pathol. 1995 Winter; 6(4): 279-287. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12114810&dopt=Abstract

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Impaired expression and promotor hypermethylation of O6methylguanine-DNA methyltransferase in retinoblastoma tissues. Author(s): Choy KW, Pang CP, To KF, Yu CB, Ng JS, Lam DS. Source: Investigative Ophthalmology & Visual Science. 2002 May; 43(5): 1344-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11980845&dopt=Abstract

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Improved clinical management of retinoblastoma through gene testing. Author(s): Raizis A, Clemett R, Corbett R, McGaughran J, Evans J, George P. Source: N Z Med J. 2002 May 24; 115(1154): 231-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12117173&dopt=Abstract

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In vitro effects of radiation on human retinoblastoma cells. Author(s): Zhang M, Stevens G, Madigan MC. Source: International Journal of Cancer. Journal International Du Cancer. 2001; 96 Suppl: 7-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11992382&dopt=Abstract

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Inactivation of both the retinoblastoma tumor suppressor and p21 by the human papillomavirus type 16 E7 oncoprotein is necessary to inhibit cell cycle arrest in human epithelial cells. Author(s): Helt AM, Funk JO, Galloway DA.


Source: Journal of Virology. 2002 October; 76(20): 10559-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12239337&dopt=Abstract ·

Inactivation of the retinoblastoma protein family can bypass the HCF-1 defect in tsBN67 cell proliferation and cytokinesis. Author(s): Reilly PT, Wysocka J, Herr W. Source: Molecular and Cellular Biology. 2002 October; 22(19): 6767-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12215534&dopt=Abstract

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Induction of VEGF gene expression by retinoic acid through Sp1binding sites in retinoblastoma Y79 cells. Author(s): Akiyama H, Tanaka T, Maeno T, Kanai H, Kimura Y, Kishi S, Kurabayashi M. Source: Investigative Ophthalmology & Visual Science. 2002 May; 43(5): 1367-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11980848&dopt=Abstract

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Inflammatory orbital pseudotumor simulating retinoblastoma in a one year old girl. Author(s): Bekibele CO, Ogunbiyi JO. Source: West Afr J Med. 2002 January-March; 21(1): 77-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12081353&dopt=Abstract

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Inhibition of Hypoxia-Induced Apoptosis by Modulation of Retinoblastoma Protein-Dependent Signaling in Cardiomyocytes. Author(s): Hauck L, Hansmann G, Dietz R, Von Harsdorf R. Source: Circulation Research. 2002 November 1; 91(9): 782-789. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12411392&dopt=Abstract

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Interaction of the retinoblastoma gene product, RB, with cyclophilin A negatively affects cyclosporin-inhibited NFAT signaling. Author(s): Cui Y, Mirkia K, Florence Fu YH, Zhu L, Yokoyama KK, Chiu R. Source: Journal of Cellular Biochemistry. 2002; 86(4): 630-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12210730&dopt=Abstract

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Interactions of SV40 large T antigen and other viral proteins with retinoblastoma tumour suppressor. Author(s): Lee C, Cho Y. Source: Reviews in Medical Virology. 2002 March-April; 12(2): 81-92. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11921304&dopt=Abstract

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Interview with the retinoblastoma family members: do they help each other? Author(s): Tonini T, Hillson C, Claudio PP. Source: Journal of Cellular Physiology. 2002 August; 192(2): 138-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12115720&dopt=Abstract

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Leiomyosarcoma in urinary bladder after cyclophosphamide therapy for retinoblastoma and review of bladder sarcomas. Author(s): Parekh DJ, Jung C, O'Conner J, Dutta S, Smith ER Jr. Source: Urology. 2002 July; 60(1): 164. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12100953&dopt=Abstract

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Letter to the editor: acute myeloid leukemia in a patient surviving retinoblastoma. Author(s): Gallegos-Castorena S, Medina-Sanson A, Gonzalez-Montalvo P, Martinez-Avalos A, Zafra de la Rosa GZ. Source: Medical and Pediatric Oncology. 2002 June; 38(6): 450. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11984811&dopt=Abstract

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Leydig cell tumor and mature teratoma: unusual non-ocular tumors associated with sexual pseudo-precocity six years after unilateral retinoblastoma. Author(s): Seber A, Antoneli CB, Spinola-Castro AM, Oyafuso MS. Source: Medical and Pediatric Oncology. 2002 April; 38(4): 285-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11920800&dopt=Abstract


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Loss of heterozygosity and mutations are the major mechanisms of RB1 gene inactivation in Chinese with sporadic retinoblastoma. Author(s): Choy KW, Pang CP, Yu CB, Wong HL, Ng JS, Fan DS, Lo KW, Chai JT, Wang J, Fu W, Lam DS. Source: Human Mutation. 2002 November; 20(5): 408. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12402348&dopt=Abstract

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Multifocal retinoblastomas treated with transpupillary thermotherapy. Author(s): Lin HY, Lee FL, Ko YC, Hsieh YL. Source: Zhonghua Yi Xue Za Zhi (Taipei). 2002 January; 65(1): 41-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11939675&dopt=Abstract

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Multiple anterior chamber cystic lesions as the first sign of advanced retinoblastoma. Author(s): Puig JJ, Arrondo E, Garcia-Arumi J, Gil JJ, Huguet P, Calatayud M. Source: Archives of Ophthalmology. 2002 October; 120(10): 1385-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12365923&dopt=Abstract

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Mushroom-shaped choroidal recurrence of retinoblastoma 25 years after therapy. Author(s): Shields CL, Piccone MR, Shields JA, Eagle RC Jr, Singer M. Source: Archives of Ophthalmology. 2002 June; 120(6): 844-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12049595&dopt=Abstract

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Mutation screening analysis of the retinoblastoma related gene RB2/p130 in sporadic ovarian cancer and head and neck squamous cell cancer. Author(s): Alvi AJ, Hogg R, Rader JS, Kuo MJ, Maher ER, Latif F. Source: Molecular Pathology : Mp. 2002 June; 55(3): 153-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12032225&dopt=Abstract

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Mutational analysis of the RB1 gene in Indian patients with retinoblastoma.

Studies 105

Author(s): Ata-ur-Rasheed M, Vemuganti G, Honavar S, Ahmed N, Hasnain S, Kannabiran C. Source: Ophthalmic Genetics. 2002 June; 23(2): 121-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12187430&dopt=Abstract ·

Noninvasive imaging of spontaneous retinoblastoma pathwaydependent tumors in mice. Author(s): Vooijs M, Jonkers J, Lyons S, Berns A. Source: Cancer Research. 2002 March 15; 62(6): 1862-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11912166&dopt=Abstract

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Nucleotide alteration of retinoblastoma protein-interacting zinc finger gene, RIZ, in human leukemia. Author(s): Sasaki O, Meguro K, Tohmiya Y, Funato T, Shibahara S, Sasaki T. Source: The Tohoku Journal of Experimental Medicine. 2002 March; 196(3): 193-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12002276&dopt=Abstract

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Ocular preservation after 36 Gy external beam radiation therapy for retinoblastoma. Author(s): Merchant TE, Gould CJ, Hilton NE, Kun LE, RodriguezGalindo C, Pratt CB, Wilson MW, Haik B. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 May; 24(4): 246-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11972090&dopt=Abstract

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Osseous choristoma of the conjunctiva simulating extraocular extension of retinoblastoma. Author(s): Marback EF, Stout TJ, Rao NA. Source: American Journal of Ophthalmology. 2002 June; 133(6): 825-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12036677&dopt=Abstract

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Overview: chemotherapy for retinoblastoma: an expanding area of clinical research. Author(s): Schouten-Van Meeteren AY, Moll AC, Imhof SM, Veerman AJ.


Source: Medical and Pediatric Oncology. 2002 June; 38(6): 428-38. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11984806&dopt=Abstract ·

Phosphorylation of retinoblastoma-related protein by the cyclin d/cyclin-dependent kinase complex is activated at the g1/s-phase transition in tobacco. Author(s): Nakagami H, Kawamura K, Sugisaka K, Sekine M, Shinmyo A. Source: The Plant Cell. 2002 August; 14(8): 1847-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12172026&dopt=Abstract

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Phosphorylation-dependent migration of retinoblastoma protein into the nucleolus triggered by binding to nucleophosmin/B23. Author(s): Takemura M, Ohoka F, Perpelescu M, Ogawa M, Matsushita H, Takaba T, Akiyama T, Umekawa H, Furuichi Y, Cook PR, Yoshida S. Source: Experimental Cell Research. 2002 June 10; 276(2): 233-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12027453&dopt=Abstract

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Photoreceptor cell differentiation in retinoblastoma demonstrated by a new immunohistochemical marker mucin-like glycoprotein associated with photoreceptor cells (MLGAPC). Author(s): Tsuji M, Goto M, Uehara F, Kaneko A, Sawai J, Yonezawa S, Ohba N. Source: Histopathology. 2002 February; 40(2): 180-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11952864&dopt=Abstract

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Physical interaction of human T-cell leukemia virus type 1 Tax with cyclin-dependent kinase 4 stimulates the phosphorylation of retinoblastoma protein. Author(s): Haller K, Wu Y, Derow E, Schmitt I, Jeang KT, Grassmann R. Source: Molecular and Cellular Biology. 2002 May; 22(10): 3327-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11971966&dopt=Abstract

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PNUTS (phosphatase nuclear targeting subunit) retinoblastoma-directed PP1 activity. Author(s): Udho E, Tedesco V, Zygmunt A, Krucher N.

inhibits

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Source: Biochemical and Biophysical Research Communications. 2002 September 27; 297(3): 463. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12270115&dopt=Abstract ·

Predilection of retinoblastoma metastases for the mandible. Author(s): Pandya J, Valverde K, Heon E, Blaser S, Gallie BL, Chan HS. Source: Medical and Pediatric Oncology. 2002 April; 38(4): 271-3. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11920795&dopt=Abstract

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Preimplantation-embryo-specific cell cycle regulation is attributed to the low expression level of retinoblastoma protein. Author(s): Iwamori N, Naito K, Sugiura K, Tojo H. Source: Febs Letters. 2002 August 28; 526(1-3): 119-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12208517&dopt=Abstract

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Presenilin 1 overexpressions in Chinese hamster ovary (CHO) cells decreases the phosphorylation of retinoblastoma protein: relevance for neurodegeneration. Author(s): Prat MI, Adamo AM, Gonzalez SA, Affranchino JL, Ikeda M, Matsubara E, Shoji M, Smith MA, Castano EM, Morelli L. Source: Neuroscience Letters. 2002 June 21; 326(1): 9-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12052526&dopt=Abstract

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Presenting signs of retinoblastoma in Congolese patients. Author(s): Kaimbo WK, Mvitu MM, Missotten L. Source: Bull Soc Belge Ophtalmol. 2002; (283): 37-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12058485&dopt=Abstract

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Quantitative analysis of apoptosis in retinoblastoma. Author(s): Tatlipinar S, Soylemezoglu F, Kiratli H, Bilgic S. Source: Clinical & Experimental Ophthalmology. 2002 April; 30(2): 131-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11886418&dopt=Abstract


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Rapid growth of retinoblastoma in a premature twin. Author(s): Abramson DH, Schefler AC, Beaverson KL, Rollins IS, Ruddat MS, Kelly CJ. Source: Archives of Ophthalmology. 2002 September; 120(9): 1232-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12215105&dopt=Abstract

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Rescue of embryonic epithelium reveals that homozygous deletion of the retinoblastoma gene confers growth factor independence and immortality, but does not influence epithelial differentiation or tissue morphogenesis. Author(s): Day KC, McCabe MT, Zhao X, Wang Y, Davis JN, Phillips J, Von Gelden M, Ried T, Kukuruga MA, Cunha GR, Hayward SW, Day ML. Source: The Journal of Biological Chemistry. 2002 August 20 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12191999&dopt=Abstract

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Retina pathology of a failed external beam-radiated group Vb retinoblastoma. Author(s): Tan HY, Chen HS, Chen WC, Lee HW. Source: Chang Gung Med J. 2002 August; 25(8): 542-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12392367&dopt=Abstract

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Retinoblastoma function is a better indicator of cellular phenotype in cultured breast adenocarcinoma cells than retinoblastoma expression. Author(s): Botos J, Smith R 3rd, Kochevar DT. Source: Experimental Biology and Medicine (Maywood, N.J.). 2002 May; 227(5): 354-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11976406&dopt=Abstract

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Retinoblastoma in a patient with an X;13 translocation and facial abnormalities consistent with 13q-syndrome. Author(s): Laquis SJ, Rodriguez-Galindo C, Wilson MW, Fleming JC, Haik BG.

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Source: American Journal of Ophthalmology. 2002 February; 133(2): 2857. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11812445&dopt=Abstract ·

Retinoblastoma in older children. Author(s): Karcioglu ZA, Abboud EB, Al-Mesfer SA, Al-Rashed W, Pilapil DH. Source: J Aapos. 2002 February; 6(1): 26-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11907476&dopt=Abstract

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Retinoblastoma metastatic to the ovary in a patient with Waardenburg syndrome. Author(s): Moshfeghi DM, Wilson MW, Haik BG, Hill DA, RodriguezGalindo C, Pratt CB. Source: American Journal of Ophthalmology. 2002 May; 133(5): 716-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11992879&dopt=Abstract

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Retinoblastoma presenting as panophthalmitis: clinicopathological study of a case. Author(s): Sundar JK, Krishnakumar S, Biswas J. Source: J Pediatr Ophthalmol Strabismus. 2002 May-June; 39(3): 178-80. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12051285&dopt=Abstract

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Retinoblastoma protein-mediated apoptosis after gamma -irradiation. Author(s): Bowen C, Birrer M, Gelmann EP. Source: The Journal of Biological Chemistry. 2002 September 23 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12297496&dopt=Abstract

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Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Author(s): Gombos DS, Kelly A, Coen PG, Kingston JE, Hungerford JL. Source: The British Journal of Ophthalmology. 2002 January; 86(1): 80-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11801509&dopt=Abstract


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Retinoblastoma tumor suppressor and genome stability. Author(s): Zheng L, Lee WH. Source: Adv Cancer Res. 2002; 85: 13-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12374284&dopt=Abstract

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Retinoblastoma with central retinal artery thrombosis that mimics extraocular disease. Author(s): Valverde K, Pandya J, Heon E, Goh TS, Gallie BL, Chan HS. Source: Medical and Pediatric Oncology. 2002 April; 38(4): 277-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11920797&dopt=Abstract

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Retinoblastoma-cyclin-dependent kinase pathway deregulation in vestibular schwannomas. Author(s): Lasak JM, Welling DB, Akhmametyeva EM, Salloum M, Chang LS. Source: The Laryngoscope. 2002 September; 112(9): 1555-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12352662&dopt=Abstract

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Retinoblastoma-related gene RB2/p130 exons 19-22 are rarely mutated in glioblastomas. Author(s): Gonzalez-Gomez P, Bello MJ, Arjona D, Alonso ME, Lomas J, De Campos JM, Vaquero J, Isla A, Gutierrez M, Rey JA. Source: Oncol Rep. 2002 September-October; 9(5): 951-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12168053&dopt=Abstract

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Retinoic acid upregulates cone arrestin expression in retinoblastoma cells through a Cis element in the distal promoter region. Author(s): Li A, Zhu X, Craft CM. Source: Investigative Ophthalmology & Visual Science. 2002 May; 43(5): 1375-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11980849&dopt=Abstract

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Risk factors for metastasis in retinoblastoma. Author(s): Finger PT, Harbour JW, Karcioglu ZA.

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Source: Survey of Ophthalmology. 2002 January-February; 47(1): 1-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11801265&dopt=Abstract ·

Risk of dying of retinoblastoma in Mexican children. Author(s): Carlos LL, Roberto RL, Victor TG, Carlos HG, Eduardo LP. Source: Medical and Pediatric Oncology. 2002 March; 38(3): 211-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11836727&dopt=Abstract

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(Neonatal) retinoblastoma in the first month of life. Author(s): Abramson DH, Du TT, Beaverson KL. Source: Archives of Ophthalmology. 2002 June; 120(6): 738-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12049578&dopt=Abstract

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13q deletion syndrome associated with retinoblastoma and clinical anophthalmos of the opposite eye. Author(s): Hadjistilianou T, Mastrangelo D, Mazzotta C, De Francesco S, Capretti C, Lore C. Source: Medical and Pediatric Oncology. 2002 April; 38(4): 293-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11920804&dopt=Abstract

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A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene. Author(s): Klutz M, Brockmann D, Lohmann DR. Source: American Journal of Human Genetics. 2002 July; 71(1): 174-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12016586&dopt=Abstract

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A perspective on chemoreduction and focal therapy for retinoblastoma. Author(s): Balasubramanya R, Pushker N, Bajaj M, Ghose S, Rani A. Source: American Journal of Ophthalmology. 2002 October; 134(4): 633. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12383837&dopt=Abstract


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A prospective study of children treated for retinoblastoma: cognitive and visual outcomes in relation to treatment. Author(s): Ek U, Seregard S, Jacobson L, Oskar K, Af Trampe E, Kock E. Source: Acta Ophthalmologica Scandinavica. 2002 June; 80(3): 294-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12059869&dopt=Abstract

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A T to C mutation in the polypyrimidine tract of the exon 9 splicing site of the RB1 gene responsible for low penetrance hereditary retinoblastoma. Author(s): Lefevre SH, Chauveinc L, Stoppa-Lyonnet D, Michon J, Lumbroso L, Berthet P, Frappaz D, Dutrillaux B, Chevillard S, Malfoy B. Source: Journal of Medical Genetics. 2002 May; 39(5): E21. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12011162&dopt=Abstract

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Adeno-associated virus protects the retinoblastoma family of proteins from adenoviral-induced functional inactivation. Author(s): Batchu RB, Shammas MA, Wang JY, Freeman J, Rosen N, Munshi NC. Source: Cancer Research. 2002 May 15; 62(10): 2982-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12019182&dopt=Abstract

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Alterations of the retinoblastoma-related gene RB2/p130 in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats. Author(s): Tsujiuchi T, Sasaki Y, Konishi Y, Tsutsumi M. Source: Molecular Carcinogenesis. 2002 October; 35(2): 57-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12325035&dopt=Abstract

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An infant with Down syndrome and retinoblastoma. A possible nonfortuitous association. Author(s): Moll AC, Imhof SM, Bouter L, den Otter W, Koten JW. Source: Ophthalmic Genetics. 2002 June; 23(2): 135-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12187432&dopt=Abstract

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Analysis of putative interactions between potyviral replication proteins and plant retinoblastoma proteins. Author(s): Oruetxebarria I, Kvarnheden A, Valkonen JP. Source: Virus Genes. 2002; 24(1): 65-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11930964&dopt=Abstract

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Association between telomerase activity and basic fibroblast growth factor up-regulation in retinoblastomas. Author(s): Kondo Y, Tanaka Y, Shields JA, Kondo S. Source: Anticancer Res. 2001 November-December; 21(6A): 3765-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11911245&dopt=Abstract

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Attenuated retinoblastoma gene product and associated E2F/retinoblastoma imbalance in anastomotic intimal hyperplasia. Author(s): Sivamurthy N, Stone DH, LoGerfo FW, Quist WC. Source: Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2002 June; 35(6): 1233-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12042736&dopt=Abstract

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Atypical macrocephaly-cutis marmorata telangiectatica congenita with retinoblastoma. Author(s): Schwartz IV, Felix TM, Riegel M, Schuler-Faccini L. Source: Clinical Dysmorphology. 2002 July; 11(3): 199-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12072801&dopt=Abstract

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Atypical retinoblastoma presentations: a challenge for the treating ophthalmologist. Author(s): McCaffery S, Wieland MR, O'Brien JM, Cooper KL, Wieland MR, Wendel RT. Source: Archives of Ophthalmology. 2002 September; 120(9): 1222-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12215103&dopt=Abstract

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Biochemical properties of the stimulatory activity of DNA polymerase alpha by the hyper-phosphorylated retinoblastoma protein. Author(s): Takemura M.


Source: Biochimica Et Biophysica Acta. 2002 June 6; 1571(2): 151-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12049795&dopt=Abstract ·

Brain necrosis after enucleation, external beam cobalt radiotherapy, and systemic chemotherapy for retinoblastoma. Author(s): Padula GD, McCormick B, Abramson DH. Source: Archives of Ophthalmology. 2002 January; 120(1): 98-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11786070&dopt=Abstract

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Brief report: conservative treatment in unilateral retinoblastoma: a preliminary report. Author(s): Hadjistilianou T, Mastrangelo D, De Francesco S, Mazzotta C. Source: Medical and Pediatric Oncology. 2002 June; 38(6): 439-41. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11984807&dopt=Abstract

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Cell-nonautonomous function of the retinoblastoma tumour suppressor protein: new interpretations of old phenotypes. Author(s): Whyatt D, Grosveld F. Source: Embo Reports. 2002 February; 3(2): 130-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11839697&dopt=Abstract

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Characterization of cardiac muscle factor 1 sequence motifs: retinoblastoma protein binding and nuclear localization. Author(s): Redkar A, deRiel JK, Xu YS, Montgomery M, Patwardhan V, Litvin J. Source: Gene. 2002 January 9; 282(1-2): 53-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11814677&dopt=Abstract

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Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization. Author(s): Suzuma K, Takahara N, Suzuma I, Isshiki K, Ueki K, Leitges M, Aiello LP, King GL.

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Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 January 22; 99(2): 721-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11805327&dopt=Abstract ·

Characterization of the gene encoding mouse retinoblastoma binding protein-7, a component of chromatin-remodeling complexes. Author(s): Yang J, Kiefer S, Rauchman M. Source: Genomics. 2002 October; 80(4): 407. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12376095&dopt=Abstract

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Chemothermotherapy in the management of retinoblastoma. Author(s): Lumbroso L, Doz F, Urbieta M, Levy C, Bours D, Asselain B, Vedrenne J, Zucker JM, Desjardins L. Source: Ophthalmology. 2002 June; 109(6): 1130-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12045055&dopt=Abstract

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Cloning and expression of a novel retinoblastoma binding protein cDNA, RBBP10. Author(s): Chen JZ, Yang QS, Wang S, Meng XF, Ying K, Xie Y, Ma YM. Source: Biochemical Genetics. 2002 August; 40(7-8): 273-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12296629&dopt=Abstract

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Current treatment of retinoblastoma. Author(s): De Potter P. Source: Current Opinion in Ophthalmology. 2002 October; 13(5): 331-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12218465&dopt=Abstract

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Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instability. Author(s): Zheng L, Flesken-Nikitin A, Chen PL, Lee WH. Source: Cancer Research. 2002 May 1; 62(9): 2498-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11980640&dopt=Abstract

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Delayed diagnosis of retinoblastoma: analysis of degree, cause, and potential consequences. Author(s): Butros LJ, Abramson DH, Dunkel IJ.


Source: Pediatrics. 2002 March; 109(3): E45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11875173&dopt=Abstract ·

Deregulated MAPK activity prevents adipocyte differentiation of fibroblasts lacking the retinoblastoma protein. Author(s): Hansen JB, Petersen RK, Jorgensen C, Kristiansen K. Source: The Journal of Biological Chemistry. 2002 July 19; 277(29): 263359. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12000769&dopt=Abstract

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Detection of Heterozygous Mutation in the Retinoblastoma Gene in a Human Pituitary Adenoma Using PCR-SSCP Analysis and Direct Sequencing. Author(s): Ikeda H, Beauchamp RL, Yoshimoto T, Yandell DW. Source: Endocr Pathol. 1995 Autumn; 6(3): 189-196. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12114739&dopt=Abstract

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Differentiation of human melanoma cells through p38 MAP kinase is associated with decreased retinoblastoma protein phosphorylation and cell cycle arrest. Author(s): Smalley KS, Eisen TG. Source: Melanoma Research. 2002 June; 12(3): 187-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12140374&dopt=Abstract

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

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Down-regulation of the retinoblastoma protein (rb) is associated with rat oligodendrocyte differentiation. Author(s): Huang Z, Tang XM, Cambi F.

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Source: Molecular and Cellular Neurosciences. 2002 February; 19(2): 25062. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11860277&dopt=Abstract ·

Editorial: chemotherapy for retinoblastoma. Author(s): Shields CL, Shields JA. Source: Medical and Pediatric Oncology. 2002 June; 38(6): 377-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11984796&dopt=Abstract

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Efficacy of induction chemotherapy in retinoblastoma, alone or combined with other adjuvant modalities. Author(s): Ghose S, Nizamuddin SH, Sethi A, Mohanti BK, Kumar H, Arya LS, Thavaraj V. Source: J Pediatr Ophthalmol Strabismus. 2002 May-June; 39(3): 143-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12051279&dopt=Abstract

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Efficacy of induction chemotherapy in retinoblastoma, alone or combined with other adjuvant modalities. Ghose S,* Nizamuddin SHM, Sethi A, Mohanti BK, Kumar H, Arya LS, Thavaraj V. J Pediatr Ophthalmol Strabismus 2002;39:143-150. Author(s): Grossniklaus H. Source: American Journal of Ophthalmology. 2002 October; 134(4): 642. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12383856&dopt=Abstract

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Electrophoretic variant of a lactate dehydrogenase isoenzyme and selective promoter methylation of the LDHA gene in a human retinoblastoma cell line. Author(s): Maekawa M, Inomata M, Sasaki MS, Kaneko A, Ushiama M, Sugano K, Takayama J, Kanno T. Source: Clinical Chemistry. 2002 November; 48(11): 1938-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12406979&dopt=Abstract

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Electroretinographic changes in the inner retinal layers of the retained eyes of patients with sporadic unilateral retinoblastoma.


Author(s): Lubinski W, Zajaczek S, Sych Z, Penkala K, Palacz O, Lubinski J. Source: Ophthalmic Genetics. 2002 June; 23(2): 99-107. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12187428&dopt=Abstract ·

Estrogen-like effects of thyroid hormone on the regulation of tumor suppressor proteins, p53 and retinoblastoma, in breast cancer cells. Author(s): Dinda S, Sanchez A, Moudgil V. Source: Oncogene. 2002 January 24; 21(5): 761-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11850804&dopt=Abstract

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Evaluation of molecular markers in low-grade diffuse astrocytomas: loss of p16 and retinoblastoma protein expression is associated with short survival. Author(s): Hilton DA, Penney M, Evans B, Sanders H, Love S. Source: The American Journal of Surgical Pathology. 2002 April; 26(4): 472-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11914625&dopt=Abstract

Vocabulary Builder Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Adenocarcinoma: Cancer that begins in cells that line certain internal organs and that have glandular (secretory) properties. [NIH] Adenoma: A noncancerous tumor. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Agonists: Drugs that trigger an action from a cell or another drug. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anophthalmos: Congenital absence of the eye or eyes. [NIH]

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Antigens: Substances that cause the immune system to make a specific immune response. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Apoptosis: A normal series of events in a cell that leads to its death. [NIH] Aromatic: Having a spicy odour. [EU] Arrestin: A 48-Kd protein of the outer segment of the retinal rods and a component of the phototransduction cascade. Arrestin quenches G-protein activation by binding to phosphorylated photolyzed rhodopsin. Arrestin causes experimental autoimmune uveitis when injected into laboratory animals. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, starshaped cells called astrocytes. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Choristoma: A mass of histologically normal tissue present in an abnormal location. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Conjunctiva: A membrane that lines the inner surface of the eyelid and also


covers the front part of the eye. Conjunctivitis is inflammation of the conjunctiva. [NIH] Cryotherapy: Any method that uses cold temperature to treat disease. [NIH] Cyclophosphamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Ectopic: Pertaining to or characterized by ectopia. [EU] Embryo: Having to do with an early stage in the development of a plant or an animal. In vertebrate animals, this stage lasts from shortly after fertilization until all major body parts appear. In particular, in humans, this stage lasts from about 2 weeks after fertilization until the end of the seventh or eighth week of pregnancy. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelium: A thin layer of tissue that covers organs, glands, and other structures within the body. [NIH] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] Erythroleukemia: Cancer of the blood-forming tissues in which large numbers of immature, abnormal red blood cells are found in the blood and bone marrow. [NIH] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Exons: Coding regions of messenger RNA included in the genetic transcript which survive the processing of RNA in cell nuclei to become part of a spliced messenger of structural RNA in the cytoplasm. They include joining and diversity exons of immunoglobulin genes. [NIH] Facial: Of or pertaining to the face. [EU] Fenretinide: A drug being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Ganciclovir: An antiviral agent used to prevent or treat cytomegalovirus infections that may occur when the body's immune system is suppressed. In

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gene therapy, ganciclovir is used with an altered herpes simplex virus-1 gene to kill advanced melanoma cells and brain tumor cells. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Glioblastoma: A general term that refers to malignant astrocytoma, a type of brain tumor. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Hematopoiesis: The forming of new blood cells. [NIH] Hepatoblastoma: A type of liver tumor that occurs in infants and children. [NIH]

Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hyperplasia: An abnormal increase in the number of cells in an organ or tissue. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertrophy: Nutrition) the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Insulin: A hormone made by the islet cells of the pancreas. Insulin controls the amount of sugar in the blood by moving it into the cells, where it can be used by the body for energy. [NIH] Laryngoscope: A thin, lighted tube used to examine the larynx (voice box). [NIH]

Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU]


Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Lymphoma: Cancer that arises in cells of the lymphatic system. [NIH] Malformation: A morphologic defect resulting from an intrinsically abnormal developmental process. [EU] Mandible: The largest and strongest bone of the FACE constituting the lower jaw. It supports the lower teeth. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Metabolite: process. [EU]

Any substance produced by metabolism or by a metabolic

Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Necrosis: Refers to the death of living tissues. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous sytem. [NIH] Nonmetastatic: Cancer that has not spread from the primary (original) site to other sites in the body. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Ophthalmic: Pertaining to the eye. [EU] Opsin: A visual pigment protein found in the retinal rods. It combines with

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retinaldehyde to form rhodopsin. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU]

Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Papillomavirus: A genus of papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH]

Parathyroid: 1. situated beside the thyroid gland. 2. one of the parathyroid glands. 3. a sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Particle: A tiny mass of material. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH]

Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH]

Radiotherapy: The treatment of disease by ionizing radiation. [EU]


Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: 1. a cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recurrence: The return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU]

Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Schwannoma: A tumor of the peripheral nervous system that begins in the nerve sheath (protective covering). It is almost always benign, but rare malignant schwannomas have been reported. [NIH] Sclerosis: A induration, or hardening; especially hardening of a part from inflammation and in diseases of the interstitial substance. The term is used chiefly for such a hardening of the nervous system due to hyperplasia of the connective tissue or to designate hardening of the blood vessels. [EU] Serine: A non-essential amino acid occurring in natural form as the Lisomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Staurosporine: A drug that belongs to the family of drugs called alkaloids. It is being studied in the treatment of cancer. [NIH] Strabismus: Deviation of the eye which the patient cannot overcome. The visual axes assume a position relative to each other different from that required by the physiological conditions. The various forms of strabismus are spoken of as tropias, their direction being indicated by the appropriate prefix, as cyclo tropia, esotropia, exotropia, hypertropia, and hypotropia. Called also cast, heterotropia, manifest deviation, and squint. [EU] Substrate: A substance upon which an enzyme acts. [EU] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears

Studies 125

to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Temozolomide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Testicular: Pertaining to a testis. [EU] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH]

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

Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Tumour: 1. swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. a new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [NIH] Ventricular: Pertaining to a ventricle. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH]

Patents 127

CHAPTER 5. PATENTS RHABDOMYOSARCOMA

ON

CHILDHOOD

Overview You can learn about innovations relating to childhood rhabdomyosarcoma by reading recent patents and patent applications. Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.31 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information.

31Adapted

from The U. S. Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.


Patents on Childhood Rhabdomyosarcoma By performing a patent search focusing on childhood rhabdomyosarcoma, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on childhood rhabdomyosarcoma: ·

Retinoblastoma protein-interacting zinc finger proteins Inventor(s): Huang; Shi (San Diego, CA) Assignee(s): The Burnham Institute (La Jolla, CA) Patent Number: 6,468,985 Date filed: March 17, 2000 Abstract: The present invention provides mammalian retinoblastoma (Rb) protein-interacting zinc finger (RIZ) proteins, nucleic acid molecules encoding the RIZ and antibodies specific for the RIZ. The invention also provides screening assays for identifying an agent that effectively alters the association of a RIZ with a second molecule, which can bind to the RIZ. The invention also provides active fragments of RIZ containing the PR domain, which can regulate transcription. In addition, the invention provides methods for introducing a nucleic acid molecule-encoding a RIZ into a cell and for A-contacting a cell with an effective agent in order to modulate a function of a cell. Such methods are useful, for example, for inducing growth of a cardiac cell or a neuronal cell in a subject and for effecting normal growth control to a tumor cell or causing differentiation of tumor cells. The invention further provides methods for detecting a RIZ in a sample by detecting the RIZ or a nucleic acid molecule encoding the RIZ. Such methods are useful to diagnose a pathology that is characterized by an increased or decreased level of a RIZ in a cell or by expression of a mutant RIZ in a cell. Excerpt(s): The retinoblastoma Rb protein is known to play a key role in controlling normal cell proliferation and differentiation. The ability of a cell to divide requires the cell to pass through the various phases of the cell cycle. Although Rb is believed to keep normal cells from dividing by maintaining them in a phase of the cell cycle known as G.sub.1 or

Patents 129

G.sub.0, the precise mechanism underlying Rb function is unknown. It is known, however, that Rb can bind various cellular proteins, including proteins involved in regulating gene transcription. Thus, Rb may exert its action by interacting with such cellular proteins. ... The present invention provides a novel mammalian Rb-interacting zinc finger protein, designated RIZ. RIZ is a nuclear phosphoprotein that acts as a cell differentiation factor. RIZ can modulate a function of a cell by binding to retinoblastoma (Rb) protein, which is involved in regulating cell proliferation. In addition, RIZ can act to regulate transcription. ... Rb is a nuclear phosphoprotein of 110 kiloDaltons (kD). that can bind DNA and is expressed in all tissue types examined thus far. The complete absence of Rb function is associated with the development of childhood retinoblastoma. In addition, Rb is mutated in a variety of cancer types, including various carcinomas and sarcomas, indicating a role for Rb in oncogenesis. Expression of exogenous Rb in various types of tumor cells suppresses the tumor phenotype (for review, see Lee et. al., J. Cell Biochem. 38:213-227 (1988)). Web site: http://www.delphion.com/details?pn=US06468985__ ·

Nucleic acid encoding a retinoblastoma binding protein (RBP-7) and polymorphic markers associated with said nucleic acid Inventor(s): Bougueleret; Lydie (Vanves, FR) Assignee(s): Genset (FR) Patent Number: 6,399,373 Date filed: June 30, 1999 Abstract: The present invention is directed to a polynucleotide comprising open reading frames defining a coding region encoding a retinoblastoma binding protein (RBP-7) as well as regulatory regions located both at the 5' end and the 3' end of said coding region. The present invention also pertains to a polynucleotide carrying the natural regulation signals of the RBP-7 gene which is useful in order to express a heterologous nucleic acid in host cells or host organisms as well as functionally active regulatory polynucleotides derived from said regulatory region. The invention also concerns polypeptides encoded by the coding region of the RBP-7 gene. The invention also deals with antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. The invention also comprises genetic markers, namely biallelic markers, that are means that may be useful for the diagnosis of diseases related to an alteration in the regulation or in the coding regions of the RBP-7 gene and for the prognosis/diagnosis of an


eventual treatment with therapeutic agents, especially agents acting on pathologies involving abnormal cell proliferation and/or abnormal cell differentiation. Excerpt(s): The present invention is directed to a polynucleotide comprising open reading frames defining a coding region encoding a retinoblastoma binding protein (RBP-7) as well as regulatory regions located both at the 5'end and the 3'end of said coding region. The present invention also pertains to a polynucleotide carrying the natural regulation signals of the RBP-7 gene which is useful in order to express a heterologous nucleic acid in host cells or host organisms as well as functionally active regulatory polynucleotides derived from said regulatory region. The invention also concerns polypeptides encoded by the coding region of the RBP-7 gene. The invention also deals with antibodies directed specifically against such polypeptides that are useful as diagnostic reagents. The invention includes genetic markers, namely biallelic markers, that are means that may be useful for the diagnosis of diseases related to an alteration in the regulation or in the coding regions of the RBP-7 gene and for the prognosis/diagnosis of and eventual treatment with therapeutic agents, especially agents acting on pathologies involving abnormal cell proliferation and/or abnormal cell differentiation. ... Tumor suppressor genes are detected in the form of inactivating mutations that are tumorigenic. The two best characterized genes of this class code for the proteins RB (Retinoblastoma protein) and p53. ... Retinoblastoma is a human childhood disease, involving a tumor in the retina. It occurs both as an inheritable trait and sporadically (by somatic mutation). Retinoblastoma arises when both copies of the RB gene are inactivated. In the inherited form of the disease, one parental chromosome carries an alteration in this region, usually a deletion. A somatic event in retinal cells that causes the loss of the other copy of the RB gene causes a tumor. Forty percent of cases are hereditary, transmitted as an autosomal dominant trait with 90% penetrance. Of these cases, around 10-15% are transmitted from an affected parent, the remaining arising as de novo germ-lime mutations. In the sporadic form of the disease, the parental chromosomes are normal, and both RB alleles are lost by somatic events. The tumor suppressor nature of RB was shown by the introduction of a single copy of RB1 into tumor cell lines lacking the gene, resulting in complete or partial suppression of the tumorigenic phenotype. Web site: http://www.delphion.com/details?pn=US06399373__

Patents 131

·

Plant retinoblastoma-associated gene Inventor(s): Gutierrezi-Armenta; Cristano (Madrid, ES), Sanz-Burgos; Andres Pelayo (Madrid, ES), Xie; Qi (Madrid, ES), Lopez; Paula Suarez (Norwich, GB) Assignee(s): Consejo Superior de Investigaciones Cientificas (Madrid, ES) Patent Number: 6,384,299 Date filed: December 14, 1998 Abstract: The present invention is based on the isolation and characterization of a plant cell DNA sequence encoding for a retinoblastoma protein. Such finding is based on the structural and functional properties of the plant retinoblastoma protein as possible regulator of the cellular cycle, of the cellular growth and of the plant cellular differentiation. For this reason, among other aspects, it is claimed the use of retinoblastoma protein or the DNA sequence which encodes for it in the growing control of vegetable cells, plants and/or vegetable virus, as well as the use of vectors, cells, plants or animals, or animal cells modified through the manipulation of the control route based on plant retinoblastoma protein. Excerpt(s): Cell cycle progression is regulated by positive and negative effectors. Among the latter, the product of the retinoblastoma susceptibility gene (Rb) controls the passage of mammalian cells through G1 phase. In mammalian cells, Rb regulates G1/S transit by inhibiting the function of the E2F family of transcription factors, known to interact with sequences in the promoter region of genes required for cellular DNA replication (see eg Weinberg, R. A. Cell 81,323 (1995); Nevins, J. R. Science 258,424 (1992)). DNA tumor viruses that infect animal cells express oncoproteins that interact with the Rb protein via a LXCXE motif, disrupting Rb-E2F complexes and driving cells into S-phase (Weinberg ibid; Ludlow, J. W. FASEB J. 7, 866 (1993); Moran, E. FASEB J. 7, 880 (1993); Vousden, K. FASEB J. 7, 872 (1993)). ... In a first aspect of the present invention there is provided the use of retinoblastoma protein in controlling the growth of plant cells and/or plant viruses. Particularly, the present invention provides control of viral infection and/or growth in plant cells wherein the virus requires the integrity of an LXCXE amino acid motif in one of its proteins, particularly, e. g., in the viral RepA protein, for normal reproduction. Particular plant viruses so controlled are Geminiviruses. ... A preferred method of control using such proteins involves applying these to the plant cell, either directly or by introduction of DNA or RNA encoding for their expression into the plant cell which it is desired to treat. By over expressing the retinoblastoma protein, or expressing an Rb protein or peptide fragment thereof that interacts with


the LXCXE motif of the virus but does not affect the normal functioning of the cell, it is possible to inhibit normal virus growth and thus also to produce infection spreading from that cell to its neighbors. Web site: http://www.delphion.com/details?pn=US06384299__ ·

Retinoblastoma fusion proteins Inventor(s): Antelman; Douglas (Encinitas, CA), Gregory; Richard J. (Westford, MA), Wills; Kenneth N. (Encinitas, CA) Assignee(s): Canji, Inc. (San Diego, CA) Patent Number: 6,379,927 Date filed: May 19, 1999 Abstract: Fusions of the transcription factor E2F and the retinoblastoma protein RB are provided, along with methods of treatment of hyperproliferative diseases. Excerpt(s): Both the retinoblastoma gene (RB) and transcription factor E2F play a critical role in cell growth control (for a review, see Adams, P. & Kaelin, W. Seminars in Cancer Biology 6:99-108 (1995)). The RB locus is frequently inactivated in a variety of human tumor cells. Reintroduction of a wild-type RB gene (e.g., Bookstein et al. Science 247:712-715 (1990)) or RB protein (pRB) (e.g., Antelman et al. Oncogene 10:697-704(1995)) into RBneg/RBmut cells can suppress growth in culture and tumorigenicity in vivo. ... One aspect of the invention is a polypeptide comprising a fusion of a transcription factor, the transcription factor comprising a DNA binding domain, and a retinoblastoma (RB) polypeptide, the RB polypeptide comprising a growth suppression domain. Another aspect of the invention is DNA encoding such a fusion polypeptide. The DNA can be inserted in an adenovirus vector. ... The retinoblastoma polypeptide can be wild-type RB, RB56, or a variant or fragment thereof. In some embodiments, the retinoblastoma polypeptide comprises amino acid residues of about 379 to about 928. Preferred amino acid substitutions of the RB polypeptide include residues 2, 608, 788, 807, and 811. Web site: http://www.delphion.com/details?pn=US06379927__

Patents 133

·

ppRB.sup.110 nuclear susceptibility gene product

phosphoprotein-the

retinoblastoma

Inventor(s): Lee; Wen-Hwa (San Diego, CA), -H. P. Lee; Eva Y. (San Diego, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,133,424 Date filed: June 7, 1995 Abstract: This invention relates in general to a phosphoprotein product of the retinoblastoma susceptibility gene. In particular, this invention relates to a phosphoprotein ppRB.sup.110 primarily located in the cell nucleus which has a DNA binding activity. The invention also relates to the amino acid sequence of the phosphoprotein and to the specific purified anti-retinoblastoma phosphoprotein antibody. The invention further relates to a method of diagnosing retinoblastoma and other retinoblastoma gene involved cancers, treating such kind of cancers and regulating the oncogenicity of other genes. Excerpt(s): This invention relates in general to a phosphoprotein product of the retinoblastoma susceptibility gene. In particular, this invention relates to a phosphoprotein ppRB.sup.110 primarily located in the cell nucleus which has a DNA binding activity. The invention also relates to the amino acid sequence of the phosphoprotein and to the specific purified anti-retinoblastoma phosphoprotein antibody. The invention further relates to a method of diagnosing retinoblastoma and other retinoblastoma gene involved cancers, treating such kind of cancers and regulating the oncogenicity of other genes. ... Retinoblastoma is a malignant tumor of the sensory layer of the retina. The neoplastic tumor is composed of primitive retinal cells, occurring often bilaterally, usually before the third year of life. It exhibits a familiar tendency. Retinoblastomas are characterized by small round cells with deeply staining nuclei, and elongated cells forming rosettes. They usually cause death by local invasion, especially along the optic nerves. ... The retinoblastoma may be hereditary but also acquired. It is the most common intraocular tumor and represents one of the prototypes of inheritable cancers. The hereditary form is characterized by early age of onset and multiple tumor foci. Acquired form occurs later in life with single-unilateral tumor (Proc. Natl. Acad. Sci., 68:820-823 [1971]; Hum. Genet., 52:1-54 [1979]; Science, 223:1028-1033 [1984]). Web site: http://www.delphion.com/details?pn=US06133424__


·

Retinoblastoma fusion polypeptides Inventor(s): Antelman; Douglas (Encinitas, CA), Gregory; Richard J. (Westford, MA), Wills; Kenneth N. (Encinitas, CA) Assignee(s): Canji, Inc. (San Diego, CA) Patent Number: 6,074,850 Date filed: February 14, 1997 Abstract: Fusions of the transcription factor E2F and the retinoblastoma protein RB are provided, along with methods of treatment of hyperproliferative diseases. Excerpt(s): Both the retinoblastoma gene (RB) and transcription factor E2F play a critical role in cell growth control (for a review, see Adams, P. & Kaelin, W. Seminars in Cancer Biology 6:99-108 (1995)). The RB locus is frequently inactivated in a variety of human tumor cells. Reintroduction of a wild-type RB gene (e.g., Bookstein et al. Science 247:712-715 (1990)) or RB protein (pRB) (e.g., Antelman et al. Oncogene 10:697-704(1995)) into RBneg/RBmut cells can suppress growth in culture and tumorigenicity in vivo. ... One aspect of the invention is a polypeptide comprising a fusion of a transcription factor, the transcription factor comprising a DNA binding domain, and a retinoblastoma (RB) polypeptide, the RB polypeptide comprising a growth suppression domain. Another aspect of the invention is DNA encoding such a fusion polypeptide. The DNA can be inserted in an adenovirus vector. ... The retinoblastoma polypeptide can be wild-type RB, RB56, or a variant or fragment thereof. In some embodiments, the retinoblastoma polypeptide comprises amino acid residues of about 379 to about 928. Preferred amino acid substitutions of the RB polypeptide include residues 2, 608, 788, 807, and 811. Web site: http://www.delphion.com/details?pn=US06074850__

·

Nucleic acids encoding novel proteins which bind to retinoblastoma protein Inventor(s): Qian; Yue-Wei (San Antonio, TX), Lee; Eva Y. H. P. (San Antonio, TX) Assignee(s): Board of Regents, The University of Texas System (Austin, TX) Patent Number: 6,071,715 Date filed: August 12, 1993

Patents 135

Abstract: The retinoblastoma protein (Rb) is the product of the retinoblastoma gene and has been found to contain mutations in retinoblastoma tumor cells. Two nuclear proteins that bind to Rb, p48 and p46 have been isolated and the genes have been cloned. These proteins bind to Rb competitively with the SV40 T antigen. p48 is shown to suppress heat shock sensitive Ras mutations in yeast and is implicated as a modulator of the retinoblastoma suppressor function of Rb. Excerpt(s): The present invention relates generally to the field of cellular regulation. More particularly, it concerns the control of cell growth as affected by the retinoblastoma protein, the implications of this control in cancers including retinoblastoma, and the interactions of oncogenes with cell cycle control proteins and other retinoblastoma associated cellular proteins. ... Retinoblastoma is a malignant cancer of the developing retina that manifests itself as an intraocular tumor in early childhood (Shields, J. A., 1983). Retinoblastoma occurs in two distinct forms (Vogel, F., 1979). In close to 40% of retinoblastoma cases, tumors appear bilaterally, may be multifocal in each eye, and appear at a very young age. Bilateral retinoblastoma is sometimes diagnosed in newborn infants. In the remaining retinoblastoma cases, tumors are unilateral, are unifocal, and generally present at about 2 years of age. ... The pattern of inheritance of retinoblastoma suggests that the wild-type alleles encode a repressor of tumor formation (Migdal, C., 1976). Evidence for the existence of tumorsuppressing genetic factors is also provided by cell fusion studies. Upon fusion of tumor cells with normal fibroblasts, lymphocytes, or keratinocytes (Harris, H., 1986a; Klein, G., et al., 1971), the malignant properties of the original tumor cells are suppressed. Web site: http://www.delphion.com/details?pn=US06071715__ ·

Retinoblastoma gene-cancer suppressor and regulator Inventor(s): Lee; Wen-Hwa (San Diego, CA), Lee; Eva Y-H. P. (San Diego, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 5,998,134 Date filed: June 7, 1995 Abstract: This invention relates in general to a genetic control of retinoblastoma and regulation of carcinogenicity. In particular this invention relates to the cloning, isolation, identification and sequencing of the retinoblastoma gene. The invention also relates to the method of use of the cloned retinoblastoma gene cDNA as a tool for diagnosing retinoblastoma, osteosarcoma and fibrosarcoma. Finally, the invention


relates to the control and regulatory mechanisms and functions of the retinoblastoma gene in the oncogenesis. Excerpt(s): This invention relates in general to a genetic control of retinoblastoma and regulation of carcinogenicity. In particular this invention relates to the cloning, isolation, identification and sequencing of the retinoblastoma gene. The invention also relates to the method of use of the cloned retinoblastoma gene cDNA as a tool for diagnosing retinoblastoma, osteosarcoma and fibrosarcoma. Finally, the invention relates to the gene therapy that replaces the defective gene in cancer cells with normal gene which should suppress cancer formation. ... Thus, under the above theory, it seems entirely plausible that cancer such as retinoblastoma may result when specific genes regulating certain types of cells are activated or inactivated. On the other hand, from the other available evidence outlined below, it is equally plausible that the retinoblastoma gene itself acts as one of the regulatory genes involved in tumorigenesis of certain tissues. ... Retinoblastoma tumors have been associated with an interstitial deletions of the long arm of chromosome 13. The deletion of a specific locus on chromosome 13 would be followed by somatic mutation with the consequence of tumor formation. (Ibid). Web site: http://www.delphion.com/details?pn=US05998134__ ·

Retinoblastoma-associated protein 1 CDNA Inventor(s): Kaelin, Jr.; William G. (Boston, MA), Flemington; Erik (Brookline, MA), DeCaprio; James A. (Wellesley, MA), Sellers; William (Brookline, MA), Livingston; David M. (Brookline, MA) Assignee(s): Dana-Farber Cancer Institute (Boston, MA) Patent Number: 5,981,723 Date filed: June 5, 1995 Abstract: We have discovered a nuclear protein in normal human cells, "retinoblastoma-associated protein 1" ("RBAP-1") that binds directly to the retinoblastoma protein pocket of the underphosphorylated form of the retinoblastoma protein ("RB") and does not bind to phosphorylated RB or to RB with inactivating mutations. The translated RBAP-1 sequence does not resemble other proteins whose sequences are known, and RBAP-1 does not contain a sequence homologous to the transforming element common to viral proteins that bind to the RB pocket. RBAP-1 and the E2F transcription activity have similar DNA-binding specificities and can bind to at least some of the same proteins, such as RB and E4.

Patents 137

Excerpt(s): The human retinoblastoma gene ("RB-1") is considered to be the prototype of a class of genes, generally known as "tumor suppressor genes", thought to be involved in suppressing neoplastic growth. Mutations in the retinoblastoma gene and dysfunction of its product have been implicated in the pathogenesis of a wide range of human tumors other than retinoblastomas, including bladder, breast, and small cell lung carcinomas, osteosarcomas, and soft tissue sarcomas. Furthermore, in cell populations where both copies of RB-1 are mutated, introduction of a wild-type copy of the gene can lead to a decrease in the growth rate or in the tumorigenicity of the cells expressing the exogenous gene (Huang et al., 1988, Science, Vol. 242, pp. 1563-1566). The retinoblastoma gene product, "RB", is believed to regulate cell growth, although the manner in which it does so is not well understood. ... We have discovered a nuclear protein in normal human cells, here termed "retinoblastoma-associated protein 1" ("RBAP-1") that, based on in vitro evidence, binds directly to the RB pocket of the underphosphorylated form of RB and does not bind to phosphorylated RB or to RB with inactivating mutations. The direct binding of RBAP-1 to RB suggests that RBAP-1 is involved in the RB signal transduction pathway. Web site: http://www.delphion.com/details?pn=US05981723__ ·

Diagnosis of retinoblastoma Inventor(s): Dryja; Thaddeus P. (Milton, MA), Friend; Stephen (Somerville, MA), Yandell; David W. (Waltham, MA) Assignee(s): Massachusetts Eye and Ear Infirmary (Boston, MA), Whitehead Institute (Cambridge, MA) Patent Number: 5,853,988 Date filed: October 8, 1992 Abstract: This invention relates to nucleic acid, or fragments thereof, encoding the retinoblastoma polypeptide, the retinoblastoma polypeptide itself, methods of detecting a defective retinoblastoma gene in human patients, and methods of treating these patients. Excerpt(s): This invention concerns the retinoblastoma gene and methods for detecting and treating patients afflicted with a defective retinoblastoma gene. ... Retinoblastoma is a neoplastic condition of the retinal cells, observed almost exclusively in children between the ages of 0 and 4 years. It affects between 1 in 34,000 and 1 in 15,000 live births in the United States. (L. E. Zimmerman, 1985, Retinoblastoma and retinocytoma, In W. H. Spencer (ed.), Ophthalmic Pathology: an Atlas and Textbook, Vol. II, Philadelphia: W. B. Saunders Co., pp. 1292-1351.) If


untreated, the malignant neoplastic retinal cells in the intraocular tumor travel to other parts-of the body, forming foci of uncontrolled growth which are always fatal. The current treatment for a retinoblastoma is enucleation of the affected eye if the intraocular tumor is large; for small intraocular tumors, radiation therapy, laser therapy, or cryotherapy is preferred. There is no known successful treatment for metastatic retinoblastoma. As with most cancers, morbidity and mortality are reduced if diagnosis can be made early in the course of the disease. ... In 30-40% of cases of retinoblastoma, the affected individual carries a heritable predisposition to retinoblastoma and can transmit this predisposition to his or her offspring as a dominant trait (A. G. Knudson, 1971, Mutation and cancer: Statistical study of retinoblastoma, Proc. Natl. Acad. Sci., Vol. 68, pp. 820-23). Carriers of this retinoblastomapredisposing trait are at a greatly elevated risk for development of several other forms of primary cancer, notably osteosarcoma and softtissue sarcoma. Web site: http://www.delphion.com/details?pn=US05853988__ ·

Therapeutic use of the retinoblastoma susceptibility gene product Inventor(s): Lee; Wen-Hwa (San Antonio, TX), Lee; Eva Y-H.P. (San Antonio, TX), Goodrich; David W. (Houston, TX), Shepard; H. Michael (Rancho Santa Fe, CA), Wang; Nan Ping (Seattle, WA), Johnson; Duane (Encinitas, CA) Assignee(s): The Regents of the University of California (Oakland, CA), Canji, Inc. (San Diego, CA) Patent Number: 5,851,991 Date filed: September 13, 1994 Abstract: This invention provides a method of preventing or inhibiting the proliferation of a pathologically proliferating cell, wherein the pathological proliferation of the cell is the result of the absence of a functional retinoblastoma protein or polypeptide in the cell. The method requires contacting the cell with an effective amount of retinoblastoma protein or polypeptide. This method also is useful to prevent or treat retinoblastoma or a secondary cancer to retinoblastoma by administering to a patient a functional retinoblastoma protein or polypeptide. Excerpt(s): One disease that would be desirable to be treated in this manner is retinoblastoma. Retinoblastoma is a malignant tumor of the sensory layer of the retina. The neoplastic tumor is composed of primitive retinal cells, occurring often bilaterally, usually before the third year of life. It exhibits a familiar tendency. Retinoblastomas are characterized by

Patents 139

small round cells with deeply stained nuclei, and elongated cells forming rosettes. They usually cause death by local invasion, especially along the optic nerves. ... The retinoblastoma may be hereditary but also acquired. It is the most common intraocular tumor and represents one of the prototypes of inheritable cancers. The hereditary form is characterized by early age of onset and multiple tumor foci. Acquired form occurs later in life with single unilateral tumor (Proc. Natl. Acad. Sci. (1971) 68:820-823; Hum. Genet. (1979) 52:1-54; Science (1984) 223:1028-1033. ... Susceptibility to hereditary retinoblastoma is transmissible to offsprings as an autosomal dominant trait with 90% penetrance, and the tumor has been and is, therefore, a prototypic model for the study of genetic determination in cancer (Am. J. Hum. Genet. (1978) 30:406-410; Cancer (1975) 35:1022-1026). Web site: http://www.delphion.com/details?pn=US05851991__ ·

Antibodies reactive with retinoblastoma binding proteins and methods of using same Inventor(s): Lee; Wen-Hwa (San Antonio, TX), Shan; Bei (San Antonio, TX) Assignee(s): Board of Regents of the University of Texas System (Austin, TX) Patent Number: 5,821,070 Date filed: October 20, 1993 Abstract: This invention provides novel antibodies specifically reactive with a nuclear retinoblastoma-associated polypeptide, wherein the polypeptide specifically binds to the protein product of the retinoblastoma gene. Also provided by this invention are antibodies specifically reactive with proteins having E2F biological activity. Methods of using these antibodies also are claimed. Excerpt(s): This invention relates to the molecular cloning of cellular genes encoding retinoblastoma-associated proteins. In a more specific aspect it relates to the identification of a gene with properties of the transcription factor E2F. ... The retinoblastoma gene (RB), the first tumor suppressor gene identified, encodes a nuclear phosphoprotein which is ubiquitously expressed in vertebrates (Friend, et al., 1986; Lee, et al., 1987b; Fung, et al., 1987). Mutations of this gene which lead to inactivation of its normal function have been found not only in 100% of retinoblastomas but also in many other adult cancers including small cell lung-carcinoma (Harbour, et al., 1988; Yokota, et al., 1988), osteosarcoma (Toguchida, et al., 1988), bladder carcinoma (Horowitz, et al., 1989),


prostate carcinoma (Bookstein, et al., 1990a) and breast cancer (Lee et al., 1988). Reconstitution of a variety of RB-deficient tumor cells with wildtype RB leads to suppression of their neoplastic phenotypes including their ability to form tumors in nude mice (Huang, et al., 1988; Sumegi, et al., 1990; Bookstein, et al., 1990b; Lee, et al., 1990; Goodrich, et al., 1992; Takahashi, et al., 1991; Chen, et al., 1992). These results provide direct evidence that RB protein is an authentic tumor suppressor. ... As the foregoing demonstrates, there clearly exists a pressing need to identify and characterize the cellular affiliates of the retinoblastoma gene. The present invention satisfies this need and provides related advantages as well. Web site: http://www.delphion.com/details?pn=US05821070__ ·

Nucleic acid molecules encoding retinoblastoma protein-interacting zinc finger proteins Inventor(s): Huang; Shi (San Diego, CA) Assignee(s): La Jolla Cancer Research Foundation (La Jolla, CA) Patent Number: 5,811,304 Date filed: June 2, 1995 Abstract: The present invention provides a nucleic acid molecule encoding a mammalian retinoblastoma protein-interacting zinc finger (RIZ) protein, which binds retinoblastoma protein. In addition, the invention provides methods for reducing the growth of a tumor cell by introducing a nucleic acid molecule encoding a RIZ into the tumor cell. Excerpt(s): The retinoblastoma Rb protein is known to play a key role in controlling normal cell proliferation and differentiation. The ability of a cell to divide requires the cell to pass through the various phases of the cell cycle. Although Rb is believed to keep normal cells from dividing by maintaining them in a phase of the cell cycle known as G.sub.1 or G.sub.0, the precise mechanism underlying Rb function is unknown. ... The present invention provides a novel mammalian Rb-interacting zinc finger protein, designated RIZ. RIZ is a nuclear phosphoprotein that acts as a cell differentiation factor. RIZ can modulate a function of a cell by binding to retinoblastoma (Rb) protein, which is involved in regulating cell proliferation. ... Rb is a nuclear phosphoprotein of 110 kiloDaltons (kD) that can bind DNA and is expressed in all tissue types examined thus far. The complete absence of Rb function is associated with the development of childhood retinoblastoma. In addition, Rb is mutated in a variety of cancer types, including various carcinomas and sarcomas, indicating a role indicating a role for Rb in oncogenesis. Expression of

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exogenous Rb in various types of tumor cells suppresses the tumor phenotype (for review, see Lee et. al., J. Cell Biochem. 38:213-227 (1988)). Web site: http://www.delphion.com/details?pn=US05811304__ ·

Recombinant retinoblastoma-associated protein 1 (E2F-1) polypeptides and cDNA Inventor(s): Kaelin, Jr.; William G. (Boston, MA), Flemington; Erik (Brookline, MA), Sellers; William (Brookline, MA), Livingston; David M. (Brookline, MA) Assignee(s): Dana-Farber Cancer Institute (Boston, MA) Patent Number: 5,759,803 Date filed: May 13, 1992 Abstract: We have discovered a nuclear protein in normal human cells, "retinoblastoma-associated protein 1" ("RBAP-1"), also known as E2F-1, that binds directly to the retinoblastoma protein pocket of the underphosphorylated form of the retinoblastoma protein ("RB") and does not bind to phosphorylated RB or to RB with inactivating mutations. The translated RBAP-1 sequence does not resemble other proteins whose sequences are known, and RBAP-1 does not contain a sequence homologous to the transforming element common to viral proteins that bind to the RB pocket. RBAP-1 and the E2F transcription activity have similar DNA-binding specificities and can bind to at least some of the same proteins, such as RB and E4. Excerpt(s): The human retinoblastoma gene ("RB-1") is considered to be the prototype of a class of genes, generally known as "tumor suppressor genes", thought to be involved in suppressing neoplastic growth. Mutations in the retinoblastoma gene and dysfunction of its product have been implicated in the pathogenesis of a wide range of human tumors other than retinoblastomas, including bladder, breast, and small cell lung carcinomas, osteosarcomas, and soft tissue sarcomas. Furthermore, in cell populations where both copies of RB-1 are mutated, introduction of a wild-type copy of the gene can lead to a decrease in the growth rate or in the tumorigenicity of the cells expressing the exogenous gene (Huang et al., 1988, Science, Vol. 242, pp. 1563-1566). The retinoblastoma gene product, "RB", is believed to regulate cell growth, although the manner in which it does so is not well understood. ... We have discovered a nuclear protein in normal human cells, here termed "retinoblastoma-associated protein 1" ("RBAP-1"), also known as E2F-1, that, based on in vitro evidence, binds directly to the RB pocket of the underphosphorylated form of RB and does not bind to phosphorylated RB or to RB with


inactivating mutations. The direct binding of RBAP-1 to RB suggests that RBAP-1 is involved in the RB signal transduction pathway. Web site: http://www.delphion.com/details?pn=US05759803__ ·

Transgenic mice which express simian SV 40 T-antigen under control of the retinoblastoma gene promoter Inventor(s): Chang; Long-Sheng (Hilliard, OH), Zhu; Lingyun (Hilliard, OH) Assignee(s): Children's Hospital, Inc. (Columbus, OH) Patent Number: 5,728,915 Date filed: May 8, 1995 Abstract: Transgenic mice whose germ cells and somatic cells contain a simian SV40 T-oncogene operably linked to the promoter of the retinoblastoma susceptibility (RB) gene effective for expression of the Toncogene in somatic cells of the mouse under control of the promoter spontaneously develop tumors of the ocular tissues as well as osteosarcomas and soft-tissue sarcomas. Such transgenic mice are useful as sources of tissue cultures of tumor cells and as animal models for the occurrence of osteosarcomas and soft-tissue sarcomas in humans and other animals. Excerpt(s): It is also known that the presence of certain defective genes in a cell can predispose the cell to tumor formation. Retinoblastoma, a cancer of the retina, is an intraocular malignancy which usually occurs in children under the age of four years at an incidence of one in about 20,000 live births. The tumor can be categorized as either sporadic (generally unilateral with a single focus of tumor formation) or heritable (frequently multifocal and bi-lateral). From genetic and epidemiological studies, Knudson, 1971, Proc. Natl. Acad. Sci. USA 68, pp.820-823, first proposed the "two-hit" hypothesis according to which two mutational events were required to induce malignant transformation. Subsequent studies confirmed that the loss or disabling of both alleles of a gene mapped to human chromosome 13 band q14 was required for the transformation. The inherited susceptibility to retinoblastoma arises from the loss of one allele, while the loss of the second allele due to mutation in a retinoblast cell results in its transformation into a tumor cell. The non-inherited form of the disease results from a random incapacitation of both alleles in a retinoblast cell. This gene, called the retinoblastoma susceptibility (RB) gene, encodes an mRNA of 4.7 kilobases that is usually mutated or deleted in tumor cells. The protein product encoded by the normal gene is a nuclear phosphoprotein (RB protein) with a molecular weight of

Patents 143

about 105-110 kDa. All retinoblastoma cells tested to date fail to synthesize a normal-sized RB protein (Lee et al., 1987, Nature, 329, pp. 642-645). However, tumor formation is suppressed when the synthesis of RB protein is restored in human RB.sup.- tumor cells by inserting a normal RB gene. The RB protein binds to single-stranded and doublestranded DNA without sequence specificity, and is expressed in virtually all cell types examined to date. Furthermore, it is known to be phosphorylated, and thereby apparently inactivated, at the G.sub.1 /S boundary of the cell cycle. Consequently, it is believed that the RB protein may play an important role in regulating cell growth in many cell types. ... Recently, the murine RB cDNA has been cloned, and the mouse RB protein showed 91% homology to the corresponding human protein (Bernards et al., 1989, Proc. Nat. Acad. Sci. USA 86, 6474-6478). Using this mouse cDNA as a probe, RB was found to be expressed early in mouse development, by at least day 11 of gestation. In adult mouse tissues, RB seems to be ubiquitously expressed. In order to determine the effect of deletion of one allele of the RB gene in mice, the embryonic stem cellgene targeting technique was used to construct mouse strains in which one allele of the RB gene was disrupted (Clarke et al. Nature 323, pp. 328330; Lee et al., 1992, Nature 359, pp. 288-294). Surprisingly, heterozygous mice did not develop retinoblastoma, but later developed a pituitary tumor. Embryos homozygous for the RB mutation died between days 14 and 15 of gestation, exhibiting neuronal cell death and defective erythropoiesis. These results suggest that RB plays an important role in the early development of the mouse. However, they shed no light on the possible role of RB in controlling differentiation of retinoblasts and other tissues at later stages of mouse development. ... A further object is to provide a transgenic animal that spontaneously develops tumors characteristic of loss of the retinoblastoma (RB) gene function. Web site: http://www.delphion.com/details?pn=US05728915__


Patent Applications on Childhood Rhabdomyosarcoma As of December 2000, U.S. patent applications are open to public viewing.32 Applications are patent requests which have yet to be granted (the process to achieve a patent can take several years). The following patent applications have been filed since December 2000 relating to childhood rhabdomyosarcoma: ·

Modified Retinoblastoma Tumor Supressor Proteins Inventor(s): Xu, Hong-Ji ; (The Woodlands, Tx), Hu, Shi-Xue; (The Woodlands, Tx), Benedict, William F.; (The Woodlands, Tx), Zhou, Yunli; (Brookline, MA) Correspondence: Pennie and Edmonds; 1155 Avenue of the Americas; New York; NY; 100362711 Patent Application Number: 20020151461 Date filed: December 22, 1999 Abstract: Disclosed are modified broad-spectrum retinoblastoma tumor suppressor proteins that have at least the same, and in most cases higher biological activity than the corresponding wild-type retinoblastoma tumor suppressor protein. Exemplary modified retinoblastoma tumor suppressor proteins have a modified N-terminal region, in particular comprising one or more deletions and/or mutations. Also disclosed are methods of making and using the modified retinoblastoma tumor suppressor proteins, particularly in circumstances where inhibition of cell growth is desired. Thus the present disclosure provides methods for treating diseases, as exemplified by, but not limited to cancer, that are characterized by abnormal cellular proliferation. Excerpt(s): The present invention relates generally to the field of molecular and cellular biology. More particularly, it concerns modifications of the retinoblastoma tumor suppressor. The present invention further relates to the use of the instant modified retinoblastoma tumor suppressors in situations where providing a tumor suppressor or normal cell growth suppressor is indicated. ... Examples of tumor suppressor genes and candidate tumor suppressor genes include, but are not limited to, the retinoblastoma (RB) gene (Friend et al., 1986; Fung et al., 1987; Lee et al., 1987a), the wild-type p53 gene (Finlay et al., 1989; Baker et al., 1990), the deleted in colon carcinoma (DCC) gene (Fearon et al., 1990a; 1990b), the neurofibromatosis type 1 (NF-1) gene (Wallace et al., 1990; Viskochil et al., 1990; Cawthon et al., 1990), the Wilms tumor

32

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

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(WT-1) gene (Call et al., 1990; Gessler et al., 1990; Pritchard-Jones et al., 1990), the von Hippel-Lindau (VHL) disease tumor suppressor gene (Duan et al., 1995), the Maspin (Zou et al., 1994), Brush-1 (Schott et al., 1994) and BRCA 1 genes (Miki et al., 1994; Futreal et al., 1994) for breast cancer, and the multiple tumor suppressor (MTS) or p1 6 gene (Serrano et al., 1993; Kamb et al., 1994). The list of putative tumor suppressor genes is large and growing, with the total number of tumor suppressor genes expected to be well beyond 50 (Knudson, 1993). ... The first tumor suppressor gene identified was the retinoblastoma (RB) gene, which causes the hereditary retinoblastoma (Knudson, 1971; Murphree and Benedict, 1984; Knudson, 1985). The retinoblastoma (RB) gene, which was cloned in the middle 1980s, is one of the best studied tumor suppressor genes. The size of the RB gene complementary DNA (cDNA), about 4.7 kb, permits ready manipulation of the gene, and has led to the insertion of the RB gene into a number of cell lines. The RB gene has been shown to be missing or defective in a majority of retinoblastomas, sarcomas of the soft tissues and bones, and in approximately 20 to 40 percent of breast, lung, prostate and bladder carcinomas (Lee et al., WO 90/05180; Bookstein et al., 1991; Benedict et al., 1990). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with childhood rhabdomyosarcoma, you can access the U.S. Patent Office archive via the Internet at no cost to you. This archive is available at the following Web address: http://www.uspto.gov/main/patents.htm. Under “Services,” click on “Search Patents.” You will see two broad options: (1) Patent Grants, and (2) Patent Applications. To see a list of granted patents, perform the following steps: Under “Patent Grants,” click “Quick Search.” Then, type “childhood rhabdomyosarcoma” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on childhood rhabdomyosarcoma. You can also use this procedure to view pending patent applications concerning childhood rhabdomyosarcoma. Simply go back to the following Web address: http://www.uspto.gov/main/patents.htm. Under “Services,” click on “Search Patents.” Select “Quick Search” under “Patent Applications.” Then proceed with the steps listed above.


Vocabulary Builder Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Osteosarcoma: A cancer of the bone that affects primarily children and

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adolescents. Also called osteogenic sarcoma. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Reconstitution: 1. a type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. the restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Somatic: 1. pertaining to or characteristic of the soma or body. 2. pertaining to the body wall in contrast to the viscera. [EU] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU]

Books 149

CHAPTER 6. BOOKS RHABDOMYOSARCOMA

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Overview This chapter provides bibliographic book references relating to childhood rhabdomyosarcoma. You have many options to locate books on childhood rhabdomyosarcoma. The simplest method is to go to your local bookseller and inquire about titles that they have in stock or can special order for you. Some parents, however, prefer online sources (e.g. www.amazon.com and www.bn.com). In addition to online booksellers, excellent sources for book titles on childhood rhabdomyosarcoma include the Combined Health Information Database and the National Library of Medicine. Once you have found a title that interests you, visit your local public or medical library to see if it is available for loan.

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “childhood rhabdomyosarcoma” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or


relevance. The following was recently catalogued by the National Library of Medicine:33 ·

Atlas of intraocular tumors. Author: Jerry A. Shields, Carol L. Shields; Year: 1999; Philadelphia: Lippincott Williams ; Wilkins, c1999; ISBN: 078171916X http://www.amazon.com/exec/obidos/ASIN/078171916X/icongroupi nterna

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Clinical challenges in paediatric oncology. Author: edited by C. Ross Pinkerton, Antony J. Michalski, Paul A. Veys; Year: 1999; Oxford: Isis Medical Media, 1999; ISBN: 1899066861 http://www.amazon.com/exec/obidos/ASIN/1899066861/icongroupin terna

·

Ocular and adnexal tumors: new and controversial aspects. Symposium sponsored by Dept. of Ophthalmology, Baylor University College of Medicine. Author: Boniuk, Milton, 1932-; Year: 1964; St. Louis, Mosby, 1964

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Polymerase chain reaction detection of retinoblastoma gene deletions in paraffin-embedded mouse lung adenocarcinomas [microform]. Author: Mark E. Churchill, M. Anne Gemmell, and Gayle E. Woloschak; Year: 1991; Argonne, Ill.: Argonne National Laboratory, [1991?] Radiotherapy of intraocular and orbital tumors. Author: with contributions by D.H. Abramson ... [et al.]; edited by W.E. Alberti and R.H. Sagerman; foreword by L.W. Brady and H.-P. Heilmann; introduction by F.A. Jakobiec; Year: 1993; Berlin; New York: SpringerVerlag, c1993; ISBN: 3540176861 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/3540176861/icongroupin terna

·

·

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Retinoblastoma, a clinical and pathologic study of 88 cases seen at the Mayo Clinic from 1915 to 1950. Author: Groom, Joseph John, 1914-; Year: 1951; [Minneapolis] 1951 Retinoblastoma, a medical and experimental study. Author: door Jan Schipper; Year: 1980; [Utrecht?: s.n., 1980?]

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a “Books” button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

33

Books 151

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Retinoblastoma. Author: edited by Frederick C. Blodi; Year: 1985; New York: Churchill Livingstone, 1985; ISBN: 0443084149 http://www.amazon.com/exec/obidos/ASIN/0443084149/icongroupin terna

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Solid tumors in children. Author: Carl Pochedly, guest editor; Year: 1979; New York: Insight Pub. Co., 1979

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Transcriptional corepressors: mediators of eukaryotic gene repression. Author: edited by Martin L. Privalsky; Year: 2001; Berlin; New York: Springer, c2001; ISBN: 3540676112 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/3540676112/icongroupin terna

·

Turning points in cataract formation, syndromes, and retinoblastoma. Author: volume editor, W. Straub; Year: 1983; Basel; New York: Karger, 1983; ISBN: 3805535643 http://www.amazon.com/exec/obidos/ASIN/3805535643/icongroupin terna

Chapters on Childhood Rhabdomyosarcoma Frequently, childhood rhabdomyosarcoma will be discussed within a book, perhaps within a specific chapter. In order to find chapters that are specifically dealing with childhood rhabdomyosarcoma, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and childhood rhabdomyosarcoma using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” By making these selections and typing in “childhood rhabdomyosarcoma” (or synonyms) into the “For these words:” box, you will only receive results on chapters in books.


General Home References In addition to references for childhood rhabdomyosarcoma, you may want a general home medical guide that spans all aspects of home healthcare. The following list is a recent sample of such guides (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): · American Academy of Pediatrics Guide to Your Child’s Symptoms: The Official, Complete Home Reference, Birth Through Adolescence by Donald Schiff (Editor), et al; Paperback - 256 pages (January 1997), Villard Books; ISBN: 0375752579; http://www.amazon.com/exec/obidos/ASIN/0375752579/icongroupinterna · Cancer: 50 Essential Things to Do by Greg Anderson, O. Carl Simonton; Paperback - 184 pages; Revised & Updated edition (August 1999), Plume; ISBN: 0452280745; http://www.amazon.com/exec/obidos/ASIN/0452280745/icongroupinterna · Cancer Encyclopedia -- Collections of Anti-Cancer & Anti-Carcinogenic Agents, Chemicals, Drugs and Substances by John C. Bartone; Paperback (January 2002), ABBE Publishers Association of Washington, DC; ISBN: 0788326791; http://www.amazon.com/exec/obidos/ASIN/0788326791/icongroupinterna · Cancer Sourcebook: Basic Consumer Health Information About Major Forms and Stages of Cancer by Edward J. Prucha (Editor); Library Binding - 1100 pages, 3rd edition (August 1, 2000), Omnigraphics, Inc.; ISBN: 0780802276; http://www.amazon.com/exec/obidos/ASIN/0780802276/icongroupinterna · Cancer Supportive Care: A Comprehensive Guide for Patients and Their Families by Ernest H. Rosenbaum, M.D., Isadora Rosenbaum, M.A.; Paperback - 472 pages (November 5, 1998), Somerville House Books Limited; ISBN: 1894042115; http://www.amazon.com/exec/obidos/ASIN/1894042115/icongroupinterna · Cancer Symptom Management: Patient Self-Care Guides (Book with CD-ROM for Windows & Macintosh) by Connie Henke Yarbro (Editor), et al; CD-ROM - 264 pages, 2nd Book & CD-Rom edition (January 15, 2000), Jones & Bartlett Publishing; ISBN: 0763711675; http://www.amazon.com/exec/obidos/ASIN/0763711675/icongroupinterna · Children with Cancer: A Comprehensive Reference Guide for Parents by Jeanne Munn Bracken; Hardcover (May 2001), Replica Books; ISBN: 0735104123; http://www.amazon.com/exec/obidos/ASIN/0735104123/icongroupinterna

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· The Children’s Hospital Guide to Your Child’s Health and Development by Alan D. Woolf (Editor), et al; Hardcover - 796 pages, 1st edition (January 15, 2001), Perseus Books; ISBN: 073820241X; http://www.amazon.com/exec/obidos/ASIN/073820241X/icongroupinterna · Diagnosis Cancer: Your Guide Through the First Few Months by Wendy Schlessel Harpham, Ann Bliss Pilcher (Illustrator); Paperback: 230 pages; Revised & Updated edition (November 1997), .W. Norton & Company; ISBN: 0393316912; http://www.amazon.com/exec/obidos/ASIN/0393316912/icongroupinterna · Helping Your Child in the Hospital: A Practical Guide for Parents by Nancy Keene, Rachel Prentice; Paperback - 176 pages, 3rd edition (April 15, 2002), O’Reilly & Associates; ISBN: 0596500114; http://www.amazon.com/exec/obidos/ASIN/0596500114/icongroupinterna · The Human Side of Cancer: Living with Hope, Coping with Uncertainty by Jimmie C. Holland, M.D., Sheldon Lewis; Paperback - 368 pages (October 2, 2001), Quill; ISBN: 006093042X; http://www.amazon.com/exec/obidos/ASIN/006093042X/icongroupinterna · Medical Emergencies & Childhood Illnesses: Includes Your Child’s Personal Health Journal (Parent Smart) by Penny A. Shore, William Sears (Contributor); Paperback - 115 pages (February 2002), Parent Kit Corporation; ISBN: 1896833187; http://www.amazon.com/exec/obidos/ASIN/1896833187/icongroupinterna · Taking Care of Your Child: A Parent’s Guide to Complete Medical Care by Robert H. Pantell, M.D., et al; Paperback - 524 pages, 6th edition (March 5, 2002), Perseus Press; ISBN: 0738206016; http://www.amazon.com/exec/obidos/ASIN/0738206016/icongroupinterna · You and Your Cancer: A Child’s Guide by Lynda Cranston, et al; Paperback - 56 pages, 1st edition (July 15, 2001), B C Decker; ISBN: 1550091476; http://www.amazon.com/exec/obidos/ASIN/1550091476/icongroupinterna

Vocabulary Builder Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a


specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical anti-inflammatory. It is also commonly used as an embedding material in histology. [NIH]

Multimedia 155

CHAPTER 7. MULTIMEDIA RHABDOMYOSARCOMA

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Overview Information on childhood rhabdomyosarcoma can come in a variety of formats. Among multimedia sources, video productions, slides, audiotapes, and computer databases are often available. In this chapter, we show you how to keep current on multimedia sources of information on childhood rhabdomyosarcoma. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine. If you see an interesting item, visit your local medical library to check on the availability of the title.

Bibliography: Multimedia on Childhood Rhabdomyosarcoma The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in childhood rhabdomyosarcoma (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on childhood rhabdomyosarcoma. For more information, follow the hyperlink indicated: ·

Ocular histology and pathology. Source: David Barsky; Year: 1974; Format: Slide; New York: Medcom, c1974


·

Oncogene research update. Source: with Robert A. Weinberg and Thaddeus P. Dryja; Year: 1988; Format: Videorecording; Secaucus, N.J.: Network for Continuing Medical Education, c1988

·

Pediatric hematology: a morphologic approach to diagnosis. Source: J.Lawrence Naiman; Year: 1972; Format: Filmstrip; Philadelphia,: Saunders, c1972

·

Physical examination of the newborn: the art and findings. Source: Pfizer Laboratories; produced by Medical Arts Productions, San Francisco; Year: 1960; Format: Motion picture; [New York]: Pfizer Laboratories, [1960?] Retinoblastoma and pseudoglioma. Source: [Daniel M. Albert, Delia N. Sang]; Year: 1981; Format: Slide; Philadelphia, PA.: F.A. Davis, c1981

· · ·

Retinoblastoma protein. Source: Edward E. Harlow; Year: 1995; Format: Sound recording; [Bethesda, Md.: National Institutes of Health, 1995] Solid tumors of childhood. Source: Charlene P. Holton, Edward S. Baum; Year: 1972; Format: Slide; [New York]: Medcom, c1972

Physician Guidelines and Databases 157

CHAPTER 8. PHYSICIAN GUIDELINES AND DATABASES Overview Doctors and medical researchers rely on a number of information sources to help children with childhood rhabdomyosarcoma. Many will subscribe to journals or newsletters published by their professional associations or refer to specialized textbooks or clinical guides published for the medical profession. In this chapter, we focus on databases and Internet-based guidelines created or written for this professional audience.

NIH Guidelines For the more common medical conditions, the National Institutes of Health publish guidelines that are frequently consulted by physicians. Publications are typically written by one or more of the various NIH Institutes. For physician guidelines, commonly referred to as “clinical” or “professional” guidelines, you can visit the following Institutes: ·

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

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

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

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National Cancer Institute (NCI); guidelines available at http://cancernet.nci.nih.gov/pdq/pdq_treatment.shtml


In this chapter, we begin by reproducing one such guideline for childhood rhabdomyosarcoma:

What Is Childhood Rhabdomyosarcoma?34 This treatment information summary on childhood rhabdomyosarcoma is an overview of prognosis, diagnosis, classification, and patient treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recently published literature are included after review by pediatric oncology specialists. Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologist, pediatric oncologist/hematologist, rehabilitation specialist, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.35 At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. The majority of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI (http://cancer.gov/clinical_trials/). Childhood rhabdomyosarcoma, a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of the cases of cancer among children 0 to 14 years and 2% of the cases among adolescents and young

The following guidelines appeared on the NCI website on Aug 26, 2002. The text was last modified Jul, 2002. The text has been adapted for this sourcebook. 35 Sanders J, Glader B, Cairo M, et al.: Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99(1): 139-141, 1997. 34


adults 15 to 19 years of age.36 It is a curable disease in the majority of children who receive optimal therapy, with more than 60% surviving 5 years after diagnosis.37 The most common primary sites for rhabdomyosarcoma are the head and neck (e.g., parameningeal, orbit, pharyngeal, etc.), the genitourinary tract, and the extremities.38 Other less common primary sites include the trunk, intrathoracic region, the gastrointestinal tract (including liver and biliary tract), and the perineal/anal region. The vast majority of cases of rhabdomyosarcoma occur sporadically with no recognized predisposing factor or risk factor,39 although a small proportion are associated with genetic conditions. These conditions include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations),40 neurofibromatosis type I,41 and Beckwith-Wiedemann syndrome (though Wilms’ tumor and hepatoblastoma are more commonly associated with this syndrome).42

Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States: sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75(8): 2186-2195, 1995. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available at: http://seer.cancer.gov/csr/1973_1996 37 Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. Journal of Clinical Oncology 13(3): 610-630, 1995. Maurer H, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71(5): 1904-1922, 1993. 38 Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. Journal of Clinical Oncology 13(3): 610-630, 1995. Maurer H, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71(5): 1904-1922, 1993. 39 Gurney JG, Young JL Jr, Roffers SD, et al.: Soft tissue sarcomas. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, NIH Pub.No. 99-4649, 1999, pp 111-123. 40 Li FP, Fraumeni JF Jr: Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. Journal of the National Cancer Institute 43(6): 1365-1373, 1969. Diller L, Sexsmith E, Gottlieb A, et al.: Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. Journal of Clinical Investigation 95(4): 1606-1611, 1995. 41 Matsui I, Tanimura M, Kobayashi N, et al.: Neurofibromatosis type 1 and childhood cancer. Cancer 72(9): 2746-2754, 1993. Hartley AL, Birch JM, Marsden HB, et al.: Neurofibromatosis in children with soft tissue sarcoma. Pediatric Hematology and Oncology 5(1): 7-16, 1988. 42 Samuel DP, Tsokos M, DeBaun MR: Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Medical and Pediatric Oncology 32(1): 38-43, 1999. 36


Prognosis The prognosis for a child or adolescent with rhabdomyosarcoma is related to the site of origin, extent and histopathology of disease.43 There are also preliminary data describing the possible prognostic significance of specific biological characteristics of rhabdomyosarcoma tumor cells. Examples of both clinical and biological factors with proven or possible prognostic significance are briefly described below. ·

Primary sites with more favorable prognoses include the orbit and nonparameningeal head and neck, paratestis and vagina (nonbladder, nonprostate genitourinary) and the biliary tract.44

·

Tumor burden at diagnosis has prognostic significance. Patients with smaller tumors (50%) than other patients with metastatic disease.113

Treatment Options under Clinical Evaluation ·

Alternating multiagent regimens: These regimens combine VAC-like treatment courses including doxorubicin with treatment courses of other drug combinations.114 While these multi-agent regimens have produced good outcomes, there have not been comparative studies showing that they are superior to the use of VAC alone.

·

Adding topoisomerase-I inhibitors (topotecan or irinotecan) treatment courses to VAC regimens: Topotecan, a topoisomerase-I inhibitor, has demonstrated significant antitumor activity in rhabdomyosarcoma xenograft models.115 The IRSG has demonstrated that topotecan is an active agent for rhabdomyosarcoma in previously untreated patients, particularly those with alveolar histology.116 The combination of cyclophosphamide with topotecan demonstrated high levels of activity in patients with recurrent rhabdomyosarcoma.117 The topotecan plus cyclophosphamide combination is being evaluated by the IRSG for children with intermediate prognosis rhabdomyosarcoma.118 Irinotecan is currently being evaluated by the IRSG for children with metastatic

113 Anderson JR, Ruby E, Link M, et al.: Identification of a favorable subset of patients (pts) with metastatic (MET) rhabdomyosarcoma (RMS): a report from the Intergroup Rhabdomyosarcoma Study Group (IRSG). Proceedings of the American Society of Clinical Oncology 16: A1836, 510a, 1997. 114 Womer RB, Daller RT, Fenton JG, et al.: Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing’s sarcomas and soft tissue sarcomas in children. European Journal of Cancer 36(1): 87-94, 2000. Arndt CA, Nascimento AG, Schroeder G, et al.: Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide. European Journal of Cancer 34(8): 1224-1229, 1998. 115 Houghton PJ, Cheshire PJ, Myers L, et al.: Evaluation of 9-dimethylaminomethyl-10hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemotherapy and Pharmacology 31(3): 229-239, 1992. 116 Pappo AS, Lyden E, Breneman J, et al.: Up-front window trial of topotecan in previously untreated children and adolescents with metastastic rhabdomyosarcoma: an Intergroup Rhabdomyosarcoma Study. Journal of Clinical Oncology 19(1): 213-219, 2001. 117 Saylors RL III, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. Journal of Clinical Oncology 19(15): 3463-3469, 2001. 118 Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. Journal of Pediatric Hematology/Oncology 23(4): 215-220, 2001.


rhabdomyosarcoma (excluding patients younger than 10 years with embryonal tumors).119 ·

High-dose chemotherapy with stem cell rescue (SCR): SCR has been evaluated in a limited number of patients with rhabdomyosarcoma.120 This treatment strategy generally uses conventional chemotherapy, radiation therapy, and surgical management for approximately 6 months to achieve significant reduction in tumor burden. Patients then receive 1 or 2 courses of myeloablative chemotherapy and subsequent SCR. Available data indicate that SCR is of no benefit in the treatment of poorrisk rhabdomyosarcoma and should be performed only as part of controlled clinical trials.121

Radiation Therapy Management Treatment Options Standard Treatment Options Radiation therapy is an effective method for achieving local control of tumor for patients with microscopic or gross residual disease following initial surgical resection or chemotherapy. Patients with completely resected tumors (Clinical Group I) of embryonal histology do well without radiation 119 Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. Journal of Pediatric Hematology/Oncology 23(4): 215-220, 2001. 120 Koscielniak E, Klingebiel TH, Peters C, et al.: Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. Bone Marrow Transplantation 19(3): 227-231, 1997. Horowitz ME, Kinsella TJ, Wexler LH, et al.: Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing’s sarcoma and rhabdomyosarcoma. Journal of Clinical Oncology 11(10): 1911-1918, 1993. Boulad F, Kernan NA, LaQuaglia MP, et al.: High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing’s sarcoma, and undifferentiated sarcoma. Journal of Clinical Oncology 16(5): 1697-1706, 1998. Carli M, Colombatti R, Oberline O, et al.: High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma. Journal of Clinical Oncology 17(9): 2796-2803, 1999. 121 Carli M, Colombatti R, Oberline O, et al.: High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma. Journal of Clinical Oncology 17(9): 2796-2803, 1999. Weigel BJ, Breitfeld PP, Hawkins D, et al.: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. Journal of Pediatric Hematology/Oncology 23(5): 272-276, 2001.


therapy,122 but, radiation therapy benefits patients with Clinical Group I tumors with alveolar or undifferentiated histology.123 As with the surgical management of patients with rhabdomyosarcoma, recommendations for radiation therapy are dependent on the site of primary disease and on the extent of disease following surgical resection. For optimal care of pediatric patients undergoing radiation treatments, it is imperative to have a radiation oncologist, radiation technicians, and nurses who are experienced in treating children. The facility should be equipped with a linear accelerator as well as capabilities to administer electron beam therapy. Computerized treatment planning, preferably with a 3-dimensional planning system, should be available. Techniques to deliver conformal radiation (e.g., intensity modulated radiation therapy, proton radiation, or interstitial/intracavitary radiation) should be considered.124 The radiation therapy dose depends predominantly on the extent of disease following the primary surgical resection. In general, patients with microscopic residual disease (clinical Group II) receive radiation therapy to approximately 4,100 cGy,125 although doses from 3,000 to 4,000 cGy may be adequate in patients receiving effective multiagent chemotherapy.126 IRS-II patients with gross residual disease (Clinical Group III) who received 4,000 to greater than 5,000 cGy had local/regional relapse rates of over 30%; higher doses of radiation (>6,000 cGy) have been associated with

Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma StudyI: a final report. Cancer 61(2): 209-220, 1988. Maurer H, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71(5): 1904-1922, 1993. 123 Wolden SL, Anderson JR, Crist WM, et al.: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma studies I to III. Journal of Clinical Oncology 17(11): 3468-3475, 1999. 124 Hug EB, Adams J, Fitzek M, et al.: Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: a novel technique. International Journal of Radiation Oncology, Biology, Physics 47(4): 979-984, 2000. 125 Wolden SL, Anderson JR, Crist WM, et al.: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma studies I to III. Journal of Clinical Oncology 17(11): 3468-3475, 1999. Raney R, Hays D, Tefft M, et al.: Rhabdomyosarcoma and the undifferentiated sarcomas. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. Philadelphia: JB Lippincott, 1989, pp 635-658. 126 Mandell L, Ghavimi F, Peretz T, et al.: Radiocurability of microscopic disease in childhood rhabdomyosarcoma with radiation doses less than 4,000 cGy. Journal of Clinical Oncology 8(9): 1536-1542, 1990. 122


unacceptable long-term toxic effects.127 Patients on the IRS-IV standard treatment arm receive approximately 5,000 cGy.128 The treated volume should be determined by the extent of tumor at diagnosis prior to surgical resection and prior to chemotherapy. A margin of 2 cm is generally used, including clinically involved nodes.129 While the volume irradiated may be modified based on guidelines for normal tissue tolerance, gross residual disease at the time of irradiation should receive fulldose treatment. The timing of radiation therapy generally allows for chemotherapy to be given for 2 to 3 months prior to the initiation of radiation therapy, with the exception of patients with parameningeal disease and evidence of meningeal extension in whom radiation therapy generally begins at the time of diagnosis.130 Radiation therapy is usually given for 5 to 6 weeks (e.g., 180 cGy per day for 28 treatment days), during which time chemotherapy is usually modified to avoid the radiosensitizing agent dactinomycin.

Heyn R, Ragab A, Raney RB, et al.: Late effects of therapy in orbital rhabdomyosarcoma in children: a report from the Intergroup Rhabdomyosarcoma Study. Cancer 57(9): 17381743, 1986. Tefft M, Lattin PB, Jereb B, et al.: Acute and late effects on normal tissues following combined chemo- and radiotherapy for childhood rhabdomyosarcoma and Ewing’s sarcoma. Cancer 37(2, Suppl): 1201-1213, 1976. 128 Donaldson SS, Asmar L, Breneman J, et al.: Hyperfractionated radiation in children with rhabdomyosarcoma: results of an Intergroup Rhabdomyosarcoma Pilot Study. International Journal of Radiation Oncology, Biology, Physics 32(4): 903-911, 1995. Maurer HM, Soft Tissue Sarcoma Committee: IRS Study IV: Phase III Comparison of VM (VCR/L-PAM) vs IE (IFF/VP-16) vs ID (IFF/DOX) in Patients with Stage 4 Rhabdomyosarcoma (Summary Last Modified 03/95), IRS-IV-STAGE/GROUP-4, clinical trial, closed, 03/01/1995. 129 Wolden SL, Anderson JR, Crist WM, et al.: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma studies I to III. Journal of Clinical Oncology 17(11): 3468-3475, 1999. 130 Maurer H, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71(5): 1904-1922, 1993. Raney RB, Tefft M, Newton WA, et al.: Improved prognosis with intensive treatment of children with cranial soft tissue sarcomas arising in nonorbital parameningeal sites: a report from the Intergroup Rhabdomyosarcoma Study. Cancer 59(1): 147-155, 1987. 127


Among the modifications of radiation therapy for specific primary sites recommended for IRS-IV patients are:131 ·

For patients with orbital tumors, precautions should be taken to shield the lens, cornea, lacrimal gland, and optic chiasm.

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Patients with bladder/prostate primary tumors that present with a large pelvic mass resulting from a distended bladder from outlet obstruction receive treatment to a volume defined by imaging studies following initial chemotherapy.

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Patients with parameningeal disease with intracranial extension in contiguity with the primary tumor, and/or cranial base bone erosion, and/or cranial nerve palsy do not require whole-brain irradiation. They should receive irradiation to the site of primary tumor with a 2 cm margin to include the meninges adjacent to the primary tumor132 and the region of intracranial extension, again with a 2 cm margin, if present. Patients with intracranial extension should begin receiving radiation therapy within 2 weeks after diagnosis.

·

Although a rare occurrence, children who present with tumor cells in the CSF, have other evidence of diffuse meningeal disease, or have multiple intraparenchymal brain metastasis from a distant primary tumor, are treated with whole brain irradiation in addition to the chemotherapy/radiation therapy for the primary tumor. Spinal irradiation may also be given in coordination with other therapies and at the investigator/physician’s discretion.

Treatment Options under Clinical Evaluation Brachytherapy using either intracavitary or interstitial implants is another method of local control and has been used in select situations for children with rhabdomyosarcoma, especially those with primary tumors at vaginal or

Donaldson SS, Asmar L, Breneman J, et al.: Hyperfractionated radiation in children with rhabdomyosarcoma: results of an Intergroup Rhabdomyosarcoma Pilot Study. International Journal of Radiation Oncology, Biology, Physics 32(4): 903-911, 1995. Maurer HM, Soft Tissue Sarcoma Committee: IRS Study IV: Phase III Comparison of VM (VCR/L-PAM) vs IE (IFF/VP-16) vs ID (IFF/DOX) in Patients with Stage 4 Rhabdomyosarcoma (Summary Last Modified 03/95), IRS-IV-STAGE/GROUP-4, clinical trial, closed, 03/01/1995. 132 Paulino AC: Role of radiation therapy in parameningeal rhabdomyosarcoma. Cancer Investigation 17(3): 223-230, 1999. 131


vulval sites.133 In a small, single-institution study, this treatment approach was associated with a high survival rate (85%) and with retention of a functional vagina in the majority of patients.134 Other sites, especially head and neck, have been treated with brachytherapy.135 Patients with initial Clinical Group III disease who then have microscopic residual disease after chemotherapy with or without delayed surgery are likely to achieve local control with radiation at doses of 4,000 cGy or more.136

Recurrent Childhood Rhabdomyosarcoma Although a patient with recurrent or progressive rhabdomyosarcoma can sometimes achieve a complete remission with secondary therapy, the longterm prognosis for most patients with recurrent disease is guarded.137 The prognosis is most favorable (50% to 70% five-year survival rates) for children who initially presented with stage 1 or group I disease and embryonal histology and whose recurrence is local or regional.138 The small number of children with botryoid histology who relapse have a similarly favorable Curran WJ, Littman P, Raney RB.: Interstitial radiation therapy in the treatment of childhood soft-tissue sarcomas. International Journal of Radiation Oncology, Biology, Physics 14(1): 169-174, 1988. Flamant F, Gerbaulet A, Nihoul-Fekete C, et al.: Long-term sequelae of conservative treatment by surgery, brachytherapy, and chemotherapy for vulval and vaginal rhabdomyosarcoma in children. Journal of Clinical Oncology 8(11): 1847-1853, 1990. Flamant F, Chassagne D, Cosset JM, et al.: Embryonal rhabdomyosarcoma of the vagina in children: consecutive treatment with curietherapy and chemotherapy. European Journal of Cancer 15(4): 527-532, 1979. Nag S, Shasha D, Janjan N, et al.: The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. International Journal of Radiation Oncology, Biology, Physics 49(4): 1033-1043, 2001. 134 Flamant F, Gerbaulet A, Nihoul-Fekete C, et al.: Long-term sequelae of conservative treatment by surgery, brachytherapy, and chemotherapy for vulval and vaginal rhabdomyosarcoma in children. Journal of Clinical Oncology 8(11): 1847-1853, 1990. 135 Nag S, Fernandes PS, Martinez-Monge R, et al.: Use of brachytherapy to preserve function in children with soft-tissue sarcomas. Oncology (Huntington NY) 13(3): 361-369; discussion 369-370, 373-374, 1999. 136 Regine WF, Fontanesi J, Kumar P, et al.: Local tumor control in rhabdomyosarcoma following low-dose irradiation: comparison of group II and select group III patients. International Journal of Radiation Oncology, Biology, Physics 31(3): 485-491, 1995. 137 Pappo A, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from IRSG. Journal of Clinical Oncology 17(11): 3487-3493, 1999. 138 Pappo A, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from IRSG. Journal of Clinical Oncology 17(11): 3487-3493, 1999. 133


prognosis.139 Most other children who relapse have an extremely poor prognosis.140 The selection of further treatment depends on many factors, including the site of recurrence and previous treatment, as well as individual patient considerations. The combination of ifosfamide/etoposide has considerable activity in the treatment of children with recurrent rhabdomyosarcoma not previously treated with these agents.141 Other regimens that have shown activity against recurrent rhabdomyosarcoma include the 2-drug combination of carboplatin given with etoposide,142 and the 3-drug combination of ifosfamide given with carboplatin and etoposide.143 The combination of cyclophosphamide plus topotecan has been shown to be active in patients with recurrent or refractory disease.144 Very intensive chemotherapy followed by autologous bone marrow reinfusion is also under investigation for patients with recurrent rhabdomyosarcoma, although a review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.145 New agents under clinical evaluation in phase I and phase II trials should be considered for these patients.

Pappo A, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from IRSG. Journal of Clinical Oncology 17(11): 3487-3493, 1999. 140 Pappo A, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from IRSG. Journal of Clinical Oncology 17(11): 3487-3493, 1999. 141 Miser JS, Kinsella TJ, Triche TJ, et al.: Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. Journal of Clinical Oncology 5(8): 1191-1198, 1987. 142 Klingebiel T, Pertl U, Hess CF, et al.: Treatment of children with relapsed soft tissue sarcoma: report of the German CESS/CWS REZ trial. Medical and Pediatric Oncology 30(5): 269-275, 1998. 143 Kung FH, Desai SJ, Dickerman JD, et al.: Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group phase I/II study. Journal of Pediatric Hematology/Oncology 17(3): 265-269, 1995. Cairo MS: The use of ifosfamide, carboplatin, and etoposide in children with solid tumors. Seminars in Oncology 22(3, Suppl 7): 23-27, 1995. 144 Saylors RL III, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. Journal of Clinical Oncology 19(15): 3463-3469, 2001. 145 Weigel BJ, Breitfeld PP, Hawkins D, et al.: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. Journal of Pediatric Hematology/Oncology 23(5): 272-276, 2001. 139


NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.146 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:147 ·

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

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

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

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

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

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

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 147 See http://www.nlm.nih.gov/databases/databases.html. 146


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

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

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

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

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

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

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

While all of the above references may be of interest to physicians who study and treat childhood rhabdomyosarcoma, the following are particularly noteworthy.

The Combined Health Information Database A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to “Brochure/Pamphlet,” “Fact Sheet,” or “Information Package” and childhood rhabdomyosarcoma using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years,” select your preferred language, and the format option “Fact Sheet.” By making these selections and typing “childhood rhabdomyosarcoma” (or synonyms) into the “For


these words:” box above, you will only receive results on fact sheets dealing with childhood rhabdomyosarcoma. The following is a sample result: ·

Childhood Cancer in California, 1988-1994 Source: Sacramento, CA, California Department of Health Services, Cancer Surveillance Section, 77 p., April 1999. Contact: California Surveillance Section, 601 North Seventh Street, MS No. 592, P.O. Box 942732, Sacramento, CA 94234-7320. (916) 327-4663. internet/email: http://www.ccrcal.org. Summary: Childhood Cancer in California, 1988 to 1994, provides information on the major diagnostic categories of cancer among California children during a 7-year period, from 1988 through 1994. The report also provides information on adolescents age 15 to 19 years. Its purpose is to provide an understandable summary of information available on childhood cancer occurrence, treatment, and outcomes. The report (1) presents an overview on childhood cancer; (2) presents an overview of childhood cancer incidence in California; (3) discusses mortality and survival trends in childhood cancer; (4) presents information on diagnosis, treatment, and survival of major childhood malignancies; (5) summarizes statistical and technical references; and (6) lists Internet sources of information on childhood cancer. Major childhood malignancies covered in the report are (1) leukemia; (2) central nervous system tumors; (3) lymphoma and other reticuloendothelial malignancies; (4) soft tissue sarcoma; (5) tumors of the sympathetic nervous system; (6) malignant bone tumors; (7) germ cell, trophoblastic, and other gonadal malignancies; (8) renal tumors; (9) carcinomas and other epithelial cancers; and (10) retinoblastoma. The report includes eight appendices which present summaries and tabulations of the frequencies of various types of cancer incidence and mortality by age, age/ethnicity and gender, and information on how the California Cancer Registry monitors information. The report also presents a listing of regional cancer registries in California.

The NLM Gateway148 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing “one-stop searching” for 148

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


many of NLM’s information resources or databases.149 One target audience for the Gateway is the Internet user who is new to NLM’s online resources and does not know what information is available or how best to search for it. This audience may include physicians and other healthcare providers, researchers, librarians, students, and, increasingly, parents and the public.150 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “childhood rhabdomyosarcoma” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Items Found Journal Articles 350586 Books / Periodicals / Audio Visual 2584 Consumer Health 294 Meeting Abstracts 2575 Other Collections 87 Total 356126

HSTAT151 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.152 HSTAT’s audience includes healthcare providers, health service researchers, policy makers, insurance companies, consumers, and the information professionals who serve these groups. HSTAT provides access to a wide variety of publications, The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 150 Other users may find the Gateway useful for an overall search of NLM’s information resources. Some searchers may locate what they need immediately, while others will utilize the Gateway as an adjunct tool to other NLM search services such as PubMed® and MEDLINEplus®. The Gateway connects users with multiple NLM retrieval systems while also providing a search interface for its own collections. These collections include various types of information that do not logically belong in PubMed, LOCATORplus, or other established NLM retrieval systems (e.g., meeting announcements and pre-1966 journal citations). The Gateway will provide access to the information found in an increasing number of NLM retrieval systems in several phases. 151 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 152 The HSTAT URL is http://hstat.nlm.nih.gov/. 149


including clinical practice guidelines, quick-reference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.153 Simply search by “childhood rhabdomyosarcoma” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists154 Some parents may wish to have access to a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. To this end, we recommend “Coffee Break,” a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.155 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.156 This site has new articles every few weeks, so it can be considered an online magazine of sorts, and intended for general background information. Access the Coffee Break Web site at http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration’s Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force’s Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 154 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 155 The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 156 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 153


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

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

·

Image Engine: Multimedia electronic medical record system that integrates a wide range of digitized clinical images with textual data stored in the University of Pittsburgh Medical Center’s MARS electronic medical record system; see the following Web site: http://www.cml.upmc.edu/cml/imageengine/imageEngine.html.

·

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

·

MedWeaver: Prototype system that allows users to search differential diagnoses for any list of signs and symptoms, to search medical literature, and to explore relevant Web sites; see http://www.med.virginia.edu/~wmd4n/medweaver.html.

·

Metaphrase: Middleware component intended for use by both caregivers and medical records personnel. It converts the informal language generally used by caregivers into terms from formal, controlled vocabularies; see the following Web site: http://www.lexical.com/Metaphrase.html.

The Genome Project and Childhood Rhabdomyosarcoma With all the discussion in the press about the Human Genome Project, it is only natural that physicians, researchers, and parents want to know about how human genes relate to childhood rhabdomyosarcoma. In the following section, we will discuss databases and references used by physicians and scientists who work in this area.

Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for


Biotechnology Information (NCBI).157 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “childhood rhabdomyosarcoma” (or synonyms) in the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. By following these links, especially the link titled “Database Links,” you will be exposed to numerous specialized databases that are largely used by the scientific community. These databases are overly technical and seldom used by the general public, but offer an abundance of information. The following is an example of the results you can obtain from the OMIM for childhood rhabdomyosarcoma: ·

Imprinting Gene Related to Retinoblastoma Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?308290

·

Retinoblastoma Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?180200

·

Retinoblastoma-binding Protein 1 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?180201

·


·


·


Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

157


·


·


·


·

Retinoblastoma-like 1 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?116957

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

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


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

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez, and then select the database that you would like to search. The databases available are listed in


the drop box next to “Search.” In the box next to “for,” enter “childhood rhabdomyosarcoma” (or synonyms) and click “Go.”

Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database158 This online resource can be quite useful. It has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At the following Web site you can also search across syndromes using an index: http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html. You can search by keywords at this Web site: http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database159 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 159 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html#mission. 158


“childhood rhabdomyosarcoma” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms). This database is extremely technical as it was created for specialists. The articles are the results which are the most accessible to non-professionals and often listed under the heading “Citations.” The contact names are also accessible to non-professionals.

Specialized References The following books are specialized references written for professionals interested in childhood rhabdomyosarcoma (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): · Advanced and Critical Care Oncology Nursing: Managing Primary Complications by Cynthia C. Chernecky (Editor), et al; Paperback - 736 pages (September 18, 1997), W B Saunders Co; ISBN: 0721668607; http://www.amazon.com/exec/obidos/ASIN/0721668607/icongroupinterna · Atlas of Pediatric Physical Diagnosis by Basil J. Zitelli, Holly W. Davis (Editor); Hardcover, 3rd edition (March 1997), Mosby-Year Book; ISBN: 0815199309; http://www.amazon.com/exec/obidos/ASIN/0815199309/icongroupinterna · Cancer: Etiology, Diagnosis, and Treatment by Walter J. Burdette; Paperback - 287 pages, 1st edition (January 15, 1998), McGraw Hill Text; ISBN: 0070089922; http://www.amazon.com/exec/obidos/ASIN/0070089922/icongroupinterna · Cancer Management: A Multidisciplinary Approach: Medical, Surgical & Radiation by Richard Pazdur (Editor), et al; Paperback - 982 pages, 5th edition (June 15, 2001), Publisher Research & Representation, Inc.; ISBN: 1891483080; http://www.amazon.com/exec/obidos/ASIN/1891483080/icongroupinterna · The Child with Cancer: Family-Centered Care in Practice by Helen Langton (Editor); Paperback - 404 pages; 1st edition (January 15, 2000), W B Saunders Co; ISBN: 0702023000; http://www.amazon.com/exec/obidos/ASIN/0702023000/icongroupinterna · Familial Cancer and Prevention: Molecular Epidemiology: A New Strategy Toward Cancer Control by Joji Utsunomiya (Editor), et al; Hardcover (April 1999), Wiley-Liss; ISBN: 0471249378; http://www.amazon.com/exec/obidos/ASIN/0471249378/icongroupinterna


· The 5-Minute Pediatric Consult by M. William Schwartz (Editor); Hardcover - 1050 pages, 2nd edition (January 15, 2000), Lippincott, Williams & Wilkins; ISBN: 0683307444; http://www.amazon.com/exec/obidos/ASIN/0683307444/icongroupinterna · Fundamentals of Cancer Epidemiology by Philip C. Nasca, Ph.D. (Editor), Pastides Harris, Ph.D., MPH (Editor); Hardcover - 368 pages, 1st edition (February 15, 2001), Aspen Publishers, Inc.; ISBN: 0834217767; http://www.amazon.com/exec/obidos/ASIN/0834217767/icongroupinterna · Helping Cancer Patients Cope: A Problem-Solving Approach by Arthur M. Nezu (Editor), et al; Hardcover - 314 pages (December 15, 1998), American Psychological Association (APA); ISBN: 1557985332; http://www.amazon.com/exec/obidos/ASIN/1557985332/icongroupinterna · Nelson Textbook of Pediatrics by Richard E. Behrman (Editor), et al; Hardcover - 2414 pages, 16th edition (January 15, 2000), W B Saunders Co; ISBN: 0721677673; http://www.amazon.com/exec/obidos/ASIN/0721677673/icongroupinterna · Quantitative Estimation and Prediction of Human Cancer Risks (Iarc Scientific Publications, 131) by Suresh H. Moolgavkar (Editor), et al; Paperback (September 1999), Oxford University Press; ISBN: 9283221311; http://www.amazon.com/exec/obidos/ASIN/9283221311/icongroupinterna · Textbook of Cancer Epidemiology by ADAMI, et al; Hardcover - 385 pages, 1st edition (July 15, 2002), Oxford University Press; ISBN: 0195109694; http://www.amazon.com/exec/obidos/ASIN/0195109694/icongroupinterna

Vocabulary Builder Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Brachytherapy: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor. Also called internal radiation, implant radiation, or interstitial radiation therapy. [NIH]


Carboplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] CSF: Cerebrospinal fluid. The fluid flowing around the brain and spinal cord. CSF is produced in the ventricles of the brain. [NIH] Cystectomy: Surgery to remove all or part of the bladder. [NIH] Cystoscope: A thin, lighted instrument used to look inside the bladder and remove tissue samples or small tumors. [NIH] Dactinomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. [NIH] Doxorubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. It is an anthracycline. [NIH] Etoposide: An anticancer drug that is a podophyllotoxin derivative and belongs to the family of drugs called mitotic inhibitors. [NIH] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Gonadal: Pertaining to a gonad. [EU] Hematologist: A doctor who specializes in treating diseases of the blood. [NIH]

Ifosfamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Incision: A cut made in the body during surgery. [NIH] Inguinal: Pertaining to the inguen, or groin. [EU] Ipsilateral: Having to do with the same side of the body. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Lacrimal: Pertaining to the tears. [EU] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH]


Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Neural: 1. pertaining to a nerve or to the nerves. 2. situated in the region of the spinal axis, as the neutral arch. [EU] Orchiectomy: Surgery to remove one or both testicles. [NIH] Pelvic: Pertaining to the pelvis. [EU] Perianal: Located around the anus. [EU] Perineal: Pertaining to the perineum. [EU] Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Postoperative: After surgery. [NIH] Prostatectomy: An operation to remove part or all of the prostate. Radical (or total) prostatectomy is the removal of the entire prostate and some of the tissue around it. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pulmonary: Relating to the lungs. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Refractory: Not readily yielding to treatment. [EU] Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the


organs in the abdomen). [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Tolerance: 1. the ability to endure unusually large doses of a drug or toxin. 2. acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU]

Topotecan: An anticancer drug that belongs to the family drugs called topoisomerase inhibitors. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vulva: The external female genital organs, including the clitoris, vaginal lips, and the opening to the vagina. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH]

Dissertations 201

CHAPTER 9. DISSERTATIONS RHABDOMYOSARCOMA

ON

CHILDHOOD

Overview University researchers are active in studying almost all known medical conditions. The result of research is often published in the form of Doctoral or Master’s dissertations. You should understand, therefore, that applied diagnostic procedures and/or therapies can take many years to develop after the thesis that proposed the new technique or approach was written. In this chapter, we will give you a bibliography on recent dissertations relating to childhood rhabdomyosarcoma. You can read about these in more detail using the Internet or your local medical library. We will also provide you with information on how to use the Internet to stay current on dissertations.

Dissertations on Childhood Rhabdomyosarcoma ProQuest Digital Dissertations is the largest archive of academic dissertations available. From this archive, we have compiled the following list covering dissertations devoted to childhood rhabdomyosarcoma. You will see that the information provided includes the dissertation’s title, its author, and the author’s institution. To read more about the following, simply use the Internet address indicated. The following covers recent dissertations dealing with childhood rhabdomyosarcoma: ·

Degradation of the Human Papillomavirus Type 16 E7 Oncoprotein and E7-mediated Degradation of the Retinoblastoma Tumor


Suppressor by Gonzalez-razzetti, Sonia Lamar; PhD from Harvard University, 2002, 164 pages http://wwwlib.umi.com/dissertations/fullcit/3051171 ·

Genetic Studies of Retinoblastoma by Godbout, Roseline; PhD from University of Toronto (Canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK62274

·

Molecular and Biochemical Characterization of Photoreceptor Phosphodiesterase in Retina and Retinoblastoma Cells by White, Joseph Brandon; PhD from the University of Alabama at Birmingham, 2001, 128 pages http://wwwlib.umi.com/dissertations/fullcit/3023985

·

Molecular Inquiries into the Functions of the Retinoblastoma Protein by Yang, Hong; PhD from Harvard University, 2002, 201 pages http://wwwlib.umi.com/dissertations/fullcit/3051330

·

Phenotypic and Genotypic Effects of Mutations in the Human Retinoblastoma Gene by Goddard, Audrey D; PhD from University of Toronto (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL54700

·

Retinoblastoma by Ohashi, Kaoru; MS from Sarah Lawrence College, 2001, 29 pages http://wwwlib.umi.com/dissertations/fullcit/1403812

·

The Deubiquitinating Enzyme Unp Interacts with the Retinoblastoma Protein by Desalle, Lauren Michelle; PhD from New York University, 2001, 161 pages http://wwwlib.umi.com/dissertations/fullcit/3009299

·

The Role of Retinoblastoma Protein and Insulin Like Growth Factor Signaling in Antiestrogen Resistance by Varma, Hemant; PhD from Michigan State University, 2001, 151 pages http://wwwlib.umi.com/dissertations/fullcit/3036765

·

The Role of the Retinoblastoma Protein in Retinal Development by Burcescu, Irina Daniela; MSC from University of Toronto (Canada), 2001, 56 pages http://wwwlib.umi.com/dissertations/fullcit/MQ63095

·

The Role of the Retinoblastoma Protein in Senescent Cell Cycle Exit, Survival, and Morphological Alteration by Alexander, Kamilah; PhD from Harvard University, 2001, 313 pages http://wwwlib.umi.com/dissertations/fullcit/3011306

Dissertations 203

Keeping Current As previously mentioned, an effective way to stay current on dissertations dedicated to childhood rhabdomyosarcoma is to use the database called ProQuest Digital Dissertations via the Internet, located at the following Web address: http://wwwlib.umi.com/dissertations. The site allows you to freely access the last two years of citations and abstracts. Ask your medical librarian if the library has full and unlimited access to this database. From the library, you should be able to do more complete searches than with the limited 2-year access available to the general public.

205

PART III. APPENDICES

ABOUT PART III Part III is a collection of appendices on general medical topics relating to childhood rhabdomyosarcoma and related conditions.

Researching Your Child’s Medications 207

APPENDIX A. RESEARCHING YOUR CHILD’S MEDICATIONS Overview There are a number of sources available on new or existing medications which could be prescribed to treat childhood rhabdomyosarcoma. While a number of hard copy or CD-Rom resources are available to parents and physicians for research purposes, a more flexible method is to use Internetbased databases. In this chapter, we will begin with a general overview of medications. We will then proceed to outline official recommendations on how you should view your child’s medications. You may also want to research medications that your child is currently taking for other conditions as they may interact with medications for childhood rhabdomyosarcoma. Research can give you information on the side effects, interactions, and limitations of prescription drugs used in the treatment of childhood rhabdomyosarcoma. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.


Your Child’s Medications: The Basics160 The Agency for Health Care Research and Quality has published extremely useful guidelines on the medication aspects of childhood rhabdomyosarcoma. Giving your child medication can involve many steps and decisions each day. The AHCRQ recommends that parents take part in treatment decisions. Do not be afraid to ask questions and talk about your concerns. By taking a moment to ask questions, your child may be spared from possible problems. Here are some points to cover each time a new medicine is prescribed: ·

Ask about all parts of your child’s treatment, including diet changes, exercise, and medicines.

·

Ask about the risks and benefits of each medicine or other treatment your child might receive.

·

Ask how often you or your child’s doctor will check for side effects from a given medication.

Do not hesitate to tell the doctor about preferences you have for your child’s medicines. You may want your child to have a medicine with the fewest side effects, or the fewest doses to take each day. You may care most about cost. Or, you may want the medicine the doctor believes will work the best. Sharing your concerns will help the doctor select the best treatment for your child. Do not be afraid to “bother” the doctor with your questions about medications for childhood rhabdomyosarcoma. You can also talk to a nurse or a pharmacist. They can help you better understand your child’s treatment plan. Talking over your child’s options with someone you trust can help you make better choices. Specifically, ask the doctor the following: ·

The name of the medicine and what it is supposed to do.

·

How and when to give your child the medicine, how much, and for how long.

·

What food, drinks, other medicines, or activities your child should avoid while taking the medicine.

·

What side effects your child may experience, and what to do if they occur.

·

If there are any refills, and how often.

·

About any terms or directions you do not understand.

160

This section is adapted from AHCRQ: http://www.ahcpr.gov/consumer/ncpiebro.htm.


·

What to do if your child misses a dose.

·

If there is written information you can take home (most pharmacies have information sheets on prescription medicines; some even offer large-print or Spanish versions).

Do not forget to tell the doctor about all the medicines your child is currently taking (not just those for childhood rhabdomyosarcoma). This includes prescription medicines and the medicines that you buy over the counter. When talking to the doctor, you may wish to prepare a list of medicines your child is currently taking including why and in what forms. Be sure to include the following information for each: ·

Name of medicine

·

Reason taken

·

Dosage

·

Time(s) of day

Also include any over-the-counter medicines, such as: ·

Laxatives

·

Diet pills

·

Vitamins

·

Cold medicine

·

Aspirin or other pain, headache, or fever medicine

·

Cough medicine

·

Allergy relief medicine

·

Antacids

·

Sleeping pills

·

Others (include names)

Learning More about Your Child’s Medications Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications the doctor has recommended for childhood rhabdomyosarcoma. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this


compendium the “U.S. Pharmacopeia (USP).” Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at www.usp.org. The USP currently provides standards for over 3,700 medications. The resulting USP DIÒ Advice for the PatientÒ can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database.161 While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopoeia (USP). It is important to read the disclaimer by the USP (http://www.nlm.nih.gov/medlineplus/drugdisclaimer.html) before using the information provided. Of course, we as editors cannot be certain as to what medications your child is taking. Therefore, we have compiled a list of medications associated with the treatment of childhood rhabdomyosarcoma. Once again, due to space limitations, we only list a sample of medications and provide hyperlinks to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to childhood rhabdomyosarcoma: Carboplatin ·

Systemic - U.S. Brands: Paraplatin http://www.nlm.nih.gov/medlineplus/druginfo/carboplatinsyste mic202115.html

Though cumbersome, the FDA database can be freely browsed at the following site: www.fda.gov/cder/da/da.htm. 161


Cisplatin ·

Systemic - U.S. Brands: Platinol; Platinol-AQ http://www.nlm.nih.gov/medlineplus/druginfo/cisplatinsystemi c202143.html

Cyclophosphamide ·

Systemic - U.S. Brands: Cytoxan; Neosar http://www.nlm.nih.gov/medlineplus/druginfo/cyclophosphami desystemic202174.html

Doxorubicin ·

Systemic - U.S. Brands: Rubex http://www.nlm.nih.gov/medlineplus/druginfo/doxorubicinsyst emic202209.html

Etoposide ·

Systemic - U.S. Brands: Etopophos; Toposar; VePesid http://www.nlm.nih.gov/medlineplus/druginfo/etoposidesyste mic202234.html

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

Reuters Health Drug Database The Reuters Health Drug Database can be searched by keyword at the hyperlink: http://www.reutershealth.com/frame2/drug.html.

Mosby’s GenRx Mosby’s GenRx database (also available on CD-Rom and book format) covers 45,000 drug products including generics and international brands. It provides information on prescribing and drug interactions. Information can


be obtained at the following http://www.genrx.com/Mosby/PhyGenRx/group.html.

hyperlink:

Physicians Desk Reference The Physicians Desk Reference database (also available in CD-Rom and book format) is a full-text drug database. The database is searchable by brand name, generic name or by indication. It features multiple drug interactions reports. Information can be obtained at the following hyperlink: http://physician.pdr.net/physician/templates/en/acl/psuser_t.htm.

Other Web Sites A number of additional Web sites discuss drug information. As an example, you may like to look at www.drugs.com which reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. which allows users to download articles on various drugs and therapeutics for a nominal fee: http://www.medletter.com/.

Drug Development and Approval The following Web sites can be valuable resources when conducting research on the development and approval of new cancer drugs: ·

FDA Home Page: Search for drugs currently in development or those which have been recently approved by the FDA. http://redir.nci.nih.gov/cgibin/redir.pl?section=Cancerinfo&destURI=http://www.fda.gov/

·

Cancer Liaison Program: Answers questions from the public about drug approval processes, cancer clinical trials, and access to investigational therapies. http://redir.nci.nih.gov/cgibin/redir.pl?section=Cancerinfo&destURI=http://www.fda.gov/oashi/c ancer/cancer.html

·

Center for Drug Evaluation and Research http://redir.nci.nih.gov/cgibin/redir.pl?section=Cancerinfo&destURI=http://www.fda.gov/cder/


·

Drug Approvals by Cancer Indications (Alphabetical List) http://redir.nci.nih.gov/cgibin/redir.pl?section=Cancerinfo&destURI=http://www.fda.gov/oashi/c ancer/cdrugalpha.html

·

Drug Approvals by Cancer Indications (Cancer Type) http://redir.nci.nih.gov/cgibin/redir.pl?section=Cancerinfo&destURI=http://www.fda.gov/oashi/c ancer/cdrugind.html

·

Electronic Orange Book of Approved Drug Products http://redir.nci.nih.gov/cgibin/redir.pl?section=Cancerinfo&destURI=http://www.fda.gov/cder/ob /default.htm

·

Guidance Documents for Industry: Contains an archive of documents describing FDA policies on specific topics. http://redir.nci.nih.gov/cgibin/redir.pl?section=Cancerinfo&destURI=http://www.fda.gov/cder/gu idance/index.htm

·

Industry Collaboration: Provides information to industry on the process for getting new drugs into clinical trials. http://ctep.cancer.gov/industry/index.html

·

Investigator’s Handbook: Provides information to investigators on specific procedures related to clinical trial development. http://ctep.cancer.gov/handbook/index.html

·

Questions and Answers About NCI’s Natural Products Branch: A fact sheet that describes the functions of this branch, which collects and analyzes specimens of plant, marine, and microbial origin for possible anticancer properties. http://cis.nci.nih.gov/fact/7_33.htm

Understanding the Approval Process for New Cancer Drugs162 Since June 1996, about 80 new cancer-related drugs, or new uses for drugs already on the market, have been approved by the U.S. Food and Drug Administration (FDA), the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs before they can go on the market. (The FDA maintains an annotated Adapted from the NCI: http://www.cancer.gov/clinical_trials/doc_header.aspx?viewid=d94cbfac-e478-4704-9052d8e8a3372b56. 162


online list of drugs approved for use with cancer since 1996.) Some of these drugs treat cancer, some alleviate pain and other symptoms, and, in one case, reduce the risk of invasive cancer in people who are considered highrisk. The FDA relied on the results of clinical trials in making every one of these approvals. Without reliable information about a drug’s effects on humans, it would be impossible to approve any drug for widespread use. When considering a new drug, the FDA faces two challenges: ·

First, making sure that the drug is safe and effective before it is made widely available;

·

Second, ensuring that drugs which show promise are made available as quickly as possible to the people they can help.

To deal with these challenges, the FDA maintains a rigorous review process but also has measures in place to make some drugs available in special cases. This aim of this section is to acquaint you with the drug approval process and point you to other resources for learning more about it.

The Role of the Federal Drug Administration (FDA) Approval is only one step in the drug development process. In fact, the FDA estimates that, on average, it takes eight and a half years to study and test a new drug before it can be approved for the general public. That includes early laboratory and animal testing, as well as the clinical trials that evaluate the drugs in humans. The FDA plays a key role at three main points in this process: ·

Determining whether or not a new drug shows enough promise to be given to people in clinical trials

·

Once clinical trials begin, deciding whether or not they should continue, based on reports of efficacy and adverse reactions

·

When clinical trials are completed, deciding whether or not the drug can be sold to the public and what its label should say about directions for use, side effects, warnings, and the like.

To make these decisions, the FDA must review studies submitted by the drug’s sponsor (usually the manufacturer), evaluate any adverse reports from preclinical studies and clinical trials (that is, reports of side effects or complications), and review the adequacy of the chemistry and manufacturing. This process is lengthy, but it is meant to ensure that only beneficial drugs with acceptable side effects will make their way into the


hands of the public. At the same time, recent legislative mandates and streamlined procedures within the FDA have accelerated the approval of effective drugs, especially for serious illnesses such as cancer. In addition, specific provisions make some drugs available to patients with special needs even before the approval process is complete.

From Lab to Patient Care By law, the Food and Drug Administration (FDA) must review all test results for new drugs to ensure that products are safe and effective for specific uses. “Safe” does not mean that the drug is free of possible adverse side effects; rather, it means that the potential benefits have been determined to outweigh any risks. The testing process begins long before the first person takes the drug, with preliminary research and animal testing. If a drug proves promising in the lab, the drug company or sponsor must apply for FDA approval to test it in clinical trials involving people. For drugs, the application, called an Investigational New Drug (IND) Application, is sent through the Center for Drug Evaluation and Research’s (CDER) IND Review Process; for biological agents, the IND is sent to the Center for Biologics Evaluation and Research (CBER). Once the IND is approved by CDER or CBER, clinical trials can begin. If the drug makes it through the clinical trials process—that is, the studies show that it is superior to current drugs—the manufacturer must submit a New Drug Application (NDA) or (for biological agents) a Biologics License Application (BLA) to the FDA. (Biological agents, such as serums, vaccines, and cloned proteins, are manufactured from substances taken from living humans or animals.) This application must include: ·

The exact chemical makeup of the drug or biologic and the mechanisms by which it is effective

·

Results of animal studies

·

Results of clinical trials

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How the drug or biologic is manufactured, processed, and packaged

·

Quality control standards

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Samples of the product in the form(s) in which it is to be administered.


Once the FDA receives the NDA or BLA from the manufacturer or developer, the formal New Drug Application Review Process or Biologics/Product License Application Review Process begins. For an overview of the entire process from start to finish, see the CDER’s visual representation of The New Drug Development Process: Steps from Test Tube to New Drug Application Review, which is available for public viewing at the following Web address: http://www.fda.gov/cder/handbook/develop.htm.

Speed versus Safety in the Approval Process The FDA’s current goal is that no more than ten months will pass between the time that a complete application is submitted and the FDA takes action on it. But the process is not always smooth. Sometimes FDA’s external advisory panels call for additional research or data. In other cases, the FDA staff asks for more information or revised studies. Some new drug approvals have taken as little as 42 days; other more difficult NDAs have spent years in the approval process.

Setting Priorities The order in which NDAs are assessed by the FDA is determined by a classification system designed to give priority to drugs with the greatest potential benefits. All drugs that offer significant medical advances over existing therapies for any disease are considered “priority” drugs in the approval process. NDAs for cancer treatment drugs are reviewed for this status primarily by the Division of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research (CDER). For Biologic License Applications (vaccines, blood products, and medicines made from animal products), the Center for Biologics Evaluation and Research (CBER) provides additional regulation and oversight.

Expert Advice The FDA relies on a system of independent advisory committees, made up of professionals from outside the agency, for expert advice and guidance in making sound decisions about drug approval. Each committee meets as needed to weigh available evidence and assess the safety, effectiveness, and appropriate use of products considered for approval. In addition, these


committees provide advice about general criteria for evaluation and scientific issues not related to specific products. The Oncologic Drugs Advisory Committee (ODAC) meets regularly to provide expert advice on cancer-related treatments and preventive drugs. Each committee is composed of representatives from the research science and medical fields. At least one member on every advisory committee must represent the consumer perspective.

Final Approval As the FDA looks at all the data submitted and the results of its own review, it applies two benchmark questions to each application for drug approval: ·

Do the results of well-controlled studies provide substantial evidence of effectiveness?

·

Do the results show the product is safe under the conditions of use in the proposed labeling? In this context, “safe” means that potential benefits have been determined to outweigh any risks.

Continued Vigilance The FDA’s responsibility for new drug treatments does not stop with final approval. The Office of Compliance in the Center for Drug Evaluation and Research (CDER) implements and tracks programs to make sure manufacturers comply with current standards and practice regulations. CDER’s Office of Drug Marketing, Advertising, and Communication monitors new drug advertising to make sure it is truthful and complete. At the Center for Biologic Evaluation and Research, biologics are followed with the same vigilance after approval. And through a system called MedWatch, the FDA gets feedback from health professionals and consumers on how the new drugs are working, any adverse reactions, and potential problems in labeling and dosage.

Online FDA Resources The following information from the FDA should help you better understand the drug approval process: ·

Center for Drug Evaluation http://www.fda.gov/cder/handbook

and

Research:


·

From Test Tube to Patient: New Drug Development in the U.S. – a special January 1995 issue of the magazine FDA Consumer: http://www.fda.gov/fdac/special/newdrug/ndd_toc.html

·

Milestones in U.S. Food and Drug Law History: http://www.fda.gov/opacom/backgrounders/miles.html

·

Drug Approvals for Cancer Indications: http://www.fda.gov/oashi/cancer/cdrug.html

Getting Drugs to Patients Who Need Them Clinical trials provide the most important information used by the FDA in determining whether a new drug shows “substantial evidence of effectiveness,” or whether an already-approved drug can be used effectively in new ways (for example, to treat or prevent other types of cancer, or at a different dosage). The FDA must certify that a drug has shown promise in laboratory and animal trials before human testing can begin. The trials process includes three main stages and involves continuous review, which ensures that the sponsor can stop the study early if major problems develop or unexpected levels of treatment benefit are found. As with all clinical trials, benefits and risks must be carefully weighed by the researchers conducting the study and the patients who decide to participate. Not everyone is eligible to participate in a clinical trial. Some patients do not fit the exact requirements for studies, some have rare forms of cancer for which only a limited number of studies are underway, and others are too ill to participate. Working with the NCI and other sponsors, the FDA has established special conditions under which a patient and his or her physician can apply to receive cancer drugs that have not yet been through the approval process. In the past, these special case applications for new drugs were grouped under the name “compassionate uses.” More recently, such uses have expanded to include more patients and more categories of investigational drugs.

Access to Investigational Drugs The process of new drug development has many parts. In the United States, until a drug has been approved by the FDA, it can generally be obtained only through several mechanisms: enrollment in a clinical trial studying the drug, an expanded access program or special exemption/compassionate use programs. For more information about investigational drugs, see “Questions


and Answers: Access to Investigational Drugs“ at http://www.cancer.gov/cancer_information/doc_img.aspx?viewid=74b62d8 4-e135-451f-9bc9-d54358ede947. “Group C” Drugs In the 1970s, researchers from the NCI became concerned about the lag between the date when an investigational drug was found to have antitumor activity and the time that drug became available on the market. Working with the FDA, the NCI established the “Group C” classification to allow access to drugs with reproducible activity. Group C drugs are provided to properly trained physicians who have registered using a special form to assure that their patient qualifies under guideline protocols for the drug. Each Group C drug protocol specifies patient eligibility, reporting methodology, and drug use. Not only does Group C designation (now called Group C/Treatment INDs) speed new drugs to patients who need them most, but the process also allows the NCI to gather important information on the safety as well as activity of the drugs in the settings in which they will be most used after final FDA approval. Drugs are placed in the Group C category by agreement between the FDA and the NCI. Group C drugs are always provided free of charge, and the Health Care Financing Administration provides coverage for care associated with Group C therapy.

Treatment INDs In 1987, the FDA began authorizing the use of new drugs still in the development process to treat certain seriously ill patients. In these cases, the process is referred to as a treatment investigational new drug application (Treatment IND). Clinical trials of the new drug must already be underway and have demonstrated positive results that are reproducible. The FDA sets guidelines about what constitutes serious and life-threatening illnesses, how much must already be known about a drug’s side effects and benefits, and where physicians can obtain the drug for treatment. For many seriously ill patients, the risks associated with taking a not-yet-completely proven drug are outweighed by the possible benefits.

Accelerated Approval “Accelerated approval” is the short-hand term for the FDA’s new review system which, in the 1990s, has been used to ensure rapid approval while at


the same time putting new safeguards into place. Accelerated approval is based on “surrogate endpoint” judgments: FDA can grant marketing approval to drugs and treatments that, according to certain indicators, prove they are likely to have beneficial effects on a disease or condition, even before such direct benefits have been shown clinically. Accelerated approval does NOT mean that additional clinical trials are not needed or that FDA stops gathering information about the effects of the drug; a follow-up study is required to demonstrate activity by more conventional endpoints.

Contraindications and Interactions (Hidden Dangers) Some of the medications mentioned in the previous discussions can be problematic for children with childhood rhabdomyosarcoma--not because they are used in the treatment process, but because of contraindications, or side effects. Medications with contraindications are those that could react with drugs used to treat childhood rhabdomyosarcoma or potentially create deleterious side effects in patients with childhood rhabdomyosarcoma. You should ask the physician about any contraindications, especially as these might apply to other medications that your child may be taking for common ailments. Drug-drug interactions occur when two or more drugs react with each other. This drug-drug interaction may cause your child to experience an unexpected side effect. Drug interactions may make medications less effective, cause unexpected side effects, or increase the action of a particular drug. Some drug interactions can even be harmful to your child. Be sure to read the label every time you give your child a nonprescription or prescription drug, and take the time to learn about drug interactions. These precautions may be critical to your child’s health. You can reduce the risk of potentially harmful drug interactions and side effects with a little bit of knowledge and common sense. Drug labels contain important information about ingredients, uses, warnings, and directions which you should take the time to read and understand. Labels also include warnings about possible drug interactions. Further, drug labels may change as new information becomes avaiable. This is why it’s especially important to read the label every time you give your child a medication. When the doctor prescribes a new drug, discuss all overthe-counter and prescription medications, dietary supplements, vitamins, botanicals, minerals and herbals your child takes. Ask your pharmacist for the package insert for each drug prescribed. The package insert provides more information about potential drug interactions.


A Final Warning At some point, you may hear of alternative medications from friends, relatives, or in the news media. Advertisements may suggest that certain alternative drugs can produce positive results for childhood rhabdomyosarcoma. Exercise caution--some of these drugs may have fraudulent claims, and others may actually hurt your child. The Food and Drug Administration (FDA) is the official U.S. agency charged with discovering which medications are likely to improve the health of patients with childhood rhabdomyosarcoma. The FDA warns to watch out for163: ·

Secret formulas (real scientists share what they know)

·

Amazing breakthroughs or miracle cures (real breakthroughs don’t happen very often; when they do, real scientists do not call them amazing or miracles)

·

Quick, painless, or guaranteed cures

·

If it sounds too good to be true, it probably isn’t true.

If you have any questions about any kind of medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

General References In addition to the resources provided earlier in this chapter, the following general references describe medications (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·

Antifolate Drugs in Cancer Therapy (Cancer Drug Discovery and Development) by Ann L. Jackman (Editor); Hardcover: 480 pages; (March 1999), Humana Press; ISBN: 0896035964; http://www.amazon.com/exec/obidos/ASIN/0896035964/icongroupinterna

·

Consumers Guide to Cancer Drugs by Gail M. Wilkes, et al; Paperback 448 pages, 1st edition (January 15, 2000), Jones & Bartlett Publishing; ISBN: 0763711705; http://www.amazon.com/exec/obidos/ASIN/0763711705/icongroupinterna

163

This section has been adapted from http://www.fda.gov/opacom/lowlit/medfraud.html.


·

Patient Education Guide to Oncology Drugs (Book with CD-ROM) by Gail M. Wilkes, et al; CD-ROM - 447 pages, 1st edition (January 15, 2000), Jones & Bartlett Publishing; ISBN: 076371173X; http://www.amazon.com/exec/obidos/ASIN/076371173X/icongroupinterna

·

The Role of Multiple Intensification in Medical Oncology by M. S. Aapro (Editor), D. Maraninchi (Editor); Hardcover (June 1998), Springer Verlag; ISBN: 3540635432; http://www.amazon.com/exec/obidos/ASIN/3540635432/icongroupinterna

Vocabulary Builder The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Cisplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH]

Researching Alternative Medicine 223

APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE Overview164 Research indicates that the use of complementary and alternative therapies is increasing. A large-scale study published in the November 11, 1998, issue of the Journal of the American Medical Association found that CAM use among the general public increased from 34 percent in 1990 to 42 percent in 1997. Several surveys of CAM use by cancer patients have been conducted with small numbers of patients. One study published in the February 2000 issue of the journal Cancer reported that 37 percent of 46 patients with prostate cancer used one or more CAM therapies as part of their cancer treatment. These therapies included herbal remedies, old-time remedies, vitamins, and special diets. A larger study of CAM use in patients with different types of cancer was published in the July 2000 issue of the Journal of Clinical Oncology . That study found that 83 percent of 453 cancer patients had used at least one CAM therapy as part of their cancer treatment. The study included CAM therapies such as special diets, psychotherapy, spiritual practices, and vitamin supplements. When psychotherapy and spiritual practices were excluded, 69 percent of patients had used at least one CAM therapy in their cancer treatment. In this chapter, we will begin by giving you a broad perspective on complementary and alternative therapies. Next, we will introduce you to official information sources on CAM relating to childhood rhabdomyosarcoma. Finally, at the conclusion of this chapter, we will provide a list of readings on childhood rhabdomyosarcoma from various authors. We will begin, however, with the National Center for 164Adapted

from the NCI: http://cis.nci.nih.gov/fact/9_14.htm


Complementary and Alternative Medicine’s (NCCAM) overview of complementary and alternative medicine.

What Is CAM?165 Complementary and alternative medicine (CAM) covers a broad range of healing philosophies, approaches, and therapies. Generally, it is defined as those treatments and healthcare practices which are not taught in medical schools, used in hospitals, or reimbursed by medical insurance companies. Many CAM therapies are termed “holistic,” which generally means that the healthcare practitioner considers the whole person, including physical, mental, emotional, and spiritual health. Some of these therapies are also known as “preventive,” which means that the practitioner educates and treats the person to prevent health problems from arising, rather than treating symptoms after problems have occurred. People use CAM treatments and therapies in a variety of ways. Therapies are used alone (often referred to as alternative), in combination with other alternative therapies, or in addition to conventional treatment (sometimes referred to as complementary). Complementary and alternative medicine, or “integrative medicine,” includes a broad range of healing philosophies, approaches, and therapies. Some approaches are consistent with physiological principles of Western medicine, while others constitute healing systems with non-Western origins. While some therapies are far outside the realm of accepted Western medical theory and practice, others are becoming established in mainstream medicine. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease. Some commonly used methods of complementary or alternative therapy include mind/body control interventions such as visualization and relaxation, manual healing including acupressure and massage, homeopathy, vitamins or herbal products, and acupuncture. Should you wish to explore non-traditional types of treatment, be sure to discuss all issues concerning treatments and therapies with your child’s healthcare provider, whether a physician or practitioner of complementary and alternative medicine. Competent healthcare management requires that the practitioner know of all conventional and alternative therapies that your child is taking. 165

Adapted from the NCCAM: http://nccam.nih.gov/nccam/fcp/faq/index.html#what-is.


The decision to use complementary and alternative treatments is an important one. Consider before selecting an alternative therapy, the safety and effectiveness of the therapy or treatment, the expertise and qualifications of the healthcare practitioner, and the quality of delivery. These topics should be considered when selecting any practitioner or therapy.

What Are the Domains of Alternative Medicine?166 The list of CAM practices changes continually. The reason being is that these new practices and therapies are often proved to be safe and effective, and therefore become generally accepted as “mainstream” healthcare practices. Today, CAM practices may be grouped within five major domains: (1) alternative medical systems, (2) mind-body interventions, (3) biologicallybased treatments, (4) manipulative and body-based methods, and (5) energy therapies. The individual systems and treatments comprising these categories are too numerous to list in this sourcebook. Thus, only limited examples are provided within each. Alternative Medical Systems Alternative medical systems involve complete systems of theory and practice that have evolved independent of, and often prior to, conventional biomedical approaches. Many are traditional systems of medicine that are practiced by individual cultures throughout the world, including a number of venerable Asian approaches. Traditional oriental medicine emphasizes the balance or disturbances of qi (pronounced chi) or vital energy in health and illness, respectively. Traditional oriental medicine consists of a group of techniques and methods including acupuncture, herbal medicine, oriental massage, and qi gong (a form of energy therapy). Acupuncture involves stimulating specific anatomic points in the body for therapeutic purposes, usually by puncturing the skin with a thin needle. Ayurveda is India’s traditional system of medicine. Ayurvedic medicine (meaning “science of life”) is a comprehensive system of medicine that places equal emphasis on body, mind, and spirit. Ayurveda strives to restore the innate harmony of the individual. Some of the primary Ayurvedic

166

Adapted from the NCCAM: http://nccam.nih.gov/nccam/fcp/classify/index.html.


treatments include diet, exercise, meditation, herbs, massage, exposure to sunlight, and controlled breathing. Other traditional healing systems have been developed by the world’s indigenous populations. These populations include Native American, Aboriginal, African, Middle Eastern, Tibetan, and Central and South American cultures. Homeopathy and naturopathy are also examples of complete alternative medicine systems. Homeopathic medicine is an unconventional Western system that is based on the principle that “like cures like,” i.e., that the same substance that in large doses produces the symptoms of an illness, in very minute doses cures it. Homeopathic health practitioners believe that the more dilute the remedy, the greater its potency. Therefore, they use small doses of specially prepared plant extracts and minerals to stimulate the body’s defense mechanisms and healing processes in order to treat illness. Naturopathic medicine is based on the theory that a medical condition is the manifestation of alterations in the processes by which the body naturally heals itself and emphasizes health restoration rather than treatment for the condition itself. Naturopathic physicians employ an array of healing practices, including the following: diet and clinical nutrition, homeopathy, acupuncture, herbal medicine, hydrotherapy (the use of water in a range of temperatures and methods of applications), spinal and soft-tissue manipulation, physical therapies (such as those involving electrical currents, ultrasound, and light), therapeutic counseling, and pharmacology. Mind-Body Interventions Mind-body interventions employ a variety of techniques designed to facilitate the mind’s capacity to affect bodily function and symptoms. Only a select group of mind-body interventions having well-documented theoretical foundations are considered CAM. For example, patient education and cognitive-behavioral approaches are now considered “mainstream.” On the other hand, complementary and alternative medicine includes meditation, certain uses of hypnosis, dance, music, and art therapy, as well as prayer and mental healing.


Biological-Based Therapies This category of CAM includes natural and biological-based practices, interventions, and products, many of which overlap with conventional medicine’s use of dietary supplements. This category includes herbal, special dietary, orthomolecular, and individual biological therapies. Herbal therapy employs an individual herb or a mixture of herbs for healing purposes. An herb is a plant or plant part that produces and contains chemical substances that act upon the body. Special diet therapies, such as those proposed by Drs. Atkins, Ornish, Pritikin, and Weil, are believed to prevent and/or control illness as well as promote health. Orthomolecular therapies aim to treat medical conditions with varying concentrations of chemicals such as magnesium, melatonin, and mega-doses of vitamins. Biological therapies include, for example, the use of laetrile and shark cartilage to treat cancer and the use of bee pollen to treat autoimmune and inflammatory conditions. Manipulative and Body-Based Methods This category includes methods that are based on manipulation and/or movement of the body. For example, chiropractors focus on the relationship between structure and function, primarily pertaining to the spine, and how that relationship affects the preservation and restoration of health. Chiropractors use manipulative therapy as an integral treatment tool. In contrast, osteopaths place particular emphasis on the musculoskeletal system and practice osteopathic manipulation. Osteopaths believe that all of the body’s systems work together and that disturbances in one system may have an impact upon function elsewhere in the body. Massage therapists manipulate the soft tissues of the body to normalize those tissues.

Energy Therapies Energy therapies focus on energy fields originating within the body (biofields) or those from other sources (electromagnetic fields). Biofield therapies are intended to affect energy fields (the existence of which is not yet experimentally proven) that surround and penetrate the human body. Some forms of energy therapy manipulate biofields by applying pressure and/or manipulating the body by placing the hands in or through these fields. Examples include Qi gong, Reiki and Therapeutic Touch.


Qi gong is a component of traditional oriental medicine that combines movement, meditation, and regulation of breathing to enhance the flow of vital energy (qi) in the body, improve blood circulation, and enhance immune function. Reiki, the Japanese word representing Universal Life Energy, is based on the belief that, by channeling spiritual energy through the practitioner, the spirit is healed and, in turn, heals the physical body. Therapeutic Touch is derived from the ancient technique of “laying-on of hands.” It is based on the premises that the therapist’s healing force affects recovery and that healing is promoted when the body’s energies are in balance. By passing their hands over the patient, these healers identify energy imbalances. Bioelectromagnetic-based therapies involve the unconventional use of electromagnetic fields to treat illnesses or manage pain. These therapies are often used to treat asthma, cancer, and migraine headaches. Types of electromagnetic fields which are manipulated in these therapies include pulsed fields, magnetic fields, and alternating current or direct current fields.

How Are Complementary and Alternative Approaches Evaluated?167 It is important that the same scientific evaluation which is used to assess conventional approaches be used to evaluate complementary and alternative therapies. A number of medical centers are evaluating complementary and alternative therapies by developing clinical trials (research studies with people) to test them. Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a rigorous scientific process, including clinical trials with large numbers of patients. Often, less is known about the safety and effectiveness of complementary and alternative methods. Some of these complementary and alternative therapies have not undergone rigorous evaluation. Others, once considered unorthodox, are finding a place in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) Consensus Conference in November 1997, acupuncture has been found to be effective in the management of chemotherapy-associated nausea and vomiting and in controlling pain associated with surgery. Some approaches, such as laetrile, have been studied and found ineffective or potentially harmful. 167Adapted

from the NCI: http://cis.nci.nih.gov/fact/9_14.htm


NCI-Sponsored Clinical Trials in Complementary and Alternative Medicine The NCI is currently sponsoring several clinical trials (research studies with patients) that study complementary and alternative treatments for cancer. Current trials include enzyme therapy with nutritional support for the treatment of inoperable pancreatic cancer, shark cartilage therapy for the treatment of non-small cell lung cancer, and studies of the effects of diet on prostate and breast cancers. Some of these trials compare alternative therapies with conventional treatments, while others study the effects of complementary approaches used in addition to conventional treatments. Patients who are interested in taking part in these or any clinical trials should talk with their doctor. More information about clinical trials sponsored by the NCI can be obtained from NCCAM (http://nccam.nih.gov, 1-888-644-6226), OCCAM (http://occam.nci.nih.gov), and the NCI’s Cancer Information Service (CIS) (http://cis.nci.nih.gov, 1-800-4-CANCER).

Questions to Ask Your Child’s Healthcare Provider about CAM When considering complementary and alternative therapies, ask your child’s healthcare provider the following questions: ·

What benefits can be expected from this therapy?

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What are the risks associated with this therapy?

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Do the known benefits outweigh the risks?

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What side effects can be expected?

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Will the therapy interfere with conventional treatment?

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Is this therapy part of a clinical trial? If so, who is sponsoring the trial?

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Will the therapy be covered by health insurance?

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How can patients and their health care providers learn more about complementary and alternative therapies?


Levels of Evidence for Human Studies of CAM for Cancer168 A classification system has been developed by the National Cancer Institute’s PDQ Adult Treatment Editorial Board to allow the ranking of human cancer treatment studies according to statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. This classification system has been adapted to allow the ranking of human studies of complementary and alternative medicine treatments for cancer. The purpose of classifying studies in this way is to assist readers in evaluating the strength of the evidence associated with particular treatments. However, not all human studies are classified. Only those reporting a therapeutic endpoint(s), such as tumor response, improvement in survival, or measured improvement in quality of life, are considered. In addition, anecdotal reports and individual case reports are not classified because important clinical details are often missing, the evidence from them is generally considered weak, and there is an increased probability that similar results (either positive or negative) will not be obtained with other patients. Furthermore, reports of case series are excluded when the description of clinical findings is so incomplete as to hinder proper assessment and interpretation.

Finding CAM References on Childhood Rhabdomyosarcoma Having read the previous discussion, you may be wondering which complementary or alternative treatments might be appropriate for childhood rhabdomyosarcoma. For the remainder of this chapter, we will direct you to a number of official sources which can assist you in researching studies and publications. Some of these articles are rather technical, so some patience may be required.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov) has created a link to the National Library of Medicine’s databases to allow parents to search for articles that specifically relate to childhood rhabdomyosarcoma and complementary medicine. To search the database, For more information, visit the NCI’s Web page dedicated to this topic: http://www.cancer.gov/cancer_information/doc.aspx?viewid=47595A5D-AD15-4F7DBAE6-DEA914E6C153

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go to the following Web site: www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “childhood rhabdomyosarcoma” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine (CAM) that are related to childhood rhabdomyosarcoma: ·

Acute myeloblastic leukemia as a second malignancy in a patient with hereditary retinoblastoma. Author(s): Nishimura S, Sato T, Ueda H, Ueda K. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 November 1; 19(21): 4182-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11689590&dopt=Abstract

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Adjuvant chemotherapy with vincristine, doxorubicin, and cyclophosphamide in the treatment of postenucleation high risk retinoblastoma. Author(s): Mustafa MM, Jamshed A, Khafaga Y, Mourad WA, Al-Mesfer S, Kofide A, El-Husseiny G, Gray A. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 1999 September-October; 21(5): 364-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10524448&dopt=Abstract

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Bean yellow dwarf virus RepA, but not rep, binds to maize retinoblastoma protein, and the virus tolerates mutations in the consensus binding motif. Author(s): Liu L, Saunders K, Thomas CL, Davies JW, Stanley J. Source: Virology. 1999 April 10; 256(2): 270-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10191192&dopt=Abstract

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Bilateral macular retinoblastoma managed by chemoreduction and chemothermotherapy. Author(s): Shields JA, Shields CL, De Potter P, Needle M. Source: Archives of Ophthalmology. 1996 November; 114(11): 1426-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8906043&dopt=Abstract


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Cellular thiol status-dependent inhibition of tumor cell growth via modulation of retinoblastoma protein phosphorylation by (-)epigallocatechin. Author(s): Kennedy DO, Kojima A, Moffatt J, Yamagiwa H, Yano Y, Hasuma T, Otani S, Matsui-Yuasa I. Source: Cancer Letters. 2002 May 8; 179(1): 25-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11880178&dopt=Abstract

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Characterization of interior cleavage of retinoblastoma protein in apoptosis. Author(s): Fattman CL, An B, Dou QP. Source: Journal of Cellular Biochemistry. 1997 December 1; 67(3): 399-408. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9361194&dopt=Abstract

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Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Author(s): Shields CL, Meadows AT, Shields JA, Carvalho C, Smith AF. Source: Archives of Ophthalmology. 2001 September; 119(9): 1269-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11545631&dopt=Abstract

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Chemoreduction in the initial management of intraocular retinoblastoma. Author(s): Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Source: Archives of Ophthalmology. 1996 November; 114(11): 1330-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8906023&dopt=Abstract

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Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Author(s): Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Singh A, Friedman DL, Naduvilath TJ. Source: American Journal of Ophthalmology. 2002 May; 133(5): 657-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11992863&dopt=Abstract


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Chemotherapeutic trials in patients with metastatic retinoblastoma. Author(s): Lonsdale D, Berry DH, Holcomb TM, Nora AH, Sullivan MP, Thurman WG, Vietti TJ. Source: Cancer Chemother Rep. 1968 October; 52(6): 631-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=5733085&dopt=Abstract

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Chemotherapy for extraocular retinoblastoma. Author(s): Pratt CB, Fontanesi J, Chenaille P, Kun LE, Jenkins JJ 3rd, Langston JW, Mounce KG, Meyer D. Source: Pediatric Hematology and Oncology. 1994 May-June; 11(3): 301-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8060814&dopt=Abstract

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Chemotherapy for retinoblastoma. Author(s): Akiyama K, Iwasaki M, Amemiya T, Yanai M. Source: Ophthalmic Paediatr Genet. 1989 June; 10(2): 111-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=2779981&dopt=Abstract

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Chemotherapy in metastatic retinoblastoma. Author(s): Kingston JE, Hungerford JL, Plowman PN. Source: Ophthalmic Paediatr Genet. 1987 March; 8(1): 69-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3587892&dopt=Abstract

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Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Author(s): Murphree AL, Villablanca JG, Deegan WF 3rd, Sato JK, Malogolowkin M, Fisher A, Parker R, Reed E, Gomer CJ. Source: Archives of Ophthalmology. 1996 November; 114(11): 1348-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8906025&dopt=Abstract

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Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Author(s): Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, Ling V, Chan HS.


Source: Archives of Ophthalmology. 1996 November; 114(11): 1321-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8906022&dopt=Abstract ·

Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Author(s): Shields CL, Shields JA, Needle M, de Potter P, Kheterpal S, Hamada A, Meadows AT. Source: Ophthalmology. 1997 December; 104(12): 2101-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9400771&dopt=Abstract

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Combined chemotherapy and local treatment in the management of intraocular retinoblastoma. Author(s): Brichard B, De Bruycker JJ, De Potter P, Neven B, Vermylen C, Cornu G. Source: Medical and Pediatric Oncology. 2002 June; 38(6): 411-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11984802&dopt=Abstract

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Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Author(s): Chan HS, DeBoer G, Thiessen JJ, Budning A, Kingston JE, O'Brien JM, Koren G, Giesbrecht E, Haddad G, Verjee Z, Hungerford JL, Ling V, Gallie BL. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1996 September; 2(9): 1499-508. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9816326&dopt=Abstract

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Complications of systemic chemotherapy as treatment of retinoblastoma. Author(s): Benz MS, Scott IU, Murray TG, Kramer D, Toledano S. Source: Archives of Ophthalmology. 2000 April; 118(4): 577-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10766148&dopt=Abstract

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Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. Author(s): Savatier P, Huang S, Szekely L, Wiman KG, Samarut J.


Source: Oncogene. 1994 March; 9(3): 809-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8108123&dopt=Abstract ·

Etoposide and carboplatin in extraocular retinoblastoma: a study by the Societe Francaise d'Oncologie Pediatrique. Author(s): Doz F, Neuenschwander S, Plantaz D, Courbon B, Gentet JC, Bouffet E, Mosseri V, Vannier JP, Mechinaud F, Desjardins L, et al. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1995 April; 13(4): 902-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7707117&dopt=Abstract

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Expression and prognostic value of the retinoblastoma tumour suppressor gene (RB-1) in childhood acute lymphoblastic leukaemia. Author(s): Sauerbrey A, Stammler G, Zintl F, Volm M. Source: British Journal of Haematology. 1996 July; 94(1): 99-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8757515&dopt=Abstract

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Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Author(s): Shields CL, Honavar SG, Shields JA, Demirci H, Meadows AT, Naduvilath TJ. Source: Archives of Ophthalmology. 2002 April; 120(4): 460-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11934319&dopt=Abstract

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Failure to activate interleukin 1beta-converting enzyme-like proteases and to cleave retinoblastoma protein in drug-resistant cells. Author(s): An B, Jin JR, Lin P, Dou QP. Source: Febs Letters. 1996 December 9; 399(1-2): 158-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8980142&dopt=Abstract

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Failure to dephosphorylate retinoblastoma protein in drug-resistant cells. Author(s): Dou QP, Lui VW. Source: Cancer Research. 1995 November 15; 55(22): 5222-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7585579&dopt=Abstract


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Forskolin and camptothecin induce a 30 kDa protein associated with melatonin production in Y79 human retinoblastoma cells. Author(s): Janavs JL, Florez JC, Pierce ME, Takahashi JS. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1995 January; 15(1 Pt 1): 298-309. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7823135&dopt=Abstract

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High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Author(s): Namouni F, Doz F, Tanguy ML, Quintana E, Michon J, Pacquement H, Bouffet E, Gentet JC, Plantaz D, Lutz P, Vannier JP, Validire P, Neuenschwander S, Desjardins L, Zucker JM. Source: European Journal of Cancer (Oxford, England : 1990). 1997 December; 33(14): 2368-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9616283&dopt=Abstract

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In vitro thermo- and thermochemo-sensitivity of retinoblastoma cells from surgical specimens. Author(s): Inomata M, Kaneko A, Kunimoto T, Saijo N. Source: International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2002 January-February; 18(1): 50-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11820468&dopt=Abstract

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Increased cyclin E level in retinoblastoma cells during programmed cell death. Author(s): Lauricella M, Giuliano M, Emanuele S, Carabillo M, Vento R, Tesoriere G. Source: Cell Mol Biol (Noisy-Le-Grand). 1998 December; 44(8): 1229-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9874510&dopt=Abstract

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Induction of apoptosis in cultured retinoblastoma cells by the protein phosphatase inhibitor, okadaic acid. Author(s): Inomata M, Saijo N, Kawashima K, Kaneko A, Fujiwara Y, Kunikane H, Tanaka Y.


Source: Journal of Cancer Research and Clinical Oncology. 1995; 121(12): 729-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7499444&dopt=Abstract ·

Induction of apoptosis in human retinoblastoma cells by topoisomerase inhibitors. Author(s): Giuliano M, Lauricella M, Vassallo E, Carabillo M, Vento R, Tesoriere G. Source: Investigative Ophthalmology & Visual Science. 1998 July; 39(8): 1300-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9660477&dopt=Abstract

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Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. Author(s): Park DS, Morris EJ, Bremner R, Keramaris E, Padmanabhan J, Rosenbaum M, Shelanski ML, Geller HM, Greene LA. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2000 May 1; 20(9): 3104-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10777774&dopt=Abstract

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Involvement of the retinoblastoma (pRb)-E2F/DP pathway during antiproliferative effects of resveratrol in human epidermoid carcinoma (A431) cells. Author(s): Adhami VM, Afaq F, Ahmad N. Source: Biochemical and Biophysical Research Communications. 2001 November 2; 288(3): 579-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11676482&dopt=Abstract

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Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines. Author(s): Li W, Fan J, Hochhauser D, Banerjee D, Zielinski Z, Almasan A, Yin Y, Kelly R, Wahl GM, Bertino JR. Source: Proceedings of the National Academy of Sciences of the United States of America. 1995 October 24; 92(22): 10436-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7479800&dopt=Abstract


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Lack of response to chemoreduction in presumed well differentiated retinoblastoma. Author(s): Singh AD, Shields CL, Shields JA. Source: J Pediatr Ophthalmol Strabismus. 2002 March-April; 39(2): 107-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11911540&dopt=Abstract

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Laminin-induced retinoblastoma cell differentiation: possible involvement of a 100-kDa cell-surface laminin-binding protein. Author(s): Albini A, Noonan DM, Melchiori A, Fassina GF, Percario M, Gentleman S, Toffenetti J, Chader GJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 1992 March 15; 89(6): 2257-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1532253&dopt=Abstract

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Medical therapy of retinoblastoma in children. Author(s): Acquaviva A, Barberi L, Bernardini C, D'Ambrosio A, Lasorella G. Source: J Neurosurg Sci. 1982 January-March; 26(1): 49-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7143085&dopt=Abstract

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Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma. Author(s): Wilson MW, Rodriguez-Galindo C, Haik BG, Moshfeghi DM, Merchant TE, Pratt CB. Source: Ophthalmology. 2001 November; 108(11): 2106-14; Discussion 2114-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11713087&dopt=Abstract

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New retinoblastoma tumors in children undergoing systemic chemotherapy. Author(s): Scott IU, Murray TG, Toledano S, O'Brien JM. Source: Archives of Ophthalmology. 1998 December; 116(12): 1685-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9869808&dopt=Abstract


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Occurrence of testicular metastasis in a child with bilateral retinoblastoma. Author(s): Kimball JC, Cangir A. Source: Cancer Treat Rep. 1979 May; 63(5): 803-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=455320&dopt=Abstract

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Pilot study of sequential combination chemotherapy in advanced and recurrent retinoblastoma. Author(s): Advani SH, Rao SR, Iyer RS, Pai SK, Kurkure PA, Nair CN. Source: Medical and Pediatric Oncology. 1994; 22(2): 125-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8259098&dopt=Abstract

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Postenucleation adjuvant therapy in high-risk retinoblastoma. Author(s): Honavar SG, Singh AD, Shields CL, Meadows AT, Demirci H, Cater J, Shields JA. Source: Archives of Ophthalmology. 2002 July; 120(7): 923-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12096963&dopt=Abstract

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

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

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

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

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

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

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Healthnotes: http://www.thedacare.org/healthnotes/

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

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TPN.com: http://www.tnp.com/

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

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WebMDÒHealth: http://my.webmd.com/drugs_and_herbs


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WellNet: http://www.wellnet.ca/herbsa-c.htm

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

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at: www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources. The following additional references describe, in broad terms, alternative and complementary medicine (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): · Alternative Medicine Definitive Guide to Cancer by W. John Diamond, et al; Hardcover - 1120 pages Package edition (March 18, 1997), Alternativemedicine.Com Books; ISBN: 1887299017; http://www.amazon.com/exec/obidos/ASIN/1887299017/icongroupinterna · Beating Cancer With Nutrition - Revised by Patrick Quillin, Noreen Quillin (Contributor); Paperback - 352 pages; Book & CD edition (January 1, 2001), Bookworld Services; ISBN: 0963837281; http://www.amazon.com/exec/obidos/ASIN/0963837281/icongroupinterna · Cancer: Increasing Your Odds for Survival - A Resource Guide for Integrating Mainstream, Alternative and Complementary Therapies by David Bognar, Walter Cronkite; Paperback (August 1998), Hunter House; ISBN: 0897932471; http://www.amazon.com/exec/obidos/ASIN/0897932471/icongroupinterna · Choices in Healing by Michael Lerner; Paperback - 696 pages; (February 28, 1996), MIT Press; ISBN: 0262621045; http://www.amazon.com/exec/obidos/ASIN/0262621045/icongroupinterna · The Gerson Therapy: The Amazing Nutritional Program for Cancer and Other Illnesses by Charlotte Gerson, Morton Walker, D.P.M.; Paperback 448 pages (October 2001), Kensington Publishing Corp.; ISBN: 1575666286; http://www.amazon.com/exec/obidos/ASIN/1575666286/icongroupinterna · Natural Compounds in Cancer Therapy by John C. Boik; Paperback - 520 pages (March 2001), Oregon Medical Press; ISBN: 0964828014; http://www.amazon.com/exec/obidos/ASIN/0964828014/icongroupinterna


· There’s No Place Like Hope: A Guide to Beating Cancer in Mind-Sized Bites by Vickie Girard, Dan Zadra (Editor); Hardcover - 161 pages (April 2001), Compendium Inc.; ISBN: 1888387416; http://www.amazon.com/exec/obidos/ASIN/1888387416/icongroupinterna · Your Life in Your Hands by Jane A. Plant, Ph.D; Hardcover - 272 pages (December 13, 2000), St. Martins Press (Trade); ISBN: 0312275617; http://www.amazon.com/exec/obidos/ASIN/0312275617/icongroupinterna For additional information on complementary and alternative medicine, ask your child’s doctor or write to: National Institutes of Health National Center for Complementary and Alternative Medicine Clearinghouse P. O. Box 8218 Silver Spring, MD 20907-8218

Vocabulary Builder Antiproliferative: Counteracting a process of proliferation. [EU] Camptothecin: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. [NIH] Inoperable: Not suitable to be operated upon. [EU] Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Nausea: An unpleasant sensation, vaguely referred to the epigastrium and abdomen, and often culminating in vomiting. [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Prostaglandins: A group of compounds derived from unsaturated 20carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase


pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH]

Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU]

Researching Nutrition 243

APPENDIX C. RESEARCHING NUTRITION Overview Since the time of Hippocrates, doctors have understood the importance of diet and nutrition to health and well-being. Since then, they have accumulated an impressive archive of studies and knowledge dedicated to this subject. Based on their experience, doctors and healthcare providers may recommend particular dietary supplements for childhood rhabdomyosarcoma. Any dietary recommendation is based on age, body mass, gender, lifestyle, eating habits, food preferences, and health condition. It is therefore likely that different patients with childhood rhabdomyosarcoma may be given different recommendations. Some recommendations may be directly related to childhood rhabdomyosarcoma, while others may be more related to general health. In this chapter we will begin by briefly reviewing the essentials of diet and nutrition that will broadly frame more detailed discussions of childhood rhabdomyosarcoma. We will then show you how to find studies dedicated specifically to nutrition and childhood rhabdomyosarcoma.


Food and Nutrition: General Principles What Are Essential Foods? Food is generally viewed by official sources as consisting of six basic elements: (1) fluids, (2) carbohydrates, (3) protein, (4) fats, (5) vitamins, and (6) minerals. Consuming a combination of these elements is considered to be a healthy diet: ·

Fluids are essential to human life as 80-percent of the body is composed of water. Water is lost via urination, sweating, diarrhea, vomiting, diuretics (drugs that increase urination), caffeine, and physical exertion.

·

Carbohydrates are the main source for human energy (thermoregulation) and the bulk of typical diets. They are mostly classified as being either simple or complex. Simple carbohydrates include sugars which are often consumed in the form of cookies, candies, or cakes. Complex carbohydrates consist of starches and dietary fibers. Starches are consumed in the form of pastas, breads, potatoes, rice, and other foods. Soluble fibers can be eaten in the form of certain vegetables, fruits, oats, and legumes. Insoluble fibers include brown rice, whole grains, certain fruits, wheat bran and legumes.

·

Proteins are eaten to build and repair human tissues. Some foods that are high in protein are also high in fat and calories. Food sources for protein include nuts, meat, fish, cheese, and other dairy products.

·

Fats are consumed for both energy and the absorption of certain vitamins. There are many types of fats, with many general publications recommending the intake of unsaturated fats or those low in cholesterol.

Vitamins and minerals are fundamental to human health, growth, and, in some cases, disease prevention. Most are consumed in your child’s diet (exceptions being vitamins K and D which are produced by intestinal bacteria and sunlight on the skin, respectively). Each vitamin and mineral plays a different role in health. The following outlines essential vitamins: ·

Vitamin A is important to the health of eyes, hair, bones, and skin; sources of vitamin A include foods such as eggs, carrots, and cantaloupe.

·

Vitamin B1, also known as thiamine, is important for the nervous system and energy production; food sources for thiamine include meat, peas, fortified cereals, bread, and whole grains.

·

Vitamin B2, also known as riboflavin, is important for the nervous system and muscles, but is also involved in the release of proteins from


nutrients; food sources for riboflavin include dairy products, leafy vegetables, meat, and eggs. ·

Vitamin B3, also known as niacin, is important for healthy skin and helps the body use energy; food sources for niacin include peas, peanuts, fish, and whole grains

·

Vitamin B6, also known as pyridoxine, is important for the regulation of cells in the nervous system and is vital for blood formation; food sources for pyridoxine include bananas, whole grains, meat, and fish.

·

Vitamin B12 is vital for a healthy nervous system and for the growth of red blood cells in bone marrow; food sources for vitamin B12 include yeast, milk, fish, eggs, and meat.

·

Vitamin C allows the body’s immune system to fight various medical conditions, strengthens body tissue, and improves the body’s use of iron; food sources for vitamin C include a wide variety of fruits and vegetables.

·

Vitamin D helps the body absorb calcium which strengthens bones and teeth; food sources for vitamin D include oily fish and dairy products.

·

Vitamin E can help protect certain organs and tissues from various degenerative diseases; food sources for vitamin E include margarine, vegetables, eggs, and fish.

·

Vitamin K is essential for bone formation and blood clotting; common food sources for vitamin K include leafy green vegetables.

·

Folic Acid maintains healthy cells and blood; food sources for folic acid include nuts, fortified breads, leafy green vegetables, and whole grains.

It should be noted that one can overdose on certain vitamins which become toxic if consumed in excess (e.g. vitamin A, D, E and K). Like vitamins, minerals are chemicals that are required by the body to remain in good health. Because the human body does not manufacture these chemicals internally, we obtain them from food and other dietary sources. The more important minerals include: ·

Calcium is needed for healthy bones, teeth, and muscles, but also helps the nervous system function; food sources for calcium include dry beans, peas, eggs, and dairy products.

·

Chromium is helpful in regulating sugar levels in blood; food sources for chromium include egg yolks, raw sugar, cheese, nuts, beets, whole grains, and meat.


·

Fluoride is used by the body to help prevent tooth decay and to reinforce bone strength; sources of fluoride include drinking water and certain brands of toothpaste.

·

Iodine helps regulate the body’s use of energy by synthesizing into the hormone thyroxine; food sources include leafy green vegetables, nuts, egg yolks, and red meat.

·

Iron helps maintain muscles and the formation of red blood cells and certain proteins; food sources for iron include meat, dairy products, eggs, and leafy green vegetables.

·

Magnesium is important for the production of DNA, as well as for healthy teeth, bones, muscles, and nerves; food sources for magnesium include dried fruit, dark green vegetables, nuts, and seafood.

·

Phosphorous is used by the body to work with calcium to form bones and teeth; food sources for phosphorous include eggs, meat, cereals, and dairy products.

·

Selenium primarily helps maintain normal heart and liver functions; food sources for selenium include wholegrain cereals, fish, meat, and dairy products.

·

Zinc helps wounds heal, the formation of sperm, and encourage rapid growth and energy; food sources include dried beans, shellfish, eggs, and nuts.

The United States government periodically publishes recommended diets and consumption levels of the various elements of food. Again, the doctor may encourage deviations from the average official recommendation based on your child’s specific condition. To learn more about basic dietary guidelines, visit the Web site: http://www.health.gov/dietaryguidelines/. Based on these guidelines, many foods are required to list the nutrition levels on the food’s packaging. Labeling Requirements are listed at the following site maintained by the Food and Drug Administration: http://www.cfsan.fda.gov/~dms/lab-cons.html. When interpreting these requirements, the government recommends that consumers become familiar with the following abbreviations before reading FDA literature:169 ·

DVs (Daily Values): A new dietary reference term that will appear on the food label. It is made up of two sets of references, DRVs and RDIs.

·

DRVs (Daily Reference Values): A set of dietary references that applies to fat, saturated fat, cholesterol, carbohydrate, protein, fiber, sodium, and potassium.

169

Adapted from the FDA: http://www.fda.gov/fdac/special/foodlabel/dvs.html.


·

RDIs (Reference Daily Intakes): A set of dietary references based on the Recommended Dietary Allowances for essential vitamins and minerals and, in selected groups, protein. The name “RDI” replaces the term “U.S. RDA.”

·

RDAs (Recommended Dietary Allowances): A set of estimated nutrient allowances established by the National Academy of Sciences. It is updated periodically to reflect current scientific knowledge.

What Are Dietary Supplements?170 Dietary supplements are widely available through many commercial sources, including health food stores, grocery stores, pharmacies, and by mail. Dietary supplements are provided in many forms including tablets, capsules, powders, gel-tabs, extracts, and liquids. Historically in the United States, the most prevalent type of dietary supplement was a multivitamin/mineral tablet or capsule that was available in pharmacies, either by prescription or “over the counter.” Supplements containing strictly herbal preparations were less widely available. Currently in the United States, a wide array of supplement products are available, including vitamin, mineral, other nutrients, and botanical supplements as well as ingredients and extracts of animal and plant origin. The Office of Dietary Supplements (ODS) of the National Institutes of Health is the official agency of the United States which has the expressed goal of acquiring “new knowledge to help prevent, detect, diagnose, and treat disease and disability, from the rarest genetic disorder to the common cold.”171 According to the ODS, dietary supplements can have an important impact on the prevention and management of medical conditions and on the maintenance of health.172 The ODS notes that considerable research on the effects of dietary supplements has been conducted in Asia and Europe where This discussion has been adapted from the NIH: http://ods.od.nih.gov/whatare/whatare.html. 171 Contact: The Office of Dietary Supplements, National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: (301) 435-2920, Fax: (301) 480-1845, E-mail: [email protected]. 172 Adapted from http://ods.od.nih.gov/about/about.html. The Dietary Supplement Health and Education Act defines dietary supplements as “a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, mineral, amino acid, herb or other botanical; or a dietary substance for use to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above; and intended for ingestion in the form of a capsule, powder, softgel, or gelcap, and not represented as a conventional food or as a sole item of a meal or the diet.” 170


the use of plant products, in particular, has a long tradition. However, the overwhelming majority of supplements have not been studied scientifically. To explore the role of dietary supplements in the improvement of health care, the ODS plans, organizes, and supports conferences, workshops, and symposia on scientific topics related to dietary supplements. The ODS often works in conjunction with other NIH Institutes and Centers, other government agencies, professional organizations, and public advocacy groups. To learn more about official information on dietary supplements, visit the ODS site at http://ods.od.nih.gov/whatare/whatare.html. Or contact: The Office of Dietary Supplements National Institutes of Health Building 31, Room 1B29 31 Center Drive, MSC 2086 Bethesda, Maryland 20892-2086 Tel: (301) 435-2920 Fax: (301) 480-1845 E-mail: [email protected]

Finding Studies on Childhood Rhabdomyosarcoma The NIH maintains an office dedicated to nutrition and diet. The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.173 IBIDS is available to the public free of charge through the ODS Internet page: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. We recommend that you start with the Consumer Database. While you may not find references for the topics that are of most interest to you, check back Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

173


periodically as this database is frequently updated. More studies can be found by searching the Full IBIDS Database. Healthcare professionals and researchers generally use the third option, which lists peer-reviewed citations. In all cases, we suggest that you take advantage of the “Advanced Search” option that allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “childhood rhabdomyosarcoma” (or synonyms) into the search box. To narrow the search, you can also select the “Title” field. The following information is typical of that found when using the “Full IBIDS Database” when searching using “childhood rhabdomyosarcoma” (or a synonym): ·

A unique case of retinoblastoma masked by retinal detachment diagnosis and management. Author(s): Division of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston 77030. Source: Cangir, A Lee, Y Y Salmonsen, P Med-Pediatr-Oncol. 1992; 20(3): 243-5 0098-1532

·

Apoptotic effects of different drugs on cultured retinoblastoma Y79 cells. Author(s): Institute of Biological Chemistry, University of Palermo, Policlinico, Palermo, Italy. Source: Lauricella, M Giuliano, M Emanuele, S Vento, R Tesoriere, G Tumour-Biol. 1998; 19(5): 356-63 0289-5447

·

Bcl-2- and CrmA-inhibitable dephosphorylation and cleavage of retinoblastoma protein during etoposide-induced apoptosis. Author(s): Department of Pharmacology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-2582, USA. Source: An, B Johnson, D E Jin, J R Antoku, K Dou, Q P Int-J-Mol-Med. 1998 January; 1(1): 131-6 1107-3756

·

Butyrate-induced G1 arrest results from p21-independent disruption of retinoblastoma protein-mediated signals. Author(s): Cancer Research Center, Boston University School of Medicine, Massachusetts 02118, USA. Source: Vaziri, C Stice, L Faller, D V Cell-Growth-Differ. 1998 June; 9(6): 465-74 1044-9523

·

cdc2-like kinase is associated with the retinoblastoma protein. Author(s): Tsukuba Research Institute, Banyu Pharmaceuticals Co. Ltd., Japan.


Source: Kitagawa, M Saitoh, S Ogino, H Okabe, T Matsumoto, H Okuyama, A Tamai, K Ohba, Y Yasuda, H Nishimura, S et al. Oncogene. 1992 June; 7(6): 1067-74 0950-9232 ·

Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. Author(s): Department of Pediatrics, Division of Oncology, The Children's Hospital of Philadelphia, PA, USA. [email protected] Source: Friedman, D L Himelstein, B Shields, C L Shields, J A Needle, M Miller, D Bunin, G R Meadows, A T J-Clin-Oncol. 2000 January; 18(1): 127 0732-183X

·

Coupled down-regulation of the RB retinoblastoma and c-myc genes antecedes cell differentiation: possible role of RB as a "status quo" gene. Author(s): Department of Pathology, Veterinary College, Cornell University, Ithaca, NY 14853-6401. Source: Yen, A Chandler, S Forbes, M E Fung, Y K T'Ang, A Pearson, R Eur-J-Cell-Biol. 1992 April; 57(2): 210-21 0171-9335

·

Elements regulating the transcription of human interstitial retinoidbinding protein (IRBP) gene in cultured retinoblastoma cells. Author(s): Department of Ophthalmology, Indiana University, Indianapolis 46202, USA. [email protected] Source: Fong, S L Fong, W B Curr-Eye-Res. 1999 April; 18(4): 283-91 02713683

·

First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. Author(s): Pediatric Department, Hematology-Oncology Unit, and Department of Radiooncology, Centre Hospitalier Universitaire Vaudois, and Jules Gonin Eye Hospital, Lausanne, Switzerland. [email protected] Source: Beck, M N Balmer, A Dessing, C Pica, A Munier, F J-Clin-Oncol. 2000 August; 18(15): 2881-7 0732-183X

·

Functional mammary gland development and oncogene-induced tumor formation are not affected by the absence of the retinoblastoma gene. Author(s): Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA. [email protected] Source: Robinson, G W Wagner, K U Hennighausen, L Oncogene. 2001 October 25; 20(48): 7115-9 0950-9232

·

Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the


extracellular-regulated kinases in human cultured airway smooth muscle. Author(s): Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne, Australia. Source: Fernandes, D Guida, E Koutsoubos, V Harris, T Vadiveloo, P Wilson, J W Stewart, A G Am-J-Respir-Cell-Mol-Biol. 1999 July; 21(1): 7788 1044-1549 ·

Glutamic acid mutagenesis of retinoblastoma protein phosphorylation sites has diverse effects on function. Author(s): Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston 77030, USA. Source: Barrientes, S Cooke, C Goodrich, D W Oncogene. 2000 January 27; 19(4): 562-70 0950-9232

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Growth arrest associated with 12-o-tetradecanoylphorbol-13-acetateinduced hematopoietic differentiation with a defective retinoblastoma tumor suppressor-mediated pathway. Author(s): Fourth Department of Internal Medicine, University of Tokyo, School of Medicine, Japan. Source: Uchimaru, K Taniguchi, T Yoshikawa, M Fujinuma, H Fujita, T Motokura, T Leuk-Res. 1998 May; 22(5): 413-20 0145-2126

·

Heme oxygenase: expression in human retina and modulation by stress agents in a human retinoblastoma cell model system. Author(s): Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892. Source: Kutty, G Hayden, B Osawa, Y Wiggert, B Chader, G J Kutty, R K Curr-Eye-Res. 1992 February; 11(2): 153-60 0271-3683

·

Identification and analysis of a retinoblastoma binding motif in the replication protein of a plant DNA virus: requirement for efficient viral DNA replication. Source: Xie, Q. Suarez Lopez, P. Gutierrez, C. EMBO-j. Oxford, U.K. : Oxford University Press. August 15, 1995. volume 14 (16) page 4073-4082. 0261-4189

·

In vitro effects of prostaglandins on human retinoblastoma cell line, Y79 cells. Author(s): Department of Ophthalmology, University of Tokyo School of Medicine, Japan. Source: Nakamura, M Koshihara, Y Fujino, Y Mochizuki, M Minoda, K Masuda, K Jpn-J-Ophthalmol. 1987; 31(4): 598-607 0021-5155


·

Inhibition of myeloma cell growth by all-trans retinoic acid is associated with upregulation of p21WAF1 and dephosphorylation of the retinoblastoma protein. Author(s): VA Westside Medical Center, Chicago, Illinois 60612, USA. Source: Lavelle, D Chen, Y H Hankewych, M Desimone, J LeukLymphoma. 1999 October; 35(3-4): 261-8 1042-8194

·

Linkage studies of the esterase D and retinoblastoma genes to canine copper toxicosis: a model for Wilson disease. Source: Yuzbasiyan Gurkan, V. Wagnitz, S. Blanton, S.H. Brewer, G.J. Genomics. Orlando, Fla. : Academic Press, Inc. January 1993. volume 15 (1) page 86-90. 0888-7543

·

Metastatic retinoblastoma to the orofacial region. Author(s): Department of Oral Surgery, Nagoya University School of Medicine, Japan. Source: Ebata, K Mizutani, H Kaneda, T Horibe, K J-Oral-MaxillofacSurg. 1991 October; 49(10): 1120-3 0278-2391

·

Neuron-specific Cdk5 kinase is responsible for mitosis-independent phosphorylation of c-Src at Ser75 in human Y79 retinoblastoma cells. Author(s): Department of Biochemistry, Yamanashi Medical University, Nakakoma, Yamanashi, 409-3898, Japan. [email protected] Source: Kato, G Maeda, S J-Biochem-(Tokyo). 1999 November; 126(5): 957-61 0021-924X

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

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

·

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

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

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


·

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

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

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

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

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


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

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

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Healthnotes: http://www.thedacare.org/healthnotes/

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

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

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WebMDÒHealth: http://my.webmd.com/nutrition

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

Vocabulary Builder The following vocabulary builder defines words used in the references in this chapter that have not been defined in previous chapters: Bacteria: A large group of single-cell microorganisms. Some cause infections and disease in animals and humans. The singular of bacteria is bacterium. [NIH]

Calcium: A mineral found in teeth, bones, and other body tissues. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH]


Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, poly- and heterosaccharides. [EU] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Extracellular: Outside a cell or cells. [EU] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Overdose: 1. to administer an excessive dose. 2. an excessive dose. [EU] Phosphorous: Having to do with or containing the element phosphorus. [NIH]

Potassium: A metallic element that is important in body functions such as regulation of blood pressure and of water content in cells, transmission of nerve impulses, digestion, muscle contraction, and heart beat. [NIH] Riboflavin:

Nutritional factor found in milk, eggs, malted barley, liver,


kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Selenium: An essential dietary mineral. [NIH] Thermoregulation: Heat regulation. [EU] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH]

Finding Medical Libraries 257

APPENDIX D. FINDING MEDICAL LIBRARIES Overview At a medical library you can find medical texts and reference books, consumer health publications, specialty newspapers and magazines, as well as medical journals. In this appendix, we show you how to quickly find a medical library in your area.

Preparation Before going to the library, highlight the references mentioned in this sourcebook that you find interesting. Focus on those items that are not available via the Internet, and ask the reference librarian for help with your search. He or she may know of additional resources that could be helpful to you. Most importantly, your local public library and medical libraries have Interlibrary Loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. NLM’s interlibrary loan services are only available to libraries. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.174

174

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


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

Medical Libraries Open to the Public In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries that are generally open to the public and have reference facilities. The following is the NLM’s list plus hyperlinks to each library Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located):175 ·

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

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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute), http://www.asmi.org/LIBRARY.HTM

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

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

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

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

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California: Gateway Health Library (Sutter Gould Medical Foundation)

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

175

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


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

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

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California: San José PlaneTree Health Library, http://planetreesanjose.org/

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California: Sutter Resource Library (Sutter Hospitals Foundation), http://go.sutterhealth.org/comm/resc-library/sac-resources.html

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California: University of California, Davis. Health Sciences Libraries

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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System), http://www.valleycare.com/library.html

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

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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.exempla.org/conslib.htm

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

·

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

·

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

·

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

·

Maine: Parkview Hospital, http://www.parkviewhospital.org/communit.htm#Library

·

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

·

Maine: Stephens Memorial Hospital Health Information Library (Western Maine Health), http://www.wmhcc.com/hil_frame.html

·

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

·

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre), http://www.deerlodge.mb.ca/library/libraryservices.shtml


·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

Michigan: Sladen Library & Center for Health Information Resources Consumer Health Information, http://www.sladen.hfhs.org/library/consumer/index.html

·

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center), http://www.saintpatrick.org/chi/librarydetail.php3?ID=41


·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

Oklahoma: Saint Francis Health System Patient/Family Resource Center (Saint Francis Health System), http://www.sfhtulsa.com/patientfamilycenter/default.asp


·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

Quebec, Canada: Medical Library (Montreal General Hospital), http://ww2.mcgill.ca/mghlib/

·

South Dakota: Rapid City Regional Hospital - Health Information Center (Rapid City Regional Hospital, Health Information Center), http://www.rcrh.org/education/LibraryResourcesConsumers.htm

·

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

·

Texas: Matustik Family Resource Center (Cook Children’s Health Care System), http://www.cookchildrens.com/Matustik_Library.html

·

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

·

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center), http://www.swmedctr.com/Home/

Your Child’s Rights and Insurance 265

APPENDIX E. YOUR CHILD’S RIGHTS AND INSURANCE Overview Parents face a series of issues related more to the healthcare industry than to their children’s medical conditions. This appendix covers two important topics in this regard: your responsibilities and your child’s rights as a patient, and how to get the most out of your child’s medical insurance plan.

Your Child’s Rights as a Patient The President’s Advisory Commission on Consumer Protection and Quality in the Healthcare Industry has created the following summary of your child’s rights as a patient.176

176Adapted

from Consumer Bill of Rights and Responsibilities: http://www.hcqualitycommission.gov/press/cbor.html#head1.


Information Disclosure Consumers have the right to receive accurate, easily understood information. Some consumers require assistance in making informed decisions about health plans, health professionals, and healthcare facilities. Such information includes: ·

Health plans. Covered benefits, cost-sharing, and procedures for resolving complaints, licensure, certification, and accreditation status, comparable measures of quality and consumer satisfaction, provider network composition, the procedures that govern access to specialists and emergency services, and care management information.

·

Health professionals. Education, board certification, and recertification, years of practice, experience performing certain procedures, and comparable measures of quality and consumer satisfaction.

·

Healthcare facilities. Experience in performing certain procedures and services, accreditation status, comparable measures of quality, worker, and consumer satisfaction, and procedures for resolving complaints.

·

Consumer assistance programs. Programs must be carefully structured to promote consumer confidence and to work cooperatively with health plans, providers, payers, and regulators. Desirable characteristics of such programs are sponsorship that ensures accountability to the interests of consumers and stable, adequate funding.

Choice of Providers and Plans Consumers have the right to a choice of healthcare providers that is sufficient to ensure access to appropriate high-quality healthcare. To ensure such choice, the Commission recommends the following: ·

Provider network adequacy. All health plan networks should provide access to sufficient numbers and types of providers to assure that all covered services will be accessible without unreasonable delay -including access to emergency services 24 hours a day and 7 days a week. If a health plan has an insufficient number or type of providers to provide a covered benefit with the appropriate degree of specialization, the plan should ensure that the consumer obtains the benefit outside the network at no greater cost than if the benefit were obtained from participating providers.

·

Access to specialists. Consumers with complex or serious medical conditions who require frequent specialty care should have direct access


to a qualified specialist of their choice within a plan’s network of providers. Authorizations, when required, should be for an adequate number of direct access visits under an approved treatment plan. ·

Transitional care. Consumers who are undergoing a course of treatment for a chronic or disabling condition at the time they involuntarily change health plans or at a time when a provider is terminated by a plan for other than cause should be able to continue seeing their current specialty providers for up to 90 days to allow for transition of care.

·

Choice of health plans. Public and private group purchasers should, wherever feasible, offer consumers a choice of high-quality health insurance plans. Access to Emergency Services

Consumers have the right to access emergency healthcare services when and where the need arises. Health plans should provide payment when a consumer presents to an emergency department with acute symptoms of sufficient severity--including severe pain--such that a “prudent layperson” could reasonably expect the absence of medical attention to result in placing that consumer’s health in serious jeopardy, serious impairment to bodily functions, or serious dysfunction of any bodily organ or part.

Participation in Treatment Decisions Consumers have the right and responsibility to fully participate in all decisions related to their healthcare. Consumers who are unable to fully participate in treatment decisions have the right to be represented by parents, guardians, family members, or other conservators. Physicians and other health professionals should: ·

Provide parents with sufficient information and opportunity to decide among treatment options consistent with the informed consent process.

·

Discuss all treatment options with a parent in a culturally competent manner, including the option of no treatment at all.

·

Ensure that persons with disabilities have effective communications with members of the health system in making such decisions.

·

Discuss all current treatments a consumer may be undergoing.

·

Discuss all risks, nontreatment.

benefits,

and

consequences

to

treatment

or


·

Give parents the opportunity to refuse treatment for their children and to express preferences about future treatment decisions.

·

Discuss the use of advance directives -- both living wills and durable powers of attorney for healthcare -- with parents.

·

Abide by the decisions made by parents consistent with the informed consent process.

Health plans, health providers, and healthcare facilities should: ·

Disclose to consumers factors -- such as methods of compensation, ownership of or interest in healthcare facilities, or matters of conscience -that could influence advice or treatment decisions.

·

Assure that provider contracts do not contain any so-called “gag clauses” or other contractual mechanisms that restrict healthcare providers’ ability to communicate with and advise parents about medically necessary treatment options for their children.

·

Be prohibited from penalizing or seeking retribution against healthcare professionals or other health workers for advocating on behalf of their patients. Respect and Nondiscrimination

Consumers have the right to considerate, respectful care from all members of the healthcare industry at all times and under all circumstances. An environment of mutual respect is essential to maintain a quality healthcare system. To assure that right, the Commission recommends the following: ·

Consumers must not be discriminated against in the delivery of healthcare services consistent with the benefits covered in their policy, or as required by law, based on race, ethnicity, national origin, religion, sex, age, mental or physical disability, sexual orientation, genetic information, or source of payment.

·

Consumers eligible for coverage under the terms and conditions of a health plan or program, or as required by law, must not be discriminated against in marketing and enrollment practices based on race, ethnicity, national origin, religion, sex, age, mental or physical disability, sexual orientation, genetic information, or source of payment.


Confidentiality of Health Information Consumers have the right to communicate with healthcare providers in confidence and to have the confidentiality of their individually identifiable healthcare information protected. Consumers also have the right to review and copy their own medical records and request amendments to their records.

Complaints and Appeals Consumers have the right to a fair and efficient process for resolving differences with their health plans, healthcare providers, and the institutions that serve them, including a rigorous system of internal review and an independent system of external review. A free copy of the Patient’s Bill of Rights is available from the American Hospital Association.177

Parent Responsibilities To underscore the importance of finance in modern healthcare as well as your responsibility for the financial aspects of your child’s care, the President’s Advisory Commission on Consumer Protection and Quality in the Healthcare Industry has proposed that parents understand the following “Consumer Responsibilities.”178 In a healthcare system that protects consumers’ rights, it is reasonable to expect and encourage consumers to assume certain responsibilities. Greater involvement by parents in their children’s care increases the likelihood of achieving the best outcome and helps support a quality-oriented, cost-conscious environment. Such responsibilities include: ·

Take responsibility for maximizing your child’s healthy habits.

·

Work collaboratively with healthcare providers in developing and carrying out your child’s agreed-upon treatment plans.

·

Disclose relevant information and clearly communicate wants and needs.

To order your free copy of the Patient’s Bill of Rights, telephone 312-422-3000 or visit the American Hospital Association’s Web site: http://www.aha.org. Click on “Resource Center,” go to “Search” at bottom of page, and then type in “Patient’s Bill of Rights.” The Patient’s Bill of Rights is also available from Fax on Demand, at 312-422-2020, document number 471124. 178 Adapted from http://www.hcqualitycommission.gov/press/cbor.html#head1. 177


·

Use the insurance company’s internal complaint and appeal processes to address your concerns.

·

Recognize the reality of risks, the limits of the medical science, and the human fallibility of the healthcare professional.

·

Be aware of a healthcare provider’s obligation to be reasonably efficient and equitable in providing care to the community.

·

Become knowledgeable about health plan coverage and options (when available) including all covered benefits, limitations, and exclusions, rules regarding use of network providers, coverage and referral rules, appropriate processes to secure additional information, and the process to appeal coverage decisions.

·

Make a good-faith effort to meet financial obligations.

·

Abide by administrative and operational procedures of health plans, healthcare providers, and Government health benefit programs.

Choosing an Insurance Plan There are a number of official government agencies that help consumers understand their healthcare insurance choices.179 The U.S. Department of Labor, in particular, recommends ten ways to make your health benefits choices work best for your family.180 1. Your options are important. There are many different types of health benefit plans. Find out which one your employer offers, then check out the plan, or plans, offered. Your employer’s human resource office, the health plan administrator, or your union can provide information to help you match your family’s needs and preferences with the available plans. The more information you have, the better your healthcare decisions will be. 2. Reviewing the benefits available. Do the plans offered cover preventive care, well-baby care, vision or dental care? Are there deductibles? Answers to these questions can help determine the out-of-pocket expenses you may face. Cheapest may not always be best. Your goal is high quality health benefits.

More information about quality across programs is provided at the following AHRQ Web site: http://www.ahrq.gov/consumer/qntascii/qnthplan.htm. 180 Adapted from the Department of Labor: http://www.dol.gov/dol/pwba/public/pubs/health/top10-text.html. 179


3. Look for quality. The quality of healthcare services varies, but quality can be measured. You should consider the quality of healthcare in deciding among the healthcare plans or options available to your family. Not all health plans, doctors, hospitals and other providers give the highest quality care. Fortunately, there is quality information you can use right now to help you compare your healthcare choices. Find out how you can measure quality. Consult the U.S. Department of Health and Human Services publication “Your Guide to Choosing Quality Health Care” on the Internet at www.ahcpr.gov/consumer. 4. Your plan’s summary plan description (SPD) provides a wealth of information. Your health plan administrator can provide you with a copy of your plan’s SPD. It outlines your family’s benefits and your legal rights under the Employee Retirement Income Security Act (ERISA), the federal law that protects your family’s health benefits. It should contain information about the coverage of dependents, what services will require a co-pay, and the circumstances under which your employer can change or terminate a health benefits plan. Save the SPD and all other health plan brochures and documents, along with memos or correspondence from your employer relating to health benefits. 5. Assess your benefit coverage as your family status changes. Marriage, divorce, childbirth or adoption, and the death of a spouse are all life events that may signal a need to change your health benefits. You, your spouse and dependent children may be eligible for a special enrollment period under provisions of the Health Insurance Portability and Accountability Act (HIPAA). Even without life-changing events, the information provided by your employer should tell you how you can change benefits or switch plans, if more than one plan is offered. If your spouse’s employer also offers a health benefits package, consider coordinating both plans for maximum coverage. 6. Changing jobs and other life events can affect your family’s health benefits. Under the Consolidated Omnibus Budget Reconciliation Act (COBRA), you, your covered spouse, and your dependent children may be eligible to purchase extended health coverage under your employer’s plan if you lose your job, change employers, get divorced, or upon occurrence of certain other events. Coverage can range from 18 to 36 months depending on your situation. COBRA applies to most employers with 20 or more workers and requires your plan to notify you of your rights. Most plans require eligible individuals to make their COBRA election within 60 days of the plan’s notice. Be sure to follow up with your plan sponsor if you don’t receive notice, and make sure you respond within the allotted time.


7. HIPAA can also help if you are changing jobs, particularly if you have a medical condition. HIPAA generally limits pre-existing condition exclusions to a maximum of 12 months (18 months for late enrollees). HIPAA also requires this maximum period to be reduced by the length of time you had prior “creditable coverage.” You should receive a certificate documenting your prior creditable coverage from your old plan when coverage ends. 8. Plan for retirement. Before you retire, find out what health benefits, if any, extend to you and your spouse during your retirement years. Consult with your employer’s human resources office, your union, the plan administrator, and check your SPD. Make sure there is no conflicting information among these sources about the benefits your family will receive or the circumstances under which they can change or be eliminated. With this information in hand, you can make other important choices, like finding out if you are eligible for Medicare and Medigap insurance coverage. 9. Know how to file an appeal if a health benefits claim is denied. Understand how your plan handles grievances and where to make appeals of the plan’s decisions. Keep records and copies of correspondence. Check your health benefits package and your SPD to determine who is responsible for handling problems with benefit claims. Contact PWBA for customer service assistance if you are unable to obtain a response to your complaint. 10. You can take steps to improve the quality of the healthcare and the health benefits your family receives. Look for and use things like Quality Reports and Accreditation Reports whenever you can. Quality reports may contain consumer ratings -- how satisfied consumers are with the doctors in their plan, for instance-- and clinical performance measures -- how well a healthcare organization prevents and treats illness. Accreditation reports provide information on how accredited organizations meet national standards, and often include clinical performance measures. Look for these quality measures whenever possible. Consult “Your Guide to Choosing Quality Health Care” on the Internet at www.ahcpr.gov/consumer.

Medicaid Illness strikes both rich and poor families. For low-income families, Medicaid is available to defer the costs of treatment. In the following pages, you will learn the basics about Medicaid as well as useful contact information on how to find more in-depth information.


Medicaid is a joint federal and state program that helps pay medical costs for some people with low incomes and limited resources. Medicaid programs vary from state to state. You can find more information about Medicaid on the HCFA.gov Web site at http://www.hcfa.gov/medicaid/medicaid.htm.

Financial Assistance for Cancer Care181 Cancer can impose heavy economic burdens. For many parents, a portion of their children’s medical expenses is paid by their health insurance plan. For individuals who do not have health insurance or who need financial assistance to cover health care costs, resources are available, including government-sponsored programs and services supported by voluntary organizations. Parents should discuss any concerns they may have about healthcare costs with the physician, medical social worker, or the business office of their hospital or clinic. The organizations and resources listed below may offer financial assistance. Organizations that provide publications in Spanish or have Spanishspeaking staff have been identified. ·

The American Cancer Society (ACS) office can provide the telephone number of the local ACS office serving your area. The local ACS office may offer reimbursement for expenses related to cancer treatment including transportation, medicine, and medical supplies. The ACS also offers programs that help cancer patients, family members, and friends cope with the emotional challenges they face. Some publications are available in Spanish. Spanish-speaking staff are available. Telephone: 1– 800–ACS–2345 (1–800–227–2345). Web site: http://www.cancer.org

·

The Candlelighters Childhood Cancer Foundation (CCCF) is a nonprofit organization that provides information, peer support, and advocacy through publications, an information clearinghouse, and a network of local support groups. CCCF maintains a list of organizations to which eligible families may apply for financial assistance. Telephone: 1–800– 366–CCCF (1–800–366–2223). Web site: http://www.candlelighters.org.

Community voluntary agencies and service organizations such as the Salvation Army, Lutheran Social Services, Jewish Social Services, Catholic Charities, and the Lions Club may offer help. These organizations are listed 181



in your local phone directory. Some churches and synagogues may provide financial help or services to their members. Fundraising is another mechanism to consider. Some parents find that friends, family, and community members are willing to contribute financially if they are aware of a difficult situation. Contact your local library for information about how to organize fundraising efforts. General assistance programs provide food, housing, prescription drugs, and other medical expenses for those who are not eligible for other programs. Funds are often limited. Information can be obtained by contacting your state or local Department of Social Services; this number is found in the local telephone directory. Hill-Burton is a program through which hospitals receive construction funds from the Federal Government. Hospitals that receive Hill-Burton funds are required by law to provide some services to people who cannot afford to pay for their hospitalization. Information about which facilities are part of this program is available by calling the toll-free number or visiting the Web site shown below. A brochure about the program is available in Spanish. Telephone: 1–800–638–0742. Web site: http://www.hrsa.gov/osp/dfcr/obtain/consfaq.htm. Income Tax Deductions Medical costs that are not covered by insurance policies sometimes can be deducted from annual income before taxes. Examples of tax deductible expenses might include mileage for trips to and from medical appointments, out-of-pocket costs for treatment, prescription drugs or equipment, and the cost of meals during lengthy medical visits. The local Internal Revenue Service office, tax consultants, or certified public accountants can determine medical costs that are tax deductible. These telephone numbers are available in the local telephone directory. Web site: http://www.irs.ustreas.gov.

The Patient Advocate Foundation The Patient Advocate Foundation (PAF) is a national nonprofit organization that provides education, legal counseling, and referrals to cancer patients and survivors concerning managed care, insurance, financial issues, job discrimination, and debt crisis matters. Telephone: 1–800–532–5274. Web site: http://www.patientadvocate.org.


Patient Assistance Programs are offered by some pharmaceutical manufacturers to help pay for medications. To learn whether a specific drug might be available at reduced cost through such a program, talk with a physician or a medical social worker.

The State Children’s Health Insurance Program The State Children’s Health Insurance Program (SCHIP) is a Federal-State partnership that offers low-cost or free health insurance coverage to uninsured children of low-wage, working parents. Callers will be referred to the SCHIP program in their state for further information about what the program covers, who is eligible, and the minimum qualifications. Telephone: 1–877–543–7669 (1–877–KIDS–NOW). Web site: http://www.insurekidsnow.gov.

Transportation There are nonprofit organizations that arrange free or reduced cost air transportation for cancer patients going to or from cancer treatment centers. Financial need is not always a requirement. To find out about these programs, talk with a medical social worker. Ground transportation services may be offered or mileage reimbursed through the local ACS or your state or local Department of Social Services.


NORD’s Medication Assistance Programs Finally, the National Organization for Rare Disorders, Inc. (NORD) administers medication programs sponsored by humanitarian-minded pharmaceutical and biotechnology companies to help uninsured or underinsured individuals secure life-saving or life-sustaining drugs.182 NORD programs ensure that certain vital drugs are available “to those families whose income is too high to qualify for Medicaid but too low to pay for their prescribed medications.” The program has standards for fairness, equity, and unbiased eligibility. It currently covers some 14 programs for nine pharmaceutical companies. NORD also offers early access programs for investigational new drugs (IND) under the approved “Treatment INDs” programs of the Food and Drug Administration (FDA). In these programs, a limited number of individuals can receive investigational drugs that have yet to be approved by the FDA. These programs are generally designed for rare medical conditions. For more information, visit www.rarediseases.org.

Additional Resources In addition to the references already listed in this chapter, you may need more information on health insurance, hospitals, or the healthcare system in general. The NIH has set up an excellent guidance Web site that addresses these and other issues. Topics include:183 ·

Health Insurance: http://www.nlm.nih.gov/medlineplus/healthinsurance.html

·

Health Statistics: http://www.nlm.nih.gov/medlineplus/healthstatistics.html

·

HMO and Managed Care: http://www.nlm.nih.gov/medlineplus/managedcare.html

·

Hospice Care: http://www.nlm.nih.gov/medlineplus/hospicecare.html

·

Medicaid: http://www.nlm.nih.gov/medlineplus/medicaid.html

·

Medicare: http://www.nlm.nih.gov/medlineplus/medicare.html

·

Nursing Homes and Long-term Care: http://www.nlm.nih.gov/medlineplus/nursinghomes.html

Adapted from NORD: http://www.rarediseases.org/cgibin/nord/progserv#patient?id=rPIzL9oD&mv_pc=30. 183 You can access this information at: http://www.nlm.nih.gov/medlineplus/healthsystem.html. 182


·

Patient’s Rights, Confidentiality, Informed Consent, Ombudsman Programs, Privacy and Patient Issues: http://www.nlm.nih.gov/medlineplus/patientissues.html

·

Veteran’s Health, Persian Gulf War, Gulf War Syndrome, Agent Orange: http://www.nlm.nih.gov/medlineplus/veteranshealth.html

More on Young People with Cancer 279

APPENDIX F. TALKING WITH YOUR CHILD ABOUT CANCER Overview184 More children than ever are surviving childhood cancer. Over the last 30 years, survival into adulthood increased from 30 percent to 80 percent. There are new and better drugs and methods to help children deal with the side effects of treatment. And children who have had cancer now have a better quality of life throughout childhood and into adulthood; fewer long-term ill effects follow the treatment. Yet, in spite of all this good news, cancer is still a serious disease. You are not alone in facing your fears; help is available. A treatment team - doctors, radiation therapists, rehabilitation specialists, dietitians, oncology nurses, and social workers, among others - can help you and your child deal with the disease. They will also help ensure that your child gets the best treatment available with as few ill effects as possible. Your first question may be, “Should I tell my child about the cancer?” You may want to protect your child, but children usually know when something is wrong. Your child may not be feeling well, may be seeing the doctor often, and may have already had some tests. Your child may notice that you are afraid. No matter how hard you try to keep information about the illness and treatment from your child, others - such as family, friends, and clinic or hospital staff - may inadvertently say things that let your child know about the cancer. In addition, it will upset your child to find out that you were not telling the truth; your child depends on you for honest answers.

184

Adapted from the NCI: http://www.cancer.gov/CancerInformation/youngpeople.


Why Should I Tell My Child? Telling your child about his or her cancer is a personal matter, and family, cultural, or religious beliefs will come into play. It is important to be open and honest with your child because children who are not told about their illness often imagine things that are not true. For example, a child may think he or she has cancer as punishment for doing something wrong. Health professionals generally agree that telling children the truth about their illness leads to less stress and guilt. Children who know the truth are also more likely to cooperate with treatment. Finally, talking about cancer often helps to bring the family closer together and makes dealing with the cancer a little easier for everyone.

Parent’s Questions Parents have many questions about talking with their children about the diagnosis. Perhaps you have asked some of these yourself

When Should My Child Be Told? Because you are probably the best judge of your child’s personality and moods, you are the best person to decide when your child should be told. Keep in mind, though, that your child is likely to know early on that something is wrong, so you may want to tell your child soon after the diagnosis. In fact, most parents say it is easiest to tell them then. Waiting days or weeks may give your child time to imagine worse things than the truth and develop fears that may be hard to dispel later. Certainly, it would be easier for your child if he or she is told before treatment starts. Who Should Tell My Child? The answer to this question is personal. As a parent, you may feel that it is best for you to tell your child. Some parents, however, find it too painful to do so. Other family members or the treatment team - doctor, nurse, or social worker - may be able to help you. They may either tell your child for you or help you explain the illness. Thinking about what you are going to say and how to say it will help you feel more relaxed. But how do you decide just what to say? Family and close friends, members of the treatment team, parents of other children who have


cancer, members of support groups (you can find information about them at the end of this booklet), and clergy members can offer ideas.

Who Should Be There? Your child needs love and support when hearing the diagnosis. Even if the doctor explains the illness, someone your child trusts and depends upon should be present. Having the support of other family members at this time can be very helpful.

What Should My Child Be Told? How much information and the best way to relate this information depends on your child’s age and what your child can understand. Being gentle, open, and honest is usually best. The following sections describe what most children in various age groups are likely to understand. These guidelines are general; each child is different. Your child may fit into more than one or none of these categories. Up to 2 Years Old Children this young do not understand cancer. They understand what they can see and touch. Their biggest concern is what is happening to them right now. They worry most about being away from their parents. After children are a year old, they think about how things feel and how to control things around them. Very young children are most afraid of medical tests. Many cry, run away, or squirm to try to control what is happening. Because children begin to think about and understand what is going on around them at about 18 months, it is best to be honest. Be truthful about trips to the hospital and explain procedures that may hurt. You can tell your child that needle sticks will hurt a minute and that it is okay to cry. Being honest lets your child know that you understand and accept his or her feelings and helps your child trust you. When you can, give your child choices. For example, if a medicine is taken by mouth, you might ask if your child would like it mixed in apple juice, grape juice, or applesauce.


2 to 7 Years Old When children are between the ages of 2 and 7, they link events to one thing. For example, they usually tie illness to a specific event such as staying in bed or eating chicken soup. Children this age often think their illness is caused by a specific action. Therefore, getting better will “just happen” or will come if they follow a set of rules. These approaches might help when talking with a child in this age group: ·

Explain that treatment is needed so the hurting will go away or so the child can get better and play without getting so tired.

·

Explain that the illness or treatment is not punishment for something the child has done, said, or thought.

·

Be honest when you explain tests and treatments. Remind the child that all of these things are being done to get rid of the cancer and to help him or her get well.

·

Use simple ways to explain the illness. For example, try talking about the cancer as a contest between “good” cells and “bad” cells. Having treatment will help the good cells to be stronger so that they can beat the bad cells. 7 to 12 Years Old

Children ages 7 to 12 are starting to understand links between things and events. For example, a child this age sees his or her illness as a set of symptoms, is less likely to believe that something he or she did caused the illness, understands that getting better comes from taking medicines and doing what the doctor says, and is able to cooperate with treatment. You can give more details when explaining cancer, but you should still use situations your child may be used to. You might say that the body is made of up different types of cells, and these cells have different jobs to do. Like people, these cells must work together to get the job done. You might describe the cancer cells as “troublemakers” that get in the way of the work of the good cells. Treatment helps to get rid of the troublemakers so that other cells can work well together.


12 Years and Older Children over 12 years old can often understand complicated relationships between events. They can think about things that have not happened to them. Teenagers tend to think of illness in terms of specific symptoms, such as tiredness, and in terms of limits or changes in their everyday activity. But because they also can understand the reason for their symptoms, you can explain cancer as a disease in which a few cells in the body go “haywire.” These “haywire” cells grow more quickly than normal cells, invade other parts of the body, and get in the way of how the body usually works. The goal of treatment is to kill the “haywire” cells. The body can then work normally again, and the symptoms will go away.

Questions Children May Ask Children are naturally curious about their disease and have many questions about cancer and cancer treatment. Your child will expect you to have answers to most questions. Children may begin to ask questions right after diagnosis or may wait until later. Here are some common questions and some ideas to help you answer them.

Why Me? A child, like an adult, wonders “Why did I get cancer?” A child may feel that it is his or her fault, that somehow he or she caused the illness. Make it clear that not even the doctors know exactly what caused the cancer. Neither you, your child, nor his or her brothers or sisters did, said, or thought anything that caused the cancer. Stress also that cancer is not contagious, and your child did not “catch” it from someone else.

Will I Get Well? Children often know about family members or friends who died of cancer. As a result, many children are afraid to ask if they will get well because they fear that the answer will be “no.” Thus, you might tell your child that cancer is a serious disease, but that treatment - such as medicine, radiation, or an operation - has helped get rid of cancer in other children, and the doctors and nurses are trying their best to cure your child’s cancer, too. Knowing that caring people - such as family, doctors, nurses, counselors, and others -


surround your child and your family may also help him or her feel more secure.

What Will Happen to Me? When your child is first diagnosed with cancer, many new and scary things will happen. While at the doctor’s office, hospital, or clinic, your child may see or play with other children with cancer who may not be feeling well, have lost their hair, or have had limbs removed because of cancer. Your child may wonder, “Will these things happen to me?” Yet, your child may be too afraid to ask questions. It is important to try to get your child to talk about these concerns. Explain ahead of time about the cancer, treatment, and possible side effects. Discuss what the doctor will do to help if side effects occur. You can also explain that there are many different types of cancer and that even when two children have the same cancer, what happens to one child will not always happen to the other. Children should be told about any changes in their treatment schedule or in the type of treatment they receive. This information helps them prepare for visits to the doctor or hospital. You may want to help your child keep a calendar that shows the days for doctor visits, treatments, or tests. Do not tell younger children about upcoming treatments far ahead of time if it makes them nervous.

Why Do I Have to Take Medicine When I Feel Okay? With cancer, your child may feel fine much of the time but need to take medicine often. Children do not understand why they have to take medicine when they feel well. You may want to remind your child of the reason for taking the medicine in the first place. For example, a child could be told: “Although you are feeling well, the bad cells are hiding. You must take the medicine for a while longer to find the bad cells and stop them from coming back.”

Talking to Your Child with Late-Stage Cancer During the past several years, health care professionals have become more aware of the needs of children who have late-stage cancer and of their families. For example, attending school half days or even for an hour a day if possible - may make your child happier. Talking with your child about


death and dying and giving your child as many choices as possible shows your child that you are being open and honest, and shows your support, love, and respect. Paying close attention to changes in your child’s behavior may give you important clues as to what your child needs and whether he or she wants to talk about dying. Including all of your children in everyday activities - such as reading, doing homework, or watching a favorite television program or video together - can help keep the family close.

Online Glossaries 287

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries and glossaries. The National Library of Medicine has compiled the following list of online dictionaries: ·

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

·

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

·

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

·

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

·

On-line Medical Dictionary (CancerWEB): http://www.graylab.ac.uk/omd/

·

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

·

Terms and Definitions (Office of Rare Diseases): http://rarediseases.info.nih.gov/ord/glossary_a-e.html

Beyond these, MEDLINEplus contains a very user-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia Web site address is http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a). Topics of interest can be researched by using keywords before continuing elsewhere, as these basic definitions and concepts will be useful in more advanced areas of research. You may choose to print various pages specifically relating to childhood rhabdomyosarcoma and keep them on file. The NIH, in particular, suggests that parents of children with childhood rhabdomyosarcoma visit the following Web sites in the ADAM Medical Encyclopedia:


·

Basic Guidelines for Retinoblastoma Retinoblastoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001030.htm

·

Signs & Symptoms for Retinoblastoma Blindness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003040.htm Painful eye Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003032.htm Poor vision Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003029.htm Pupil, white spots Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003315.htm

·

Diagnostics and Tests for Retinoblastoma CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm CT scan of the head Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003786.htm Echoencephalogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003797.htm Head and eye echoencephalogram Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003797.htm

Online Glossaries 289

MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Ultrasound Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003336.htm ·

Surgery and Procedures for Retinoblastoma Laser surgery Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002958.htm

·

Background Topics for Retinoblastoma Chemotherapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002324.htm Iris Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002386.htm

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

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

·

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

·

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

·

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

Glossary 291

CHILDHOOD RHABDOMYOSARCOMA GLOSSARY The following is a complete glossary of terms used in this sourcebook. The definitions are derived from official public sources including the National Institutes of Health [NIH] and the European Union [EU]. After this glossary, we list a number of additional hardbound and electronic glossaries and dictionaries that you may wish to consult. Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Acetylglucosamine: The N-acetyl derivative of glucosamine. [NIH] Adenocarcinoma: Cancer that begins in cells that line certain internal organs and that have glandular (secretory) properties. [NIH] Adenoma: A noncancerous tumor. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Agonists: Drugs that trigger an action from a cell or another drug. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anemia: A condition in which the number of red blood cells is below normal. [NIH] Anophthalmos: Congenital absence of the eye or eyes. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antigens: Substances that cause the immune system to make a specific immune response. [NIH]


Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Apoptosis: A normal series of events in a cell that leads to its death. [NIH] Aromatic: Having a spicy odour. [EU] Arrestin: A 48-Kd protein of the outer segment of the retinal rods and a component of the phototransduction cascade. Arrestin quenches G-protein activation by binding to phosphorylated photolyzed rhodopsin. Arrestin causes experimental autoimmune uveitis when injected into laboratory animals. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, starshaped cells called astrocytes. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH] Bacteria: A large group of single-cell microorganisms. Some cause infections and disease in animals and humans. The singular of bacteria is bacterium. [NIH]

Bereavement: Refers to the whole process of grieving and mourning and is associated with a deep sense of loss and sadness. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biopsy: The removal of cells or tissues for examination under a microscope. When only a sample of tissue is removed, the procedure is called an incisional biopsy or core biopsy. When an entire tumor or lesion is removed, the procedure is called an excisional biopsy. When a sample of tissue or fluid is removed with a needle, the procedure is called a needle biopsy or fineneedle aspiration. [NIH] Bladder: The organ that stores urine. [NIH] Brachytherapy: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor. Also called internal radiation, implant radiation, or interstitial radiation therapy. [NIH]

Glossary 293

Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Calcium: A mineral found in teeth, bones, and other body tissues. [NIH] Camptothecin: An anticancer drug that belongs to the family of drugs called topoisomerase inhibitors. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, poly- and heterosaccharides. [EU] Carboplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cataract: An opacity, partial or complete, of one or both eyes, on or in the lens or capsule, especially an opacity impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). [EU] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Charities: Social welfare organizations with programs designed to assist individuals in times of need. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body


tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choristoma: A mass of histologically normal tissue present in an abnormal location. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Cisplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis. [NIH] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Conjunctiva: A membrane that lines the inner surface of the eyelid and also covers the front part of the eye. Conjunctivitis is inflammation of the conjunctiva. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Cryotherapy: Any method that uses cold temperature to treat disease. [NIH] CSF: Cerebrospinal fluid. The fluid flowing around the brain and spinal cord. CSF is produced in the ventricles of the brain. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyclophosphamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Cystectomy: Surgery to remove all or part of the bladder. [NIH] Cystoscope: A thin, lighted instrument used to look inside the bladder and remove tissue samples or small tumors. [NIH] Dactinomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU]

Glossary 295

Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Doxorubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. It is an anthracycline. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] Embryo: Having to do with an early stage in the development of a plant or an animal. In vertebrate animals, this stage lasts from shortly after fertilization until all major body parts appear. In particular, in humans, this stage lasts from about 2 weeks after fertilization until the end of the seventh or eighth week of pregnancy. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelium: A thin layer of tissue that covers organs, glands, and other structures within the body. [NIH] Epitopes: Sites on an antigen that interact with specific antibodies. [NIH] Erythroleukemia: Cancer of the blood-forming tissues in which large numbers of immature, abnormal red blood cells are found in the blood and bone marrow. [NIH] Erythropoiesis: The production of erythrocytes. [EU] Esophageal: Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach. [NIH] Etoposide: An anticancer drug that is a podophyllotoxin derivative and belongs to the family of drugs called mitotic inhibitors. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exons: Coding regions of messenger RNA included in the genetic transcript which survive the processing of RNA in cell nuclei to become part of a spliced messenger of structural RNA in the cytoplasm. They include joining and diversity exons of immunoglobulin genes. [NIH] Extracellular: Outside a cell or cells. [EU] Extremity: A limb; an arm or leg (membrum); sometimes applied specifically to a hand or foot. [EU] Facial: Of or pertaining to the face. [EU]


Femoral: Pertaining to the femur, or to the thigh. [EU] Fenretinide: A drug being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Ganciclovir: An antiviral agent used to prevent or treat cytomegalovirus infections that may occur when the body's immune system is suppressed. In gene therapy, ganciclovir is used with an altered herpes simplex virus-1 gene to kill advanced melanoma cells and brain tumor cells. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioblastoma: A general term that refers to malignant astrocytoma, a type of brain tumor. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonadal: Pertaining to a gonad. [EU] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Hematologist: A doctor who specializes in treating diseases of the blood. [NIH]

Hematology: A subspecialty of internal medicine concerned with morphology, physiology, and pathology of the blood and blood-forming tissues. [NIH] Hematopoiesis: The forming of new blood cells. [NIH]

Glossary 297

Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hepatoblastoma: A type of liver tumor that occurs in infants and children. [NIH]

Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Histology: The study of tissues and cells under a microscope. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hyperplasia: An abnormal increase in the number of cells in an organ or tissue. [NIH] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hypertrophy: Nutrition) the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Idiopathic: Describes a disease of unknown cause. [NIH] Ifosfamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Incision: A cut made in the body during surgery. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Inguinal: Pertaining to the inguen, or groin. [EU] Inoperable: Not suitable to be operated upon. [EU] Insulin: A hormone made by the islet cells of the pancreas. Insulin controls the amount of sugar in the blood by moving it into the cells, where it can be used by the body for energy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intraocular: Within the eye. [EU] Iodine: A nonmetallic element of the halogen group that is represented by


the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH]

Ipsilateral: Having to do with the same side of the body. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Lacrimal: Pertaining to the tears. [EU] Laryngoscope: A thin, lighted tube used to examine the larynx (voice box). [NIH]

Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoma: Cancer that arises in cells of the lymphatic system. [NIH] Malformation: A morphologic defect resulting from an intrinsically abnormal developmental process. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH]

Glossary 299

Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Mammography: The use of x-rays to create a picture of the breast. [NIH] Mandible: The largest and strongest bone of the FACE constituting the lower jaw. It supports the lower teeth. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medulloblastoma: A malignant brain tumor that begins in the lower part of the brain and can spread to the spine or to other parts of the body. Medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Metabolite: process. [EU]

Any substance produced by metabolism or by a metabolic

Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or


different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Myeloma: Cancer that arises in plasma cells, a type of white blood cell. [NIH] Nausea: An unpleasant sensation, vaguely referred to the epigastrium and abdomen, and often culminating in vomiting. [EU] Necrosis: Refers to the death of living tissues. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Neural: 1. pertaining to a nerve or to the nerves. 2. situated in the region of the spinal axis, as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous sytem. [NIH] Neurosurgeon: A doctor who specializes in surgery on the brain, spine, and other parts of the nervous system. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nonmetastatic: Cancer that has not spread from the primary (original) site to other sites in the body. [NIH]

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Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [NIH] Oncology: The study of cancer. [NIH] Oncology nurse: A nurse who specializes in treating and caring for people who have cancer. [NIH] Ophthalmic: Pertaining to the eye. [EU] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opsin: A visual pigment protein found in the retinal rods. It combines with retinaldehyde to form rhodopsin. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU]

Orchiectomy: Surgery to remove one or both testicles. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: 1. to administer an excessive dose. 2. an excessive dose. [EU] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palliative: 1. affording relief, but not cure. 2. an alleviating medicine. [EU] Papillomavirus: A genus of papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH]

Paraffin: A mixture of solid hydrocarbons obtained from petroleum. It has a wide range of uses including as a stiffening agent in ointments, as a lubricant, and as a topical anti-inflammatory. It is also commonly used as an embedding material in histology. [NIH] Parathyroid: 1. situated beside the thyroid gland. 2. one of the parathyroid glands. 3. a sterile preparation of the water-soluble principle(s) of the


parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Particle: A tiny mass of material. [EU] Pathologist: A doctor who identifies diseases by studying cells and tissues under a microscope. [NIH] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvic: Pertaining to the pelvis. [EU] Perianal: Located around the anus. [EU] Perineal: Pertaining to the perineum. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phosphorous: Having to do with or containing the element phosphorus. [NIH]

Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Potassium: A metallic element that is important in body functions such as regulation of blood pressure and of water content in cells, transmission of nerve impulses, digestion, muscle contraction, and heart beat. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance

Glossary 303

from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH]

Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Prostaglandins: A group of compounds derived from unsaturated 20carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostatectomy: An operation to remove part or all of the prostate. Radical (or total) prostatectomy is the removal of the entire prostate and some of the tissue around it. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH]

Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH]

Pulmonary: Relating to the lungs. [NIH] Punishment: The application of an unpleasant stimulus or penalty for the purpose of eliminating or correcting undesirable behavior. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiology: The use of radiation (such as x-rays) or other imaging technologies (such as ultrasound and magnetic resonance imaging) to diagnose or treat disease. [NIH]


Radiotherapy: The treatment of disease by ionizing radiation. [EU] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: 1. a cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Reconstitution: 1. a type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. the restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU]

Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Resected: Surgical removal of part of an organ. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is

Glossary 305

pigmented, whereas the inner nine layers are transparent. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Schwannoma: A tumor of the peripheral nervous system that begins in the nerve sheath (protective covering). It is almost always benign, but rare malignant schwannomas have been reported. [NIH] Sclerosis: A induration, or hardening; especially hardening of a part from inflammation and in diseases of the interstitial substance. The term is used chiefly for such a hardening of the nervous system due to hyperplasia of the connective tissue or to designate hardening of the blood vessels. [EU] Screening: Checking for disease when there are no symptoms. [NIH] Selenium: An essential dietary mineral. [NIH] Serine: A non-essential amino acid occurring in natural form as the Lisomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Somatic: 1. pertaining to or characteristic of the soma or body. 2. pertaining to the body wall in contrast to the viscera. [EU] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to


other parts of the body. [NIH] Staurosporine: A drug that belongs to the family of drugs called alkaloids. It is being studied in the treatment of cancer. [NIH] Strabismus: Deviation of the eye which the patient cannot overcome. The visual axes assume a position relative to each other different from that required by the physiological conditions. The various forms of strabismus are spoken of as tropias, their direction being indicated by the appropriate prefix, as cyclo tropia, esotropia, exotropia, hypertropia, and hypotropia. Called also cast, heterotropia, manifest deviation, and squint. [EU] Substrate: A substance upon which an enzyme acts. [EU] Supratentorial: Located in the upper part of the brain. [NIH] Systemic: Affecting the entire body. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Temozolomide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Testicular: Pertaining to a testis. [EU] Thalassemia: A group of hereditary hemolytic anemias in which there is decreased synthesis of one or more hemoglobin polypeptide chains. There are several genetic types with clinical pictures ranging from barely detectable hematologic abnormality to severe and fatal anemia. [NIH] Thermoregulation: Heat regulation. [EU] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH]

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

Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH]

Glossary 307

Topotecan: An anticancer drug that belongs to the family drugs called topoisomerase inhibitors. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Tumour: 1. swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. a new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Unresectable: Unable to be surgically removed. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urology: A surgical specialty concerned with the study, diagnosis, and treatment of diseases of the urinary tract in both sexes and the genital tract in the male. It includes the specialty of andrology which addresses both male genital diseases and male infertility. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Ventricular: Pertaining to a ventricle. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vulva: The external female genital organs, including the clitoris, vaginal lips, and the opening to the vagina. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH]


General Dictionaries and Glossaries While the above glossary is essentially complete, the dictionaries listed here cover virtually all aspects of medicine, from basic words and phrases to more advanced terms (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·

The Cancer Dictionary by Roberta Altman, Michael J., Md Sarg; Paperback - 368 pages, 2nd Revised edition (November 1999), Checkmark Books; ISBN: 0816039542; http://www.amazon.com/exec/obidos/ASIN/0816039542/icongroupinterna

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Dictionary of Medical Acronymns & Abbreviations by Stanley Jablonski (Editor), Paperback, 4th edition (2001), Lippincott Williams & Wilkins Publishers, ISBN: 1560534605, http://www.amazon.com/exec/obidos/ASIN/1560534605/icongroupinterna

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Dictionary of Medical Terms : For the Nonmedical Person (Dictionary of Medical Terms for the Nonmedical Person, Ed 4) by Mikel A. Rothenberg, M.D, et al, Paperback - 544 pages, 4th edition (2000), Barrons Educational Series, ISBN: 0764112015, http://www.amazon.com/exec/obidos/ASIN/0764112015/icongroupinterna

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A Dictionary of the History of Medicine by A. Sebastian, CD-Rom edition (2001), CRC Press-Parthenon Publishers, ISBN: 185070368X, http://www.amazon.com/exec/obidos/ASIN/185070368X/icongroupinterna

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Dorland’s Illustrated Medical Dictionary (Standard Version) by Dorland, et al, Hardcover - 2088 pages, 29th edition (2000), W B Saunders Co, ISBN: 0721662544, http://www.amazon.com/exec/obidos/ASIN/0721662544/icongroupinterna

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Dorland’s Electronic Medical Dictionary by Dorland, et al, Software, 29th Book & CD-Rom edition (2000), Harcourt Health Sciences, ISBN: 0721694934, http://www.amazon.com/exec/obidos/ASIN/0721694934/icongroupinterna

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Dorland’s Pocket Medical Dictionary (Dorland’s Pocket Medical Dictionary, 26th Ed) Hardcover - 912 pages, 26th edition (2001), W B Saunders Co, ISBN: 0721682812, http://www.amazon.com/exec/obidos/ASIN/0721682812/icongroupinterna /103-4193558-7304618

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Melloni’s Illustrated Medical Dictionary (Melloni’s Illustrated Medical Dictionary, 4th Ed) by Melloni, Hardcover, 4th edition (2001), CRC PressParthenon Publishers, ISBN: 85070094X, http://www.amazon.com/exec/obidos/ASIN/85070094X/icongroupinterna

Glossary 309

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Stedman’s Electronic Medical Dictionary Version 5.0 (CD-ROM for Windows and Macintosh, Individual) by Stedmans, CD-ROM edition (2000), Lippincott Williams & Wilkins Publishers, ISBN: 0781726328, http://www.amazon.com/exec/obidos/ASIN/0781726328/icongroupinterna

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Stedman’s Medical Dictionary by Thomas Lathrop Stedman, Hardcover 2098 pages, 27th edition (2000), Lippincott, Williams & Wilkins, ISBN: 068340007X, http://www.amazon.com/exec/obidos/ASIN/068340007X/icongroupinterna

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Stedman’s Oncology Words by Beverly J. Wolpert (Editor), Stedmans; Paperback - 502 pages, 3rd edition (June 15, 2000), Lippincott, Williams & Wilkins; ISBN: 0781726549; http://www.amazon.com/exec/obidos/ASIN/0781726549/icongroupinterna

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Tabers Cyclopedic Medical Dictionary (Thumb Index) by Donald Venes (Editor), et al, Hardcover - 2439 pages, 19th edition (2001), F A Davis Co, ISBN: 0803606540, http://www.amazon.com/exec/obidos/ASIN/0803606540/icongroupinterna


INDEX A Abdominal....................169, 170, 198, 305 Acetylglucosamine.................................85 Adenocarcinoma..................108, 241, 301 Adjuvant.................75, 117, 171, 234, 239 Agonists .................................................81 Alleles ................74, 80, 84, 130, 135, 142 Analogous......................................84, 173 Anemia ....................24, 46, 119, 294, 306 Anophthalmos......................................111 Antibody......121, 133, 146, 154, 291, 297, 299 Antigens.......................................146, 291 Antiproliferative....................................237 Apoptosis ....... 73, 84, 85, 107, 109, 232, 236, 237, 249 Aromatic ................................................81 Arrestin ................................................110 Astrocytoma.................................121, 296 Autologous.......................14, 15, 179, 184 Axillary .................................................174 B Bacteria ......147, 222, 244, 253, 292, 305, 307 Bereavement .........................................33 Bilateral..........................................70, 239 Biliary...................159, 160, 163, 166, 170 Biochemical .....77, 80, 118, 119, 291, 292 Biopsy.......12, 13, 20, 166, 169, 170, 171, 172, 173, 174, 292 Bladder ....... 12, 103, 137, 139, 141, 145, 163, 170, 171, 172, 182, 197, 294 Brachytherapy .....................................183 Bypass .................................................102 C Calcium........................................245, 246 Camptothecin ......................197, 236, 298 Capsules..............................................247 Carbohydrate.......................................246 Carboplatin ..........................184, 235, 236 Carcinoma ......73, 92, 139, 144, 237, 241, 301 Cardiac ..................................82, 114, 128 Cardiovascular.......................................82 Cataract ...............................151, 153, 293 Cervical....................................31, 45, 293 Cholesterol ..................................244, 246 Choristoma ..........................................105 Choroid ..................................................50 Chromosomal ..............................122, 300 Chromosome .........77, 130, 136, 142, 163

Cobalt.................................................. 114 Colon........................... 144, 146, 192, 294 Conception............................................ 78 Conjunctiva ......................... 105, 120, 294 Cornea ................................................ 182 Cryotherapy .................................. 75, 138 Curative......................... 33, 158, 254, 300 Cyclophosphamide .... 103, 175, 176, 178, 184, 231, 236 Cystectomy ................................. 171, 172 Cystoscope ......................................... 172 D Dactinomycin ...................... 175, 176, 181 Degenerative ...................................... 245 Diarrhea .............................................. 244 Distal ........................... 110, 165, 198, 303 Doxorubicin ................................. 178, 231 E Ectopic .................................................. 82 Embryo................................ 107, 121, 297 Endogenous.......................................... 95 Epithelial ............................. 101, 108, 187 Epithelium ................... 108, 123, 298, 301 Erythropoiesis ..................................... 143 Etoposide ............ 177, 178, 184, 236, 249 Exogenous .. 120, 129, 137, 141, 146, 295 Exons .................................. 110, 120, 295 Extracellular ........................ 120, 251, 296 Extremity ..................... 161, 168, 173, 174 F Facial ............................................ 75, 108 Femoral............................................... 174 Fenretinide ............................................ 76 Fibroblasts .................... 77, 116, 135, 234 Fibrosarcoma.............................. 135, 136 G Ganciclovir ............................ 75, 121, 296 Gastrointestinal ................................... 159 Genitourinary ..... 159, 160, 161, 163, 166, 168, 170, 173 Genotype .............................. 77, 123, 302 Gestation............................................. 143 Gland . 123, 125, 182, 250, 255, 301, 303, 306 Glycoprotein................................ 106, 162 Gonadal .............................................. 187 Grade .................................. 118, 121, 296 H Hematologist ....................................... 158 Hematology......................................... 156 Hemophilia ............................................ 24

Index 311

Hepatoblastoma ............................72, 159 Herpes .................................121, 296, 297 Histology.......12, 154, 155, 160, 162, 163, 164, 177, 178, 179, 183, 301 Homologous ....74, 83, 118, 136, 141, 291 Hypertrophy ...........................................82 I Ifosfamide ....................176, 177, 178, 184 Incision ................................................170 Induction ................................73, 117, 179 Inguinal ................................................170 Inoperable............................................229 Interstitial ....124, 136, 180, 182, 196, 250, 292, 305 Intraocular.......51, 77, 133, 135, 138, 139, 142, 150, 232, 233, 234, 238, 250 Ipsilateral .....................................168, 171 Irinotecan.............................................178 Iris ........................................197, 294, 298 L Lacrimal ...............................................182 Lesion ............................20, 122, 292, 298 Lethal .....................................................77 Leucine ..................................................77 Leukaemia ...........................................235 Leukemia ....... 24, 70, 72, 103, 105, 106, 187, 192, 231 Localization..........................................114 Lymph .....12, 45, 161, 165, 166, 167, 168, 170, 171, 174, 176, 196, 292, 293 Lymphocyte .................................154, 299 Lymphoma.......................70, 72, 187, 192 M Malignancy ..........123, 142, 231, 232, 301 Mammary.............................................250 Mammography.......................................31 Mandible ..............................................107 Manifest .......................................124, 306 Melanoma..............77, 116, 121, 192, 296 Meninges .............................................182 Mesenchymal ..............................168, 176 Metabolite ............................................247 Metastasis ...........................110, 182, 239 Mitosis .................................................252 Modulator.............................................135 Molecular ....... 73, 77, 78, 81, 82, 84, 118, 139, 142, 144, 162, 163, 185, 189, 191, 202 Molecule ......124, 128, 140, 146, 299, 304 Morphogenesis ....................................108 Mosaicism..............................................70 Mutagenesis ........................................251 Myeloma ..............................................252 N Nausea ................................................228 Necrosis...............................................114

Neoplastic ........... 133, 137, 138, 140, 141 Neural ................................................. 173 Neuroblastoma ......................... 50, 70, 72 Neuronal ..................................... 128, 143 Neurons .............................. 146, 237, 300 Niacin .................................................. 245 Nonmetastatic ............... 75, 167, 176, 177 Non-small cell lung cancer.................. 229 O Oncogene ..... 74, 122, 142, 192, 250, 301 Oncologist ..................... 46, 158, 180, 301 Oncology........... 16, 26, 43, 150, 158, 279 Oncology nurse................................... 279 Ophthalmic.................................... 76, 250 Opsin..................................................... 78 Orbital ...... 102, 150, 169, 170, 175, 180, 181, 182 Orchiectomy........................................ 170 Osteosarcoma ............ 135, 136, 138, 139 Ovary .......................................... 107, 109 Overdose ............................................ 245 P Paediatric ............................................ 150 Palliative................................................ 33 Papillomavirus .................................... 101 Paraffin................................................ 150 Parathyroid.................................. 123, 301 Pelvic .......... 123, 170, 172, 173, 182, 303 Perianal............................................... 163 Perineal............................................... 159 Pharmacologic ...................... 76, 125, 307 Phenotype ....... 74, 77, 84, 108, 123, 129, 130, 141, 302 Phosphorous....................................... 246 Phosphorylation ... 80, 84, 85, 87, 91, 106, 107, 114, 116, 232, 250, 251, 252 Pleomorphic ........................................ 162 Plexus ................................................... 50 Ploidy .......................................... 164, 165 Polymorphic ........................................ 129 Polypeptide .. 46, 132, 134, 137, 138, 139, 306 Postnatal ............................................... 71 Postoperative ...................................... 170 Potassium ........................................... 246 Preclinical...................................... 75, 214 Predisposition ..................................... 138 Prenatal........................................... 70, 71 Progression...... 73, 74, 77, 78, 79, 81, 85, 116, 131 Progressive ................... 75, 125, 183, 307 Prostaglandins .................................... 251 Prostate.. 75, 81, 140, 145, 170, 171, 172, 182, 192, 198, 223, 229, 303 Prostatectomy..................... 172, 198, 303 Proximal ...................... 120, 170, 174, 295


Psychotherapy.....................................223 Pulmonary ...........................................174 Punishment..................................280, 282 R Radiotherapy ....... 75, 114, 171, 180, 181, 232, 233 Randomized ........................................176 Receptor ....................................77, 81, 87 Recombinant .........................................78 Rectal ..................................................173 Rectum ................146, 172, 198, 294, 304 Recurrence ..................104, 172, 183, 235 Refractory ....................169, 170, 178, 184 Regeneration ...............................147, 304 Regimen ......................175, 176, 177, 184 Registries.............................................187 Relapse ...............................180, 183, 184 Remission............................183, 198, 304 Resected ....161, 165, 167, 171, 174, 175, 179 Resection....165, 166, 167, 168, 169, 170, 174, 175, 179, 180, 181 Retina .......4, 78, 130, 133, 135, 138, 142, 251, 255, 305 Retinoid ...............................................250 Retroperitoneal ............................170, 171 Riboflavin.............................................244 S Sclerosis ..............................................100 Screening ..................55, 57, 59, 104, 128 Selenium..............................................246 Serine ..............................................84, 85 Skeletal ................................................158 Skull .....................................................168 Somatic...... 125, 130, 136, 142, 254, 299, 306 Spectrum .............................................144 Sporadic ..........70, 78, 104, 117, 130, 142 Squamous ...........................104, 241, 301 Staging ..12, 160, 162, 166, 171, 174, 175

Strabismus .................................. 124, 306 Substrate............................................... 91 Supratentorial ....................................... 50 Systemic ................. 13, 75, 114, 234, 238 T Telomerase......................................... 113 Temozolomide ...................................... 76 Teratoma............................................. 103 Testicular ............................................ 239 Thalassemia.......................................... 24 Thermoregulation................................ 244 Threonine........................................ 84, 85 Thrombosis ......................................... 110 Thymidine ............................................. 75 Thyroid ... 77, 87, 118, 123, 125, 254, 255, 298, 301, 306 Thyroxine ............................................ 246 Tolerance .................................... 181, 199 Topotecan ................................... 178, 184 Toxicity.................................... 75, 76, 177 Toxicology..................................... 71, 186 Transplantation ........... 13, 14, 15, 51, 179 Tumour........................ 103, 109, 114, 235 U Unresectable......... 50, 165, 168, 176, 177 Urinary ................ 103, 125, 197, 296, 307 Uterus ... 45, 170, 172, 173, 199, 293, 307 V Vaccine ....................................... 118, 291 Vagina....... 160, 163, 170, 172, 173, 183, 199, 307 Vestibular ............................................ 110 Vincristine ........... 175, 176, 177, 178, 231 Virus..... 78, 106, 112, 121, 131, 231, 251, 296 Vitreous............................... 235, 242, 307 Vulva ................................................... 173 X Xenograft ............................................ 178

Index 313


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