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

THE OFFICIAL PARENT’S SOURCEBOOK on NEUROBLASTOMA J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS...

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THE OFFICIAL PARENT’S SOURCEBOOK

on

NEUROBLASTOMA

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 Neuroblastoma: 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: 0-597-83356-7 1. Neuroblastoma-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 neuroblastoma.

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 neuroblastoma. 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 neuroblastoma, 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 Retinoblastoma

·

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 ..................................................................................................................... 3 Moving Forward................................................................................................... 4

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

Overview............................................................................................................... 9 What Is Neuroblastoma? .................................................................................... 11 Stage Information ............................................................................................... 12 Treatment Option Overview .............................................................................. 13 Treatment by Stage............................................................................................. 15 To Learn More .................................................................................................... 17 About PDQ......................................................................................................... 18 More Guideline Sources ..................................................................................... 20 Vocabulary Builder............................................................................................. 25

CHAPTER 2. SEEKING GUIDANCE ....................................................... 29

Overview............................................................................................................. 29 Associations and Neuroblastoma........................................................................ 29 Finding More Associations................................................................................. 33 Cancer Support Groups...................................................................................... 34 The Cancer Information Service ......................................................................... 36 Finding Cancer Resources in Your Community................................................ 39 Finding Doctors Who Specialize in Cancer Care ............................................... 42 Selecting Your Child’s Doctor............................................................................ 44 Working with Your Child’s Doctor.................................................................... 46 Getting a Second Opinion .................................................................................. 46 Finding a Cancer Treatment Facility ................................................................. 47 Questions and Answers about Children’s Cancer Centers ................................ 49 Additional Cancer Support Information ............................................................ 51 Vocabulary Builder............................................................................................. 52

CHAPTER 3. CLINICAL TRIALS AND NEUROBLASTOMA ..................... 53

Overview............................................................................................................. 53 Recent Trials on Neuroblastoma ........................................................................ 56 Benefits and Risks............................................................................................... 80 Clinical Trials and Insurance Coverage ............................................................. 82 Increasing the Likelihood of Insurance Coverage for Trials ............................... 85 If Your Insurance Claim Is Denied after the Trial Has Begun .......................... 87 Government Initiatives to Expand Insurance Coverage for Trials .................... 90 Keeping Current on Clinical Trials.................................................................... 91

viii Contents

General References.............................................................................................. 92 Vocabulary Builder............................................................................................. 93

PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL.................................................. 99 CHAPTER 4. STUDIES ON NEUROBLASTOMA .................................... 101

Overview........................................................................................................... 101 The Combined Health Information Database ................................................... 101 Federally-Funded Research on Neuroblastoma ................................................ 105 E-Journals: PubMed Central ............................................................................ 120 The National Library of Medicine: PubMed .................................................... 125 Vocabulary Builder........................................................................................... 145

CHAPTER 5. PATENTS ON NEUROBLASTOMA ................................... 155

Overview........................................................................................................... 155 Patents on Neuroblastoma................................................................................ 156 Patent Applications on Neuroblastoma............................................................ 157 Keeping Current ............................................................................................... 157 Vocabulary Builder........................................................................................... 157

CHAPTER 6. BOOKS ON NEUROBLASTOMA ...................................... 159

Overview........................................................................................................... 159 Book Summaries: Federal Agencies .................................................................. 159 The National Library of Medicine Book Index ................................................. 161 Chapters on Neuroblastoma ............................................................................. 165 General Home References ................................................................................. 168 Vocabulary Builder........................................................................................... 169

CHAPTER 7. MULTIMEDIA ON NEUROBLASTOMA ............................ 173

Overview........................................................................................................... 173 Bibliography: Multimedia on Neuroblastoma .................................................. 173 Vocabulary Builder........................................................................................... 174

CHAPTER 8. PHYSICIAN GUIDELINES AND DATABASES ................... 175

Overview........................................................................................................... 175 NIH Guidelines................................................................................................. 175 What Is Neuroblastoma? .................................................................................. 176 Cellular Classification ...................................................................................... 183 Stage Information ............................................................................................. 184 Treatment Option Overview ............................................................................ 187 Neuroblastoma Risk-Based Treatment Plan..................................................... 187 Localized Resectable Neuroblastoma ................................................................ 190 Localized Unresectable Neuroblastoma ............................................................ 192 Low-Risk Localized Unresectable Neuroblastoma............................................ 193 High Risk Localized Unresectable Neuroblastoma........................................... 194 Regional Neuroblastoma................................................................................... 194 Low Risk Regional Neuroblastoma................................................................... 196

Contents

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Intermediate Risk Regional Neuroblastoma ..................................................... 197 High Risk Regional Neuroblastoma ................................................................. 198 Disseminated Neuroblastoma........................................................................... 198 Intermediate Risk Disseminated Neuroblastoma ............................................. 202 High Risk Disseminated Neuroblastoma.......................................................... 202 Treatment Options for Stage 4S Neuroblastoma ............................................. 203 Low Risk Stage 4S Neuroblastoma................................................................... 204 Intermediate Risk Stage 4S Neuroblastoma ..................................................... 205 High Risk Stage 4S Neuroblastoma ................................................................. 205 Recurrent Neuroblastoma................................................................................. 206 Recurrent Neuroblastoma in Patients Initially Classified as Low Risk........... 207 Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk .......................................................................................................................... 209 Recurrent Neuroblastoma in Patients Initially Classified as High Risk.......... 209 NIH Databases.................................................................................................. 210 Other Commercial Databases ........................................................................... 214 The Genome Project and Neuroblastoma ......................................................... 214 Specialized References....................................................................................... 218 Vocabulary Builder........................................................................................... 220

CHAPTER 9. DISSERTATIONS ON NEUROBLASTOMA ........................ 223

Overview........................................................................................................... 223 Dissertations on Neuroblastoma ...................................................................... 223 Keeping Current ............................................................................................... 224 Vocabulary Builder........................................................................................... 225

PART III. APPENDICES .................................................. 227 APPENDIX A. RESEARCHING YOUR CHILD’S MEDICATIONS ........... 229

Overview........................................................................................................... 229 Your Child’s Medications: The Basics.............................................................. 230 Learning More about Your Child’s Medications ............................................. 231 Commercial Databases...................................................................................... 234 Drug Development and Approval .................................................................... 235 Understanding the Approval Process for New Cancer Drugs......................... 236 The Role of the Federal Drug Administration (FDA)...................................... 237 Getting Drugs to Patients Who Need Them .................................................... 241 Contraindications and Interactions (Hidden Dangers) ................................... 243 A Final Warning .............................................................................................. 244 General References............................................................................................ 244 Vocabulary Builder........................................................................................... 245

APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE ................... 247

Overview........................................................................................................... 247 What Is CAM? ................................................................................................. 248 What Are the Domains of Alternative Medicine?............................................ 249 Finding CAM References on Neuroblastoma................................................... 254

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Contents

Additional Web Resources................................................................................ 264 General References............................................................................................ 266 Vocabulary Builder........................................................................................... 267

APPENDIX C. RESEARCHING NUTRITION ......................................... 269

Overview........................................................................................................... 269 Food and Nutrition: General Principles........................................................... 270 Finding Studies on Neuroblastoma .................................................................. 274 Federal Resources on Nutrition........................................................................ 278 Additional Web Resources................................................................................ 279 Vocabulary Builder........................................................................................... 279

APPENDIX D. FINDING MEDICAL LIBRARIES.................................... 281

Overview........................................................................................................... 281 Preparation ....................................................................................................... 281 Finding a Local Medical Library ...................................................................... 282 Medical Libraries Open to the Public............................................................... 282

APPENDIX E. YOUR CHILD’S RIGHTS AND INSURANCE ................... 289

Overview........................................................................................................... 289 Your Child’s Rights as a Patient ...................................................................... 289 Parent Responsibilities ..................................................................................... 293 Choosing an Insurance Plan............................................................................. 294 Medicaid ........................................................................................................... 296 Financial Assistance for Cancer Care............................................................... 297 NORD’s Medication Assistance Programs ..................................................... 300 Additional Resources ........................................................................................ 300

APPENDIX F. TALKING WITH YOUR CHILD ABOUT CANCER ........... 303

Overview........................................................................................................... 303 Why Should I Tell My Child? .......................................................................... 304 Parent’s Questions ........................................................................................... 304 What Should My Child Be Told? ..................................................................... 305 Questions Children May Ask ........................................................................... 307 Talking to Your Child with Late-Stage Cancer................................................ 308

ONLINE GLOSSARIES.................................................... 311 Online Dictionary Directories.......................................................................... 318

NEUROBLASTOMA GLOSSARY ................................. 319 General Dictionaries and Glossaries ................................................................ 343

INDEX................................................................................... 345

Introduction

1

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

Neuroblastoma

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 Neuroblastoma 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 neuroblastoma, 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 neuroblastoma. 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 neuroblastoma 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 on

Introduction

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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 neuroblastoma (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 neuroblastoma. It also gives you sources of information that can help you find a doctor in your local area specializing in treating neuroblastoma. Collectively, the material presented in Part I is a complete primer on basic research topics for neuroblastoma. Part II moves on to advanced research dedicated to neuroblastoma. 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 neuroblastoma. 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 neuroblastoma 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 neuroblastoma and their families.

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

Neuroblastoma Child

4

Neuroblastoma

In addition to synonyms and related conditions, physicians may refer to neuroblastoma 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 neuroblastoma:4 ·

171.8 malignant pelvo-abdominal neoplasm

·

173.4 cervical neoplasm

·

194.0 malignant neoplasm of adrenal medulla

·

195.1 thoracic neoplasm

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 neuroblastoma. 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 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 neuroblastoma, parents will often log on to the Internet, type words into a search engine, and receive several Web site listings which are mostly 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

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 neuroblastoma 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 neuroblastoma, 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

7

PART I: THE ESSENTIALS

ABOUT PART I Part I has been edited to give you access to what we feel are “the essentials” on neuroblastoma. 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 neuroblastoma 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

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CHAPTER 1. THE ESSENTIALS ON NEUROBLASTOMA: GUIDELINES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines on neuroblastoma. 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 neuroblastoma can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

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 neuroblastoma. 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 physicians. Among them are 97 scientists who have won the Nobel Prize for achievement in medicine.

5

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

10 Neuroblastoma

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 neuroblastoma 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.

·

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

·

Collects and disseminates information on cancer.

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

·

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 neuroblastoma.

What Is Neuroblastoma?7 Neuroblastoma is a solid cancerous tumor that begins in nerve tissue in the neck, chest, abdomen, or pelvis, but usually originates in the abdomen in the tissues of the adrenal gland. By the time it is diagnosed, the cancer usually has spread (metastasized), most commonly to the lymph nodes, liver, lungs, bones, and bone marrow. Neuroblastoma is predominantly a tumor of early childhood; two thirds of children with neuroblastoma are diagnosed when they are younger than 5 years of age. It is often present at birth but usually is not detected until later; in rare cases, neuroblastoma can be detected before birth by fetal ultrasound. The most common symptoms of neuroblastoma are the result of pressure by the tumor or bone pain from cancer that has spread to the bone. Protruding eyes and dark circles around the eyes are common and are caused by cancer that has spread to the area behind the eye. Neuroblastomas may compress the spinal cord, causing paralysis. Fever, anemia, and high blood pressure are found occasionally. Rarely, children may have severe watery diarrhea, uncoordinated or jerky muscle movements, or uncontrollable eye movement.

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

12 Neuroblastoma

If your child has symptoms that may be caused by neuroblastoma, his or her doctor will conduct a careful examination and order laboratory tests and special x-rays. A computed tomographic (CT) scan, a diagnostic test that uses computers and x-rays to create pictures of the body, may be performed. A magnetic resonance imaging (MRI) scan, a diagnostic test similar to a CT scan, but which uses magnetic waves instead of x-rays, may also be performed. Often, removal of tissue from the tumor and/or bone marrow is required to determine whether neuroblastoma exists. A small sample of the tissue may be surgically removed and examined under a microscope. This is called a biopsy. Sometimes a biopsy is done by making a small hole and using a needle to extract a sample of the tissue. Your child’s chance of recovery (prognosis) and choice of treatment depend on the stage of your child’s cancer (how far the cancer has spread), your child’s age at diagnosis, the location of the tumor, and evaluation of the tumor cells under a microscope.

Stage Information Once neuroblastoma is found, more tests will be done to find out if the cancer has spread from where it started to surrounding tissues or other parts of the body. This is called staging. Your child’s doctor needs to know the stage of the disease to plan treatment. Although there are several staging systems currently available for neuroblastoma, for the purposes of treatment the disease is categorized as follows: Localized Resectable The cancer is confined to the site of origin, there is no evidence of spread, and the cancer can be surgically removed. Localized Unresectable The cancer is confined to the site of origin, but the cancer cannot be completely removed surgically.

Guidelines 13

Regional The cancer has extended beyond the site of origin to regional lymph nodes and/or surrounding organs or tissues, but has not spread to distant parts of the body.

Disseminated The cancer has spread from the site of origin to distant lymph nodes, bone, liver, skin, bone marrow, and/or other organs (except as defined for stage 4S). Stage 4S Stage 4S neuroblastoma is also called “special” neuroblastoma because it is treated differently. The cancer is localized, with dissemination (spread) limited to liver, skin, and/or, to a very limited extent, bone marrow. Recurrent Recurrent neuroblastoma means that the cancer has come back (recurred) or continued to spread (progressed) after it has been treated. It may come back in the original site or in another part of the body.

Treatment Option Overview There are treatments for all children with neuroblastoma. Treatment options are related to age at diagnosis, tumor location, stage of disease, regional lymph node involvement, and tumor biology. Four types of treatment are used: ·

Surgery (removing the tumor in an operation)

·

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

·

Chemotherapy (using drugs to kill cancer cells and shrink tumors)

·

Bone marrow transplantation (replacing the patient’s bone marrow with healthy bone marrow)

14 Neuroblastoma

More than one method of treatment may be used, depending on the needs of the patient.

Surgery Surgery is used when possible to remove as much of the cancer as possible. If the cancer cannot be removed, surgery may be limited to a biopsy of the cancer.

Radiation Therapy Radiation therapy uses high-energy rays (radiation) to damage or kill cancer cells and shrink tumors. Radiation usually comes from a machine outside the body (external beam radiation therapy). Chemotherapy Chemotherapy is the use of drugs to kill cancer cells and shrink tumors. Chemotherapy drugs may be taken by mouth or injected into a vein (intravenous) or a muscle. Chemotherapy is called a systemic treatment because the drug enters the bloodstream, travels through the body, and can kill cancer cells throughout the body. Chemotherapy may be given after the tumor has been surgically removed to kill any remaining cancer cells; this is called adjuvant chemotherapy. Chemotherapy can also be given before surgery to shrink the cancer so that it can be removed during surgery; this is called neoadjuvant chemotherapy. Bone Marrow Transplantation Bone marrow transplantation is a procedure in which healthy bone marrow is given to replace bone marrow destroyed by treatment with high doses of anticancer drugs or radiation. Transplantation may be autologous (the patient’s own marrow saved earlier and possibly treated with drugs to kill any cancer cells), allogeneic (marrow from a healthy “matched” donor, usually a brother or sister), or syngeneic (marrow from an identical twin).

Guidelines 15

Treatment by Stage For the purposes of treatment presented here, neuroblastoma is categorized as localized resected, localized unresected, regional, disseminated, and special. Your child may receive treatment that is considered standard based on its effectiveness in a number of people in past studies, or you may choose to enter your child in 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 people with cancer. Clinical trials are ongoing in most parts of the country for most stages of neuroblastoma. If you want more information, call the Cancer Information Service at 1-800-4CANCER (1-800-422-6237); TTY at 1-800-332-8615.

Localized Resectable Neuroblastoma Your child’s treatment may be one of the following: ·

Surgery to remove the cancer.

·

Surgery plus adjuvant chemotherapy.

·

Surgery plus radiation therapy.

Localized Unresectable Neuroblastoma Initial treatment generally consists of surgical removal of as much of the cancer as possible followed by chemotherapy. A second surgery may be performed to remove any cancer that remains, and radiation therapy may then be given.

Regional Neuroblastoma Treatment depends on your child’s age. If your child is younger than 1 year of age, treatment may include the following: ·

Surgery to remove the cancer.

·

Chemotherapy.

16 Neuroblastoma

If your child is older than 1 year of age, treatment may be one of the following: ·

Surgery to remove the cancer.

·

Surgery followed by chemotherapy.

·

Chemotherapy with or without radiation therapy to reduce the tumor, followed by surgery.

·

Multi-drug chemotherapy.

·

Radiation therapy.

·

A clinical trial of new methods of treatment. Listings of current clinical trials are available on PDQ or by calling the National Cancer Institute’s Cancer Information Service at 1-800-4-CANCER.

Disseminated Neuroblastoma Your child’s treatment may be one of the following: ·

Multi-drug chemotherapy with or without surgery and/or radiation therapy.

·

Chemotherapy followed by peripheral stem cell transplantation and 13cis retinoic acid.

·

A clinical trial of new methods of treatment. Listings of current clinical trials are available on PDQ or by calling the National Cancer Institute’s Cancer Information Service at 1-800-4-CANCER.

Stage 4S Neuroblastoma Children with this special type of neuroblastoma may not require therapy. You may want to have your child take part in a clinical trial of new methods of treatment. Listings of current clinical trials are available on PDQ or by calling the National Cancer Institute’s Cancer Information Service at 1-800-4CANCER.

Recurrent Neuroblastoma The selection of treatment of recurrent or progressive neuroblastoma depends on the location and extent of the recurrence or progression and on the previous therapy as well as individual patient considerations. A clinical

Guidelines 17

trial may be appropriate. Listings of current clinical trials are available on PDQ or by calling the National Cancer Institute’s Cancer Information Service at 1-800-4-CANCER.

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.

18 Neuroblastoma

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

Guidelines 19

information summaries. The summaries are reviewed regularly and changes 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

20 Neuroblastoma

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 neuroblastoma 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 neuroblastoma. 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 neuroblastoma. 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. Recently, MEDLINEplus listed the following as being relevant to neuroblastoma: ·

Guides On Neuroblastoma Neuroblastoma http://www.nlm.nih.gov/medlineplus/neuroblastoma.html Neuroblastoma http://www.nlm.nih.gov/medlineplus/ency/article/001408.htm

·

Guides on Human Anatomy and Systems Cancers Topics http://www.nlm.nih.gov/medlineplus/cancers.html

Guidelines 21

·

Other Guides Ganglioneuroblastoma http://www.nlm.nih.gov/medlineplus/ency/article/001436.htm

Within the health topic page dedicated to neuroblastoma, the following was recently recommended to parents: ·

General/Overviews What Is Neuroblastoma? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_1X_What_is_neuroblastoma_31?sitearea=&level=

·

Diagnosis/Symptoms Can Neuroblastoma Be Found Early? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_3X_Can_neuroblastoma_be_found_early_31?sitearea=&level= Gene Chips Accurately Diagnose Four Complex Childhood Cancers Source: National Human Genome Research Institute http://www.nih.gov/news/pr/may2001/nhgri-30.htm How Is Neuroblastoma Diagnosed? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_3X_How_is_neuroblastoma_diagnosed_31?sitearea=&level= How Is Neuroblastoma Staged? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_3X_How_is_neuroblastoma_staged_31?sitearea=&level=

·

Treatment Neuroblastoma (PDQ): Treatment Source: National Cancer Institute http://www.cancer.gov/cancer_information/doc_pdq.aspx?version= patient&viewid=eb787dfc-d074-4716-9284-be3281d0018c

22 Neuroblastoma

·

Nutrition Nutrition for Children with Cancer Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/PED/PED_3_1_nutrit ion_for_children_with_cancer?

·

Specific Conditions/Aspects Do We Know What Causes Neuroblastoma? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_2X_Do_we_know_what_causes_neuroblastoma_31?sitearea=PED What are the Differences Between Cancers in Adults and in Children? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_1X_What_are_the_differences_between_cancers_in_adults_and_in_ children_31?sitearea=&level= What Should You Ask Your Child's Doctor About Neuroblastoma? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_5X_What_should_you_ask_your_physician_about_neuroblastoma_ 31?sitearea=CRI Young People with Cancer: A Handbook for Parents Source: National Cancer Institute http://www.cancer.gov/templates/page_print.aspx?viewid=2944f6e 7-996c-47b0-ad4e-23d8fbe9e033

·

From the National Institutes of Health Neuroblastoma Source: National Cancer Institute http://www.cancer.gov/cancer_information/cancer_type/neuroblas toma/

·

Organizations American Cancer Society http://www.cancer.org/ National Cancer Institute http://www.cancer.gov/

Guidelines 23

·

Prevention/Screening Neuroblastoma (PDQ): Screening Source: National Cancer Institute http://www.nci.nih.gov/cancerinfo/pdq/screening/neuroblastoma /patient/ What Are the Risk Factors For Neuroblastoma? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_2X_What_are_the_risk_factors_for_neuroblastoma_31?sitearea=PE D

·

Research What's New in Neuroblastoma Research and Treatment? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_6X_Whats_new_in_neuroblastoma_research_and_treatment_31?site area=CRI

·

Statistics What Are the Key Statistics About Neuroblastoma? Source: American Cancer Society http://www.cancer.org/eprise/main/docroot/CRI/content/CRI_2_ 4_1X_What_are_the_key_statistics_for_neuroblastoma_31?sitearea=&l evel=

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.

24 Neuroblastoma

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 “neuroblastoma” or synonyms.

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 neuroblastoma. 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.

PEDBASE Similar to NORD, PEDBASE covers relatively rare disorders, limited mainly to pediatric conditions. PEDBASE was designed by Dr. Alan Gandy. To access the database, which is more oriented to researchers than parents, you can view the current list of conditions covered at the following Web site: http://www.icondata.com/health/pedbase/pedlynx.htm. 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

·

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

·

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

Guidelines 25

·

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

·

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

·

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

·

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

·

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: Abdomen: The part of the body that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [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] Allogeneic: Taken from different individuals of the same species. [NIH] Anemia: A condition in which the number of red blood cells is below normal. [NIH] 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, 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] 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] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH]

26 Neuroblastoma

Gallium: A rare, metallic element designated by the symbol, Ga, atomic number 31, and atomic weight 69.72. [NIH] Ganglioneuroblastoma: A moderately malignant neoplasm composed of primitive neuroectodermal cells dispersed in myxomatous or fibrous stroma intermixed with mature ganglion cells. It may undergo transformation into a neuroblastoma. It arises from the sympathetic trunk or less frequently from the adrenal medulla, cerebral cortex, and other locations. Cervical ganglioneuroblastomas may be associated with HORNER SYNDROME and the tumor may occasionally secrete vasoactive intestinal peptide, resulting in chronic diarrhea. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Intravenous: IV. Into a vein. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [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] MRI: Magnetic resonance imaging (mag-NET-ik REZ-o- nans IM-a-jing). A procedure in which a magnet linked to a computer is used to create detailed pictures of areas inside the body. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [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] Paralysis: Loss of ability to move all or part of the body. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH]

Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] 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] Recurrence: The return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH]

Guidelines 27

Resected: Surgical removal of part of an organ. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [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

Unresectable: Unable to be surgically removed. [NIH]

Seeking Guidance 29

CHAPTER 2. SEEKING GUIDANCE Overview Some parents are comforted by the knowledge that a number of organizations dedicate their resources to helping people with neuroblastoma. 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 Neuroblastoma 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

30 Neuroblastoma

·

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) 458-6223 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

·

National Childhood Cancer Foundation Address: National Childhood Cancer Foundation 440 East Huntington Drive, Suite 300, Arcadia, CA 91066-6012 Telephone: (626) 447-1674 Toll-free: (800) 458-6223 Fax: (626) 447-6359 Email: nccf- [email protected] Web Site: http://www.nccf.org/nccf/ Background: The National Childhood Cancer Foundation (NCCF) is a charitable foundation that supports pediatric cancer treatment and research projects at over 115 pediatric medical institutions in the United States, Canada, and Australia. This network of pediatric medical institutions and over 2,800 pediatric cancer specialists is known as the Children's Cancer Group (CCG), a national cooperative research organization that was founded in 1955 to promote the development of new treatments and cures for cancers affecting children and young adults. The National Childhood Cancer Foundation, which was established in 1990 as the sponsor of the CCG, seeks grants, gifts, and bequests from individuals, foundations, corporations, and other

Seeking Guidance 31

organizations to support research, education, and advocacy for the needs of children with cancer. The NCCF's mission is to reduce and eventually eliminate the impacts of cancer that affect children and young adults. The Foundation works to accomplish its mission by supporting cooperative laboratory and clinical research that is designed to improve the treatment, survival, and cure of cancer; to discover new agents for treatment; and to obtain and apply new scientific information on the biology, causes, and possible prevention of cancers of infants, children, adolescents, and young adults. The NCCF is also committed to improving access to state-of-the-art interdisciplinary team care of children and young adults with cancer and advocating for the needs of patients and the institutions providing such care. The National Childhood Cancer Foundation also has a web site that enables visitors to locate CCG institutions and CCG clinical trial protocols. The site also provides facts about childhood cancer, press releases, and links to other information sources. Relevant area(s) of interest: Neuroblastoma ·

Neuroblastoma Children's Cancer Society Address: Neuroblastoma Children's Cancer Society P.O. Box 957672, Hoffman Estates, IL 60195 Telephone: (847) 490-4240 Toll-free: (800) 532-5162 Fax: (847) 490-0705 Email: None. Web Site: http://www.granitewebworks.com/nccs.htm Background: The Neuroblastoma Children's Cancer Society is a not-forprofit voluntary organization dedicated to significantly accelerating potential cures for neuroblastoma and its related children's cancers and to improve the quality of life of affected individuals and their families. The organization is an advocate for children and their families and is dedicated to providing support in the following ways: promoting research by highly trained medical professionals; providing research grant awards to medical specialists locally and nationwide; educating health care professionals on early detection and the latest advances in treatments and diagnosis; maintaining updated information on current treatment and diagnosis; maintains updated information on current treatments; providing moral, practical, and emotional support for affected individuals and their families through newsletters, Internet interaction, toll-free telephone support, etc.; and providing a resource booklet that lists non- profit organizations and other resources that offer support for affected families. Consisting of 500 members, the Society

32 Neuroblastoma

produces educational materials including a resource handbook and a newsletter entitled 'HOPE for Families and Friends of Children With Neuroblastoma.'. Relevant area(s) of interest: Neuroblastoma ·

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) 458-6223 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

Seeking Guidance 33

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 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 neuroblastoma. 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 “neuroblastoma” (or a synonym) or the name of a topic, and the site will list information contained in the database on all relevant organizations.

34 Neuroblastoma

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 “neuroblastoma”. 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 “neuroblastoma” (or synonyms) into the “For these words:” box, you will only receive results on organizations dealing with neuroblastoma. 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 “neuroblastoma” (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.

9

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

Seeking Guidance 35

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. 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.

36 Neuroblastoma

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. 10

This section has been adapted from the NCI: http://cis.nci.nih.gov/fact/2_5.htm.

Seeking Guidance 37

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,

·

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

·

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– 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;

·

Written materials from the NCI;

·

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

·

Assistance in quitting smoking from information specialists trained in smoking cessation counseling.

38 Neuroblastoma

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;

·

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

·

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.

·

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.

·

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

·

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

Seeking Guidance 39

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. 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.

11

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

40 Neuroblastoma

·

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.

Seeking Guidance 41

·

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 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

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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).

12

Adapted from the NCI: http://cis.nci.nih.gov/fact/7_47.htm.

Seeking Guidance 43

·

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 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

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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?

13 This

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

Seeking Guidance 45

·

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?

·

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).

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. 14

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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.

·

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 neuroblastoma.

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 This section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm. 16 This section was adapted from the NCI: http://www.cancer.gov/CancerInformation/youngpeople. 15

Seeking Guidance 47

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.

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?

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

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·

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. 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.

Seeking Guidance 49

·

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. 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.

18

This section has been adapted from the NCI: http://cis.nci.nih.gov/fact/1_21.htm.

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·

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

Seeking Guidance 51

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.

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

52 Neuroblastoma

Vocabulary Builder 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] 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] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [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 53

CHAPTER 3. CLINICAL TRIALS AND NEUROBLASTOMA 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 neuroblastoma.

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 neuroblastoma 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

54 Neuroblastoma

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 neuroblastoma.

·

Phase III. Finally, researchers conduct Phase III trials to find out how new treatments for neuroblastoma 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 neuroblastoma 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 neuroblastoma. In other clinical trials, where a new surgery or device (not a medicine) is being tested, patients in the control group may receive a “sham treatment.”

Clinical Trials 55

This treatment, like a placebo, has no effect on neuroblastoma 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 neuroblastoma 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 neuroblastoma. 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.

56 Neuroblastoma

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 Neuroblastoma 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 neuroblastoma.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. ·

Antineoplaston Therapy in Treating Recurrent, or Refractory Neuroblastoma

Patients With Metastatic,

Condition(s): recurrent neuroblastoma; disseminated neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma; regional neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Burzynski Research Institute Purpose - Excerpt: RATIONALE: Antineoplastons are naturally occurring substances found in urine. Antineoplastons may inhibit growth of cancer cells. PURPOSE: Phase II trial to study the effectiveness of antineoplaston therapy in treating patients who have metastatic, recurrent, or refractory neuroblastoma. Phase(s): Phase II 20

These are listed at www.ClinicalTrials.gov.

Clinical Trials 57

Study Type: Treatment Contact(s): Texas; Burzynski Research Institute, Houston, Texas, 77055, United States; Recruiting; Stanislaw R. Burzynski 713-335-5697. Study chairs or principal investigators: Stanislaw R. Burzynski, Study Chair; Burzynski Research Institute Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003513;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Arsenic Trioxide in Treating Patients With Advanced Neuroblastoma or Other Childhood Solid Tumors Condition(s): childhood soft tissue sarcoma; childhood liver cancer; bone cancer; brain tumor; eye cancer; kidney tumor Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Memorial Sloan-Kettering Cancer Center Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. PURPOSE: Phase II trial to study the effectiveness of arsenic trioxide in treating children who have advanced neuroblastoma or other solid tumors. Phase(s): Phase II Study Type: Treatment Contact(s): New York; Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States; Recruiting; Brian H. Kushner 212639-6793. Study chairs or principal investigators: Brian H. Kushner, Study Chair; Memorial Sloan-Kettering Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00024258;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

beta-Glucan and Monoclonal Antibody in Treating Patients With Metastatic Neuroblastoma Condition(s): disseminated neuroblastoma; recurrent neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Memorial Sloan-Kettering Cancer Center

58 Neuroblastoma

Purpose - Excerpt: RATIONALE: Biological therapies such as beta-glucan use different ways to stimulate the immune system and stop cancer cells from growing. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining beta-glucan and monoclonal antibody may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of combining beta-glucan and monoclonal antibody in treating patients who have metastatic neuroblastoma. Phase(s): Phase I Study Type: Treatment Contact(s): New York; Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States; Recruiting; Nai-Kong V. Cheung 212-639-8401. Study chairs or principal investigators: Nai-Kong V. Cheung, Study Chair; Memorial Sloan-Kettering Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00037011;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Biological Therapy in Treating Children With Refractory or Recurrent Neuroblastoma or Other Tumors Condition(s): recurrent childhood soft tissue sarcoma; recurrent osteosarcoma; unspecified childhood solid tumor, protocol specific; metastatic osteosarcoma; recurrent neuroblastoma; recurrent melanoma; metastatic childhood soft tissue sarcoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Children's Oncology Group Purpose - Excerpt: RATIONALE: Biological therapies such as hu14.18interleukin-2 fusion protein use different ways to stimulate the immune system and stop cancer cells from growing. PURPOSE: Phase I trial to study the effectiveness of hu14.18-interleukin-2 fusion protein in treating children who have refractory or recurrent neuroblastoma or other tumors. Phase(s): Phase I Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003750;jsessionid=FB8550 A371C882045C8F9C93E43BC900

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·

Chemotherapy and Radiation Therapy in Treating Infants With Tumors of the Brain Condition(s): childhood choroid plexus tumor; childhood supratentorial ependymoma; childhood central nervous system germ cell tumor; childhood infratentorial ependymoma; regional neuroblastoma; localized resectable neuroblastoma; localized unresectable neuroblastoma; untreated childhood supratentorial primitive neuroectodermal tumors; untreated childhood medulloblastoma; newly diagnosed childhood ependymoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Pediatric Brain Tumor Consortium 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. Combining radiation therapy with chemotherapy may kill more tumor cells. PURPOSE: Phase I/II trial to study the effectiveness of chemotherapy and radiation therapy in treating infants who have tumors of the brain. Phase(s): Phase I; Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00005063;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

Chemotherapy and Surgery Followed by Peripheral Stem Cell Transplantation in Treating Patients With Metastatic Neuroblastoma Condition(s): stage 4S neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): United Kingdom Children's Cancer Study Group; Societe Francaise Oncologie Pediatrique Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs to kill more tumor cells. Chemotherapy, given before and after surgery, followed by peripheral stem cell transplantation may be an effective treatment for metastatic neuroblastoma. PURPOSE: Phase II trial to study the effectiveness of

60 Neuroblastoma

chemotherapy, given before and after surgery, followed by peripheral stem cell transplantation in treating patients who have metastatic neuroblastoma. Phase(s): Phase II; MEDLINEplus consumer health information Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00024193;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

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 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=FB8550 A371C882045C8F9C93E43BC900

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·

Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Central Nervous System Cancer Condition(s): adult central nervous system germ cell tumor; adult medulloblastoma; adult oligodendroglioma; recurrent adult brain tumor; adult anaplastic astrocytoma; recurrent esthesioneuroblastoma of the paranasal sinus and nasal cavity; primary central nervous system lymphoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Comprehensive Cancer Center

Institute

(NCI);

Herbert

Irving

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 chemotherapy combined with peripheral stem cell transplantation in treating patients who have central nervous system cancer. Phase(s): Phase II Study Type: Treatment Contact(s): New York; Herbert Irving Comprehensive Cancer Center, New York, New York, 10032, United States; Recruiting; Charles S. Hesdorffer 212-305-4907. Study chairs or principal investigators: Charles S. Hesdorffer, Study Chair; Herbert Irving Comprehensive Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00007982;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Chemotherapy, Radiation Therapy, and Monoclonal Antibody Therapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; localized resectable neuroblastoma; recurrent neuroblastoma; peripheral blood stem cell transplantation; localized unresectable neuroblastoma; stage 4S neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Gesellschaft fur Padiatrische Onkologie und Hamatologie Germany Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or

62 Neuroblastoma

die. Radiation therapy uses high-energy x-rays to damage tumor cells. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy used to kill tumor cells. Combining these therapies may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining chemotherapy, radiation therapy, and monoclonal antibody therapy with or without peripheral stem cell transplantation in treating patients who have neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00017225;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

CHP677: I-Metaiodobenzylguanidine (I-MIBG) therapy for refractory neuroblastoma: a Phase II study Condition(s): Neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: 131I-metaiodobenzylguanidine (131I-MIBG) is a norepinephrine analog that concentrates in adrenergic tissue and therefore holds promise for cell-specific treatment of neuroblastoma. This is a dual institution, Phase II study of 131I-MIBG administered at the previously defined maximum practical dose of 18 mCi/kg to children with relapsed or refractory neuroblastoma. Phase(s): Phase II Study Type: Interventional Contact(s): Pennsylvania; Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, United States; Recruiting; John M. Maris, M.D. 215-590-5242 Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00013806;jsessionid=FB8550 A371C882045C8F9C93E43BC900

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·

Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; localized resectable neuroblastoma; recurrent neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Pediatric Oncology Group; Children's Cancer Group 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: Randomized phase III trial to compare the effectiveness of peripheral stem cell transplantation using either treated or untreated peripheral stem cells following combination chemotherapy in treating patients who have neuroblastoma. Phase(s): Phase III Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00004188;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

Combination Chemotherapy Before Surgery in Treating Children With Localized Neuroblastoma Condition(s): localized unresectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Societe Internationale d'Oncologie Pediatrique; United Kingdom Children's Cancer Study Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving chemotherapy drugs before surgery may shrink the tumor so that it can be removed during surgery. PURPOSE: Phase III trial to determine the effectiveness of combination chemotherapy given before surgery in treating children who have localized neuroblastoma. Phase(s): Phase III Study Type: Treatment Contact(s): see Web site below

64 Neuroblastoma

Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00025428;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Combination Chemotherapy Followed by Surgery and Peripheral Stem Cell or Bone Marrow Transplantation in Treating Infants With Newly Diagnosed Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; localized resectable neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): European Infant Neuroblastoma Study 1999 Group 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 or 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 given before surgery followed by peripheral stem cell or bone marrow transplantation in treating infants who have newly diagnosed neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00025649;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

Combination Chemotherapy Followed by Surgery in Treating Infants With Newly Diagnosed Neuroblastoma Condition(s): disseminated neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): European Infant Neuroblastoma Study 1999 Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug, and giving them before surgery, may shrink the tumor so that it can be removed during surgery. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy followed by surgery in treating infants who have newly diagnosed neuroblastoma.

Clinical Trials 65

Phase(s): Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00025623;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Combination Chemotherapy Followed by Surgery in Treating Infants With Newly Diagnosed Neuroblastoma. Condition(s): localized unresectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): European Infant Neuroblastoma Study 1999 Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving a chemotherapy drug before surgery may shrink the tumor so that it can be removed during surgery. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy followed by surgery in treating infants who have newly diagnosed neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00025597;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

Combination Chemotherapy in Treating Children With Neuroblastoma Condition(s): disseminated neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma; regional neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Pediatric Oncology Group; Children's Cancer Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Combination chemotherapy plus surgery may be an effective treatment for neuroblastoma. PURPOSE: Phase III trial to determine the effectiveness of combination chemotherapy consisting of carboplatin,

66 Neuroblastoma

etoposide, cyclophosphamide, and doxorubicin, followed by surgery to remove the tumor, in treating young patients with neuroblastoma. Phase(s): Phase III Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003093;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Combination Chemotherapy Diagnosed Neuroblastoma

in

Treating

Infants

With

Newly

Condition(s): disseminated neuroblastoma; stage 4S neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): European Infant Neuroblastoma Study 1999 Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of different combination chemotherapy regimens in treating infants who have newly diagnosed neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00025610;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Combination Chemotherapy With or Without Filgrastim Before Surgery, High-Dose Chemotherapy, and Radiation Therapy Followed by Isotretinoin With or Without Monoclonal Antibody in Treating Patients With Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Societe Internationale d'Oncologie Pediatrique Purpose - Excerpt: RATIONALE: Colony-stimulating factors such as filgrastim may increase the number of immune cells found in bone marrow or peripheral blood and may help a person's immune system

Clinical Trials 67

recover from the side effects of chemotherapy. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining isotretinoin and monoclonal antibodies may kill any remaining tumor cells following surgery. It is not yet known which treatment regimen is more effective in treating neuroblastoma. PURPOSE: Randomized phase III trial to determine the effectiveness of combination chemotherapy with or without filgrastim before surgery, high-dose chemotherapy, and radiation therapy followed by isotretinoin with or without monoclonal antibody in treating patients who have neuroblastoma. Phase(s): Phase III Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00030719;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Isotretinoin With or Without Monoclonal Antibody, Interleukin 2, and Sargramostim Following Stem Cell Transplantation in Treating Patients With Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Children's Oncology Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Interleukin-2 and sargramostim may stimulate a person's white blood cells to kill cancer cells. It is not yet known if chemotherapy is more effective with or without monoclonal antibody therapy, interleukin 2, and sargramostim following stem cell transplantation in treating neuroblastoma. PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy with or without monoclonal antibody, interleukin-2, and sargramostim following stem cell transplantation in treating patients who have neuroblastoma. Phase(s): Phase III

68 Neuroblastoma

Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00026312;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Melphalan and Buthionine Sulfoximine Followed by Bone Marrow or Peripheral Stem Cell Transplantation in Treating Children With Recurrent or Refractory Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; recurrent neuroblastoma; localized unresectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Children's Hospital Los Angeles 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 bone marrow or peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of melphalan and buthionine sulfoximine followed by bone marrow or peripheral stem cell transplantation in treating children who have recurrent or refractory neuroblastoma. Phase(s): Phase I Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00005835;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

Monoclonal Antibody Therapy Plus Etoposide in Treating Patients With Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; recurrent neuroblastoma; localized unresectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Memorial Sloan-Kettering Cancer Center Purpose - Excerpt: RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor killing substances to them

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without harming normal cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining monoclonal antibody therapy with chemotherapy may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of monoclonal antibody therapy plus etoposide in treating patients who have neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): New York; Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States; Recruiting; Nai-Kong V. Cheung 212-639-8401. Study chairs or principal investigators: Nai-Kong V. Cheung, Study Chair; Memorial Sloan-Kettering Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00004110;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Monoclonal Antibody Therapy Plus Sargramostin in Treating Patients With Advanced Neuroblastoma Condition(s): recurrent neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Memorial Sloan-Kettering Cancer Center Purpose - Excerpt: RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining colony-stimulating factors, such as sargramostim, with monoclonal antibodies may be an effective treatment for advanced neuroblastoma. PURPOSE: Phase II trial to study the effectiveness of monoclonal antibody 3F8 plus sargramostim in treating patients who have advanced neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): New York; Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States; Recruiting; Brian H. Kushner 212639-6793. Study chairs or principal investigators: Brian H. Kushner, Study Chair; Memorial Sloan-Kettering Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00002560;jsessionid=FB8550 A371C882045C8F9C93E43BC900

70 Neuroblastoma

·

Multiple Therapies Neuroblastoma

in

Treating

Patients

With

Advanced

Condition(s): disseminated neuroblastoma; regional neuroblastoma; recurrent neuroblastoma; localized unresectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Memorial Sloan-Kettering 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. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage tumor cells. Biological therapies use different ways to stimulate the immune system and stop cancer cell from growing. Combining different types of therapies may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining chemotherapy, monoclonal antibody therapy, surgery, peripheral stem cell transplantation, radiation therapy, and biological therapy in treating patients who have advanced neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): New York; Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States; Recruiting; Nai-Kong V. Cheung 212-639-8401. Study chairs or principal investigators: Nai-Kong V. Cheung, Study Chair; Memorial Sloan-Kettering Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00040872;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Neuroblastoma Vaccine for Treatment of High-Risk Neuroblastoma After Chemotherapy Condition(s): Neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Baylor College of Medicine; Texas Children's Hospital Purpose - Excerpt: PRIMARY OBJECTIVE To determine the percentage of patients with high risk neuroblastoma in first or subsequent partial response or better, or with microscopic residual bone marrow disease,

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who demonstrate an immunological anti-tumor response at any time during, and for up to 12 months from initiation of, treatment with subcutaneous injections of autologous neuroblastoma cells, genetically modified by adenoviral vectors to secrete interleukin-2 (IL-2) (autologous neuroblastoma vaccine) SECONDARY OBJECTIVES 1. To determine the toxicity of the autologous neuroblastoma vaccine given according to this schedule 2. To obtain preliminary data on the effect of vaccine administration on progression-free survival from high-risk neuroblastoma Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): Heidi V Russell, MD 832-822-4885 [email protected]; Texas; Texas Children's Hospital, Houston, Texas, 77030, United States; Recruiting; Heidi V Russell, MD 832-822-4885 [email protected]. Study chairs or principal investigators: Heidi V Russell, MD, Principal Investigator; Baylor College of Medicine Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00048386;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

P-glycoprotein Antagonist, Tariquidar, in Combination with Doxorubicin (Adriamycin), Vinorelbine (Navelbine), or Docetaxel to Treat Children with Solid Tumors Condition(s): Brain Rhabdomyosarcoma

Tumor;

Ewing's

Sarcoma;

Neuroblastoma;

Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This study will examine the safety and side effects of tariquidar in children and adolescents with cancer and test whether it can improve current anticancer drug treatments. Tumor resistance to chemotherapy is a major problem in cancer treatment. Studies have found that a protein (P-glycoprotein) on some cancer cells pumps anticancer drugs out of the cells, reducing treatment effectiveness. In laboratory tests, an experimental drug called tariquidar has blocked pumping by this protein. It is being used in this study to try to increase amounts of the anticancer drugs vinorelbine (Navelbinea), doxorubicin (Adriamycin) or docetaxel (Taxotere) in cancer cells. Patients between 2 and 18 years of age with solid tumors-including rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, liver tumors, germ cell

72 Neuroblastoma

tumors, and primary brain tumors-who have relapsed or who do not respond to frontline therapy and have no other treatment options may be eligible for this study. Candidates will be screened with a medical history, physical and neurological examinations, blood and urine tests, electrocardiogram, MUGA (nuclear medicine scan of the heart) and radiologic studies to evaluate the extent of disease. Participants will receive tariquidar plus either doxorubicin, vinorelbine or docetaxel, depending on the type of cancer, previous treatments, and side effects of prior treatment. Patients taking doxorubicin will also receive GCSF, a drug that helps boost the immune system, and dexrazoxane, a medicine to lessen the harmful effects of doxorubicin on the heart. Patients taking docetaxel will also receive GCSF, plus medicines to prevent an allergic reaction to the docetaxel. Treatment will be given in 21-day cycles for no more than eight cycles. The first treatment cycle for each regimen begins with a baseline Sestamibi scan-an imaging procedure that uses the radioactive drug Tc-99m Sestamibi. This drug accumulates in tumor cells and is eliminated from them in much the same way that some cancer drugs are eliminated from cells. The drug is injected into a vein and a series of pictures taken with a camera that detects radioactivity shows where the radioactive Sestamibi distributes in the body, including in the cancer, liver and heart. This procedure can monitor for effects of tariquidar on resistance to therapy. The day after the Sestamibi scan, tariquidar is given intravenously (through a vein), followed by another Sestamibi scan. On the third day, tariquidar is given, followed by the treatment drug (doxorubicin, vinorelbine or docetaxel). Patients taking vinorelbine will repeat the tariquidar and vinorelbine doses 1 week after the first. Sestamibi scans are done during the first treatment cycle only for each drug regimen. In addition, for the first treatment cycle only, 17 blood samples of less than one-half teaspoon each are drawn to study the pharmacology of tariquidar (i.e., how the drug works in the body), and another 17 samples are taken to study the pharmacology of the chemotherapy drug. A device, such as a heparin lock, is put in place to avoid having multiple needlesticks for these blood draws. Routine blood tests are done twice a week and various tests, such as X-rays, CT and MRI scans are done periodically to follow the progress of the cancer throughout the treatment period. Patients taking doxorubicin will also have an echocardiogram or MUGA to evaluate heart function. Patients are examined by a doctor at least once a week. Phase(s): Phase I Study Type: Interventional

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Contact(s): Maryland; National Cancer Institute (NCI), 9000 Rockville Pike Bethesda, Maryland, 20892, United States; Recruiting; Elizabeth Fox, M.D. 3014026641 [email protected] Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00011414;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Phase I Trial of ABT-751 in Children with Solid Tumors Condition(s): Neoplasms Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: This study will determine the side effects and maximum tolerated dose of the experimental drug ABT-751 that can be safely given to children and young adults with solid tumors. ABT-751 belongs to a new class of anticancer drugs that hamper the replication of cancer cells. It works by binding to a protein called tubulin. Other drugs that work this way include vincristine, vinblastine, vinorelbine, paclitaxel, and docetaxel. In laboratory studies, ABT-751 kills cancer cells that are resistant to vincristine and paclitaxel. Patients up to 18 years of age with solid tumors (rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, liver tumors germ cell tumors, primary brain tumors, and other solid tumors) whose disease has relapsed, or whose tumor no longer responds to standard treatment, may be eligible for this study. Candidates will be screened with a history and physical, and neurological examinations, blood and urine tests, echocardiogram (heart ultrasound), and imaging studies to evaluate the extent of disease. Participants will take one ABT-751 capsule a day for 7 days each treatment cycle. A treatment cycle will be 21 to 28 days, depending on how long it takes the patient to recover from the drug side effects. The drug dose will be increased gradually in successive groups of patients if side effects of the previous dose were acceptable. Patients may continue treatment unless their disease worsens with ABT-751 or irreversible side effects occur. They will undergo the following evaluations during this study: - Physical examinations-weekly - Routine blood tests-twice a week - CT or MRI scans to evaluate the size of the tumor-after the first treatment cycle and then after every other cycle - Echocardiogram to evaluate heart structure and function - before starting treatment and then before every even-numbered cycle (cycle 2, 4, 6, and so on) - Blood tests to study how the body handles ABT-751-during the first treatment cycle. For this test, 8 blood samples of one teaspoon or less each will be drawn

74 Neuroblastoma

on the first day of ABT-751 therapy and one blood sample will be drawn on days 2, 5, and 7 before taking the drug. If possible, blood will be collected through a small plastic catheter placed in a vein (heparin lock or Hickman line or port-a-cath) to avoid multiple needle sticks. - Blood test to study the effects of ABT-751 on normal blood cells. For this test, blood samples of 2 teaspoons or less each will be drawn before the first dose of ABT-751, and 6 and 24 hours after the first dose-first treatment cycle only. - 24-hour urine collection-after the first dose of ABT-751 - Magnetic resonance imaging (MRI) with gadolinium contrast to analyze the effect of ABT-751 on blood flow to the tumor. This test will be done only in some patients. It will be done before starting the first treatment cycle and repeated 2 to 3 days after starting treatment. MRI uses a magnetic field and radio waves to show structural and chemical changes in tissues. For the procedure, the patient lies still on a stretcher that is moved into the MRI scanner (a narrow cylinder containing the magnet). Earplugs are worn to muffle loud noises caused by electrical switching of radio frequency circuits used in the scanning process. A gadolinium contrast material is injected to brighten the images. Phase(s): Phase I Study Type: Interventional Contact(s): Maryland; National Cancer Institute (NCI), 9000 Rockville Pike Bethesda, Maryland, 20892, United States; Recruiting; Wendy Goodspeed, R.N. 3015944762 [email protected] Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00032266;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Radiolabeled Monoclonal Antibody Therapy After Radiation Therapy in Treating Patients With Primary Brain Tumors Condition(s): adult glioblastoma multiforme; adult central nervous system germ cell tumor; adult malignant meningioma; adult pineal parenchymal tumor; adult medulloblastoma; adult noninfiltrating astrocytoma; adult oligodendroglioma; adult anaplastic astrocytoma; mixed gliomas; adult well-differentiated mildly and moderately anaplastic astrocytoma; localized resectable neuroblastoma; adult craniopharyngioma; recurrent adult brain tumor; adult meningioma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Duke Comprehensive Cancer Center

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Purpose - Excerpt: RATIONALE: Monoclonal antibodies can locate tumor cells and deliver tumor-killing substances, such as radioactive iodine, to them without harming normal cells. PURPOSE: Phase I trial to study the effectiveness of radiolabeled monoclonal antibody after radiation therapy in treating patients with newly diagnosed primary brain tumors that can be surgically resected. Phase(s): Phase I; Phase II Study Type: Treatment Contact(s): North Carolina; Duke Comprehensive Cancer Center, Durham, North Carolina, 27710, United States; Recruiting; David Allen Reardon 919-684-5301. Study chairs or principal investigators: Darell D. Bigner, Study Chair; Duke Comprehensive Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003484;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Radiolabeled Monoclonal Antibody Therapy in Treating Patients With Primary or Metastatic Brain Tumors Condition(s): brain metastases; recurrent neuroblastoma; adult glioblastoma multiforme; adult central nervous system germ cell tumor; adult malignant meningioma; adult pineal parenchymal tumor; adult medulloblastoma; adult noninfiltrating astrocytoma; adult oligodendroglioma; adult anaplastic astrocytoma; mixed gliomas; adult well-differentiated mildly and moderately anaplastic astrocytoma; localized resectable neuroblastoma; adult craniopharyngioma; recurrent adult brain tumor; adult meningioma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Duke Comprehensive Cancer Center Purpose - Excerpt: RATIONALE: Radiolabeled monoclonal antibodies can locate tumor cells and deliver radioactive tumor-killing substances to them without harming normal cells. This may be effective treatment for primary or metastatic brain tumors. PURPOSE: Phase I trial to study the effectiveness of radiolabeled monoclonal antibody therapy in treating patients with primary or metastatic brain tumors. Phase(s): Phase I; Phase II Study Type: Treatment Contact(s): North Carolina; Duke Comprehensive Cancer Center, Durham, North Carolina, 27710, United States; Recruiting; David Allen

76 Neuroblastoma

Reardon 919-684-5301. Study chairs or principal investigators: Darell D. Bigner, Study Chair; Duke Comprehensive Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003461;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Rebeccamycin Analog in Treating Children With Relapsed or Refractory Neuroblastoma Condition(s): recurrent neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Memorial Sloan-Kettering Cancer Center Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. PURPOSE: Phase II trial to study the effectiveness of rebeccamycin analog in treating children with relapsed or refractory neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): New York; Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, United States; Recruiting; Tanya Trippett 212639-8267. Study chairs or principal investigators: Tanya Trippett, Study Chair; Memorial Sloan-Kettering Cancer Center Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003737;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

Surgery in Treating Children With Neuroblastoma Condition(s): recurrent neuroblastoma; disseminated neuroblastoma; stage 4S neuroblastoma; localized resectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): National Cancer Institute (NCI); Children's Cancer Group; Pediatric Oncology Group Purpose - Excerpt: RATIONALE: Surgery alone may be effective in treating children with neuroblastoma. PURPOSE: Phase III trial to study the effectiveness of surgery alone in treating children who have neuroblastoma. Phase(s): Phase III Study Type: Treatment

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003119;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

Surgery in Treating Patients With Neuroblastoma Condition(s): localized unresectable neuroblastoma; localized resectable neuroblastoma Study Status: This study is currently recruiting patients. Sponsor(s): Societe Internationale d'Oncologie Pediatrique Purpose - Excerpt: RATIONALE: Surgery may be an effective treatment for neuroblastoma. PURPOSE: Phase II trial to study the effectiveness of surgery in treating patients who have neuroblastoma. Phase(s): Phase II Study Type: Treatment Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00003122;jsessionid=FB8550 A371C882045C8F9C93E43BC900

·

Corticotropin With or Without Immunoglobulin in Treating Abnormal Muscle Movement in Patients With Neuroblastoma Condition(s): disseminated neuroblastoma; regional neuroblastoma; localized resectable neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma Study Status: This study is not yet open for patient recruitment. Sponsor(s): National Cancer Institute (NCI); Children's Oncology Group Purpose - Excerpt: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Steroid therapy decreases inflammation. Combining chemotherapy and steroid therapy with immunoglobulin may be effective in treating abnormal muscle movement associated with neuroblastoma. PURPOSE: Randomized phase II trial to compare the effectiveness of combining corticotropin with or without immunoglobulin in treating patients who have abnormal trunk muscle movements associated with neuroblastoma. Phase(s): Phase II Study Type: Treatment

78 Neuroblastoma

Contact(s): Gregory H. Reaman 202-884-2147. Study chairs or principal investigators: Gregory H. Reaman, Study Chair; Children's Oncology Group Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00033293;jsessionid=FB8550 A371C882045C8F9C93E43BC900 ·

New Therapeutic Strategies for Patients with Ewing's Sarcoma Family of Tumors, High Risk Rhabdomyosarcoma, and Neuroblastoma Condition(s): Ewing's Sarcoma; Neuroblastoma; Rhabdomyosarcoma Study Status: This study is completed. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: The prognosis for patients with metastatic Ewing's sarcoma family of tumors (ESF), rhabdomyosarcoma (RMS), and neuroblastoma (NBL) remains dismal, with less than 25% long-term disease-free survival. Though less grave, the prognosis for cure for other high-risk patients is approximately 50%. New treatment strategies, including the identification of highly active new agents, maximizing the dose intensity of the most active standard drugs, and the development of improved methods of consolidation to eradicate microscopic residual disease, are clearly needed to improve the outcome of these patients. This protocol will address these issues by commencing with a Phase II window, for the highest risk patients, to evaluate a series of promising drugs with novel mechanisms of action. All patients will then receive 5 cycles of dose-intensive "best standard therapy" with doxorubicin (adriamycin), vincristine, and cyclophosphamide (VAdriaC). Patients at high risk of relapse will continue onto a phase I consolidation regimen consisting of three cycles of dose-escalated Melphalan, Ifosfamide, Mesna, and Etoposide (MIME). Peripheral blood stem cell transfusions (PBSCT) and recombinant human G-CSF will be used as supportive care measures to allow maximal dose-escalation of this combination regimen. Phase(s): Phase II Study Type: Interventional Contact(s): Maryland; National Cancer Institute (NCI), 9000 Rockville Pike Bethesda, Maryland, 20892, United States Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00001335;jsessionid=FB8550 A371C882045C8F9C93E43BC900

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·

Phase I Trial and Pharmacokinetic Study of TLC D-99 in Pediatric Patients with Refractory Solid Tumors Condition(s): Glioma; Neoplasm; Nephroblastoma; Neuroblastoma; Rhabdomyosarcoma Study Status: This study is completed. Sponsor(s): National Cancer Institute (NCI) Purpose - Excerpt: Doxorubicin is one of the most effective and most widely used chemotherapeutic agents in the treatment of childhood cancers. Its broad spectrum of activity includes both hematological malignancies and solid tumors. However, its clinical usefulness is limited by the development of doxorubicin-induced cardiotoxicity, which is related to the cumulative dose of the drug, and children are at higher risk for this cardiotoxicity than are adults. Encapsulation of doxorubicin within liposomes reduces its acute and chronic toxicities, including cardiotoxicity. TLC D-99 is a liposomal formulation of doxorubicin in egg phosphatidylcholine/cholesterol liposomes. Fifteen phase I and phase II clinical trials of TLC D-99 have been conducted in over 400 adults, and 3 randomized phase III trials in women with breast cancer are ongoing (overall more than 700 adults have been treated with TLC D-99). Acute toxicity was less than would have been expected, even at higher than standard doses. A phase I trial and pharmacokinetic study of this liposome encapsulated formulation of doxorubicin will be conducted in children, to assess the drug's spectrum of toxicity at standard doses of doxorubicin and at doses of TLC D-99 that were tolerable in adults. Phase(s): Phase I Study Type: Interventional Contact(s): Maryland; National Cancer Institute (NCI), 9000 Rockville Pike Bethesda, Maryland, 20892, United States Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00001798;jsessionid=FB8550 A371C882045C8F9C93E43BC900

80 Neuroblastoma

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 neuroblastoma. 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 neuroblastoma. 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.

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. 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

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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).

82 Neuroblastoma

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

22

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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.

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.

84 Neuroblastoma

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.

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

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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:

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

86 Neuroblastoma

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;

·

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.

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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 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.

24

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

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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 739 Thimble Shoals Boulevard, Suite 704 Newport News, VA 23606 (757) 873-6668 E-mail: [email protected]

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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.

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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: 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. 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 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 “neuroblastoma” (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

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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/

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

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·

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: Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal cells. [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] Antineoplastons: Substances isolated from normal human blood and urine being tested as a type of treatment for some tumors and AIDS. [NIH] Astrocytoma: A tumor that begins in the brain or spinal cord in small, starshaped cells called astrocytes. [NIH] Carboplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Cardiotoxicity: Toxicity that affects the heart. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH]

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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] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Craniopharyngioma: A benign brain tumor that may be considered malignant because it can damage the hypothalamus, the area of the brain that controls body temperature, hunger, and thirst. [NIH] Cyclophosphamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Dexrazoxane: A drug used to protect the heart from the toxic effects of anthracycline drugs such as doxorubicin. It belongs to the family of drugs called chemoprotective agents. [NIH] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH] Doxorubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. It is an anthracycline. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH] Etoposide: An anticancer drug that is a podophyllotoxin derivative and belongs to the family of drugs called mitotic inhibitors. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Gadolinium: Gadolinium. An element of the rare earth family of metals. It has the atomic symbol Gd, atomic number 64, and atomic weight 157.25. Its oxide is used in the control rods of some nuclear reactors. [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] Heparin: A drug that helps prevent blood clots from forming. It belongs to the family of drugs called anticoagulants (blood thinners). [NIH] Ifosfamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Immunoglobulin: A protein that acts as an antibody. [NIH] Inflammation: A response of redness, swelling, pain, and a feeling of heat in

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certain areas which is meant to protect tissues affected by injury or disease. [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]

Isotretinoin: A drug that belongs to the family of drugs called retinoids. It is used in the treatment of acne and psoriasis and is being studied in cancer prevention. Also called 13-cis retinoic acid. [NIH] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution to the tumor site is improved. [NIH] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lymphoma: Cancer that arises in cells of the lymphatic system. [NIH] Medulloblastoma: A malignant brain tumor that begins in the lower part of the brain and can spread to the spine or to other parts of the body. Medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melphalan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Meningioma: A type of tumor that occurs in the meninges, the membranes that cover and protect the brain and spinal cord. Meningiomas usually grow slowly. [NIH] Mesna: A drug that helps protect the kidneys and bladder from the toxic effects of anticancer drugs such as ifosfamide and cyclophosphamide. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Mime: Facial expression. (NOT: mimicry = adaptation for survival in which an organism takes on the semblance another organism or a non-living object.) [EU] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephroblastoma: A malignant kidney tumor made up of three cell types: blastemal, stromal, and epithelial, but not all present in every case. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic

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sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Oligodendroglioma: A rare, slow-growing tumor that begins in brain cells called oligodendrocytes, which provide support and nourishment for cells that transmit nerve impulses. Also called oligodendroglial tumor. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Paclitaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Radioactive: Giving off radiation. [NIH] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] Radiolabeled: Any compound that has been joined with a radioactive substance. [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] Rebeccamycin: An anticancer drug that belongs to the family of drugs called antineoplastic antibiotics. [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] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Sarcoma: A cancer of the bone, cartilage, fat, muscle, blood vessels or other connective or supportive tissue. [NIH] Sargramostim: A colony-stimulating factor that stimulates the production of blood cells, especially platelets, during chemotherapy. It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called GM-CSF. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial

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s.) or the complete range of manifestations of a disease. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Subcutaneous: Beneath the skin. [NIH] Supratentorial: Located in the upper part of the brain. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] 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] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH]

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PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL

ABOUT PART II In Part II, we introduce you to additional resources and advanced research on neuroblastoma. 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 neuroblastoma. In Part II, as in Part I, our objective is not to interpret the latest advances on neuroblastoma 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 neuroblastoma is suggested.

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CHAPTER 4. STUDIES ON NEUROBLASTOMA Overview Every year, academic studies are published on neuroblastoma 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 neuroblastoma. 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 neuroblastoma 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 neuroblastoma, 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

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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 “neuroblastoma” (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: ·

Report on a Workshop of the UICC Project on Evaluation of Screening for Cancer Source: International Journal of Cancer. 46(5):761-769, November 15, 1990. Summary: The fifth report of the International Union Against Cancer (UICC) Project on the Evaluation of Screening for Cancer summarizes information presented at a workshop at which researchers evaluated screening for individual cancer sites or groups of sites. Information focuses on breast cancer screening, cervical cancer screening, ovarian cancer screening, colorectal cancer screening, and stomach cancer screening. Researchers looked for the first time at melanoma, neuroblastoma, nasopharyngeal carcinoma, and prostate cancer sites. For each site, the report describes work done internationally, draws conclusions, and makes recommendations for research. The report also examines issues relevant to the evaluation of screening: (1) Privacy laws, (2) screening test sensitivity and proportionate incidence, (3) the need for intermediate end-points that can be used for evaluation before mortality or incidence data become available, (4) models to enhance the understanding of the natural history of screen detected lesions and the process of screening, and (5) the application of different considerations to case control studies of screening when mortality is the endpoint than when incidence of disease is the endpoint. 8 references.

·

Radiotherapy for Metastases to the Mandible in Children Source: Journal of Oral and Maxillofacial Surgery. 60(3): 269-271. March 2002. Contact: Available from W.B. Saunders Company. Periodicals Department, P.O. Box 629239, Orlando, FL 32862-8239. (800) 654-2452. Website: www.harcourthealth.com. Summary: This article presents a retrospective review of all children treated since 1979 at the authors' institution with radiation therapy for

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symptomatic metastases (spread of cancer) that involved the mandible (lower jaw). Nine children were treated with 1 or more courses of radiotherapy for symptomatic metastases that involve the mandible. Six children had a neuroblastoma, 1 had angiosarcoma of the liver, 1 had adenocarcinoma of the rectum, and 1 had peripheral primitive neuroectodermal tumor (Ewing's sarcoma) of the spine. In 3 children, the mandible was the first bone involved by metastases. Seven children were treated with short intensive courses of radiotherapy consisting of 1 to 3 fractions to a total dose of 400 to 1,200 cGy. One child received 2,400 cGy in 6 fractions, and another child received 3,000 cGy in 10 fractions. Three children were treated with second courses of radiotherapy at 1, 2, and 5 months, respectively, from the initial course of radiotherapy. All children had received chemotherapy. All children died of disseminated disease at 5 to 59 months from their initial diagnosis, 5 to 29 months from the detection of metastases to bone, and only 6 days to 17 months (median, 20 months) from the first treatment of metastases to the mandible. The authors conclude that the outlook for children with metastases that involve the mandible is very poor, and the authors recommend short intensive courses of radiotherapy consisting of 1 to 3 treatments to total doses of 400 to 1,200 cGy for palliation of pain. 1 table. 7 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 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

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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

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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 Neuroblastoma The U.S. Government supports a variety of research studies relating to neuroblastoma 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 CRISP Web 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 neuroblastoma 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 neuroblastoma and related conditions. In some cases, 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 neuroblastoma:

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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Project Title: Cellular Immunotherapy for Neuroblastoma with CTL Clones Principal Investigator & Institution: Jensen, Michael C.; Dr.; City of Hope National Medical Center Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2001; Project Start 7-SEP-2001; Project End 1-AUG2003 Summary: (Provided by applicant): Disease relapse is the leading cause of mortality for children diagnosed with disseminated neuroblastoma despite the use of highly intensive front-line therapy. Studies conducted in our laboratory have focused on developing strategies to target neuroblastoma with adoptively transferred T lymphocytes genetically modified to express a chimeric immunoreceptor, designated CE7R, for redirected recognition of a neuroblastoma-specific epitope on the L1-CAM adhesion molecule. The engineering of CE7R was accomplished by assembling a cDNA construct encoding a single-chain antibody extracellular domain derived from the murine CE7 hybridoma fused to the cytoplasmic tail of the T cell receptor CD3 complex zeta chain (scFvFc:zeta). In vitro culture systems have been developed for genetically modifying human T cells with naked plasmid DNA by electroporation and expanding modified clones to numbers in excess of 10e10. Ex vivo expanded CE7R scFvFc:zeta-expressing cytotoxic T lymphocyte (CTL) clones specifically recognize human neuroblastoma tumor cells and are activated for tumor cell cytolysis and cytokine secretion. These pre-clinical studies have provided the rationale to explore the therapeutic utility of cellular immunotherapy with autologous CTL clones engineered to express the CE7R chimeric immunoreceptor and the selection/suicide fusion protein HyTK in children with recurrent/refractory disseminated neuroblastoma. The in vivo persistence, anti-tumor activity, and immunogenicity of infused clones will be assessed following adoptive transfer in order to delineate how the in vivo biology of ex vivo expanded CE7R+ CTL might be further optimized. The specific aims of this project are: 1.) To evaluate the safety and toxicity of adoptively transferred CE7R+/HyTK+ CD8+ CTL clones in children with recurrent/refractory neuroblastoma. 2.) To quantitate the anti-tumor activity of infused clones in patients with measurable disease. 3.) To study the persistence of transferred clones in research participants by Q-PCR and the impact of administering exogenous IL-2 on the duration and magnitude of in vivo persistence. 4.) To assess in this patient population the development of antibody and cellular immune responses against the scFvFc:zeta and HyTK chimeric proteins. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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Project Title: Genetics Neuroblastoma

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Principal Investigator & Institution: Weiss, William A.; Neurology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2000; Project Start 0-SEP-2000; Project End 1-AUG2005 Summary: (Adapted from the Applicant's Abstract): Neuroblastoma, a tumor of peripheral neural crest origin, is the third most common tumor of childhood. The broad, longterm objective of this project is to find genes that contribute to tumorigenesis in a multi-step transgenic mouse model for neuroblastoma. The transgenic mouse model to be used in this study is tumor prone. as a result of over-expression of the human MYCN gene in the peripheral neural crest. Since tumorigenesis in the mouse is initiated using a gene relevant to human neuroblastoma, it is likely that the additional genetic lesions which contribute to neuroblastoma formation in the mouse will be in genes relevant to neuroblastoma in children. Using PCR analysis of microsatellite markers, we have identified 6 chromosomal or subchromosomal regions that show consistent abnormalities in mouse tumors. Four of these were syntenic with corresponding regions of abnormality in human neuroblastoma. A region on the proximal part of chromosome 10 was affected in 30% of tumors and has been localized to an interval of less than 16 cM. Over the five years of this award, our goal is to identify the genetic region most amenable to further study, and to find the gene corresponding to that subchromosomal region. In specific aim 1, we will refine our primary screen to further localize the six regions that contributes to neuroblastoma in the mouse. We will also analyze tumors for differentiation, angiogenesis, apoptosis, proliferation, and invasion, to seek biological correlates for specific regions of LOH. We will focus subsequent positional cloning efforts on chromosome 10 unless our refined screens identify a more compelling region. In specific aim 11, we will further characterize a single genetic region which cooperates with MYCN to cause neuroblastoma in the mouse. We will analyze additional tumors and additional microsatellite markers to localize this interval to 12 cM a size appropriate for positional cloning. We will then construct a physical map and contig of this region to identify the corresponding genes. Candidate genes will be tested for expression and mutation in mouse tumors. Health Relatedness: Genes identified as important for the malignant progression of neuroblastoma in the mouse can be tested directly for their role in neuroblastoma in humans. Given the poor outcome associated with childhood neuroblastoma, this work has the

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potential to increase our understanding of the pathogenesis of neuroblastoma, and may result in improved therapies for children with this disorder. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Immunosuppressive Neuroblastoma Tumor Gangliosides Principal Investigator & Institution: Ladisch, Stephan K.; Professor and Scientific Director; Children's Research Institute 111 Michigan Ave Nw Washington, Dc 20010 Timing: Fiscal Year 2000; Project Start 1-MAY-1986; Project End 1-MAR2003 Summary: The goal of this renewal proposal is to characterize inhibition of antitumor immune responses by tumor gangliosides in vivo. The general hypothesis underlying this work is that gangliosides are shed by tumor cells, act as intercellular signaling molecules, block the cellular immune response, and protect tumor cells from host immune destruction. Findings of significant shedding and of potent immunosuppressive activity of human neuroblastoma gangliosides, and new preliminary data showing inhibition of murine cellular immune response to syngeneic tumor cells by these molecules, lay the foundation to directly test the hypothesis that tumor gangliosides downregulate host cellular immune responses to syngeneic tumor cell both in vitro and in vivo. Two approaches will be used to obtain neuroblastoma tumor gangliosides, homogeneous in both carbohydrate and ceramide structure, in large quantities: isolation from human neuroblastoma tumors (natural) and chemical synthesis (synthetic). All gangliosides will be further purified by HPLC to remove potential traces of contaminants prior to biological study. Molecular structures of the gangliosides will be confirmed by mass spectrometry and chemical methods. The delineation of inhibitory effects of tumor gangliosides upon both the afferent (priming) and efferent (effector function) phases of the cellular immune response in murine tumor models in vivo will be complemented by determination of the effects of these same gangliosides on the human cellular immune response in vitro. The in vivo studies will be performed in two murine syngeneic tumor models, FBL erythroleukemia and B78H1 melanoma. The proposed studies will conclusively demonstrate downregulation of syngeneic antitumor immune response by neuroblastoma tumor gangliosides in vivo. They will provide the foundation for future investigations (longer term aims) to elucidate the molecular mechanism(s) of inhibition by tumor gangliosides and to develop strategies to eliminate these immunosuppressive molecules (such as removal of gangliosides from the circulation or modulation of

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ganglioside biosynthesis and shedding by pharmacologic agents), with the ultimate goal of achieving improved therapeutic approaches to neuroblastoma and other neuroectodermal tumors such as melanoma. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Neuroblastoma-Specific MRI Contrast Agents Principal Investigator & Institution: Voss, Stephan D.; Children's Hospital (Boston) 300 Longwood Ave Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 7-SEP-2002; Project End 1-AUG2007 Summary: (provided by applicant): Neuroblastoma is the most common pediatric malignancy diagnosed in the first year of life. More than onehalf of these children have disseminated disease at the time of diagnosis. Magnetic resonance imaging (MRI) is crucial in the diagnostic imaging evaluation of neuroblastoma, however, no neuroblastoma-specific MRI contrast agents currently exist. We propose to create neuroblastomaspecific MRI contrast agents by conjugating low-molecular weight peptide ligands (<2000 MW) that bind to the surface of neuroblastoma cells with monocrystalline iron oxide nanoparticles (MIONs). In addition to their ease of synthesis, low-molecular weight ligands have several attractive pharmacological and biochemical properties, including rapid biodistribution, excellent tissue penetration, and lack of immunogenicity. MIONs are ultrasmall (approximately 20 nm hydrodynamic radius) dextran-coated iron oxide superparamagnetic colloids that alter T2weighted MRI contrast enhancement. Recent reports have suggested that MIONs can be conjugated to peptides and proteins to generate cellspecific contrast enhancement. To generate neuroblastoma-specific MRI imaging reagents, we will employ the following systematic approach. The conjugation of peptides to MIONs will be optimized using a previously described neuropeptide Y1 (NPY-1)-Iike molecule that binds with high affinity to neuroblastoma cells. Complete in vitro characterization of the MION/NPY-1 conjugate will be performed including binding affinity, kinetics, sub-cellular localization, and MRI contrast enhancement of living cells. In addition, NPY/MION conjugates will be evaluated in vivo using human neuroblastoma tumor xenografts established in nu/nu mice. Since NPY-1 has relative, but not absolute specificity for neuroblastoma cells, we will, in parallel, search for novel peptide ligands that bind to the surface of these cells. Using differential peptide phage display screening of two cell lines, one an aggressive neuroblastoma and the other its chemically-differentiated benign counterpart, we will attempt to discover peptides specific for the malignant phenotype. Conjugation of these novel peptides to MIONs

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could result in contrast agents with higher specificity than is possible with NPY-1 derivatives. As imaging technologies such as MRI have continued to improve, the integration of basic genetic and molecular biologic discoveries into development of novel tissue-specific contrast agents has lagged behind. This study presents a generalizable approach to producing tumor cell-specific MRI contrast reagents, and should permit improved diagnosis, and hence treatment, of neuroblastoma in children. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Neurotrophic Mechanisms in Neuroblastoma Principal Investigator & Institution: Schor, Nina F.; Professor and Chief of Child Neurology; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213 Timing: Fiscal Year 2000; Project Start 4-DEC-1999; Project End 0-NOV2003 Summary: For the past several years, our laboratory has been involved in the design and preclinical development of specifically targeted chemotherapeutic approaches to neuroblastoma. In the course of this work and recent work of other laboratories, it has become clear that resistance of neuroblastoma to chemotherapy correlates with the expression of tumor cell receptors for neurotrophins like nerve growth factor (NGF). Specifically, NGF can protect neuroblastoma cells from apoptosis induced by a variety of mechanically distinct chemotherapeutic agents. Two cell surface receptors have been identified for NGF. TrkA binds NGF with high affinity, while p75 binds this peptide with low affinity. Recent circumstantial evidence from several laboratories, including our own, has led to the hypothesis that the role of each of the receptors in the anti-apoptotic (and therefore chemoresistive) effect of NGF is critically dependent on the ratio of p75 to TrkA on the neuroblastoma cell surface. Preliminary data from other laboratories indicates that the p75/TrkA ratio correlates with clinical failure of chemotherapy. Using human neuroblastoma cells genetically engineered to differ only in their p75/TrkA ratio, and a series of novel highly selective p75 and TrkA ligands designed and synthesized by our coinvestigator, we propose to definitively test this hypothesis both in vitro and in a nude mouse xenograft model of neuroblastoma. We will also define the downstream mechanistic changes in signal transduction that result from changes in the p75/TrkA ratio. These studies will identify therapeutic targets linked to the p75/TrkA ratio of neuroblastoma cells, and will begin to develop NGF analogues as potential therapeutic agents

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for overcoming NGF-mediated resistance chemotherapeutic agent-induced apoptosis.

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Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Patterns of Ganglioside Expression in Neuroblastoma Principal Investigator & Institution: Kaucic, Karen L.; Children's Research Institute 111 Michigan Ave Nw Washington, Dc 20010 Timing: Fiscal Year 2002; Project Start 1-FEB-2002; Project End 1-JAN2004 Summary: (Provided by applicant): Gangliosides are membrane-bound glycolipid molecules found in all vertebrate tissues, but particularly prominent in neural tissue. They are synthesized via two pathways designated "a" (predominant in adult brain), and "b" (predominant in fetal brain). Experimental evidence supports a role for gangliosides in the clinical behavior of several human tumors, including neuroblastoma. Our preliminary data demonstrate that fetal patterns of ganglioside biosynthesis predominate in neuroblastoma tumors from patients less than 1 year of age, those with low stage disease, whereas the adult patterns predominate in tumors from older children and those with disseminated disease. Our data also demonstartes improved outcome among NB patients with tumors containing a predomince (less than 60 percent) of "b" pathway gangliosides. Further, we have demonstrated that the downstream "b" pathway ganglioside, GT1b is absent from disseminated tumors, but not from lower stage tumors. In light of our work and published studies demonstrating that the "b" pathway gangliosides GD1b, GT1b, and GQ1b (immediately downstream from GD2) are absent in aggressive tumors, we hypothesize that the lack of terminal "b" pathway gangliosides may be related to the aggressive behavior of certain neuroblastomas, and is attributable to a defect in one of the "b" pathway biosynthetic enzymes. We will test this hypothesis by elucidating the association between patterns of "b" pathway ganglioside biosynthesis and the clinical behavior of neuroblastoma tumors. We will then delineate the enzymatic lesions associated with altered ganglioside biosynthesis in these tumors. These studies will pinpoint the ganglioside marker(s) associated with aggressive disease in neuroblastoma, and provide the basis for the development of a model system to test potential therapies aimed at modulating altered ganglioside biosynthesis as an approach to improving the clinical outcome of patients with aggressive neuroblastoma. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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Project Title: Regulation of Apoptosis in Neuroblastoma Principal Investigator & Institution: Castle, Valerie P.; Associate Professor; Pediatrics; University of Michigan at Ann Arbor Ann Arbor, Mi 48109 Timing: Fiscal Year 2000; Project Start 1-MAY-1997; Project End 0-APR2003 Summary: This is application proposing to determine whether failure to undergo programmed cell death contributes to the pathogenesis of human neuroblastoma. Specifically, the investigator proposes to determine whether oncogene products which modulate programmed cell death (PCD) influence whether oncogene products which modulate programmed cell death (PCD) influence the malignant phenotype of neuroblastoma. The investigator previously determined that Bcl-2, which suppresses PCD, is present in pretreatment neuroblastoma tumore biopsies, and that, when deregulated, inhibits neuroblastoma tumor biopsies, and that, when deregulated, inhibits chemotherapy-induced PCD in neuroblastoma. Based on these prior findings, the investigator seeks to extend these observations in a system in which it is proposed that neuroblastoma is a disease resulting from failed apoptosis. The first aim will address the issue of oncogene cooperativity in the malignant phenotype of neuroblastoma,, specifically whether Bcl-2, in its capacity to inhibit apoptosis, cooperates with N-myc to transform cells. The second aim is proposed to determine whether Bcl-xs expression will lead to neuroblastoma cell death and enhanced response to chemotherapy (by pirating existing cell machinery). The third specific aim proposes to determine the expression of the death gene and survival gene in normal tissue from which neuroblastoma is thought to arise. The investigator feels these experiments will address the molecular link between the benign lesions and malignant neuroblastoma. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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Project Title: Role of Neurotrophin Receptors in Neuroblastoma Principal Investigator & Institution: Yamashiro, Darrell J.; Pediatrics; Columbia University Health Sciences Ogc New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 1-JUL-2001; Project End 0-JUN2006 Summary: (Adapted from the investigator's abstract) Neuroblastoma has a wide spectrum of clinical behavior, with tumors regressing spontaneously in infants, to widely metastatic disease and poor outcome despite intensive chemotherapy and bone marrow transplantation. The biological mechanism for these disparate clinical behaviors is likely to

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involve the neurotrophin receptors TrkA, TrkB, and TrkC, and their respective ligands, NGF, BDNF, and NT3. Favorable neuroblastomas express TrkA and TrkC, but not NGF or NT3. In contrast, unfavorable, metastatic neuroblastomas express TrkB and BDNF. Based on these observations we have proposed a model in which TrkA and TrkC promote favorable neuroblastoma by inducing neuronal d~(ferentiation, while an autocrine loop of TrkB and BDNF promotes unfavorable neuroblastoma by enhancing tumor growth, cell survival, and metastasis. In support of this model, studies have shown that TrkA and TrkC can induce neuronal differentiation, that TrkB can increase cell survival, stimulate cell invasiveness, and is chemoprotective. TrkB can also increase the expression of vascular endothelial growth factor (VEGF), suggesting that TrkB can induce angiogenesis, a critical step in tumor proliferation and metastases. The overall goal of this grant to obtain in vivo evidence for the Trk-NBL model. Our experiments will focus on TrkB and the autocrine/paracrine loop formed with BDNF, with the results compared with TrkC and NT3. For the in vivo studies we will use a xenograft model in the nude mouse that we have developed in our laboratory that produces large primary tumors and metastases to lung, liver, or bone marrow. Aim 1. We hypothesize that in vivo, TrkB promotes cell survival, proliferation, and metastases, while TrkC promotes differentiation. We will compare the ability of TrkB and TrkC to promote cell survival, tumor growth, metastases, differentiation, and protect against chemotherapy in vivo. Aim 2. We hypothesize that an autocrine or paracrine loop of BDNF/TrkB or NT3/TrkC promotes cell survival and differentiation. We will determine if autocrine expression of BDNF or NT3 in neuroblastoma cell lines or fibroblasts promotes differentiation or survival. Aim 3. We hypothesize that Trk receptors regulate angiogenesis in neuroblastoma. We will determine if TrkB and TrkC regulate the expression of VEGF and determine the signal pathways involved. We will determine if TrkB and TrkC protect neuroblastoma against hypoxia induced by anti-VEGF agents. By systematically comparing TrkB with TrkC in vivo, these studies will allow us to determine the validity of the Trk-NBL model. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Significance of Genetic Alterations in Neuroblastoma Principal Investigator & Institution: Maris, John M.; Assistant Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 1-AUG-2002; Project End 1-JUL2007

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Summary: Neuroblastoma is a common and often fatal childhood malignancy of the peripheral nervous system. There is marked heterogeneity in disease presentation; clinical course and outcome. However, the majority of patients have locally aggressive and/or metastatic disease that is often refractory to intensive multimodal therapies. Clinical variables such as age at diagnosis, disease stage and histopathologic grade are important in distinguishing between these divergent phenotypes, but biological and genetic features of the tumor provide critical additional prognostic information. Our group and others have identified nonrandom genomic alterations that occur in specific subsets of cases. Thus, we hypothesize that the pattern of somatically acquired genomic alterations present at diagnosis in primary neuroblastomas can independently predict clinical course and disease outcome. We will test this hypothesis through a prospective and systematic analysis of genomic-based candidate prognostic markers in all neuroblastoma patients enrolled on Children's Oncology Group (COG) clinical trials. In addition, we plan to identify new genetic alterations critical to the development of the highly malignant subset of neuroblastomas. First, we will determine the independent prognostic significance of allelic alterations at chromosome bands 1p36, 11q23, 14q32 and 17q23-25 when these variables are entered into a multivariate analysis, individually and in combinations, with all current prognostic variables. Second, we will develop a microarray-based molecular diagnostic approach for neuroblastoma by using a customized cDNAbased neuroblastoma-specific "chip". This array should provide a standardized approach to sensitive, specific and reproducible detection of clinically relevant tumor-specific alterations. Third, we will identify novel prognostic markers critical to the development of high-risk disease. We will perform clinical correlative studies in a prospectively identified group of 150 representative cases to determine the clinical significance of recently described genomic alterations. Promising candidate markers would then by analyzed in the full patient cohort. In addition, we will perform genome-wide expression profiling designed to identify the unique patterns of gene expression present in strictly defined clinicobiological subsets. The successful completion of the proposed research will allow us to unequivocally define the genetic alterations present in human neuroblastoma and to use these data to predict clinical phenotype and response to treatment. These studies will therefore provide the infrastructure necessary to apply tumor- specific data to treatment planning algorithms for future patients with neuroblastoma, and thus this project may contribute to improved survival probabilities. It is also expected that these studies will identify novel genes and/or pathways that are unique to the high-risk subset of tumors. It is expected

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that these will be of prognostic importance and serve as specific targets for developmental therapeutics. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: T Lymphocyte Responses to Human Neuroblastoma Principal Investigator & Institution: Nuchtern, Jed G.; Surgery; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2000; Project Start 5-AUG-1998; Project End 1-JUL2003 Summary: (Applicant's Abstract) Neuroblastoma is the most common extra-cranial solid tumor in children. Attempts to develop an effective immunotherapy for neuroblastoma have been relatively unsuccessful. In spite of these failures, compelling clinical evidence suggests that these tumors can elicit a protective immune response under some circumstances. Significant progress toward useful immunotherapy of other cancers has been made using tumor-specific cytotoxic T lymphocytes (CTL) to define tumor antigens which are capable of stimulating a therapeutic immune response. In contrast to the ease of generating neuroblastoma-specific CTL in murine models, several groups have reported difficulty producing human CTL against this neoplasm. The PI has recently succeeded in generating tumor- specific CTL from several neuroblastoma patients. In this project he proposes to use these CTL to advance immunotherapy of this neoplasm. The specific aims of this project are: 1) to use these CTL to test the hypothesis that neuroblastoma tumor-specific antigens exist, to identify these antigens at the molecular levels, and to interpret their expression patterns in the context of tumor immunology and biology; 2) to define the optimal conditions for CTL generation in vitro in order to elicit these T cells from currently resistant tumors and extend the effectiveness of adoptive immunotherapy; and 3) to test the hypothesis the defined neuroblastoma tumor antigens can replace and surpass native tumor cells in the generation of anti-tumor CTL responses. By identifying one or more neuroblastoma tumor antigens and defining the optimal conditions for generating an anti-tumor CTL response, this project will accelerate the development of immunotherapy for this important pediatric cancer. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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Project Title: Immunocytokine Therapy Principal Investigator & Institution: Seeger, Robert C.; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027

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Timing: Fiscal Year 2000; Project Start 6-JUL-2000; Project End 1-MAY2005 Summary: (Applicant's Description) The long-term goal of this project is to develop immunotherapy with anti-neuroblastoma antibodies that will be effective against primary and metastatic tumor cells, even if they are resistant to other agents. The hypotheses are (1) Neutrophil mediated ADCC is primarily due to loss of plasma membrane integrity (necrosis) and so will not be affected by resistance to apoptosis. (2) Neutrophil ADCC will be increased (a) by promoting effector-target cell adhesion that activates degranulation and production of reactive oxygen species; and (b) by sensitizing tumor cells to cytotoxic effects of neutrophils. (3) Neutrophil migration into tumor sites will occur with antibody targeted delivery of GM-CSF. Our preliminary studies indicate (1) that and retinoid resistant neuroblastoma cell lines are susceptible to neutrophil ADCC mediated by anti-ganglioside GD2 antibody, especially an antiGD2/GM-CSF fusion protein (immunocytokine); (2) that neutrophil FcyRII and Mac-1 (CD11b/CD18) are required for ADCC; and (3) that treatment of neuroblastoma cells with 13-cis-retinoic acid, interferon-y, fenretinide, or buthionine sulfoximine increases ADCC. The specific aims are (1) to determine if there is cross resistance between neutrophil ADCC mediated by anti-GD2/GM-CSF (hu14.18/GM-CSF) and other agents and to understand why tumor cell lines vary in their sensitivity to ADCC; (2) to determine if maximizing neutrophil - neuroblastoma cell conjugates increases ADCC; (3) to determine if subjecting neuroblastoma cells to oxidative and ceramide related stress increases ADCC and (4) to evaluate localization of hu14.18/GM-CSF and neutrophils to neuroblastoma cells in murine models. Research Design. Neutrophil ADCC mediated by hu14.18/GM-CSF against 29 MYCN amplified and non-amplified neuroblastoma cell lines with a range of sensitivities to chemotherapeutic agents, retinoic acid, and fenretinide will be evaluated with digital image microscopy to quantify loss of calcein fluorescence from pre-loaded target cells. A new three-color flow cytometry ADCC assay will be used to evaluate expression of cell surface molecules by neuroblastoma cells (e.g., GD2) and neutrophils (e.g., Mac-l, FcyR, CD63) and the relationship to (a) the frequency of neutrophil-conjugated vs. non-conjugated tumor cells; (b) neutrophil: tumor cell ratio in conjugates and (c) kinetic aspects of ADCC (neutrophil-tumor cell conjugates; degranulation; production of ROS; and tumor cell membrane disruption). These assays will be used to maximize neutrophil ADCC with the agents that increase neutrophil neuroblastoma conjugates and that subject neuroblastoma cells to oxidative and ceramide related stress. Immunodeficient SCID mice with local and metastatic human neuroblastomas will be used to test localization of hu14.18/GM-CSF to primary and metastatic sites,

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including bone marrow. Agents that enhance ADCC in vitro, as well as anti-angiogenic agents, will be tested for their effect upon immunocytokine and neutrophil localization. This research should establish immunocytokine mediated neutrophil ADCC as a potentially effective therapy for high-risk neuroblastoma. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Molecular Mechanism of NDP Kinase a in Tumor Metastasis Principal Investigator & Institution: Chang, Christina L.; Medicine; University of California San Diego 9500 Gilman Dr San Diego, Ca 92093 Timing: Fiscal Year 2000; Project Start 5-JAN-2000; Project End 1-DEC2004 Summary: The long-term goal of this project is to understand how human NDP kinase A (NDPK-A) is involved in tumor metastasis, a major cause of death in cancer patients. An increased NDPK-A level is strongly correlated with high metastatic potential of neuroblastoma. This suggests that NDPK-A may be a metastasis promoter in this cancer. In addition, we have detected the Serl20 yields Gly mutation of NDPK-A in 26 percent of patients with metastatic neuroblastoma. Although NDPK-A is known to function as a phosphate transferase and participate in nucleic acid metabolism, this enzymatic activity is not correlated with tumor metastasis, suggesting other function(s) of NDPK-A in tumor progression. In fact, our preliminary data demonstrate that NDPK-A can function as a transcription factor in vitro by binding to a cis-acting element in the c-myc gene and activating c-myc transcription. We hypothesize that NDPK-A promotes the metastasis of neuroblastoma by deregulating c-myc transcription. Five specific aims are proposed to test facets of the hypothesis in neuroblastoma cell and SCID mice model systems: (1) Examine if alterations in the protein level and structure of NDPK-A affect nuclear localization of NDPK-A. (2) Examine if alterations in the protein level and structure of NDPK-A enhance cell growth and invasiveness. (3) Determine if neuroblastoma cells expressing an altered protein level and structure of NDPK-A promote tumor formation and metastasis in SCID mice. (4) Study the deregulation of c-myc transcription by NDPK-A in vivo. (5) Elucidate the potential target genes which are regulated by NDPK-A. Findings from the proposed in-vitro and in-vivo studies will establish whether NDPK-A promotes the metastasis of neuroblastoma. The results may point to one or more specific cellular processes that are affected by alterations in the protein level and structure of NDPK-A. We will also obtain new information regarding the deregulation of c-myc transcription by NDPK-A.

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Furthermore, identification of the consensus sequence recognized by NDPK-A will allow the identification of its potential target genes and expand our understanding of the NDPK-A network. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Radioreceptor Guided Surgery of Neural Crest Tumors Principal Investigator & Institution: O'dorisio, M. Sue Susan.; Chief, Pediatric Oncology & Hematology; Pediatrics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 7-SEP-2000; Project End 1-AUG2004 Summary: (Adapted from the investigator's abstract) Neural crest stem cells differentiate into multiple tissues, including the peripheral and enteric nervous systems, the adrenal medulla, and melanocytes. Neural crest tumors derived from these precursors include neuroblastoma in children, neuroendocrine tumors of the gut and melanoma in adults. Neural crest tumors share common biological features, which may render them susceptible to similar treatments. Our work has demonstrated expression of somatostatin receptors in both primary tumors and cell lines. We have demonstrated the utility of radiolabeled somatostatin analogues in imaging neuroendocrine tumors. Our innovative technique for radioreceptor guided surgery has been utilized to successfully guide surgical extirpation of occult tumor in both adult and pediatric patients with neural crest derived tumors. Preliminary data demonstrates expression of somatostatin receptors in neuroblastoma, neuroendocrine tumors of the gut and melanoma. We therefore hypothesize that somatostatin receptors can be exploited as diagnostic and therapeutic targets in neural crest tumors. We propose to test this hypothesis in animal models of neuroblastoma followed by clinical trials in both male and female children and adults. We have designed and synthesized several unique somatostatin analogues with high affinity and potent physiologic effects at sst1 and sst2. We will characterize their affinity for other somatostatin receptors [sst3, sst4 and sst5] and test their growth inhibitory potential against neuroblastoma call lines and primary tumor cells in culture. Specific sst1 and sst2 analogues will be labeled with 123Iodine for scintigraphy, or 125Iodine for radioreceptor guided surgery will be tested in a xenograft model of disseminated neuroblastoma. Children with neuroblastoma will be entered into a clinical study to test the feasibility and specificity of somatostatin scintigraphy and radioreceptor guided surgery in detection and cytoreduction of neuroblastoma. This will provide image guided surgical therapy of neuroblastoma and will also provide whole body and tumor dosimetry

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data, which can then be applied to radiotherapy of neuroblastoma using (90)Y-DOTA-peptides, which target somatostatin receptors on malignant cells. Adults with neuroendocrine tumors will be entered into a study to test feasibility and specificity of radioreceptor guided surgery. Patients will be recruited from our nationally recognized, multidisciplinary neuroendocrine tumor clinic to participate in this trial of image guided surgical therapy. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Vascular Endothelial Cell Integrins in Angiogenesis Principal Investigator & Institution: Durden, Donald L.; Associate Professor of Pedieatrics, Bioc; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2000; Project Start 6-JUL-2000; Project End 1-MAY2005 Summary: (Applicant's Description) Recent evidence has established the importance of the alpha v Beta 3 and alpha v Beta 5 integrins and their interaction with matrix in tumor-induced angiogenesis. High-risk neuroblastoma is associated with active angiogenesis, suggesting that integrins and matrix degrading proteases play a role in this disease. We recently showed that ceramide, a lipid second messenger important in apoptosis, increases in endothelial cells following inhibition of integrin alpha v Beta 3- and alpha v Beta 5-mediated anchorage. The goals of this project are to define the potential of alpha v Beta 3 and/or alpha v Beta 5 and their interaction with proteolyzed collagen as targets for antiangiogenic treatment in neuroblastoma and to improve the efficacy of this anti-angiogenic approach by combining it with modifiers of intracellular ceramide metabolism. Our preliminary data supports the following hypothesis: (1) antagonism of integrins alpha v Beta 3 and alpha v Beta 5, which are potentially important to neuroblastoma angiogenesis, will provide a mechanism for attack of tumor endothelium and improve treatment of high-risk neuroblastoma; (2) manipulation of signaling pathways to increase endogenous endothelial ceramide and/or inactivate survival kinases will enhance the anti-angiogenic response of neuroblastoma. Our work will consist of three Specific Aims: (1) to define the angiogenic phenotype of primary untreated neuroblastomas with regard to expression of alpha v Beta 3, alpha v Beta 5, proteolyzed collagen, MMP-9 and PAI-1 using immunohistochemistry; (2) to analyze endothelial signaling pathways regulated by ceramide under conditions of anoikis induced by antagonism of alpha v Beta 3 or alpha v Beta 5 integrins and/or ceramide challenge; (3) to use alpha v Beta 3 and alpha v Beta 5 antagonists and agents which interfere with ceramide-regulated

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pathways in in vivo models for local and metastatic neuroblastoma to determine which individual or synergistic antitumor effects. Research Design: The feasibility of treating neuroblastoma with anti-angiogenic treatments directed against integrin alpha v Beta 3 and alpha v Beta 5 or direct antagonism of proteolyzed type V collagen will be examined using in vivo and in vitro models. The signal transduction pathways regulated by ceramide that function in endothelial anoikis will be identified using experiments in cell culture. This integrated approach will likely yield novel therapeutic agents for the treatment of neuroblastoma and other tumors. 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 “neuroblastoma” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for neuroblastoma in the PubMed Central database: ·

A [beta]-Lactone Related to Lactacystin Induces Neurite Outgrowth in a Neuroblastoma Cell Line and Inhibits Cell Cycle Progression in an Osteosarcoma Cell Line by G Fenteany, RF Standaert, GA Reichard, EJ Corey, and SL Schreiber; 1994 April 12 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=43576

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A mammalian homolog of unc-53 is regulated by all-trans retinoic acid in neuroblastoma cells and embryos by R. A. Merrill, L. A. Plum, M. E. Kaiser, and M. Clagett-Dame; 2002 March 19 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=122539

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 Recombinant Antibody-Interleukin 2 Fusion Protein Suppresses Growth of Hepatic Human Neuroblastoma Metastases in Severe Combined Immunodeficiency Mice by H Sabzevari, SD Gillies, BM Mueller, JD Pancook, and RA Reisfeld; 1994 September 27 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=44866

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A Region of Consistent Deletion in Neuroblastoma Maps within Human Chromosome 1p36.2-36.3 by PS White, JM Maris, C Beltinger, E Sulman, HN Marshall, M Fujimori, BA Kaufman, JA Biegel, C Allen, C Hilliard, MB Valentine, AT Look, H Enomoto, S Sakiyama, and GM Brodeur; 1995 June 6 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41727

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Activated Estrogen Receptor Mediates Growth Arrest and Differentiation of a Neuroblastoma Cell Line by ZQ Ma, E Spreafico, G Pollio, S Santagati, E Conti, E Cattaneo, and A Maggi; 1993 April 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=46377

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Branched Polyamines Cure Prion-Infected Neuroblastoma Cells by Surachai Supattapone, Holger Wille, Lisa Uyechi, Jiri Safar, Patrick Tremblay, Francis C. Szoka, Fred E. Cohen, Stanley B. Prusiner, and Michael R. Scott; 2001 April 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=114138

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Cannabinoids Inhibit N-Type Calcium Channels in NeuroblastomaGlioma Cells by K Mackie and B Hille; 1992 May 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=48964

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Ciliary Neurotrophic Factor Coordinately Activates Transcription of Neuropeptide Genes in a Neuroblastoma Cell Line by AJ Symes, MS Rao, SE Lewis, SC Landis, SE Hyman, and JS Fink; 1993 January 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=45705

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Cytoplasmically sequestered wild-type p53 protein in neuroblastoma is relocated to the nucleus by a C-terminal peptide by Anne G. Ostermeyer, Erik Runko, Blonka Winkfield, Brand Ahn, and Ute M. Moll; 1996 December 24 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=26379

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Direct Coupling of Opioid Receptors to Both Stimulatory and Inhibitory Guanine Nucleotide-Binding Proteins in F-11

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Neuroblastoma-Sensory Neuron Hybrid Cells by RA Cruciani, B Dvorkin, SA Morris, SM Crain, and MH Makman; 1993 April 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=46228 ·

Distinct mechanisms of cell cycle arrest control the decision between differentiation and senescence in human neuroblastoma cells by Linda J. Wainwright, Anna Lasorella, and Antonio Iavarone; 2001 July 31 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=55432

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Endogenous Intracellular Glutathionyl Radicals are Generated in Neuroblastoma Cells Under Hydrogen Peroxide Oxidative Stress by H Kwak, H Yim, PB Chock, and MB Yim; 1995 May 9 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41988

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Expression Cloning of an ATP Receptor from Mouse Neuroblastoma Cells by KD Lustig, AK Shiau, AJ Brake, and D Julius; 1993 June 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=46665

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Gene therapy with a single chain interleukin 12 fusion protein induces T cell-dependent protective immunity in a syngeneic model of murine neuroblastoma by Holger N. Lode, Torsten Dreier, Rong Xiang, Nissi M. Varki, Angray S. Kang, and Ralph A. Reisfeld; 1998 March 3 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=19380

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HEN1 and HEN2: A Subgroup of Basic Helix-Loop-Helix Genes That are Coexpressed in a Human Neuroblastoma by L Brown, R Espinosa, III, MML Beau, MJ Siciliano, and R Baer; 1992 September 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=49946

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Histone H2A-mediated transient cytokine gene delivery induces efficient antitumor responses in murine neuroblastoma by Danuta Balicki, Ralph A. Reisfeld, Ursula Pertl, Ernest Beutler, and Holger N. Lode; 2000 October 10 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=17229

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Identification of Nuclear [tau] Isoforms in Human Neuroblastoma Cells by PA Loomis, TH Howard, RP Castleberry, and LI Binder; 1990 November 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=54968

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Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma by Xao X. Tang, Huaqing Zhao, Marjorie E. Robinson, Brian Cohen, Avital Cnaan, Wendy London, Susan L. Cohn, Nai-Kong V.

Studies 123

Cheung, Garrett M. Brodeur, Audrey E. Evans, and Naohiko Ikegaki; 2000 September 26 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=27127 ·

Inactivation of the NF1 Gene in Human Melanoma and Neuroblastoma Cell Lines Without Impaired Regulation of GTP[center dot]Ras by MR Johnson, AT Look, JE DeClue, MB Valentine, and DR Lowy; 1993 June 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=46756

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MYCN is Retained in Single Copy at Chromosome 2 Band p23-24 During Amplification in Human Neuroblastoma Cells by R Corvi, LC Amler, L Savelyeva, M Gehring, and M Schwab; 1994 June 7 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=44028

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Normal Human Serum Contains a Natural IgM Antibody Cytotoxic for Human Neuroblastoma Cells by MW Ollert, K David, C Schmitt, A Hauenschild, R Bredehorst, R Erttmann, and C Vogel; 1996 April 30 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=39567

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Olfactory Neuroblastoma is a Peripheral Primitive Neuroectodermal Tumor Related to Ewing Sarcoma by PHB Sorensen, JK Wu, KW Berean, JF Lim, W Donn, HF Frierson, CP Reynolds, D Lopez-Terrada, and TJ Triche; 1996 February 6 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=40026

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Overexpression of Nonconvertible PrPc[Delta]114 --121 in ScrapieInfected Mouse Neuroblastoma Cells Leads to trans-Dominant Inhibition of Wild-Type PrPSc Accumulation by Christina Holscher, Hajo Delius, and Alexander Burkle; 1998 February http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=124590

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Phosphatidylinositol 3-Kinase, Cdc42, and Rac1 Act Downstream of Ras in Integrin-Dependent Neurite Outgrowth in N1E-115 Neuroblastoma Cells by Shula Sarner, Robert Kozma, Sohail Ahmed, and Louis Lim; 2000 January 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=85071

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Potential Dengue Virus-Triggered Apoptotic Pathway in Human Neuroblastoma Cells: Arachidonic Acid, Superoxide Anion, and NF[kappa]B Are Sequentially Involved by Jia-Tsrong Jan, Bor-Horng Chen, Shiou-Hwa Ma, Chiu-I Liu, Hui-Ping Tsai, Han-Chung Wu, Shian-Yuan Jiang, Kuen-Der Yang, and Men-Fang Shaio; 2000 September 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=116379

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Retinoic Acid Receptor [gamma]1 (RAR[gamma]1) Levels Control RAR[beta]2 Expression in SK-N-BE2(c) Neuroblastoma Cells and Regulate a Differentiation-Apoptosis Switch by Nicoletta Ferrari, Magnus Pfahl, and Giovanni Levi; 1998 November http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=109234

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Reversible Structural Alterations of Undifferentiated and Differentiated Human Neuroblastoma Cells Induced by Phorbol Ester by IS Tint, EM Bonder, HH Feder, CP Reboulleau, JM Vasiliev, and IM Gelfand; 1992 September 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=49876

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Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody by Masato Enari, Eckhard Flechsig, and Charles Weissmann; 2001 July 31 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=55414

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Scrapie Prions Selectively Modify the Stress Response in Neuroblastoma Cells by J Tatzelt, J Zuo, R Voellmy, M Scott, U Hartl, SB Prusiner, and WJ Welch; 1995 March 28 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=42335

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Serologic Response to the Borrelia burgdorferi Flagellin Demonstrates an Epitope Common to a Neuroblastoma Cell Line by E Fikrig, R Berland, M Chen, S Williams, LH Sigal, and RA Flavell; 1993 January 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=45624

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Successful Transmission of Three Mouse-Adapted Scrapie Strains to Murine Neuroblastoma Cell Lines Overexpressing Wild-Type Mouse Prion Protein by Noriyuki Nishida, David A. Harris, Didier Vilette, Hubert Laude, Yveline Frobert, Jacques Grassi, Danielle Casanova, Ollivier Milhavet, and Sylvain Lehmann; 2000 January 1 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=111542

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The [gamma]134.5 Gene of Herpes Simplex Virus 1 Precludes Neuroblastoma Cells from Triggering Total Shutoff of Protein Synthesis Characteristic of Programed Cell Death in Neuronal Cells by J Chou and B Roizman; 1992 April 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=48847

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Wild-Type p53 Protein Undergoes Cytoplasmic Sequestration in Undifferentiated Neuroblastomas but not Differentiated Tumors by UM Moll, M LaQuaglia, J Benard, and G Riou; 1995 May 9 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=41953

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

111In-pentetreotide versus bone scintigraphy in the detection of bony metastases of neuroblastoma. Author(s): Juweid ME, Menda Y, O'Dorisio MS, Bushnell D, Blake M, Madsen M, Johnson J, Graham MM. Source: Nuclear Medicine Communications. 2002 October; 23(10): 983-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12352597&dopt=Abstract

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6R-Tetrahydrobiopterin induces dopamine synthesis in a human neuroblastoma cell line, LA-N-1. A cellular model of DOPA-responsive dystonia. Author(s): Zuddas A, Mancosu C, Lilliu V, Sorrentino G, di Porzio U, Cianchetti C.

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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126 Neuroblastoma

Source: Brain Research. 2002 July 12; 943(2): 257-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12101048&dopt=Abstract ·

A brief commentary on "Chromosomal aberrations in neuroblastoma cell lines identified by cross species color banding and chromosome painting". Author(s): Vandesompele J, Speleman F. Source: Cancer Genetics and Cytogenetics. 2002 June; 135(2): 196. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12127407&dopt=Abstract

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A case of primary cerebral neuroblastoma in adolescence. Author(s): White BD, Pozza CH, Davies R, Hanieh A. Source: Australasian Radiology. 2002 March; 46(1): 60-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11966589&dopt=Abstract

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A rapid, nongenomic action of glucocorticoids in rat B103 neuroblastoma cells. Author(s): Han JZ, Lin W, Lou SJ, Qiu J, Chen YZ. Source: Biochimica Et Biophysica Acta. 2002 August 19; 1591(1-3): 21-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12183051&dopt=Abstract

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A single mutation in the E2 glycoprotein important for neurovirulence influences binding of sindbis virus to neuroblastoma cells. Author(s): Lee P, Knight R, Smit JM, Wilschut J, Griffin DE. Source: Journal of Virology. 2002 June; 76(12): 6302-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12021363&dopt=Abstract

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Accelerated Differentiation in Response to Retinoic Acid After Retrovirally Mediated Gene Transfer of GAP-43 into Mouse Neuroblastoma Cells. Author(s): Morton AJ, Buss TN. Source: The European Journal of Neuroscience. 1992; 4(10): 910-916. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12106426&dopt=Abstract

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Accumulation of N-CAM 180 at Contact Sites Between Neuroblastoma Cells and Latex Beads Coated with Extracellular Matrix Molecules. Author(s): Pollerberg GE, Nolte C, Schachner M. Source: The European Journal of Neuroscience. 1990; 2(10): 879-887. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12106095&dopt=Abstract

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Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines. Author(s): Miyake I, Hakomori Y, Shinohara A, Gamou T, Saito M, Iwamatsu A, Sakai R. Source: Oncogene. 2002 August 29; 21(38): 5823-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12185581&dopt=Abstract

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Activation of the phosphatidylinositol 3-kinase/Akt signaling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells. Author(s): Lopez-Carballo G, Moreno L, Masia S, Perez P, Barettino D. Source: The Journal of Biological Chemistry. 2002 July 12; 277(28): 25297304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12000752&dopt=Abstract

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Adrenocorticotropic hormone in the aetiology and regression of neuroblastoma. Author(s): Tucker G. Source: Medical Hypotheses. 2002 August; 59(2): 117. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12208196&dopt=Abstract

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All-trans-retinoic acid induces nuclear factor kappaB activation and matrix metalloproteinase-9 expression and enhances basement membrane invasivity of differentiation-resistant human SK-N-BE 9N neuroblastoma Cells. Author(s): Farina AR, Masciulli MP, Tacconelli A, Cappabianca L, De Santis G, Gulino A, Mackay AR.

128 Neuroblastoma

Source: Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research. 2002 August; 13(8): 34354. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12193473&dopt=Abstract ·

Amino acid transport in a human neuroblastoma cell line is regulated by the type I insulin-like growth factor receptor. Author(s): Wang HS, Wasa M, Okada A. Source: Life Sciences. 2002 May 31; 71(2): 127-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12031683&dopt=Abstract

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Amplified MYCN in human neuroblastoma: paradigm for the translation of molecular genetics to clinical oncology. Author(s): Schwab M. Source: Annals of the New York Academy of Sciences. 2002 June; 963: 6373. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12095930&dopt=Abstract

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Analysis of cytogenetic aberrations in esthesioneuroblastomas by comparative genomic hybridization. Author(s): Riazimand SH, Brieger J, Jacob R, Welkoborsky HJ, Mann WJ. Source: Cancer Genetics and Cytogenetics. 2002 July 1; 136(1): 53-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12165452&dopt=Abstract

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Anandamide-induced neuroblastoma cell rounding via the CB1 cannabinoid receptors. Author(s): Ishii I, Chun J. Source: Neuroreport. 2002 April 16; 13(5): 593-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11973452&dopt=Abstract

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Antiproliferative effect of nitric oxide on epidermal growth factorresponsive human neuroblastoma cells. Author(s): Murillo-Carretero M, Ruano MJ, Matarredona ER, Villalobo A, Estrada C.

Studies 129

Source: Journal of Neurochemistry. 2002 October; 83(1): 119-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12358735&dopt=Abstract ·

Antisense peptide nucleic acids conjugated to somatostatin analogs and targeted at the n-myc oncogene display enhanced cytotoxity to human neuroblastoma IMR32 cells expressing somatostatin receptors. Author(s): Sun L, Fuselier J, Murphy W, Coy D. Source: Peptides. 2002 September; 23(9): 1557. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12217415&dopt=Abstract

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Association of galectin-1- but not galectin-3-dependent parameters with proliferation activity in human neuroblastomas and small cell lung carcinomas. Author(s): Gabius HJ, Andre S, Gunsenhauser I, Kaltner H, Kayser G, Kopitz J, Lahm H, Harms D, Szymas J, Kayser K. Source: Anticancer Res. 2002 January-February; 22(1A): 405-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12017323&dopt=Abstract

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ATP-driven, Na(+)-independent inward Cl- pumping in neuroblastoma cells. Author(s): Bettendorff L, Lakaye B, Margineanu I, Grisar T, Wins P. Source: Journal of Neurochemistry. 2002 May; 81(4): 792-801. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12065638&dopt=Abstract

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Biologically relevant orthotopic neuroblastoma xenograft models: primary adrenal tumor growth and spontaneous distant metastasis. Author(s): Khanna C, Jaboin JJ, Drakos E, Tsokos M, Thiele CJ. Source: In Vivo. 2002 March-April; 16(2): 77-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12073775&dopt=Abstract

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Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I. Author(s): Yowler BC, Kensinger RD, Schengrund CL.

130 Neuroblastoma

Source: The Journal of Biological Chemistry. 2002 September 6; 277(36): 32815-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12089155&dopt=Abstract ·

Breakpoint position on 17q identifies the most aggressive neuroblastoma tumors. Author(s): Lastowska M, Cotterill S, Bown N, Cullinane C, Variend S, Lunec J, Strachan T, Pearson AD, Jackson MS. Source: Genes, Chromosomes & Cancer. 2002 August; 34(4): 428-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12112532&dopt=Abstract

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Breast-feeding and neuroblastoma, USA and Canada. Author(s): Daniels JL, Olshan AF, Pollock BH, Shah NR, Stram DO. Source: Cancer Causes & Control : Ccc. 2002 June; 13(5): 401-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12146844&dopt=Abstract

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Bupivacaine inhibits human neuronal Kv3 channels in SH-SY5Y human neuroblastoma cells. Author(s): Friederich P, Benzenberg D, Urban BW. Source: British Journal of Anaesthesia. 2002 June; 88(6): 864-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12173206&dopt=Abstract

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Ca(2+) stores and capacitative Ca(2+) entry in human neuroblastoma (SH-SY5Y) cells expressing a familial Alzheimer's disease presenilin-1 mutation. Author(s): Smith IF, Boyle JP, Vaughan PF, Pearson HA, Cowburn RF, Peers CS. Source: Brain Research. 2002 September 13; 949(1-2): 105-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12213305&dopt=Abstract

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Ca(2+)-independent caspase-3 but not Ca(2+)-dependent caspase-2 activation induced by oxidative stress leads to SH-SY5Y human neuroblastoma cell apoptosis. Author(s): Amoroso S, D'Alessio A, Sirabella R, Di Renzo G, Annunziato L.

Studies 131

Source: Journal of Neuroscience Research. 2002 May 15; 68(4): 454-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11992472&dopt=Abstract ·

Caffeine induces apoptosis in human neuroblastoma cell line sk-N-mc. Author(s): Jang MH, Shin MC, Kang IS, Baik HH, Cho YH, Chu JP, Kim EH, Kim CJ. Source: Journal of Korean Medical Science. 2002 October; 17(5): 674-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12378022&dopt=Abstract

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Calretinin and calbindin D-28k, but not parvalbumin protect against glutamate-induced delayed excitotoxicity in transfected N18-RE 105 neuroblastoma-retina hybrid cells. Author(s): D'Orlando C, Celio MR, Schwaller B. Source: Brain Research. 2002 August 2; 945(2): 181-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12126880&dopt=Abstract

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Caspase 3 expression is altered in a coculture model of neuroblastoma. Author(s): Beierle EA, Dai W, Langham MR Jr, Copeland EM 3rd, Chen MK. Source: The Journal of Surgical Research. 2002 August; 106(2): 323-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12175987&dopt=Abstract

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cGMP/protein kinase G-dependent inhibition of N-type Ca2+ channels induced by nitric oxide in human neuroblastoma IMR32 cells. Author(s): D'Ascenzo M, Martinotti G, Azzena GB, Grassi C. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2002 September 1; 22(17): 7485-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12196571&dopt=Abstract

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Challenge of therapy in advanced neuroblastoma. Author(s): Lai HS. Source: Acta Paediatr Taiwan. 2002 March-April; 43(2): 65-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12041618&dopt=Abstract

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Characteristics and outcome of thoracic neuroblastoma. Author(s): Haberle B, Hero B, Berthold F, von Schweinitz D. Source: European Journal of Pediatric Surgery : Official Journal of Austrian Association of Pediatric Surgery . [et Al] = Zeitschrift Fur Kinderchirurgie. 2002 June; 12(3): 145-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12101494&dopt=Abstract

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Characterization of a Voltage-dependent Calcium Current in the Human Neuroblastoma Cell Line SH-SY5Y During Differentiation. Author(s): Toselli M, Masetto S, Rossi P, Taglietti V. Source: The European Journal of Neuroscience. 1991 June; 3(6): 514-522. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12106483&dopt=Abstract

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Characterization of cholera toxin B subunit-induced Ca2+ influx in neuroblastoma cells: Evidence for a voltage-independent GM1 ganglioside-associated Ca2+ channel. Author(s): Fang Y, Xie X, Ledeen RW, Wu G. Source: Journal of Neuroscience Research. 2002 September 1; 69(5): 66980. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12210833&dopt=Abstract

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Characterization of F-actin depolymerization as a major toxic event induced by pectenotoxin-6 in neuroblastoma cells. Author(s): Leira F, Cabado AG, Vieytes MR, Roman Y, Alfonso A, Botana LM, Yasumoto T, Malaguti C, Rossini GP. Source: Biochemical Pharmacology. 2002 June 1; 63(11): 1979-88. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12093474&dopt=Abstract

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Characterization of L-glutamine transport by a human neuroblastoma cell line. Author(s): Wasa M, Wang HS, Okada A. Source: American Journal of Physiology. Cell Physiology. 2002 June; 282(6): C1246-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11997238&dopt=Abstract

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Cholesterol-dependent modulation of the toxicity of HIV-1 coat protein gp120 in human neuroblastoma cells.

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Author(s): Maccarrone M, Navarra M, Catani V, Corasaniti MT, Bagetta G, Finazzi-Agro A. Source: Journal of Neurochemistry. 2002 September; 82(6): 1444-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12354292&dopt=Abstract ·

Chronic neuroblastoma. Author(s): Kushner BH, Kramer K, Cheung NK. Source: Cancer. 2002 September 15; 95(6): 1366-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12216106&dopt=Abstract

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Chronic treatment with nicotine or potassium attenuates depolarisation-evoked noradrenaline release from the human neuroblastoma SH-SY5Y. Author(s): Agis-Torres A, Ball SG, Vaughan PF. Source: Neuroscience Letters. 2002 October 18; 331(3): 167-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12383923&dopt=Abstract

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CHS 828 inhibits neuroblastoma growth in mice alone and in combination with antiangiogenic drugs. Author(s): Svensson A, Backman U, Jonsson E, Larsson R, Christofferson R. Source: Pediatric Research. 2002 May; 51(5): 607-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11978885&dopt=Abstract

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Circulating MYCN DNA as a tumor-specific marker in neuroblastoma patients. Author(s): Combaret V, Audoynaud C, Iacono I, Favrot MC, Schell M, Bergeron C, Puisieux A. Source: Cancer Research. 2002 July 1; 62(13): 3646-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12097268&dopt=Abstract

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Coeliac disease and ganglioneuroblastoma: an unusual association. Author(s): Barbato M, Clerico A, Viola F, Dito L, Schiavetti A, Cucchiara S.

134 Neuroblastoma

Source: Medical and Pediatric Oncology. 2002 September; 39(3): 215-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12210456&dopt=Abstract ·

Co-expression of trkA and p75 neurotrophin receptor in extracranial olfactory neuroblastoma cells. Author(s): Zhao SP, Zhou XF. Source: Neuropathology and Applied Neurobiology. 2002 August; 28(4): 301-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12175342&dopt=Abstract

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Comparison of forward planned conformal radiation therapy and inverse planned intensity modulated radiation therapy for esthesioneuroblastoma. Author(s): Zabel A, Thilmann C, Zuna I, Schlegel W, Wannenmacher M, Debus J. Source: The British Journal of Radiology. 2002 April; 75(892): 356-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12000695&dopt=Abstract

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Comparison of the cell immunophenotype of metastatic and primary foci in stage IV-S neuroblastoma. Author(s): Nowicki M, Miskowiak B. Source: Folia Histochem Cytobiol. 2002; 40(3): 297-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12219840&dopt=Abstract

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Complicated mechanisms of class II transactivator transcription deficiency in small cell lung cancer and neuroblastoma. Author(s): Yazawa T, Ito T, Kamma H, Suzuki T, Okudela K, Hayashi H, Horiguchi H, Ogata T, Mitsui H, Ikeda M, Kitamura H. Source: American Journal of Pathology. 2002 July; 161(1): 291-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12107114&dopt=Abstract

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Computer graphic to design the esthesioneuroblastoma. Author(s): Burekhovich S, Ghosh BC.

approach

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Studies 135

Source: Journal of Surgical Oncology. 2002 August; 80(4): 222-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12210038&dopt=Abstract ·

Congenital heart disease and neuroblastoma: just coincidence? Author(s): Holzer R, Franklin RC. Source: Archives of Disease in Childhood. 2002 July; 87(1): 61-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12089127&dopt=Abstract

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Constitutively Active NFkappa B Is Required for the Survival of S-type Neuroblastoma. Author(s): Bian X, Opipari AW Jr, Ratanaproeksa AB, Boitano AE, Lucas PC, Castle VP. Source: The Journal of Biological Chemistry. 2002 November 1; 277(44): 42144-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12198114&dopt=Abstract

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Contemporary therapeutic options for children with high risk neuroblastoma. Author(s): Sterba J. Source: Neoplasma. 2002; 49(3): 133-40. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12097996&dopt=Abstract

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Contribution of HPLC mass screening for neuroblastoma to a decrease in mortality. Author(s): Nishi M, Takeda T, Hatae Y, Hanai J, Fujita K, Ichimiya H, Tanaka T. Source: J Exp Clin Cancer Res. 2002 March; 21(1): 73-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12071533&dopt=Abstract

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Co-occurrence of neuroblastoma and nephroblastoma in an infant with Fanconi's anemia. Author(s): Bissig H, Staehelin F, Tolnay M, Avoledo P, Richter J, Betts D, Bruder E, Kuhne T.

136 Neuroblastoma

Source: Human Pathology. 2002 October; 33(10): 1047-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12395380&dopt=Abstract ·

Correspondence re: J. Mora et al., Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell. Cancer Res., 61: 6892-6898, 2001. Author(s): Shimada H. Source: Cancer Research. 2002 May 15; 62(10): 2987-8; Discussion 2988-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12025836&dopt=Abstract

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CpG-oligodeoxynucleotide rejection of a neuroblastoma in A/J mice does not induce a paraneoplastic disease. Author(s): Auf G, Chen L, Fornes P, Le Clanche C, Delattre JY, Carpentier AF. Source: Neuroscience Letters. 2002 July 26; 327(3): 189-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12113909&dopt=Abstract

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Cyclin D1-dependent regulation of B-myb activity in early stages of neuroblastoma differentiation. Author(s): Cesi V, Tanno B, Vitali R, Mancini C, Giuffrida ML, Calabretta B, Raschella G. Source: Cell Death and Differentiation. 2002 November; 9(11): 1232-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12404122&dopt=Abstract

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Dendritic cells for NK/LAK activation: rationale for multicellular immunotherapy in neuroblastoma patients. Author(s): Valteau-Couanet D, Leboulaire C, Maincent K, Tournier M, Hartmann O, Benard J, Beaujean F, Boccaccio C, Zitvogel L, Angevin E. Source: Blood. 2002 October 1; 100(7): 2554-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12239169&dopt=Abstract

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Detection of N-myc amplification by FISH in immature areas of fixed neuroblastomas: more efficient than Southern blot/PCR. Author(s): Sartelet H, Grossi L, Pasquier D, Combaret V, Bouvier R, Ranchere D, Plantaz D, Munzer M, Philip T, Birembaut P, Zahm JM, Bergeron C, Gaillard D, Pasquier B.

Studies 137

Source: The Journal of Pathology. 2002 September; 198(1): 83-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12210067&dopt=Abstract ·

Detection procedures for neuroblastoma cells metastatic to blood and bone marrow: blinded comparison of chromogranin A heminested reverse transcription polymerase chain reaction to tyrosine hydroxylase nested reverse transcription polymerase chain reaction and to anti-GD2 immunocytology. Author(s): Pagani A, Macri L, Faulkner LB, Tintori V, Paoli A, Garaventa A, Bussolati G. Source: Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B. 2002 June; 11(2): 98-106. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12045713&dopt=Abstract

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Determination of brevetoxins in shellfish by the neuroblastoma assay. Author(s): Truman P, Stirling DJ, Northcote P, Lake RJ, Seamer C, Hannah DJ. Source: J Aoac Int. 2002 September-October; 85(5): 1057-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12374404&dopt=Abstract

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Disparity between ionic mediators of volume regulation and apoptosis in N1E 115 mouse neuroblastoma cells. Author(s): O'Reilly N, Xia Z, Fiander H, Tauskela J, Small DL. Source: Brain Research. 2002 July 12; 943(2): 245-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12101047&dopt=Abstract

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Distinct cytogenetic pathways of advanced-stage neuroblastoma tumors, detected by spectral karyotyping. Author(s): Stark B, Jeison M, Bar-Am I, Glaser-Gabay L, Mardoukh J, Luria D, Feinmesser M, Goshen Y, Stein J, Abramov A, Zaizov R, Yaniv I. Source: Genes, Chromosomes & Cancer. 2002 July; 34(3): 313-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12007192&dopt=Abstract

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Double High-dose Chemotherapy with Autologous Stem Cell Transplantation in Patients with High-risk Neuroblastoma: A Pilot Study in a Single Center.

138 Neuroblastoma

Author(s): Sung KW, Yoo KH, Chung EH, Cho EJ, Jung HL, Koo HH, Lee SK, Lim do H, Kim DY, Kim DW, Kim HR, Kim SW. Source: Journal of Korean Medical Science. 2002 August; 17(4): 537-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12172052&dopt=Abstract ·

Doxorubicin resistant neuroblastoma cells secrete factors that activate AKT and attenuate cytotoxicity in drug-sensitive cells. Author(s): Emran MA, Rebbaa A, Mirkin BL. Source: Cancer Letters. 2002 August 8; 182(1): 53-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12175523&dopt=Abstract

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Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells. Author(s): Hopkins-Donaldson S, Yan P, Bourloud KB, Muhlethaler A, Bodmer JL, Gross N. Source: Oncogene. 2002 September 5; 21(39): 6132-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12203125&dopt=Abstract

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Dynamic change of neural cell adhesion molecule polysialylation on human neuroblastoma (IMR-32) and rat pheochromocytoma (PC-12) cells during growth and differentiation. Author(s): Poongodi GL, Suresh N, Gopinath SC, Chang T, Inoue S, Inoue Y. Source: The Journal of Biological Chemistry. 2002 August 2; 277(31): 28200-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12023285&dopt=Abstract

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Ectopic expression of necdin induces differentiation of mouse neuroblastoma cells. Author(s): Kobayashi M, Taniura H, Yoshikawa K. Source: The Journal of Biological Chemistry. 2002 November 1; 277(44): 42128-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12198120&dopt=Abstract

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Effects of 60 Hz electromagnetic field exposure on APP695 transcription levels in differentiating human neuroblastoma cells. Author(s): Rao RR, Halper J, Kisaalita WS.

Studies 139

Source: Bioelectrochemistry (Amsterdam, Netherlands). 2002 July; 57(1): 9-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12049751&dopt=Abstract ·

Effects of gravitational and magnetic fields on transplanted neuroblastoma vascularity. Author(s): Batkin S, Tabrah FL. Source: Life Sci Space Res. 1978; 16: 63-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11965662&dopt=Abstract

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Effects of irradiated tumor vaccine and continuous localized infusion of granulocyte-macrophage colony-stimulating factor on neuroblastomas in mice. Author(s): Chen Y, Lin SM, Lai HS, Tseng SH, Chen WJ. Source: Journal of Pediatric Surgery. 2002 September; 37(9): 1298-304. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12194120&dopt=Abstract

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Efficacy and toxicity of a virus-directed enzyme prodrug therapy purging method: preclinical assessment and application to bone marrow samples from neuroblastoma patients. Author(s): Wagner LM, Guichard SM, Burger RA, Morton CL, Straign CM, Ashmun RA, Harris LC, Houghton PJ, Potter PM, Danks MK. Source: Cancer Research. 2002 September 1; 62(17): 5001-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12208753&dopt=Abstract

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Endogenous receptor for melanin-concentrating hormone in human neuroblastoma Kelly cells. Author(s): Schlumberger S, Jaggin V, Tanner H, Eberle A. Source: Biochemical and Biophysical Research Communications. 2002 October 18; 298(1): 54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12379219&dopt=Abstract

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Endoscopic removal of esthesioneuroblastoma. Author(s): Cakmak O, Ergin NT, Yilmazer C, Kayaselcuk F, Barutcu O.

140 Neuroblastoma

Source: International Journal of Pediatric Otorhinolaryngology. 2002 July 9; 64(3): 233-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12090952&dopt=Abstract ·

Endothelins may modulate invasion and proliferation of Ewing's sarcoma and neuroblastoma. Author(s): Berry P, Burchill S. Source: Clinical Science (London, England : 1979). 2002 September 1; 103 Suppl 1: 322S-6S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12193114&dopt=Abstract

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Establishment of cisplatin-resistant variants of human neuroblastoma cell lines, TGW and GOTO, and their drug cross-resistance profiles. Author(s): Iwasaki I, Sugiyama H, Kanazawa S, Hemmi H. Source: Cancer Chemotherapy and Pharmacology. 2002 October; 50(4): 341. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12357310&dopt=Abstract

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Esthesioneuroblastoma in children. Author(s): Kumar M, Fallon RJ, Hill JS, Davis MM. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2002 AugustSeptember; 24(6): 482-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12218598&dopt=Abstract

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Esthesioneuroblastoma: case report. Author(s): Gondim J, Ramos F Jr, Azevedo J, Carrero FP Jr, Tella OI Jr. Source: Arquivos De Neuro-Psiquiatria. 2002 June; 60(2-A): 303-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12068366&dopt=Abstract

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Esthesioneuroblastoma: irradiation alone and surgery alone are not enough. Author(s): Gruber G, Laedrach K, Baumert B, Caversaccio M, Raveh J, Greiner R.

Studies 141

Source: International Journal of Radiation Oncology, Biology, Physics. 2002 October 1; 54(2): 486-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12243826&dopt=Abstract ·

Estrogen receptor ligands affect mitochondrial activity in SH-SY5Y human neuroblastoma cells. Author(s): Simpson PB, Woollacott AJ, Moneer Z, Rand V, Seabrook GR. Source: Neuroreport. 2002 May 24; 13(7): 957-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12004198&dopt=Abstract

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Evoked intracellular Ca2+ elevations in HT4 neuroblastoma cells. Author(s): Han JZ, Lin W, Chen YZ. Source: Neuroreport. 2002 June 12; 13(8): 1089-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12060815&dopt=Abstract

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Evolving significance of prognostic markers associated with treatment improvement in patients with stage 4 neuroblastoma. Author(s): Mora J, Gerald WL, Qin J, Cheung NK. Source: Cancer. 2002 May 15; 94(10): 2756-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12173347&dopt=Abstract

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Expression of folate sensitive and aphidicolin induced chromosomal fragile sites in familial neuroblastoma. Author(s): Ankathil R, Kusumakumary P, Priyakumary T, Krishnan Nair M. Source: J Exp Clin Cancer Res. 2002 September; 21(3): 383-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12385582&dopt=Abstract

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Expression of insulin-like growth factor-binding protein 5 in neuroblastoma cells is regulated at the transcriptional level by c-Myb and B-Myb via direct and indirect mechanisms. Author(s): Tanno B, Negroni A, Vitali R, Pirozzoli MC, Cesi V, Mancini C, Calabretta B, Raschella G.

142 Neuroblastoma

Source: The Journal of Biological Chemistry. 2002 June 28; 277(26): 2317280. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11973331&dopt=Abstract ·

Expression of prolactin receptors and regulation of cell proliferation by prolactin, corticotropin-releasing factor, and corticosterone in a neuroblastoma cell line. Author(s): Mohammad YN, Perone M, Wang L, Ingleton PM, Castro MG, Lovejoy DA. Source: Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire. 2002; 80(4): 475-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12234101&dopt=Abstract

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Expression of prolactin-releasing peptide and its receptor in the human adrenal glands and tumor tissues of adrenocortical tumors, pheochromocytomas and neuroblastomas. Author(s): Takahashi K, Totsune K, Murakami O, Sone M, Noshiro T, Hayashi Y, Sasano H, Shibahara S. Source: Peptides. 2002 June; 23(6): 1135-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12126742&dopt=Abstract

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Expression of the periostin mRNA level in neuroblastoma. Author(s): Sasaki H, Sato Y, Kondo S, Fukai I, Kiriyama M, Yamakawa Y, Fuji Y. Source: Journal of Pediatric Surgery. 2002 September; 37(9): 1293-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12194119&dopt=Abstract

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Flavopiridol inhibits vascular endothelial growth factor production induced by hypoxia or picolinic acid in human neuroblastoma. Author(s): Rapella A, Negrioli A, Melillo G, Pastorino S, Varesio L, Bosco MC. Source: International Journal of Cancer. Journal International Du Cancer. 2002 June 10; 99(5): 658-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12115498&dopt=Abstract

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Fluorescence in situ hybridization analyses of chromosome band 1p36 in neuroblastoma detect two classes of alterations.

Studies 143

Author(s): Spitz R, Hero B, Westermann F, Ernestus K, Schwab M, Berthold F. Source: Genes, Chromosomes & Cancer. 2002 July; 34(3): 299-305. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12007190&dopt=Abstract ·

Frequent low level expression in Ewing sarcoma family tumors and widespread absence of the metastasis suppressor KAI1/CD82 in neuroblastoma. Author(s): Aryee DN, Ambros I, Ambros PF, Muehlbacher K, Luegmayr A, Yoshie O, Kovar H. Source: Pediatric Research. 2002 August; 52(2): 279-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12149507&dopt=Abstract

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GADD153 and 12-lipoxygenase mediate fenretinide-induced apoptosis of neuroblastoma. Author(s): Lovat PE, Oliverio S, Ranalli M, Corazzari M, Rodolfo C, Bernassola F, Aughton K, Maccarrone M, Hewson QD, Pearson AD, Melino G, Piacentini M, Redfern CP. Source: Cancer Research. 2002 September 15; 62(18): 5158-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12234979&dopt=Abstract

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Gastrin-releasing peptide is a growth factor for human neuroblastomas. Author(s): Kim S, Hu W, Kelly DR, Hellmich MR, Evers BM, Chung DH. Source: Annals of Surgery. 2002 May; 235(5): 621-9; Discussion 629-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11981207&dopt=Abstract

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Genetic parameters of neuroblastomas. Author(s): Westermann F, Schwab M. Source: Cancer Letters. 2002 October 28; 184(2): 127-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12127685&dopt=Abstract

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Genome-wide expression profiling of 8-chloroadenosine- and 8-chlorocAMP-treated human neuroblastoma cells using radioactive human cDNA microarray. Author(s): Park GH, Choe J, Choo HJ, Park YG, Sohn J, Kim MK.

144 Neuroblastoma

Source: Experimental & Molecular Medicine. 2002 July 31; 34(3): 184-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12216110&dopt=Abstract ·

Genotypic m3-Muscarinic Receptors Preferentially Inhibit M-currents in DNA-transfected NG108-15 Neuroblastoma x Glioma Hybrid Cells. Author(s): Robbins J, Caulfield MP, Higashida H, Brown DA. Source: The European Journal of Neuroscience. 1991; 3(8): 820-824. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12106468&dopt=Abstract

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Glial cell line-derived neurotrophic factor up-regulates the expression of tyrosine hydroxylase gene in human neuroblastoma cell lines. Author(s): Xiao H, Hirata Y, Isobe K, Kiuchi K. Source: Journal of Neurochemistry. 2002 August; 82(4): 801-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12358785&dopt=Abstract

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Glucocorticoids induce neuroendocrine cell differentiation and increase expression of N-myc in N-type human neuroblastoma cells. Author(s): Ross RA, Hein AM, Braca JA 3rd, Spengler BA, Biedler JL, Scammell JG. Source: Oncol Res. 2002; 13(2): 87-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12392156&dopt=Abstract

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Glutathione S-transferase and P-glycoprotein expressions in neuroblastoma. Author(s): Kutlik MT, Ayhan A, Gogus S, Yalcin B, Caglar M, Buyukpamukcu M. Source: Pediatric Hematology and Oncology. 2002 July-August; 19(5): 337-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12078865&dopt=Abstract

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Hydroxyl free radicals induce cell differentiation in SK-N-MC neuroblastoma cells. Author(s): Oravecz K, Kalka D, Jeney F, Cantz M, Zs-Nagy I. Source: Tissue & Cell. 2002 February; 34(1): 33-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11989968&dopt=Abstract

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Hypercalcemia induced by 13-cis-retinoic acid in a patient with neuroblastoma. Author(s): Belden TL, Ragucci DP. Source: Pharmacotherapy. 2002 May; 22(5): 645-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12013365&dopt=Abstract

Vocabulary Builder Adenocarcinoma: Cancer that begins in cells that line certain internal organs and that have glandular (secretory) properties. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]

Aetiology: Study of the causes of disease. [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiosarcoma: A type of cancer that begins in the lining of blood vessels. [NIH]

Anoikis: Apoptosis triggered by loss of contact with the extracellular matrix. [NIH] Antiangiogenic: vessels. [NIH]

Having to do with reducing the growth of new blood

Antigens: Substances that cause the immune system to make a specific immune response. [NIH] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Aphidicolin:

An antiviral antibiotic produced by Cephalosporium

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aphidicola and other fungi. It inhibits the growth of eukaryotic cells and certain animal viruses by selectively inhibiting the cellular replication of DNA polymerase II or the viral-induced DNA polymerases. The drug may be useful for controlling excessive cell proliferation in patients with cancer, psoriasis or other dermatitis with little or no adverse effect upon nonmultiplying cells. [NIH] Apoptosis: A normal series of events in a cell that leads to its death. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Borrelia: A genus of gram-negative, anaerobic, helical bacteria, various species of which produce relapsing fever in man and other animals. [NIH] Calcium: A mineral found in teeth, bones, and other body tissues. [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] Carcinogen: Any substance that causes cancer. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [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] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Chemoprotective: A quality of some drugs used in cancer treatment. Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [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]

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Cisplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] Collagen: A fibrous protein found in cartilage and other connective tissue. [NIH]

Colloids: Two-phase systems in which one is uniformly dispersed in another as particles small enough so they cannot be filtered or will not settle out. The dispersing or continuous phase or medium envelops the particles of the discontinuous phase. All three states of matter can form colloids among each other. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytotoxic: Cell-killing. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endothelium: The layer of epithelial cells that lines the cavities of the heart and of the blood and lymph vessels, and the serous cavities of the body, originating from the mesoderm. [EU] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] 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] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU]

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Extracellular: Outside a cell or cells. [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] Flagellin: A protein with a molecular weight of 40,000 isolated from bacterial flagella. At appropriate pH and salt concentration, three flagellin monomers can spontaneously reaggregate to form structures which appear identical to intact flagella. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [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] Glutamine: An amino acid used in nutrition therapy. It is also being studied for the treatment of diarrhea caused by radiation therapy to the pelvis. [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] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Hepatic: Refers to the liver. [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] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrogen: Hydrogen. The first chemical element in the periodic table. It has

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the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Immunity: The condition of being immune; the protection against infectious disease conferred either by the immune response generated by immunization or previous infection or by other nonimmunologic factors (innate i.). [EU] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: responses. [NIH]

Describes the ability to lower immune system

Immunotherapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also called biological therapy or biological response modifier (BRM) therapy. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] 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] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and -gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Intracellular: Inside a cell. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Lesion: An area of abnormal tissue change. [NIH] LH: A small glycoprotein hormone secreted by the anterior pituitary. LH plays an important role in controlling ovulation and in controlling secretion of hormones by the ovaries and testes. [NIH] Lipoxygenase:

An enzyme of the oxidoreductase class that catalyzes

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reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5-lipoxygenase, arachidonate 12lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [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] 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] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Mandible: The largest and strongest bone of the FACE constituting the lower jaw. It supports the lower teeth. [NIH] 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] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Cells in the skin that produce and contain the pigment called melanin. [NIH] Membrane: A very thin layer of tissue that covers a surface. [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] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] 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

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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] Necrosis: Refers to the death of living tissues. [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] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH]

Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neutrophil: A type of white blood cell. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Occult: Obscure; concealed from observation, difficult to understand. [EU] 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] Otorhinolaryngology: That branch of medicine concerned with medical and surgical treatment of the head and neck, including the ears, nose and throat. [EU]

Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as

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opposed to calendar age. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] 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 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] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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] 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] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Rectum: The last 8 to 10 inches of the large intestine. [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

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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] Retrospective: Looking back at events that have already taken place. [NIH] Scrapie: A fatal disease of the nervous system in sheep and goats, characterized by pruritus, debility, and locomotor incoordination. It is caused by proteinaceous infectious particles called prions. [NIH] Secretion: 1. the process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. any substance produced by secretion. [EU] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Stomach: An organ that is part of the digestive system. It helps in the digestion of food by mixing it with digestive juices and churning it into a thin liquid. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU]

Thoracic: Having to do with the chest. [NIH] 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] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [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] Xenograft: The cells of one species transplanted to another species. [NIH]

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Patents 155

CHAPTER 5. PATENTS ON NEUROBLASTOMA Overview You can learn about innovations relating to neuroblastoma 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.

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Patents on Neuroblastoma By performing a patent search focusing on neuroblastoma, 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 neuroblastoma: ·

Neuroblastoma-associated regulator gene Inventor(s): Ellmeier; Wilfried (Modling, AT), Weith; Andreas (Vienna, AT) Assignee(s): Boehringer Ingelheim International GmbH (DE), Genentech, Inc. (S. San Francisco, CA) Patent Number: 5,683,878 Date filed: June 6, 1995 Abstract: Disclosed is a gene situated in the region of the neuroblastoma consensus deletion 1p36.2-p36.1 which codes for a helix-loop-helix protein with the designation HEIR-1. The loss of this gene is significantly correlated with allelic tumor deletions in neuroblastomas and expression of this correlates inversely both N-myc overexpression in tumors and with N-myc expression in normal development. The cDNA and antibodies coding for HEIR-1 are used for the diagnosis of pathological conditions associated with aberration in the region of the neuroblastoma consensus deletion. Excerpt(s): The invention relates to a gene which is affected significantly by tumour-specific deletions in human neuroblastomas and is involved in tumorigenesis. ... Allelic deletions in specific regions of the genome, which occur significantly frequently in tumour genomes, are used as marking points for the position of tumour suppressor genes (Weinberg, 1991). In investigations of human neuroblastomas, a consensus deletion was defined in chromosome 1p36.2-p36.1 (Weith et al., 1989). The allelic loss of this section in about 80-90% of the tumours investigated led to the supposition that a gene which prevents tumours is located in this region. ... iii) is from a neuroblastoma patient. Web site: http://www.delphion.com/details?pn=US05683878__

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Patent Applications on Neuroblastoma 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).

Keeping Current In order to stay informed about patents and patent applications dealing with neuroblastoma, 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 “neuroblastoma” (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 neuroblastoma. You can also use this procedure to view pending patent applications concerning neuroblastoma. 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 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]

32

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

Books 159

CHAPTER 6. BOOKS ON NEUROBLASTOMA Overview This chapter provides bibliographic book references relating to neuroblastoma. You have many options to locate books on neuroblastoma. 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 neuroblastoma 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.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “neuroblastoma” (or synonyms) into the “For these words:” box. You will only receive results on books. You should check back periodically with this database which is updated every 3 months. The following is a typical result when searching for books on neuroblastoma: ·

Quantitative Methods for the Evaluation of Cancer Screening Source: New York, NY, Oxford University Press Inc., 161 p., 2001.

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Contact: Oxford University Press Inc., 198 Madison Avenue, New York, NY 10016. Summary: Quantitative Methods for the Evaluation of Cancer Screening grew out of a workshop in Paris held in 1997 under the direction of the Institut National de la Sante et de la Recherche Medicale. It presents an introduction to cancer screening and methods used for evaluating screening programs. Chapter topics include (1) a brief history of cancer screening evaluation techniques; (2) important influences on the effectiveness and costs to be considered in the evaluation of cancer screening; (3) contamination and noncompliance in screening trials; (4) evaluating periodic cancer screening without a randomized control group; (5) Markov chain models of breast tumor progression and its arrest by screening; (6) metastases at diagnosis as a key to understanding the natural history of breast cancer; (7) use of an illness-to-death model to predict the effects of different breast screening internals; (8) some practical considerations of screening, evaluating, and monitoring; (9) use of routine data to monitor and evaluate cervical screening; (10) interpretation of the effect of population screening using routine incidence and mortality data; (11) optimal use of Papanicolaou smear screening for cervical cancer; (12) population-based breast cancer screening programs; (13) assessment of a colorectal cancer screening program taking account of the natural history of the disease; and (14) screening for neuroblastoma in children. ·

Advances in Cancer Screening Source: Boston, MA, Kluwer Academic Publishers, 198 p., 1996. Contact: Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA 02061. Summary: Advances in Cancer Screening, a volume in the Cancer Treatment and Research series, determines the extent to which requirements for the introduction of population-based screening programs have been met, focusing on research from the last decade. Screening is important for cancer control, but it is potentially a major consumer of health care resources. The benefits from cancer screening are not always realized because of biological and organizational reasons. From the viewpoint of epidemiology, this book addresses (1) issues important to many cancer screening sites, (2) general principles that apply to screening, and (3) advances in the understanding of the genetic basis of some cancers. Chapter topics include (1) the public health basis of cancer screening; (2) the theoretical and economic basis of cancer screening; (3) advances in screening for cervical, colorectal, breast, prostate, gastric, and lung cancers; (4) advances in screening for

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melanoma and neuroblastoma; (5) screening for high-risk families; and (6) screening in developing countries. The book is intended to be a valuable resource for (1) everyone interested in cancer screening, (2) government and nongovernment organizations concerned with cancer control, (3) cancer researchers, and (4) members of national cancer societies. ·

Cancer Screening Source: Geneva, Switzerland, International Union Against Cancer (UICC), 438 p., 1991. Contact: Cambridge University Press, 40 West 20th Street, New York, NY 10011-4211. Summary: Cancer Screening, published by the International Union Against Cancer, provides papers presented at a Project on Evaluation of Screening for Cancer workshop. The workshop's goal was to update conclusions for screening of cancer sites previously considered and to evaluate some new sites. The monograph contains 10 sections of papers discussing international experiences with the current states of the art in screening for breast, colorectal, cervical, ovarian, malignant melanoma, prostate, neuroblastoma, stomach, and nasopharyngeal cancers. Researchers discuss screening organization, indications for and effects of organized screening, and screening evaluations. Researchers also report on results of screening trials in developing and in developed countries. The final section discusses methodological issues including recent developments in breast cancer screening modeling, surrogate measures in the design of breast screening trials, case-control studies of screening, and new approaches to the evaluation of screening. The workshop was held at Selwyn College, Cambridge, United Kingdom, on April 2 through 5, 1990.

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 “neuroblastoma” (or synonyms) into the search box, and select “books only.”

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From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:33 ·

Advances in neuroblastoma research: proceedings of the Third Symposium on Advances in Neuroblastoma Research held in the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, May 1984. Author: editors, Audrey E. Evans, Giulio J. D'Angio, Robert C. Se; Year: 1985; New York: Liss, c1985; ISBN: 0845150251 http://www.amazon.com/exec/obidos/ASIN/0845150251/icongroupin terna

·

Advances in neuroblastoma research 4: proceedings of the Sixth Symposium on Advances in Neuroblastoma Research, held in Philadelphia, Pennsylvania, May 13-15, 1993. Author: editors, Audrey E. Evans ... [et al.]; Year: 1994; New York: Wiley-Liss, c1994; ISBN: 0471014540 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/0471014540/icongroupin terna

·

Advances in neuroblastoma research. Author: editor, Audrey E. Evans; Year: 1980; New York: Raven Press, c1980; ISBN: 0890044597 http://www.amazon.com/exec/obidos/ASIN/0890044597/icongroupin terna

·

Apparently beneficial effects of concurrent infections, inflammation or fever, and of bacterial toxin therapy on neuroblastoma [by] George A. Fowler and Helen C. Nauts. Author: Fowler, George A., 1914-; Year: 1970; New York, 1970

·

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

·

Desensitization of muscarinic cholinergic receptor-mediated cyclic guanosine 3',5'-monophosphate formation in mouse neuroblastoma

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

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cells. Author: by Lee-Yuan Liu-Chen; Year: 1980; [Minneapolis?: s.n.], 1980 ·

Human neuroblastoma: recent advances in clinical and genetic analysis. Author: editor, Manfred Schwab; co-editors, Gian Paolo Tonini and Jean Bénard; Year: 1993; Chur; Philadelphia: Harwood Academic Publishers, c1993; ISBN: 3718653532 http://www.amazon.com/exec/obidos/ASIN/3718653532/icongroupin terna

·

Molecular biology and genetics of childhood cancers: approaches to neuroblastoma. Author: editors, M. Sluyser and A. Voûte [sic]; Year: 1988; Chichester: E. Horwood; New York: Halsted Press, 1988; ISBN: 0470212373 (Halsted Press) http://www.amazon.com/exec/obidos/ASIN/0470212373/icongroupin terna

·

Monetary costs of childhood cancer to the families of patients. Author: J. Horsman ... [et al.]; Year: 1994; Ontario: CHEPA, 1994

·

Neuroblastoma: a clinicopathological study of fiftyfour children. Author: by Judit Mäkinen; Year: 1970; Helsinki: University of Helsinki, 1970

·

Neuroblastoma: a descriptive study of cases diagnosed in Illinois children less than 15 years old in 1985-1988. Author: authors, Celan J. Alo, Holly L. Howe, Byron J. Francis; Year: 1990; Springfield, Ill.: Illinois Dept. of Public Health, Division of Epidemiologic Studies, [1990]

·

Neuroblastoma: clinical and biological manifestations. Author: edited by Carl Pochedly; Year: 1982; New York: Elsevier Biomedical, c1982; ISBN: 0444007024 http://www.amazon.com/exec/obidos/ASIN/0444007024/icongroupin terna

·

Neuroblastoma: dedicated to Audrey E. Evans. Author: edited by Garrett M. Brodeur... [et al.]; Year: 2000; Amsterdam; New York: Elsevier, 2000; ISBN: 044450222X (alk. paper) http://www.amazon.com/exec/obidos/ASIN/044450222X/icongroupi nterna

·

Neuroblastoma: mIBG in diagnosis and management. Author: Judy Moyes, V. Ralph McCready, Ann Fullbrook; [with contributions from Sue L. Fielding, Maggie A. Flower, B.G. Tyrwhitt-Drake]; Year: 1989; London; New York: Springer-Verlag, c1989; ISBN: 0387195432 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/0387195432/icongroupin terna

·

Neuroblastoma: tumor biology and therapy. Author: editor, Carl Pochedly; Year: 1990; Boca Raton: CRC Press, c1990; ISBN: 0849301572

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http://www.amazon.com/exec/obidos/ASIN/0849301572/icongroupin terna ·

Neuroblastoma in 88 children: clinical features, prognostic factors, results, and late effects of therapy. Author: by Mikael Kajanti; Year: 1983; Helsinki: [s.n.], 1983; ISBN: 951934733X (pbk.)

·

Neuroblastoma sympathicum. Author: Josef Koutecký; [from the Czech manuscript translated by Jirí Harrer]; Year: 1984; Praha: Univerzita Karlova, c1984

·

Neuroblastomas; biochemical studies. Author: Bohuon, C; Year: 1966; Berlin, Springer, 1966

·

Neurology of neuroblastoma: neuroblastoma as a neurobiological disease. Author: Nina Felice Schor; Year: 2002; Norwell, Mass.: Kluwer Academic, c2002; ISBN: 1402071442 (alk. paper) http://www.amazon.com/exec/obidos/ASIN/1402071442/icongroupin terna

·

Pediatric surgical oncology: update on Wilms' tumor, neuroblastoma, and rhabdomyosarcoma. Author: Anthony Shaw, Patricia N. Konrad; Year: 1984; Chicago: Year Book Medical Publishers, c1984

·

Roentgenologic aspects of neuroblastoma. Author: Kincaid, Owings Wilson, 1921-; Year: 1956; [Minneapolis] 1956

·

Selected abstracts on childhood neuroblastoma. Author: Ayten Cangir, consulting reviewer; Year: 1986; [Bethesda, Md.?]: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health; Springfield, Va.: National Technical Information Service [distributor], [1986]

·

Studies on the muscarinic receptors in neuroblastoma cells. Author: by Esam El-Din El Fakahany; Year: 1981; [Minneapolis?: s.n.], 1981

·

Surgery of childhood tumors. Author: edited by Robert Carachi, Amir F. Azmy, Jay L. Grosfeld; Year: 1999; London: Arnold; New York: Oxford University Press, 1999; ISBN: 0340692693 http://www.amazon.com/exec/obidos/ASIN/0340692693/icongroupin terna

·

Transport of lithium by cultured mouse neuroblastoma and rat glioma cells. Author: by Robert Albert Gorkin; Year: 1980; [Minneapolis?: s.n.], 1980

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Chapters on Neuroblastoma Frequently, neuroblastoma will be discussed within a book, perhaps within a specific chapter. In order to find chapters that are specifically dealing with neuroblastoma, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and neuroblastoma 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 “neuroblastoma” (or synonyms) into the “For these words:” box, you will only receive results on chapters in books. The following is a typical result when searching for book chapters on neuroblastoma: ·

Screening for Early Detection of Cancer Source: in Complete Guide to Preventing Cancer: How You Can Reduce Your Risks. Revised 1994. Whelan, E. Amherst, NY, Prometheus Books, pp. 339-373, 385, Revised 1994. Contact: Prometheus Books, 59 John Glenn Drive, Amherst, NY 14229. (716) 691-0133. Summary: Screening for Early Detection of Cancer, a chapter in Complete Guide to Preventing Cancer: How You Can Reduce Your Risks, discusses cancer screening as a way to detect cancers early in their development, to provide the patient with a greater chance of cure. Screening methods for detecting cancer (1) should be sensitive (detect 30 to 90 percent of people with cancer), (2) should be specific (ensure that the test is accurate), (3) have a low potential risk to the patient, and (4) should be inexpensive. For a screening test to be useful (1) there must be a reasonable chance of detecting the cancer, (2) the benefits must be greater than the potential harm of the procedure, and (3) early detection of the cancer by the screening test must also improve the chances of survival. The following recommendations for cancer screening reflect consideration by many scientists. Screening methods for breast cancer include breast selfexamination, clinical breast examination, mammography, thermography, and sonography. Researchers recommend a baseline mammogram for women under age 40, a mammogram every 1 to 2 years for women aged 40-50, an annual breast examination and mammogram for women over age 50, and physical examination of the breasts by a physician every 3 years for women aged 20-40. Neuroblastoma, the most common solid tumor of infancy and early childhood, can be detected through a simple urine test. The Papanicolaou (Pap) smear test for cervical cancer in

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women involves scraping cell samples from the outer portion of the cervix and the endocervical canal. The American College of Obstetricians and Gynecologists (ACOG) recommends that all women have a Pap smear performed by age 18 or when sexually active, whichever comes first. Women with multiple sexual partners should have annual followup examinations. The ACOG also recommends that women in long-term relationships who have had three negative annual Pap smears in a row may undergo screening less often. Screening methods for colon and rectal cancer include the stool guaiac slide test; digital examination; and examination with a proctoscope, flexible sigmoidoscope, colonoscope, or a barium enema x-ray. Individuals over age 50 should have a yearly test for occult blood and a flexible sigmoidoscopy every 3 years. Screening for prostate cancer includes the digital rectal examination, ultrasonography, and the prostate-specific antigen test, which is controversial. ·

Screening for Neuroblastoma: State of the Art on Screening for Neuroblastoma Source: in Cancer Screening. Miller, A.B.; Chamberlain, J.; Day, N.E.; Hakama, M.; Prorok, P.C.; eds. Cambridge, England, Cambridge University Press, pp. 323-353, 1991. Contact: Press Syndicate of the University of Cambridge, 40 West 20th Street, New York, NY 10011-4211. Summary: Screening for Neuroblastoma: State of the Art on Screening for Neuroblastoma, a section in Cancer Screening, reviews methods, trials, and studies associated with the detection of neuroblastoma. Chapters describe (1) studies in Japan, (2) preliminary experience in the North of England, and (3) proposals for an evaluative study. Japanese studies suggest that screening for neuroblastoma can reduce mortality, but these results must still be replicated in other countries. Presently, screening for neuroblastoma in countries aside from Japan cannot be recommended as public health policy. In the studies from Japan, the two different peaks of neuroblastoma incidence suggest that cases detectable at 6 months may be prenatal in origin. The later peak after 1 year may represent later onset and poorer prognosis, not readily influenced by screening. Screening at 6 months may not be enough to diagnose cases in the later age peak, especially those generally diagnosed at the average of 4 years. Therefore, it appears that investigation should focus on screening at 1 year versus at 6 months or no screening. There is also concern about management of children with positive tests in whom tumors are not found; this would likely involve repeat tests after an interval and performing a blind laparotomy if there was a rising titer in the test. Additional studies have been proposed; aside from the United Kingdom study, a controlled study

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was started recently in North America, with screening in Quebec and other North American regions serving as controls. ·

Connective Tissue Lesions Source: in Regezi, J.A. and Sciubba, J.J. Oral Pathology: Clinical Pathologic Correlations. 3rd ed. Philadelphia, PA: W.B. Saunders Company. 1999. p. 176-216. Contact: Available from W.B. Saunders Company. Book Order Fulfillment Department, 6277 Sea Harbor Drive, Orlando, FL 32821-9854. (800) 545-2522. Fax (800) 874-6418. Website: www.wbsaunders.com. Price: $63.95. ISBN: 0721677312. Summary: This chapter on connective tissue lesions is from a pathology textbook that presents current concepts of oral and maxillofacial pathology in order to enhance the reader's diagnostic skills through the use of differential diagnosis strategies. The text offers readers detailed guidance of etiology, pathogenesis, clinical features, histopathology, differential diagnosis, and treatment of oral diseases of the mucosa, submucosa, and bone. This lengthy chapter covers fibrous connective tissue lesions, including reactive hyperplasias and neoplasms; vascular lesions, including reactive lesions, congenital lesions, and neoplasms; neural lesions, including reactive lesions and neoplasms; and lesions of muscles and fat. Specific lesions discussed include pyogenic granuloma and peripheral giant cell granulomata, peripheral fibroma, generalized gingival hyperplasia, traumatic fibroma, denture-induced fibrous hyperplasia, myxoma, nasopharyngeal angiofibroma, nodular fasciitis, fibrosarcoma, benign and malignant fibrous histiocytoma, venous varix, hemangioma, lymphangioma, hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, traumatic neuroma, granular cell tumors, schwannoma, neurofibroma, mucosal neuromas, palisaded encapsulated neuroma, neurogenic sarcoma, olfactory neuroblastoma, myositis ossificans, leiomyoma and leiomyosarcoma, rhabdomyoma and rhabdomyosarcoma, and lipoma and liposarcoma. 47 figures. 6 tables. 34 references.

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General Home References In addition to references for neuroblastoma, 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/icongroupintern a · 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/icongroupintern a · 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 Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [NIH] Carcinogenic: Producing carcinoma. [EU]

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Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Cholinergic: Resembling acetylcholine in pharmacological stimulated by or releasing acetylcholine or a related compound. [EU]

action;

Colonoscope: A thin, lighted tube used to examine the inside of the colon. [NIH]

Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Enema: The injection of a liquid through the anus into the large bowel. [NIH] Fibroma: A benign tumor of fibrous or fully developed connective tissue. [NIH]

Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Gastric: Having to do with the stomach. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. [NIH] Hemangiopericytoma: A type of cancer involving blood vessels and soft tissue. [NIH] Hyperplasia: An abnormal increase in the number of cells in an organ or tissue. [NIH] Laparotomy: A surgical incision made in the wall of the abdomen. [NIH] Leiomyoma: A benign smooth-muscle tumor, usually in the uterus or gastrointestinal tract. Also called fibroid. [NIH] Leiomyosarcoma: A tumor of the muscles in the uterus, abdomen, or pelvis. [NIH]

Lipoma: A benign tumor composed of fat cells. [NIH] Liposarcoma: A rare cancer of the fat cells. [NIH] Lithium: Lithium. An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH] Mammogram: An x-ray of the breast. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Myositis: Inflammation of a voluntary muscle. [EU] Neuroma: A tumor that arises in nerve cells. [NIH] Paediatric: Of or relating to the care and medical treatment of children;

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belonging to or concerned with paediatrics. [EU] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] 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] Sigmoidoscope: A thin, lighted tube used to view the inside of the colon. [NIH]

Sigmoidoscopy: Inspection of the lower colon using a thin, lighted tube called a sigmoidoscope. Samples of tissue or cells may be collected for examination under a microscope. Also called proctosigmoidoscopy. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Thermography: Measurement of the regional temperature of the body or an organ by infrared sensing devices, based on self-emanating infrared radiation. [NIH] Ultrasonography: A procedure in which sound waves (called ultrasound) are bounced off tissues and the echoes are converted to a picture (sonogram). [NIH]

Multimedia 173

CHAPTER 7. MULTIMEDIA ON NEUROBLASTOMA Overview Information on neuroblastoma 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 neuroblastoma. 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 Neuroblastoma 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 neuroblastoma (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 neuroblastoma. For more information, follow the hyperlink indicated: ·

Application of cell kinetics to the treatment of neuroblastomas. Source: University of Texas System Cancer Center M. D. Anderson Hospital and Tumor Institute; Year: 1976; Format: Videorecording; Houston: The Institute, 1976

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·

Best of neuroblastoma time-lapse photography. Source: National Institutes of Health; Format: Motion picture; [Bethesda, Md.: National Institutes of Health, 196u]

Vocabulary Builder Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH]

Physician Guidelines and Databases 175

CHAPTER 8. PHYSICIAN GUIDELINES AND DATABASES Overview Doctors and medical researchers rely on a number of information sources to help children with neuroblastoma. 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

·

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

·

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

·

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

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

What Is Neuroblastoma?34 This treatment information summary on neuroblastoma 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 oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to 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, there are clinical trials 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/). Neuroblastoma is predominantly a tumor of early childhood, with twothirds of the cases presenting in children younger than 5 years of age. In rare cases, neuroblastoma can be discovered prenatally by fetal

The following guidelines appeared on the NCI website on Aug. 26, 2002. The text was last modified in July 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

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ultrasonography.36 Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. The most common symptoms are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common and arise from retrobulbar metastasis. Extensive bone marrow metastasis may result in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases occurs in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord, causing paralysis. Fever, anemia, and hypertension are found occasionally. Multifocal neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.37 Rarely, children may have severe watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor. Children with neuroblastoma rarely may present with paraneoplastic neurologic findings including cerebellar ataxia or opsoclonus/myoclonus.38 The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.39 Unlike other neuroblastomas, the primary tumor usually is diffusely infiltrated with lymphocytes.40 Patients who present with this syndrome often have neuroblastomas with favorable biologic features and are likely to survive, although tumor-related deaths have been reported. Neurologic dysfunction is most often a presenting symptom but may arise after removal of the tumor. Opsoclonus/myoclonus is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation.41 Some patients may clinically respond to removal of the Jennings RW, LaQuaglia MP, Leong K, et al.: Fetal neuroblastoma: prenatal diagnosis and natural history. Journal of Pediatric Surgery 28(9): 1168-1174, 1993. 37 Hiyama E, Yokoyama T, Hiyama K, et al.: Multifocal neuroblastoma. Biologic behavior and surgical aspects. Cancer 88(8): 1955-1963, 2000. 38 Azizkhan RG, Haase GM: Current biologic and therapeutic implications in the surgery of neuroblastoma. Seminars in Surgical Oncology 9(6): 493-501, 1993. 39 Connolly AM, Pestronk A, Mehta S, et al.: Serum autoantibodies in children opsoclonusmyoclonus syndrome: an analysis of antigenic targets in neural tissues. Journal of Pediatrics 130(6): 878-884, 1997. Rudnick E, Khakoo Y, Antunes NL, et al.: Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies--a report from the Children’s Cancer Group study. Medical and Pediatric Oncology 36(6): 612-622, 2001. 40 Cooper R, Khakoo Y, Matthay KK, et al.: Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features--a report from the Children’s Cancer Group. Medical and Pediatric Oncology 36(6): 623-629, 2001. 41 Rudnick E, Khakoo Y, Antunes NL, et al.: Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies--a report from the Children’s Cancer Group study. Medical and Pediatric Oncology 36(6): 612-622, 2001. Pranzatelli MR: The neurobiology of the opsoclonus-myoclonus syndrome. Clinical Neuropharmacology 15(3): 186-228, 1992. 36

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neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone (ACTH) treatment is thought to be effective, but some patients do not respond to ACTH.42 Various drugs, plasmapheresis, and intravenous gamma-globulin have been reported to be effective in selected cases.43 It has been suggested that the long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly by means of its immunosuppressive effects.44

Diagnosis The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be discriminated from other small round blue cell tumors of childhood (such as lymphomas, primitive neuroectodermal tumor, and rhabdomyosarcoma) by conventional light microscopy. Evidence for sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, or by finding elevated levels of serum catecholamines (dopamine, norepinephrine) or urine catecholamine metabolites: vanillamandelic acid (VMA), homovanillic acid (HVA). The minimum criterion for a diagnosis of neuroblastoma that has been established by international agreement is based on one of the following: ·

An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of serum catecholamines or urinary catecholamine metabolites).

Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al.: Opsoclonus-ataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Pediatrics 109(1): 86-98, 2002. 42 Connolly AM, Pestronk A, Mehta S, et al.: Serum autoantibodies in children opsoclonusmyoclonus syndrome: an analysis of antigenic targets in neural tissues. Journal of Pediatrics 130(6): 878-884, 1997. Pranzatelli MR: The neurobiology of the opsoclonus-myoclonus syndrome. Clinical Neuropharmacology 15(3): 186-228, 1992. 43 Pranzatelli MR: The neurobiology of the opsoclonus-myoclonus syndrome. Clinical Neuropharmacology 15(3): 186-228, 1992. Russo C, Cohn SL, Petruzzi MJ, et al.: Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Medical and Pediatric Oncology 28(4): 284-288, 1997. 44 Russo C, Cohn SL, Petruzzi MJ, et al.: Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Medical and Pediatric Oncology 28(4): 284-288, 1997.

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·

The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically positive clumps of cells) and increased levels of serum catecholamines or urinary catecholamine metabolites as described above.45

Approximately 70% of all patients with neuroblastoma have metastatic disease at diagnosis. The prognosis for patients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, and (in patients older than 1 year of age) regional lymph node involvement. Other conventional prognostic variables include the site of the primary tumor and tumor histology (see Cellular Classification section below).46 Children of any age with localized neuroblastoma and infants younger than 1 year of age with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival.47 Older children with advanced-stage disease, however, have a significantly decreased chance for cure despite intensive therapy. As an example, aggressive multiagent chemotherapy has resulted in a 2-year survival rate of approximately 20% in older children with stage IV neuroblastoma.48 Neuroblastoma in the

Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11(8): 1466-1477, 1993. 46 Adams, GA, Shochat SJ, Smith EI, et al.: Thoracic neuroblastoma: a Pediatric Oncology Group study. Journal of Pediatric Surgery 28(3): 372-378, 1993. Evans AE, Albo V, D’Angio GJ, et al.: Factors influencing survival of children with nonmetastatic neuroblastoma. Cancer 38(2): 661-666, 1976. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 5962, 1983. Cotterill SJ, Pearson AD, Pritchard J, et al.: Clinical prognostic factors in 1277 patients with neuroblastoma: results of the European Neuroblastoma Study Group ‘Survey’ 1982-1992. European Journal of Cancer 36(7): 901-908, 2000. 47 Adams, GA, Shochat SJ, Smith EI, et al.: Thoracic neuroblastoma: a Pediatric Oncology Group study. Journal of Pediatric Surgery 28(3): 372-378, 1993. Brodeur GM, Azar C, Brother M, et al.: Neuroblastoma: effect of genetic factors on prognosis and treatment. Cancer 70(6, Suppl): 1685-1694, 1992. 48 Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children’s Research Hospital experience, 1962-1988. Journal of Clinical Oncology 9(9): 1599-1608, 1991. McWilliams NB, Hayes FA, Green AA, et al.: Cyclophosphamide/doxorubicin vs. cisplatin/teniposide in the treatment of children older than 12 months of age with disseminated neuroblastoma: a Pediatric Oncology Group randomized phase II study. Medical and Pediatric Oncology 24(3): 176-180, 1995. 45

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adolescent or adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course.49

Biologic Variables A number of biologic variables have been studied in children with this tumor. Of particular importance are Shimada histology, aneuploidy of tumor DNA, and amplification of the N-myc oncogene within tumor tissue since treatment decisions may be based on these factors.50 An open biopsy is usually needed to obtain adequate tissue for determination of these biological characteristics. Hyperdiploid tumor DNA is associated with a favorable prognosis,51 especially in infants with neuroblastoma,52 while Nmyc amplification is associated with a poor prognosis regardless of patient age.53 In contrast to N-myc gene amplification, the degree of expression of Franks LM, Bollen A, Seeger RC, et al.: Neuroblastoma in adults and adolescents: an indolent course with poor survival. Cancer 79(10): 2028-2035, 1997. 50 Cotterill SJ, Pearson AD, Pritchard J, et al.: Clinical prognostic factors in 1277 patients with neuroblastoma: results of the European Neuroblastoma Study Group ‘Survey’ 1982-1992. European Journal of Cancer 36(7): 901-908, 2000. Brodeur GM, Azar C, Brother M, et al.: Neuroblastoma: effect of genetic factors on prognosis and treatment. Cancer 70(6, Suppl): 1685-1694, 1992. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(4): 581-591, 1991. Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children’s Cancer Group study. Journal of Clinical Oncology 18(6): 1260-1268, 2000. Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma: a multivariate analysis of 182 cases. American Journal of Pediatric Hematology/Oncology 14(3): 207-215, 1992. Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998. 51 Ladenstein R, Ambros IM, Potschger U, et al.: Prognostic significance of DNA ditetraploidy in neuroblastoma. Medical and Pediatric Oncology 36(1): 83-92, 2001. 52 Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(4): 581-591, 1991. 53 Brodeur GM, Azar C, Brother M, et al.: Neuroblastoma: effect of genetic factors on prognosis and treatment. Cancer 70(6, Suppl): 1685-1694, 1992. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(4): 581-591, 1991. Tonini GP, Boni L, Pession A, et al.: MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. Journal of Clinical Oncology 15(1): 85-93, 1997. 49

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the N-myc gene in the tumor does not predict prognosis.54 Amplification of N-myc is associated with deletion of chromosome 1p and gain of the long arm of chromosome 17(17q), the latter of which independently predicts a poor prognosis.55 Expression of the gene encoding one of the high-affinity neurotrophin receptors (termed TRK-A ), is associated with good prognosis tumors.56 Increased levels of telomerase RNA,57 elevated serum ferritin,58 elevated serum lactate dehydrogenase,59 and the persistence of neuroblastoma cells in bone marrow during or after chemotherapy are each associated with poor prognosis.60 Biologic staging consisting of N-myc copy Maris JM, Weiss MJ, Guo C, et al.: Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children’s Cancer Group study. Journal of Clinical Oncology 18(9): 1888-1899, 2000. Cohn SL, London WB, Huang D, et al.: MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN. Journal of Clinical Oncology 18(21): 3604-3613, 2000. 55 Bown N, Lastowska M, Cotterill S, et al.: 17q gain in neuroblastoma predicts adverse clinical outcome. Medical and Pediatric Oncology 36(1): 14-19, 2001. Bown N, Cotterill S, Lastowska M, et al.: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. New England Journal of Medicine 340(25): 1954-1961, 1999. 56 Nakagawara A, Arima-Nakagawara M, Scavarda NJ, et al.: Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. New England Journal of Medicine 328(12): 847-854, 1993. 57 Poremba C, Hero B, Goertz HG, et al.: Traditional and emerging molecular markers in neuroblastoma prognosis: the good, the bad and the ugly. Klinische Padiatrie 213(4): 186190, 2001. 58 Hann HW, Evans AE, Siegel SE, et al.: Prognostic importance of serum ferritin in patients with stages III and IV neuroblastoma: the Childrens Cancer Study Group experience. Cancer Research 45(6): 2843-2848, 1985. 59 Shuster JJ, McWilliams NB, Castleberry R, et al.: Serum lactate dehydrogenase in childhood neuroblastoma: a Pediatric Oncology Group recursive partitioning study. American Journal of Clinical Oncology 15(4): 295-303, 1992. 60 Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma: a multivariate analysis of 182 cases. American Journal of Pediatric Hematology/Oncology 14(3): 207-215, 1992. Hann HW, Evans AE, Siegel SE, et al.: Prognostic importance of serum ferritin in patients with stages III and IV neuroblastoma: the Childrens Cancer Study Group experience. Cancer Research 45(6): 2843-2848, 1985. Shuster JJ, McWilliams NB, Castleberry R, et al.: Serum lactate dehydrogenase in childhood neuroblastoma: a Pediatric Oncology Group recursive partitioning study. American Journal of Clinical Oncology 15(4): 295-303, 1992. Massaron S, Seregni E, Luksch R, et al.: Neuron-specific enolase evaluation in patients with neuroblastoma. Tumour Biology 19(4): 261-268, 1998. De Bernardi B, Pianca C, Boni L, et al.: Disseminated neuroblastoma (stage IV and IV-S) in the first year of life: outcome related to age and stage. Italian Cooperative Group on Neuroblastoma. Cancer 70(6): 1625-1633, 1992. Combaret V, Gross N, Lasset C, et al.: Clinical relevance of CD44 cell-surface expression and N-myc gene amplification in a multicentric analysis of 121 pediatric neuroblastomas. Journal of Clinical Oncology 14(1): 25-34, 1996. 54

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number and age is useful in defining prognosis and treatment of stage III neuroblastoma.61

Clinical Trials Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted. This may be done in a randomized study of 2 treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy. The current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan62 but remains controversial.63 A large population-based North American study in which most infants in Quebec were screened at ages 3 weeks and 6 months has shown that screening detects many neuroblastomas with favorable characteristics64 that would never have been detected clinically, apparently because the tumors would have spontaneously regressed. There was no reduction in the incidence of Reynolds CP, Seeger RC: Detection of minimal residual disease in bone marrow during or after therapy as a prognostic marker for high-risk neuroblastoma. Journal of Pediatric Hematology/Oncology 23(3): 150-152, 2001. Burchill SA, Lewis IJ, Abrams KR, et al.: Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year. Journal of Clinical Oncology 19(6): 1795-1801, 2001. Seeger RC, Reynolds CP, Gallego R, et al.: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children’s Cancer Group study. Journal of Clinical Oncology 18(24): 4067-4076, 2000. 61 Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998. 62 Sawada T: Past and future of neuroblastoma screening in Japan. American Journal of Pediatric Hematology/Oncology 14(4): 320-326, 1992. 63 Murphy SB, Cohn SL, Craft AW, et al.: Do children benefit from mass screening for neuroblastoma? Consensus statement from the American Cancer Society workshop on neuroblastoma screening. Lancet 337(8737): 344-346, 1991. 64 Woods WG, Lemieux B, Leclerc JM, et al.: Screening for neuroblastoma (NB) in North America: the Quebec Project. In: Evans AE, Biedler JL, Brodeur GM, et al., eds.: Advances in Neuroblastoma Research 4. Wiley-Liss, Inc, 1994, pp 377-382. Takeuchi LA, Hachitanda Y, Woods WG, et al.: Screening for neuroblastoma in North America. Preliminary results of a pathology review from the Quebec Project. Cancer 76(11): 2363-2371, 1995.

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advanced-stage neuroblastomas with unfavorable biological characteristics in older children. This strongly suggests that screening for neuroblastoma at ages 3 weeks and 6 months will not decrease mortality and morbidity.65 The ongoing collection of population-based mortality data in the Quebec study will allow more definitive conclusions regarding the public health benefits of neuroblastoma screening. Recent studies have suggested that selected infants who appear to have asymptomatic, small, low stage neuroblastoma detected by screening, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.66

Cellular Classification One clinicopathologic staging system, devised by Shimada, involves evaluation of tumor specimens for the amount of stromal development, the degree of neuroblastic maturation, and the mitosis-karyorrhexis index of the neuroblastic cells.67 Favorable and unfavorable prognoses are defined on the bases of these histologic parameters and on patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies.68 Neuroblastomas containing many differentiating cells, termed ganglioneuroblastomas, tend to have favorable biological properties and have a better prognosis.69 Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348(9043): 1682-1687, 1996. 66 Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: a 5-year prospective study at a single institution 18(16): 3012-3017, 2000. 67 Chatten J, Shimada H, Sather HN, et al.: Prognostic value of histopathology in advanced neuroblastoma: a report from the Children Cancer Study Group. Human Pathology 19(10): 1187-1198, 1988. Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86(2): 364-372, 1999. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(9): 2451-2461, 2001. 68 Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86(2): 364-372, 1999. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(9): 2451-2461, 2001. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001. 69 Kubota M, Suita S, Tajiri T, et al.: Analysis of the prognostic factors relating to better clinical outcome in ganglioneuroblastoma. Journal of Pediatric Surgery 35(1): 92-95, 2000. Umehara S, Nakagawa A, Matthay KK, et al.: Histopathology defines prognostic subsets of ganglioneuroblastoma, nodular. Cancer 89(5): 1150-1161, 2000. 65

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Stage Information The descriptions used in the treatment section of this document (localized, regional, disseminated, and special) are based on The International Neuroblastoma Staging System (INSS). Combining elements from the previously used Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) staging systems, the INSS has now replaced these two staging systems. Current Children’s Oncology Group (COG) protocols specify that the INSS stage be defined for all patients and used in combination with patient age and tumor biology to assign all patients to risk groups that determine treatment. The COG neuroblastoma risk group assignment schema (INSS stage, patient age, tumor biology) is outlined in Table I below. A description of the INSS staging system follows this table. A thorough evaluation for metastatic disease should be performed prior to therapy initiation. The following investigations are recommended:70 1) Bone marrow should be assessed by bilateral posterior iliac crest marrow aspirates and trephine (core) bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy specimens must contain at least 1 cm of marrow (excluding cartilage). 2) Bone should be assessed by MIBG scan (applicable to all sites of disease) and by technetium 99 scan if the results of the MIBG scan are negative or unavailable. Plain radiographs of positive lesions are recommended. 3) Palpable lymph nodes should be clinically examined and histologically confirmed. Nonpalpable lymph nodes should be assessed by computerized tomography (CT) scan with three-dimensional (3D) measurements. 4) The abdomen and liver should be assessed by CT scan and/or magnetic resonance imaging (MRI). Ultrasound is considered suboptimal for accurate 3D measurements. 5) The chest should be examined by anteroposterior and lateral chest radiography. CT scans and/or MRI are necessary if the results are positive or if abdominal disease extends into the chest. 6) Lumbar puncture should be avoided as CNS metastasis at diagnosis is rare and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.71

Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11(8): 1466-1477, 1993. 71 Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 91(8): 1510-1519, 2001. 70

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Neuroblastoma Risk Grouping The following table outlines the COG neuroblastoma risk group assignment schema. The risk group assignment determines the treatment plan for each patient. Patients assigned to the Low, Intermediate, and High Risk groups have an overall survival of greater than 90%, 70% to 90%, and greater than 30% respectively, three years after diagnosis. Table 1: Children’s Oncology Risk Group Assignment Schema

Group

Neuroblastoma

------------------------------------------------------------------------------|INSS | Age |MYCN |Shimada |DNA |Risk |Stage | |Status |Histology |Ploidy |Group |________|_______________|_____________|_______________|_________|____________ |1 | 0-21y |Any |Any |Any |Low |________|_______________|_____________|_______________|_________|____________ |2A/2B* | <365d |Any |Any |Any |Low | | >or=365d-21y |Non-Amp |Any ||Low | | >or=365d-21y |Amp |Fav ||Low | | >or=365d-21y |Amp |Unfav ||High |________|_______________|_____________|_______________|_________|____________ |3*** | <365d |Non-Amp |Any |Any |Intermediate | | <365d |Amp |Any |Any |High | | >or=365d-21y |Non-Amp |Fav ||Intermediate | | >or=365d-21y |Non-Amp |Unfav ||High | | >or=365d-21y |Amp |Any ||High |________|_______________|_____________|_______________|_________|____________ |4*** | <365d |Non-Amp |Any |Any |Intermediate | | <365d |Amp |Any |Any |High | | >or=365d-21y |Any |Any ||High |________|_______________|_____________|_______________|_________|_____________ |4S** | <365d |Non-Amp |Fav |>1 |Low | | <365d |Non-Amp |Any |=1 |Intermediate | | <365d |Non-Amp |Unfav |Any |Intermediate | | <365d |Amp |Any |Any |High |________|_______________|_____________|_______________|_________|_____________ Biology Defined By: MYCN Status: Shimada Histopathology: DNA Ploidy:

Amplified (Amp) vs. Non-Amplified (Non-Amp) Favorable (Fav) vs. Unfavorable (Unfav) DNA Index (DI) >1or=1; hypodiploid tumors (with DI <1) will be treated as a tumor with a DI>1. (DNA index <1 (hypodiploid) to be considered favorable ploidy.)

* INSS 2A/2B symptomatic patients with spinal cord compression, neurologic deficits or other symptoms will be treated on the LOW RISK NB Study with immediate chemotherapy for 4 cycles (Course 1). ** INSS 4S infants with favorable biology and clinical symptoms will be treated on the LOW RISK NB Study with immediate chemotherapy until asymptomatic (2-4 cycles). Clinical symptoms defined as: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or IVC compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.

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*** INSS 3 or 4 patients with clinical symptoms as above (or in the investigator’s opinion it is in the best interest of the patient) will receive immediate chemotherapy.

International Neuroblastoma Staging System (INSS) In North America, the COG is investigating a risk-based neuroblastoma treatment plan that assigns all patients to Low, Intermediate and High Risk groups based on age, INSS stage and tumor biology. Risk groups are defined in the table above. The INSS combines certain features of the previously used POG and CCG systems.72 It has been shown to identify distinct prognostic groups.73 ·

Stage 1: localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive).

·

Stage 2A: localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.

·

Stage 2B: localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.

·

Stage 3: unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline is defined as the vertebral column.

Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11(8): 1466-1477, 1993. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. Journal of Clinical Oncology 6(12): 1874-1881, 1988. 73 Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11(8): 1466-1477, 1993. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. Journal of Clinical Oncology 6(12): 1874-1881, 1988. Castleberry RP, Shuster JJ, Smith EI, et al.: The Pediatric Oncology Group experience with the international staging system criteria for neuroblastoma. Journal of Clinical Oncology 12(11): 2378-2381, 1994. 72

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Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column. ·

Stage 4: any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S).

·

Stage 4S: localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow (limited to infants less than 1 year of age). Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered to be stage IV disease. The results of the metaiodobenzylguanidine (MIBG) scan (if performed) should be negative for disease in the bone marrow.

Treatment Option Overview For the purposes of treatment presented here, neuroblastoma is categorized as localized resectable, localized unresectable, regional, disseminated, and special. The presence of lymph nodes involved with tumor may also affect the treatment plan for patients with resectable nonmetastatic tumors, so regional nodes should be sampled in this patient population. Treatment of patients is also determined by the biological characteristics of the tumor. Accurate determination of biological characteristics such as Shimada histology usually requires an open biopsy. Urinary excretion of the catecholamine metabolites vanillamandelic acid (VMA) and homovanillic acid (VMA) per milligram excreted creatinine should be measured prior to therapy. If elevated, these markers can be used to determine the persistence of disease.

Neuroblastoma Risk-Based Treatment Plan In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan which assigns all patients to Low, Intermediate and High Risk groups based on age, INSS stage, and tumor biology (Shimada histology, N-myc gene amplification, and DNA ploidy).74 (Risk groups are defined in Table 1 of the Stage Information section of this summary). In patients without metastatic disease, initial surgery is Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001.

74

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performed to establish the diagnosis, to resect as much of the primary tumor as safely possible, to accurately stage disease through sampling of regional lymph nodes that are not adherent to the tumor, and to obtain adequate tissue for biologic studies. Low Risk Treatment for patients categorized as Low Risk (Table 1) consists most commonly of surgery alone but in some cases surgery combined with 6 to 12 weeks of chemotherapy. The chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.75

Intermediate Risk Patients categorized as Intermediate Risk (Table 1) are treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above.76

High Risk In contrast, patients categorized as High Risk (Table 1) are generally treated with aggressive multiagent chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide, and high dose cisplatin. After a response to chemotherapy, resection of the primary tumor may be attempted, followed by myeloablative chemotherapy, sometimes including total-body irradiation, rescued with autologous stem cell transplantation. Irradiation of residual tumor and original sites of metastases is often performed before, during, or after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and retinoic acid improve outcome in patients categorized as High Risk.77 Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 76 Baker D, Children’s Cancer Group: Phase III Study of Combination Chemotherapy in Children With Intermediate-Risk Neuroblastoma (Summary Last Modified 07/2001), CCGA3961, clinical trial, active, 01/15/1998. 77 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 75

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Radiation Radiation therapy is reserved for patients with symptomatic life- or organthreatening tumor that does not respond rapidly enough to chemotherapy, or for Intermediate Risk patients whose tumor has responded incompletely to both chemotherapy and attempted resection and also has unfavorable biologic characteristics. Relapse Therapy for Low and Intermediate Risk Patients As part of the COG treatment plan, specific relapse therapy is defined for Low and Intermediate Risk patients determined by patient age at recurrence, stage and biology of the recurrence. Symptomatic spinal cord compression should be treated urgently. Neurologic recovery is more likely the less the severity of compromise and the shorter the duration of symptoms. Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgical laminectomy. However, laminectomy may result in later scoliosis, and chemotherapy is often needed whether or not surgery or radiation is used.78 The COG neuroblastoma treatment plan utilizes immediate chemotherapy for cord compression in patients classified as Low or Intermediate Risk.79 Recent studies suggest that selected presumed neuroblastomas detected in infants by screening may safely be observed without obtaining a definitive histologic diagnosis and without surgical intervention, thus avoiding potential complications of surgery in the newborn.80 The experience with tumors detected by mass urinary catecholamine metabolite screening in Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. Journal of Clinical Oncology 19(4): 1047-1055, 2001. De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. Journal of Clinical Oncology 19(1): 183-190, 2001. 79 Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. Baker D, Children’s Cancer Group: Phase III Study of Combination Chemotherapy in Children With Intermediate-Risk Neuroblastoma (Summary Last Modified 07/2001), CCGA3961, clinical trial, active, 01/15/1998. 80 Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: a 5-year prospective study at a single institution 18(16): 3012-3017, 2000. Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal masses. Journal of Pediatric Surgery 31(1): 153-155, 1996. 78

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Japan appears to be applicable to tumors detected by prenatal or perinatal ultrasound in the United States. Twenty-six infants who had presumed Evans stage I, II, or IVS by imaging, urinary VMA and HVA levels less than 50 micrograms per milligram creatinine, no tumor involvement of great vessels or invasion into the spinal canal, and tumor size less than 5 centimeters were observed frequently with imaging. Biopsy and tissue diagnosis were not obtained initially. The tumor increased in size in about one-third of the infants and was resected without any apparent increase in stage. All had favorable biologic features. In two-thirds, after observation for 6 to 73 months, no surgery has been performed, the VMA and HVA have normalized, and in several cases the tumors have become undetectable by imaging.81 The COG is currently investigating systematic observation without surgery for infants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound. The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Localized Resectable Neuroblastoma Localized disease includes those with International Neuroblastoma Staging System (INSS) stage 1 disease. These children, of any age, have a cure rate of greater than 90%.82 Treatment Options Complete gross resection produces disease-free survivals that are indistinguishable from those obtained with surgery plus adjuvant Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: a 5-year prospective study at a single institution 18(16): 3012-3017, 2000. 82 Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 5962, 1983. Evans AR, Brand W, de Lorimier A, et al.: Results in children with local and regional neuroblastoma managed with and without vincristine, cyclophosphamide, and imidazolecarboxamide: a report from the Children’s Cancer Study Group. American Journal of Clinical Oncology 7(1): 3-7, 1984. Alvarado CS, London WB, Look AT, et al.: Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group study. Journal of Pediatric Hematology/Oncology 22(3): 197-205, 2000. 81

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chemotherapy or surgery plus radiation therapy.83 A small percentage of patients require therapy for recurrence but usually have good outcomes. However, in light of other information relating to prognosis, including patient age, the Shimada grade, ferritin, NSE, LDH, and N-myc amplification, further therapy may be indicated. Poorer outcomes are noted for patients with tumors having N-myc amplification or those who are older (>2 years old) with unfavorable histology or positive nodes.84

Neuroblastoma Treatment Plan In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns all patients to Low, Intermediate, and High Risk groups based on age, INSS stage, and tumor biology (N-myc gene amplification, Shimada histology, and DNA ploidy).85 Any INSS stage 1 tumor is categorized as Low Risk (Table 1), and chemotherapy is recommended only for life- or organ-threatening symptoms that cannot be relieved by safe surgical resection of the mass. Such symptoms include respiratory distress, renal or bowel ischemia, spinal cord compression, gastrointestinal or genitourinary obstruction, or 86 coagulopathy. Radiation therapy is reserved for patients with symptomatic life- or organ-threatening tumor that does not respond rapidly enough to chemotherapy. Recent studies suggest that selected presumed neuroblastomas detected in infants by screening may be safely observed without surgical intervention.87 The COG is investigating systematic Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 5962, 1983. Evans AR, Brand W, de Lorimier A, et al.: Results in children with local and regional neuroblastoma managed with and without vincristine, cyclophosphamide, and imidazolecarboxamide: a report from the Children’s Cancer Study Group. American Journal of Clinical Oncology 7(1): 3-7, 1984. Alvarado CS, London WB, Look AT, et al.: Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group study. Journal of Pediatric Hematology/Oncology 22(3): 197-205, 2000. 84 Perez CA, Matthay KK, Atkinson JB, et al.: Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a Children’s Cancer Group study. Journal of Clinical Oncology 18(1): 18-26, 2000. 85 Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001. 86 Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 87 Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: a 5-year prospective study at a single institution 18(16): 3012-3017, 2000. 83

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observation without diagnostic surgery for selected infants with presumed INSS stage 1 neuroblastoma detected by prenatal or perinatal ultrasound.

Localized Unresectable Neuroblastoma Localized unresectable disease includes those with International Neuroblastoma Staging System (INSS) stage 2A disease. In these patients, there are no metastases to regional lymph nodes, but the tumor is not completely resected. The probability of long-term survival is 75% to 90% depending on age of patient, favorable biologic features, and therapy delivered.88

Treatment Options The initial management generally consists of biopsy followed by chemotherapy or systematic observation based upon the extent of resection.89

Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal masses. Journal of Pediatric Surgery 31(1): 153-155, 1996. 88 Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 5962, 1983. Ninane J, Pritchard J, Morris-Jones PH, et al.: Stage II neuroblastoma: adverse prognostic significance of lymph node involvement. Archives of Disease in Childhood 57(6): 438-442, 1982. Evans AE, Albo V, D’Angio GJ, et al.: Cyclophosphamide treatment of patients with localized and regional neuroblastoma: a randomized study. Cancer 38(2): 655-660, 1976. Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998. Rubie H, Plantaz D, Coze C, et al.: Localised and unresectable neuroblastoma in infants: excellent outcome with primary chemotherapy. Medical and Pediatric Oncology 36(1): 247250, 2001. 89 Evans AE, Albo V, D’Angio GJ, et al.: Cyclophosphamide treatment of patients with localized and regional neuroblastoma: a randomized study. Cancer 38(2): 655-660, 1976. Rubie H, Plantaz D, Coze C, et al.: Localised and unresectable neuroblastoma in infants: excellent outcome with primary chemotherapy. Medical and Pediatric Oncology 36(1): 247250, 2001. Nitschke R, Smith EI, Altshuler G, et al.: Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group Study. Journal of Clinical Oncology 9(7): 1181-1188, 1991. McGuire WA, Simmons DL, Grosfeld JL, et al.: Stage II neuroblastoma--does adjuvant irradiation contribute to cure? Medical and Pediatric Oncology 13(3): 117-121, 1985. Haase GM, Wong KY, deLorimier AA, et al.: Improvement in survival after excision of primary tumor in stage III neuroblastoma. Journal of Pediatric Surgery 24(2): 194-200, 1989.

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Second-look operation may be used subsequently to remove residual tumor, and radiation therapy may be given to patients with residual disease following second-look operation. The chemotherapeutic agents most commonly used include cyclophosphamide and doxorubicin, with cisplatin and either teniposide or etoposide reserved for more resistant tumors. Shortterm therapy for 4 to 6 months is usually adequate. However, in light of other information relating to prognosis, including patient age, the Shimada grade, ferritin, NSE, LDH, and N-myc amplification, either more or less therapy may be indicated. Recent studies suggest that selected presumed neuroblastomas detected in infants by screening or by prenatal or perinatal ultrasound, may be safely observed without surgical intervention.90

Neuroblastoma Treatment Plan In North America, the Children’s Oncology Group is investigating a riskbased neuroblastoma treatment plan which assigns all patients to Low, Intermediate, and High Risk groups based on age, INSS stage, and tumor biology (N-myc amplification, Shimada histology, and DNA ploidy).91

Low-Risk Localized Unresectable Neuroblastoma INSS stage 2 tumors in infants and those in older children that have favorable Shimada histology are categorized as Low Risk (Table 1), and chemotherapy is given only if less than 50% of the tumor has been resected. Patients in whom more than 50% of the tumor has been resected are systematically observed, as regression of residual disease is expected to occur in most. Patients categorized as Low Risk in whom less than 50% of the tumor is resected at diagnosis are treated with chemotherapy. Also, immediate chemotherapy is recommended for life- or organ-threatening symptoms that cannot be relieved by safe surgical resection of the mass. Such symptoms include respiratory distress, renal or bowel ischemia, spinal cord compression, gastrointestinal or genitourinary obstruction, or coagulopathy. The chemotherapy is given for 12 to 24 weeks and consists of Garaventa A, de Bernardi B, Pianca C, et al.: Localized but unresectable neuroblastoma: treatment and outcome of 145 cases. Journal of Clinical Oncology 11(9): 1770-1779, 1993. 90 Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: a 5-year prospective study at a single institution 18(16): 3012-3017, 2000. Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal masses. Journal of Pediatric Surgery 31(1): 153-155, 1996. 91 Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001.

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moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.92 Radiation therapy is reserved for patients with symptomatic life- or organ-threatening tumor that does not respond rapidly to chemotherapy.

High Risk Localized Unresectable Neuroblastoma Patients who are INSS stage 2A, over one year of age, and in whom the tumor has both unfavorable Shimada histology and N-myc gene amplification are categorized as High Risk (Table 1). These patients are generally treated with aggressive multiagent chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide and high dose cisplatin. After a response to chemotherapy, resection of the primary tumor may be attempted, followed by myeloablative chemotherapy and/or radiotherapy with autologous bone marrow or peripheral blood stem cell transplantation. Irradiation of residual tumor may be performed before, during, or after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and post-chemotherapy retinoic acid improve outcome in patients categorized as High Risk.93

Regional Neuroblastoma Regional neuroblastoma includes those with International Neuroblastoma Staging System (INSS) stage 2B (tumor spread to nonadherent ipsilateral lymph nodes) or stage 3 disease (tumor involving both sides of the midline by virtue of either invasion into normal tissue or lymph node metastasis). Infants younger than 1 year of age have a greater than 80% chance of cure while older children have a cure rate of 50% to 70% with current, relatively intensive therapy.94 In a recent study, those with favorable and unfavorable

Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 93 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 94 Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. Journal of Clinical Oncology 9(5): 789-795, 1991. 92

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biologic features (Shimada histology and N-myc gene amplification) have event-free survival rates of almost 100% and about 50%, respectively.95 In those cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given.96 Treatment options for patients younger than 1 year of age: ·

Surgical resection of the primary tumor may be possible at diagnosis or as a delayed procedure. Complete resection of the primary tumor, either as a primary or secondary procedure, may improve outcome.97 Select groups of patients whose tumors have favorable biologic features may not require treatment other than surgery.98

·

Chemotherapy with cyclophosphamide and doxorubicin, cisplatin with teniposide or etoposide or vincristine with cisplatin and teniposide or etoposide for more resistant tumors.99

Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. Journal of the National Cancer Institute 89(5): 373-380, 1997. Castleberry RP, Shuster JJ, Altshuler G, et al.: Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study. Journal of Clinical Oncology 10(8):1299-1304, 1992. West DC, Shamberger RC, Macklis RM, et al.: Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents. Journal of Clinical Oncology 11(1): 84-90, 1993. 95 Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998. 96 Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominal neuroblastoma. Journal of Pediatric Surgery 33(2): 161-164, 1998. 97 Haase GM, Wong KY, deLorimier AA, et al.: Improvement in survival after excision of primary tumor in stage III neuroblastoma. Journal of Pediatric Surgery 24(2): 194-200, 1989. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. Journal of Pediatric Surgery 30(7): 937-941, 1995. 98 Kushner BH, Cheung NK, LaQuaglia MP, et al.: International neuroblastoma staging system stage 1 neuroblastoma: a prospective study and literature review. Journal of Clinical Oncology 14(7): 2174-2180, 1996. 99 Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. Journal of the National Cancer Institute 89(5): 373-380, 1997. Castleberry RP, Shuster JJ, Altshuler G, et al.: Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study. Journal of Clinical Oncology 10(8):1299-1304, 1992.

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Treatment options for patients older than 1 year of age: ·

Surgical resection of the primary tumor may be possible at diagnosis or following tumor reduction with chemotherapy with or without radiation therapy. Complete resection of the primary tumor, either prior to chemotherapy or as a secondary procedure, may improve outcome.100 Select groups of patients whose tumors have favorable biologic features may not require treatment other than surgery.101

·

Aggressive chemotherapy using combinations of cyclophosphamide, doxorubicin, cisplatin, and teniposide or etoposide.102

·

Radiation therapy to nodal drainage areas may improve outcome.103

Neuroblastoma Treatment Plan In North America, the Children’s Oncology Group is investigating a riskbased neuroblastoma treatment plan that assigns all patients to Low, Intermediate, and High Risk groups based on age, INSS stage, and tumor biology (N-myc gene amplification, Shimada histology, and DNA ploidy).104

Low Risk Regional Neuroblastoma All INSS stage 2B (tumor spread to nonadherent ipsilateral lymph nodes) neuroblastomas in infants and those in older children that have favorable Shimada histology are categorized as Low Risk (Table 1). Chemotherapy is given only if less than 50% of the tumor has been resected. Patients in whom more than 50% of the tumor has been resected are systematically observed, Haase GM, Wong KY, deLorimier AA, et al.: Improvement in survival after excision of primary tumor in stage III neuroblastoma. Journal of Pediatric Surgery 24(2): 194-200, 1989. 101 Kushner BH, Cheung NK, LaQuaglia MP, et al.: International neuroblastoma staging system stage 1 neuroblastoma: a prospective study and literature review. Journal of Clinical Oncology 14(7): 2174-2180, 1996. 102 Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. Journal of Clinical Oncology 9(5): 789-795, 1991. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. Journal of the National Cancer Institute 89(5): 373-380, 1997. 103 Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. Journal of Clinical Oncology 9(5): 789-795, 1991. 104 Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001. 100

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as regression of residual disease is expected to occur in most. Patients categorized as Low Risk in whom less than 50% of the tumor is resected at diagnosis are treated with chemotherapy. Also, immediate chemotherapy is recommended for life- or organ-threatening symptoms that cannot be relieved by safe surgical resection of the mass. Such symptoms include respiratory distress, renal or bowel ischemia, spinal cord compression, gastrointestinal or genitourinary obstruction, or coagulopathy. The chemotherapy is given for 6 to 12 weeks and consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.105

Intermediate Risk Regional Neuroblastoma Infants less than one year of age with INSS stage 3 neuroblastoma without N-myc gene amplification and children over one year of age with INSS stage 3 tumors having both favorable Shimada histology and absence of N-myc gene amplification are classified as Intermediate Risk (Table 1). Patients classified as Intermediate Risk with tumors with favorable and unfavorable biological properties (Shimada histology, N-myc gene amplification, and DNA ploidy) are treated with 12 weeks and 24 weeks of chemotherapy respectively. Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.106 In patients classified as Intermediate Risk with favorable biology, radiation therapy is reserved for patients with symptomatic life- or organ-threatening tumor that does not respond rapidly enough to chemotherapy. In patients classified as Intermediate Risk with unfavorable biologic features, radiation therapy is given if residual viable tumor remains after 24 weeks of chemotherapy and second look surgery.

Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 106 Baker D, Children’s Cancer Group: Phase III Study of Combination Chemotherapy in Children With Intermediate-Risk Neuroblastoma (Summary Last Modified 07/2001), CCGA3961, clinical trial, active, 01/15/1998. 105

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High Risk Regional Neuroblastoma ·

Patients who are INSS stage 2B, over one year of age, and in whom the tumor has both unfavorable Shimada histology and N-myc gene amplification, are classified as High Risk (Table 1).

·

Infants less than one year of age with INSS stage 3 disease and N-myc gene amplification are classified as High Risk

·

Children over one year of age with INSS stage 3 disease and either Nmyc gene amplification or unfavorable Shimada histology are also classified as High Risk.

Both myeloablative therapy and retinoic acid improve outcome in patients classified as High Risk.107 These patients are generally treated with aggressive multiagent chemotherapy consisting of very high doses of the drugs listed above but also including ifosfamide and high dose cisplatin. After response to chemotherapy, resection of the primary tumor is attempted, followed by myeloablative chemotherapy and radiotherapy with autologous stem cell transplantation. Irradiation of residual tumor is often performed before, during or after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months.108

Disseminated Neuroblastoma Disseminated disease includes those with International Neuroblastoma Staging System (INSS) stage 4 disease. Differentiating patients with stage 4S (“special”) neuroblastoma from other disseminated disease patients is important; stage 4S patients should be treated as described in the treatment section on stage 4S neuroblastoma. Survival of patients with disseminated disease is strongly dependent on age. Children younger than 1 year of age at diagnosis have a good chance of long-term survival (5-year disease-free survival rate of 50%-80%),109 with outcome particularly dependent on tumor Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 108 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 109 Paul SR, Tarbell NJ, Korf B, et al.: Stage IV neuroblastoma in infants: long-term survival. Cancer 67(6): 1493-1497, 1991. Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children’s Research Hospital experience, 1962-1988. Journal of Clinical Oncology 9(9): 1599-1608, 1991. 107

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cell ploidy (hyperploidy confers a favorable prognosis while diploidy predicts early treatment failure).110 For children older than 1 year of age, long-term survival ranges from 10% to 40%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.111 A randomized study was performed comparing high-dose therapy with purged autologous bone marrow transplantation versus 3 cycles of intensive consolidation chemotherapy. The 3-year event-free survival was significantly better in the autologous bone marrow transplantation arm (34%) compared to the consolidation chemotherapy arm (18%). In addition, patients on this study were subsequently randomized to stop therapy or to receive 6 months of 13 cis-retinoic acid.112 The use of 13 cisretinoic acid can induce differentiation and inhibit growth of neuroblastoma in vitro. Overall, the 3-year event-free survival from the time of the second randomization was 47% for patients receiving 13 cis-retinoic acid and 25% for patients randomized to receive no further therapy. For patients randomized to receive 13 cis-retinoic acid, an apparent advantage in 3-year event-free survival was seen for stage IV patients (40% vs 18%), high-risk stage III patients (77% vs 49%), patients randomized to receive consolidation chemotherapy alone (32% vs 16%), patients randomized to receive autologous bone marrow transplantation (55% vs 39%), and patients with MYCN gene amplification (39% vs 13%). Based on these results, future clinical trials will build upon autologous stem cell transplantation and cisretinoic acid for high-risk neuroblastoma.113

Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(4): 581-591, 1991. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. Journal of the National Cancer Institute 89(5): 373-380, 1997. 111 Cotterill SJ, Pearson AD, Pritchard J, et al.: Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group “Survey”. Medical and Pediatric Oncology 36(1): 235-238, 2001. Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. Journal of Clinical Oncology 19(13): 3163-3172, 2001. 112 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 113 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 110

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The potential benefit of aggressive surgical approaches to achieve complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally demonstrated. Two studies reported that complete resection of the primary tumor at diagnosis improved survival; however, the outcome in these patients may be more dependent on the biology of the tumor, which itself may determine resectability, than on the extent of surgical resection.114 Treatment Options for INSS Stage 4 disease: ·

Intensive conventional chemotherapy, using combinations of carboplatin, ifosfamide, cyclophosphamide, doxorubicin, cisplatin, teniposide or etoposide, and vincristine.115 Surgery and radiation therapy may be used with chemotherapy, depending on the clinical presentation, biological properties of the tumor, and response to treatment. Post-chemotherapy treatment includes 13 cis-retinoic acid.116

Haase GM, O’Leary MC, Ramsay NK, et al.: Aggressive surgery combined with intensive chemotherapy improves survival in poor-risk neuroblastoma. Journal of Pediatric Surgery 26(9): 1119-1124, 1991. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. Journal of Pediatric Surgery 30(7): 937-941, 1995. Shorter NA, Davidoff AM, Evans AE, et al.: The role of surgery in the management of stage IV neuroblastoma: a single institution study. Medical and Pediatric Oncology 24(5): 287-291, 1995. 115 Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children’s Research Hospital experience, 1962-1988. Journal of Clinical Oncology 9(9): 1599-1608, 1991. Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. Hartmann O, Pinkerton CR, Philip T, et al.: Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma. Journal of Clinical Oncology 6(1): 44-50, 1988. Cheung NK, Kushner BH, LaQuaglia M, et al.: N7: a novel multi-modality therapy of high risk neuroblastoma (NB) in children diagnosed over 1 year of age. Medical and Pediatric Oncology 36(1): 227-230, 2001. Pinkerton CR, Zucker JM, Hartmann O, et al.: Short duration, high dose, alternating chemotherapy in metastatic neuroblastoma (ENSG 3C induction regimen). British Journal of Cancer 62(2): 319-323, 1990. 116 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 114

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·

Myeloablative chemotherapy and stem cell reconstitution following several courses of intensive chemotherapy.117 Surgery and radiation therapy may be used with chemotherapy, depending on the clinical presentation, biological properties of the tumor, and response to treatment. Post-chemotherapy treatment includes 13 cis-retinoic acid.118

Under evaluation: ·

Monoclonal antibody therapy following chemotherapy.119

·

Targeted radiation therapy with 131I-MIBG.120

·

Tandem myeloablation and stem cell transplantation.121

·

Inclusion of myeloablative doses of 131I-MIBG prior to stem cell transplantation.122

Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. Philip T, Zucker JM, Bernard JL, et al.: Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: is cure possible in a small subgroup? Journal of Clinical Oncology 9(6): 10371044, 1991. Matthay KK, Seeger RC, Reynolds CP, et al.: Allogeneic versus autologous purged bone marrow transplantation for neuroblastoma: a report from the Childrens Cancer Group. Journal of Clinical Oncology 12(11): 2382-2389, 1994. McCowage GB, Vowels MR, Shaw PJ, et al.: Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and totalbody irradiation. Journal of Clinical Oncology 13(11): 2789-2795, 1995. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(1): 152-158, 1991. 118 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 119 Cheung NK, Kushner BH, Cheung IY, et al.: Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. Journal of Clinical Oncology 16(9): 3053-3060, 1998. 120 Garaventa A, Bellagamba O, Lo Piccolo MS, et al.: I-metaiodobenzulguanidine (131IMIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients. British Journal of Cancer 81(8): 1378-1384, 1999. 121 Frappaz D, Michon J, Coze C, et al.: LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis. Journal of Clinical Oncology 18(3): 468-476, 2000. Grupp SA, Stern JW, Bunin N, et al.: Rapid-sequence tandem transplant for children with high-risk neuroblastoma. Medical and Pediatric Oncology 35(6): 696-700, 2000. 122 Miano M, Garaventa A, Pizzitola MR, et al.: Megatherapy combining I(131) metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma. Bone Marrow Transplantation 27(6): 571-574, 2001. 117

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Neuroblastoma Treatment Plan In North America, the Children’s Oncology Group is investigating a riskbased neuroblastoma treatment plan that assigns all patients to Low, Intermediate, and High Risk groups based on age, INSS stage, and tumor biology (N-myc gene amplification, Shimada histology, and DNA ploidy).123

Intermediate Risk Disseminated Neuroblastoma Infants less than one year of age at diagnosis with INSS stage 4 neuroblastoma that does not have N-myc amplification are categorized as Intermediate Risk (Table 1).124 These infants are treated with 12 weeks of chemotherapy if the tumor has both favorable Shimada histology and hyperdiploidy, and 24 weeks of chemotherapy if not. Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.125 In patients categorized as Intermediate Risk with favorable biology, radiation therapy is reserved for patients with symptomatic life- or organ-threatening tumor that does not respond rapidly enough to chemotherapy. In patients categorized as Intermediate Risk with unfavorable biological features, radiation therapy is given if residual viable tumor remains after 24 weeks of chemotherapy and second look surgery.

High Risk Disseminated Neuroblastoma ·

Infants less than one year of age at diagnosis with INSS stage 4 neuroblastoma with N-myc gene amplification126 are classified as High Risk.

Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001. 124 Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children’s Cancer Group study. Journal of Clinical Oncology 18(6): 1260-1268, 2000. 125 Baker D, Children’s Cancer Group: Phase III Study of Combination Chemotherapy in Children With Intermediate-Risk Neuroblastoma (Summary Last Modified 07/2001), CCGA3961, clinical trial, active, 01/15/1998. 126 Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children’s Cancer Group study. Journal of Clinical Oncology 18(6): 1260-1268, 2000. 123

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·

Older children with INSS stage 4 neuroblastoma with any biological features (N-myc gene amplification, Shimada histology, DNA ploidy) are considered High Risk. (Table 1)

Patients classified as High Risk should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide and high dose cisplatin. After a response to chemotherapy, resection of the primary tumor may be attempted, followed by myeloablative chemotherapy, sometimes including total-body irradiation, rescued by autologous bone marrow or peripheral blood stem cell transplantation. Irradiation of residual tumor may be performed before, during or after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and post-chemotherapy retinoic acid improve outcome in patients categorized as High Risk.127 Information about ongoing clinical trials is available from the NCI (http://cancer.gov/clinical_trials/).

Treatment Options for Stage 4S Neuroblastoma The treatment of children with stage 4S disease is controversial.128 Children with this special pattern of neuroblastoma may not require therapy, although the development of complications, such as functional compromise from massive hepatomegaly, is an indication for intervention, especially in infants younger than 2 to 3 months of age.129 In a study of 80 infants with 4S Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 128 Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? Journal of Clinical Oncology 14(5): 1537-1544, 1996. Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the Pediatric Oncology Group experience. Journal of Clinical Oncology 16(6): 2007-2017, 1998. 129 Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? Journal of Clinical Oncology 14(5): 1537-1544, 1996. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children’s Cancer Group study. Journal of Clinical Oncology 18(3): 477-486, 2000. Hsu LL, Evans AE, D’Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Medical and Pediatric Oncology 27(6): 521-528, 1996. 127

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disease, those who were asymptomatic had 100% survival with supportive care only, and patients with symptoms had an 81% survival rate when they received low-dose chemotherapy.130 Resection of the primary tumor is not associated with improved outcome.131 Neuroblastoma Treatment Plan In North America, the Children’s Oncology Group is investigating a neuroblastoma treatment plan based on assignment to Low, Intermediate, and High Risk groups based on age, INSS stage, and tumor biology (N-myc gene amplification, Shimada histology, and DNA ploidy).132

Low Risk Stage 4S Neuroblastoma Infants less than one year of age at diagnosis with INSS stage 4S neuroblastoma are categorized as Low Risk if the tumor biologic properties are all favorable, that is, N-myc not amplified, favorable Shimada histology, and hyperdiploid DNA (Table 1). Chemotherapy is recommended only for life- or organ-threatening symptoms that cannot be relieved by safe surgical resection of the mass. Such symptoms include respiratory distress, renal or bowel ischemia, spinal cord compression, gastrointestinal or genitourinary obstruction, or coagulopathy.133 Radiation therapy is reserved for patients with symptomatic life- or organ-threatening tumor that does not respond rapidly enough to chemotherapy. When required, chemotherapy is given for Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IVS neuroblastoma with supportive care or minimal therapy: a Children’s Cancer Group study. Journal of Clinical Oncology 18(3): 477-486, 2000. 131 Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? Journal of Clinical Oncology 14(5): 1537-1544, 1996. Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the Pediatric Oncology Group experience. Journal of Clinical Oncology 16(6): 2007-2017, 1998. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children’s Cancer Group study. Journal of Clinical Oncology 18(3): 477-486, 2000. 132 Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001. 133 Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 130

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6 weeks, and only continued for a full 12 weeks if necessary to treat symptoms as described above. Specific therapy for recurrence or progression of disease is also specified by the treatment plan.134

Intermediate Risk Stage 4S Neuroblastoma Infants less than one year of age at diagnosis with INSS stage 4S neuroblastoma without amplification of the N-myc gene, but with unfavorable Shimada histology, diploid DNA or both, are classified as Intermediate Risk (Table 1). These infants are treated with 24 weeks of chemotherapy consisting of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.135 Radiation therapy is given if residual viable tumor remains after 24 weeks of chemotherapy and second look surgery.

High Risk Stage 4S Neuroblastoma Infants less than one year of age at diagnosis with INSS stage 4S neuroblastoma having amplification of the N-myc gene are classified as High Risk (Table 1). These infants should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, but often also including ifosfamide and high dose cisplatin. After a response to chemotherapy, resection of the primary tumor may be attempted, followed by myeloablative chemotherapy, and/or radiotherapy with autologous bone marrow or peripheral blood stem cell transplantation. Irradiation of residual tumor may be performed during or after myeloablative therapy. Post recovery, patients are treated with oral 13cis-retinoic acid for 6 months. Both myeloablative therapy and postchemotherapy retinoic acid improve outcome of patients classified as High Risk.136

Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 135 Baker D, Children’s Cancer Group: Phase III Study of Combination Chemotherapy in Children With Intermediate-Risk Neuroblastoma (Summary Last Modified 07/2001), CCGA3961, clinical trial, active, 01/15/1998. 136 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 134

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Recurrent Neuroblastoma The prognosis and treatment of recurrent or progressive neuroblastoma depends on many factors including initial stage, tumor biological characteristics at recurrence, the site and extent of the recurrence or progression, and on the previous treatment as well as individual patient considerations. When recurrence is widespread, the prognosis is usually poor despite additional intensive therapy.137 In selected cases, recurrence may be treated successfully with limited interventions. The combination of cyclophosphamide plus topotecan has been shown to be active in patients with recurrent or refractory disease.138 Unlike at initial presentation, central nervous system involvement is common. Inward compression of the brain from cranial metastases can occur, and rarely meningeal and isolated intracranial metastasis occur. Early recognition and treatment of central nervous system involvement may result in reduced neurologic impairment.139 Clinical trials are appropriate and should be considered.140 Information about ongoing clinical trials is available from the NCI (http://cancer.gov/clinical_trials).

Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(1): 152-158, 1991. Castel V, Canete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses and refractory neuroblastoma. Medical and Pediatric Oncology 35(6): 724-726, 2000. 138 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. 139 Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 91(8): 1510-1519, 2001. Blatt J, Fitz C, Mirro J: Recognition of central nervous system metastases in children with metastatic primary extracranial neuroblastoma. Pediatric Hematology and Oncology 14(3): 233-241, 1997. 140 Hayes FA, Green AA: Second complete remission (CR) in children with metastatic neuroblastoma (NB). Proceedings of the American Society of Clinical Oncology 4: C-921, 237, 1985. Philip T, Gentet JC, Carrie C, et al.: Phase II studies of combinations of drugs with high-dose carboplatin in neuroblastoma (800 mg/m2 to 1 g 250/m2): a report from the LMCE group. Progress in Clinical and Biological Research 271: 573-582, 1988. Cheung NK, Lazarus H, Miraldi FD, et al.: Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma. Journal of Clinical Oncology 5(9): 1430-1440, 1987. 137

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Children’s Oncology Group Treatment Plan In North America, the Children’s Oncology Group is investigating a riskbased neuroblastoma plan that assigns all patients to Low, Intermediate, and High Risk groups based on age, INSS stage, and tumor biology (N-myc gene amplification, Shimada histology, and DNA ploidy).141 Treatment of recurrent disease is determined by the risk group at the time of diagnosis (Table 1), extent of disease at recurrence, patient age at recurrence, and the tumor biology at recurrence. If tumor is unavailable for biological studies at recurrence, the biology of the tumor at the time of diagnosis is used to help determine treatment.

Recurrent Neuroblastoma in Patients Initially Classified as Low Risk Local/regional recurrence is resected if possible: ·

Those with favorable biology are observed if resection is total or near total; while those with favorable biology and a less than near total resection are treated with 12 weeks of chemotherapy.

·

Infants less than one year of age at the time of local/regional recurrence, whose tumors have any unfavorable biologic properties, are observed if resection is total or near total. If the resection is less than near total, these same infants are treated with 24 weeks of chemotherapy.

Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.142 Older children with local recurrence with either Frappaz D, Michon J, Hartmann O. et al.: Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study. Journal of Clinical Oncology 10(10): 1592-1601, 1992. Matthay KK, DeSantes K, Hasegawa B, et al.: Phase I dose escalation of 131Imetaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. Journal of Clinical Oncology 16(1): 229-236, 1998. Evans AE, August CS, Kamani N, et al.: Bone marrow transplantation for high risk neuroblastoma at the Children’s Hospital of Philadelphia: an update. Medical and Pediatric Oncology 23(4): 323-327, 1994. 141 Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92(10): 2699-2708, 2001. 142 Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998.

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unfavorable Shimada histology or N-myc gene amplification have a poor prognosis and should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide and high dose cisplatin. Both myeloablative therapy and post-chemotherapy retinoic acid may improve outcome of patients with a poor prognosis.143

Metastatic Recurrence Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as Low Risk (Table 1) and less than one year of age at recurrence, whether the patient has INSS stage 1, 2, or 4S at the time of diagnosis is treated according to tumor biology: ·

If the biology is completely favorable, the metastasis is in a 4S pattern, and the recurrence or progression is within 3 months of diagnosis, the patient is observed systematically.

·

If the metastatic progression or recurrence with completely favorable biology occurs greater than 3 months after diagnosis or not in a 4S pattern, then the primary tumor is resected if possible and 12 to 24 weeks of chemotherapy given, depending on response.

·

If the tumor in the infant with metastatic recurrence or progression has unfavorable Shimada histology and/or is diploid, the primary tumor is resected if possible and 24 weeks of chemotherapy is given.

Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.144 Any child initially categorized as Low Risk who is over one year of age at the time of metastatic recurrent or progressive disease usually has a poor prognosis and should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide and high dose cisplatin. Both myeloablative

Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 144 Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 143

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therapy and post-chemotherapy retinoic acid may improve outcome of patients with a poor prognosis.145

Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk Local/Regional Recurrence Local regional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of 12 weeks of chemotherapy is treated surgically. If resection is less than near total, then 12 additional weeks of chemotherapy is given. Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.146

Metastatic Recurrence If the recurrence is metastatic and/or occurs while on chemotherapy or within 3 months of completing chemotherapy and/or has unfavorable biologic properties, the prognosis is poor and the patient should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and post-chemotherapy retinoid acid may improve outcome of patients with a poor prognosis.147

Recurrent Neuroblastoma in Patients Initially Classified as High Risk Any recurrence in patients initially classified as High Risk signifies a poor prognosis. Tumor has recurred in spite of the administration of aggressive Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 146 Strother DR, Pediatric Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma (Summary Last Modified 08/2001), POG-P9641, clinical trial, active, 03/01/1998. 147 Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cisretinoic acid. New England Journal of Medicine 341(16): 1165-1173, 1999. 145

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high dose combination chemotherapy, often with myeloablative therapy plus stem cell rescue. Phase I or II clinical trials are appropriate and should be considered.148

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.149 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:150 ·

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

·

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

·

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

·

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

·

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related

148 Castel V, Canete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses and refractory neuroblastoma. Medical and Pediatric Oncology 35(6): 724-726, 2000. 149 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). 150 See http://www.nlm.nih.gov/databases/databases.html.

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health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html ·

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

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

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

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

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

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

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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 neuroblastoma, the following are particularly noteworthy.

The NLM Gateway151 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

151

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

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many of NLM’s information resources or databases.152 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.153 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “neuroblastoma” (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 2583 Consumer Health 294 Meeting Abstracts 2575 Other Collections 87 Total 356125

HSTAT154 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.155 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, including clinical practice guidelines, quick-reference guides for clinicians, 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). 153 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. 154 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 155 The HSTAT URL is http://hstat.nlm.nih.gov/. 152

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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.156 Simply search by “neuroblastoma” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists157 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.158 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.159 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. 157 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 158 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. 159 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. 156

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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 Neuroblastoma 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 neuroblastoma. 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

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Biotechnology Information (NCBI).160 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 “neuroblastoma” (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 neuroblastoma: ·

Deleted in Neuroblastoma 5 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?605763

·

Neuroblastoma Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?256700

·

Neuroblastoma Candidate Region, Suppression of Tumorigenicity 1 Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?600613

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Neuroblastoma Ras Viral Oncogene Homolog Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?164790

·

Neuroblastoma Stage 4s Gene Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?602942

·

V-myc Avian Myelocytomatosis Viral-related Neuroblastoma-derived Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?164840

Oncogene,

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.

160

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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

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·

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

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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

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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 “neuroblastoma” (or synonyms) and click “Go.”

Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database161 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.

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 161

218 Neuroblastoma

The Genome Database162 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 “neuroblastoma” (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 neuroblastoma (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: Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html#mission. 162

Physician Guidelines and Databases 219

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

220 Neuroblastoma

· 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 ACTH: Adrenocorticotropic hormone. [EU] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Loss of muscle coordination. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Catecholamines: A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] CNS: Central nervous system. The brain and spinal cord. [NIH] Contralateral: Having to do with the opposite side of the body. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Criterion: A standard by which something may be judged. [EU] Diploidy: The chromosomal constitution of somatic cells, in which each type of chromosome is represented twice. Symbol: 2N or 2X. [NIH] Distention: The state of being distended or enlarged; the act of distending. [EU]

Ecchymosis: A small haemorrhagic spot, larger than a petechia, in the skin or mucous membrane forming a nonelevated, rounded or irregular, blue or purplish patch. [EU] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Hematologist: A doctor who specializes in treating diseases of the blood. [NIH]

Hemorrhage: Bleeding or escape of blood from a vessel. [NIH]

Physician Guidelines and Databases 221

Hepatomegaly: Enlargement of the liver. [EU] Hypertension: Abnormally high blood pressure. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Ipsilateral: Having to do with the same side of the body. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Meningeal: Refers to the meninges, the tissue covering the brain and spinal cord. [NIH] Microgram: A unit of mass (weight) of the metric system, being onemillionth of a gram (10-6 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] Milligram: A measure of weight. A milligram is approximately 450,000times smaller than a pound and 28,000-times smaller than an ounce. [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] Nephrectomy: Surgery to remove a kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes, and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor but not the entire kidney. [NIH] Nonmetastatic: Cancer that has not spread from the primary (original) site to other sites in the body. [NIH] Pancytopenia: Deficiency of all cell elements of the blood; aplastic anaemia. [EU]

Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periorbital: Situated around the orbit, or eye socket. [EU] Plasmapheresis: The process of separating certain cells from the plasma in the blood by a machine; only the cells are returned to the person. Plasmapheresis can be used to remove excess antibodies from the blood. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Proptosis: Forward projection or displacement especially of the eyeball :

222 Neuroblastoma

exophthalmos. [EU] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Radiography: The making of film records (radiographs) of internal structures of the body by passage of x-rays or gamma rays through the body to act on specially sensitized film. [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] Retrobulbar: Behind the pons. [EU] Technetium: The first artificially produced element and a radioactive fission product of uranium. The stablest isotope has a mass number 99 and is used diagnostically as a radioactive imaging agent. Technetium has the atomic symbol Tc, atomic number 43, and atomic weight 98.91. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Teniposide: An anticancer drug that is a podophyllotoxin derivative and belongs to the family of drugs called mitotic inhibitors. [NIH] Tomography: A series of detailed pictures of areas inside the body; the pictures are created by a computer linked to an x-ray machine. [NIH] Topotecan: An anticancer drug that belongs to the family drugs called topoisomerase inhibitors. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vertebral: Of or pertaining to a vertebra. [EU]

Dissertations 223

CHAPTER 9. DISSERTATIONS ON NEUROBLASTOMA 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 neuroblastoma. 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 Neuroblastoma ProQuest Digital Dissertations is the largest archive of academic dissertations available. From this archive, we have compiled the following list covering dissertations devoted to neuroblastoma. 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 neuroblastoma: ·

A Fluorescence, Phosphorus-31 Nmr and Lithium-7 Nmr Spectroscopy Study of Lithium(+)/magnesium(2+) Competition, and of Lithium(+) Transport and Binding in Human Neuroblastoma and

224 Neuroblastoma

Lymphoblastoma Cells by Layden, Brian Thomas; PhD from Loyola University of Chicago, 2001, 188 pages http://wwwlib.umi.com/dissertations/fullcit/3015518 ·

A Study on Novel Biological Activities of Pro-igf-i E-peptides in Human Neuroblastoma Cells by Kuo, Ya-huei; PhD from the University of Connecticut, 2001, 188 pages http://wwwlib.umi.com/dissertations/fullcit/3034018

·

BHLH Transcription Factors in Differentiating Neuroblastoma Cells by Grynfeld, Anna; PhD from Lunds Universitet (Sweden), 2001, 110 pages http://wwwlib.umi.com/dissertations/fullcit/f315921

·

Involvement Ofbcl-2 Andp53 Genes in the Survival of Human Catecholaminergic Neuroblastoma Sh-sy5y Cells by Tieu, Kim; PhD from the University of Saskatchewan (Canada), 2001, 182 pages http://wwwlib.umi.com/dissertations/fullcit/NQ63933

·

Maternal and Paternal Medication Use and Neuroblastoma in the Offspring by Cook, Michael Nolan; PhD from the University of North Carolina at Chapel Hill, 2001, 240 pages http://wwwlib.umi.com/dissertations/fullcit/3031815

·

Power Frequency Electromagnetic Field Effects on App695 Transcription Levels in Differentiating Human Neuroblastoma Cells by Rao, Raj Raghavendra; PhD from University of Georgia, 2001 http://wwwlib.umi.com/dissertations/fullcit/f567713

·

Studies on Differentiation of Neuroblastoma, Using Ng108-15 Cells As a Model by Ghahary, Aziz; PhD from the University of Manitoba (Canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL47832

·

Turnover of Fatty Acyl Chains in the Phospholipids of Neuroblastoma Cells and Subcellular Membranes by Chakravarthy, Balu Rajagopalachar; PhD from Dalhousie University (Canada), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL22522

·

Visualization and Characterization of Cell Surface Glycoproteins on Mouse Neuroblastoma Cells by Maher, Pamela A; PhD from the University of British Columbia (Canada), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK49992

Keeping Current As previously mentioned, an effective way to stay current on dissertations dedicated to neuroblastoma is to use the database called ProQuest Digital

Dissertations 225

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.

Vocabulary Builder Glycoproteins: Conjugated protein-carbohydrate compounds including mucins, mucoid, and amyloid glycoproteins. [NIH] Membranes: Thin layers of tissue which cover parts of the body, separate adjacent cavities, or connect adjacent structures. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH]

227

PART III. APPENDICES

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

Researching Your Child’s Medications 229

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 neuroblastoma. 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 Internet-based 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 neuroblastoma. Research can give you information on the side effects, interactions, and limitations of prescription drugs used in the treatment of neuroblastoma. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

230 Neuroblastoma

Your Child’s Medications: The Basics163 The Agency for Health Care Research and Quality has published extremely useful guidelines on the medication aspects of neuroblastoma. 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 neuroblastoma. 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.

·

What to do if your child misses a dose.

163

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

Researching Your Child’s Medications 231

·

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 neuroblastoma). 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 neuroblastoma. 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

232 Neuroblastoma

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.164 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 neuroblastoma. 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 neuroblastoma: Carboplatin ·

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

Cisplatin ·

Systemic - U.S. Brands: Platinol; Platinol-AQ http://www.nlm.nih.gov/medlineplus/druginfo/cisplatinsystemi c202143.html

Though cumbersome, the FDA database can be freely browsed at the following site: www.fda.gov/cder/da/da.htm. 164

Researching Your Child’s Medications 233

Cyclophosphamide ·

Systemic - U.S. Brands: Cytoxan; Neosar http://www.nlm.nih.gov/medlineplus/druginfo/cyclophosphami desystemic202174.html

Dacarbazine ·

Systemic - U.S. Brands: DTIC-Dome http://www.nlm.nih.gov/medlineplus/druginfo/dacarbazinesyst emic202178.html

Doxorubicin ·

Systemic - U.S. Brands: Rubex http://www.nlm.nih.gov/medlineplus/druginfo/doxorubicinsyst emic202209.html

Dronabinol ·

Systemic - U.S. Brands: Marinol http://www.nlm.nih.gov/medlineplus/druginfo/dronabinolsyste mic202210.html

Epinephrine ·

Ophthalmic - U.S. Brands: Epifrin; Epinal; Eppy/N; Glaucon http://www.nlm.nih.gov/medlineplus/druginfo/epinephrineoph thalmic202213.html

Etoposide ·

Systemic - U.S. Brands: Etopophos; Toposar; VePesid http://www.nlm.nih.gov/medlineplus/druginfo/etoposidesyste mic202234.html

Ifosfamide ·

Systemic - U.S. Brands: IFEX http://www.nlm.nih.gov/medlineplus/druginfo/ifosfamidesyste mic202293.html

Melphalan ·

Systemic - U.S. Brands: Alkeran http://www.nlm.nih.gov/medlineplus/druginfo/melphalansyste mic202345.html

234 Neuroblastoma

Mesna ·

Systemic - U.S. Brands: MESNEX http://www.nlm.nih.gov/medlineplus/druginfo/mesnasystemic2 02352.html

Metoclopramide ·

Systemic - U.S. Brands: Octamide; Reglan http://www.nlm.nih.gov/medlineplus/druginfo/metoclopramide systemic202364.html

Teniposide ·

Systemic - U.S. Brands: Vumon http://www.nlm.nih.gov/medlineplus/druginfo/teniposidesyste mic203661.html

Vincristine ·

Systemic - U.S. Brands: Oncovin; Vincrex http://www.nlm.nih.gov/medlineplus/druginfo/vincristinesyste mic202594.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

Researching Your Child’s Medications 235

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/

236 Neuroblastoma

·

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 Drugs165 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. 165

Researching Your Child’s Medications 237

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

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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

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Results of clinical trials

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How the drug or biologic is manufactured, processed, and packaged

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Quality control standards

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Samples of the product in the form(s) in which it is to be administered.

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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

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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:

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·

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

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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

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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

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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 neuroblastoma--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 neuroblastoma or potentially create deleterious side effects in patients with neuroblastoma. 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

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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 neuroblastoma. 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 neuroblastoma. The FDA warns to watch out for166: ·

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:

166

This section has been adapted from http://www.fda.gov/opacom/lowlit/medfraud.html.

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0763711705; http://www.amazon.com/exec/obidos/ASIN/0763711705/icongroupinterna ·

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] Dacarbazine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Dronabinol: A synthetic pill form of delta-9-tetrahydrocannabinol (THC), an active ingredient in marijuana that is used to treat nausea and vomiting associated with cancer chemotherapy. [NIH] Metoclopramide: A drug that prevents or reduces nausea and vomiting. [NIH]

Ophthalmic: Pertaining to the eye. [EU]

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APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE Overview167 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 neuroblastoma. Finally, at the conclusion of this chapter, we will provide a list of readings on neuroblastoma from various authors. We will begin, however, with the

167Adapted

from the NCI: http://cis.nci.nih.gov/fact/9_14.htm

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National Center for Complementary and Alternative Medicine’s (NCCAM) overview of complementary and alternative medicine.

What Is CAM?168 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. 168

Adapted from the NCCAM: http://nccam.nih.gov/nccam/fcp/faq/index.html#what-is.

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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?169 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

169

Adapted from the NCCAM: http://nccam.nih.gov/nccam/fcp/classify/index.html.

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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.

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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.

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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?170 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. 170Adapted

from the NCI: http://cis.nci.nih.gov/fact/9_14.htm

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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?

·

What are the risks associated with this therapy?

·

Do the known benefits outweigh the risks?

·

What side effects can be expected?

·

Will the therapy interfere with conventional treatment?

·

Is this therapy part of a clinical trial? If so, who is sponsoring the trial?

·

Will the therapy be covered by health insurance?

·

How can patients and their health care providers learn more about complementary and alternative therapies?

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Levels of Evidence for Human Studies of CAM for Cancer171 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 Neuroblastoma Having read the previous discussion, you may be wondering which complementary or alternative treatments might be appropriate for neuroblastoma. 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 neuroblastoma and complementary medicine. To search the database, go to the following Web 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

171

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site: www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “neuroblastoma” (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 neuroblastoma: ·

131I]metaiodobenzylguanidine and high-dose chemotherapy with bone marrow rescue in advanced neuroblastoma. Author(s): Corbett R, Pinkerton R, Tait D, Meller S. Source: J Nucl Biol Med. 1991 October-December; 35(4): 228-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1823824&dopt=Abstract

·

A new bis-indole, KARs, induces selective M arrest with specific spindle aberration in neuroblastoma cell line SH-SY5Y. Author(s): Comin-Anduix B, Agell N, Bachs O, Ovadi J, Cascante M. Source: Molecular Pharmacology. 2001 December; 60(6): 1235-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11723230&dopt=Abstract

·

A phase I dose escalation of combination chemotherapy with granulocyte-macrophage-colony stimulating factor in patients with neuroblastoma. Author(s): Fernandez MC, Krailo MD, Gerbing RR, Matthay KK. Source: Cancer. 2000 June 15; 88(12): 2838-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10870069&dopt=Abstract

·

A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Societe Francaise d'Oncologie Pediatrique. Author(s): Philip T, Ghalie R, Pinkerton R, Zucker JM, Bernard JL, Leverger G, Hartmann O. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1987 June; 5(6): 941-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3585448&dopt=Abstract

·

A polymer-dependent increase in phosphorylation of beta-tubulin accompanies differentiation of a mouse neuroblastoma cell line. Author(s): Gard DL, Kirschner MW.

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Source: The Journal of Cell Biology. 1985 March; 100(3): 764-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=2857724&dopt=Abstract ·

A randomized trial of 13-Cis retinoic acid in children with advanced neuroblastoma after high-dose therapy. Author(s): Kohler JA, Imeson J, Ellershaw C, Lie SO. Source: British Journal of Cancer. 2000 November; 83(9): 1124-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11027423&dopt=Abstract

·

A saturation threshold for taxol cytotoxicity in human glial and neuroblastoma cells. Author(s): Helson L, Helson C, Malik S, Ainsworth S, Mangiardi J. Source: Anti-Cancer Drugs. 1993 August; 4(4): 487-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8104544&dopt=Abstract

·

A virus-directed enzyme prodrug therapy approach to purging neuroblastoma cells from hematopoietic cells using adenovirus encoding rabbit carboxylesterase and CPT-11. Author(s): Meck MM, Wierdl M, Wagner LM, Burger RA, Guichard SM, Krull EJ, Harris LC, Potter PM, Danks MK. Source: Cancer Research. 2001 July 1; 61(13): 5083-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11431345&dopt=Abstract

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Actions of pyrethroid insecticides on voltage-gated chloride channels in neuroblastoma cells. Author(s): Ray DE, Sutharsan S, Forshaw PJ. Source: Neurotoxicology. 1997; 18(3): 755-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9339822&dopt=Abstract

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Adult ganglioneuroblastoma of the anterior mediastinum. Author(s): Nagashima Y, Miyagi Y, Tanaka Y, Miyashita M, Shigematsu S, Aoki I, Nakatani Y, Misugi K. Source: Pathology, Research and Practice. 1997; 193(10): 727-32; Discussion 733. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9505266&dopt=Abstract

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Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26. Author(s): Shafford EA, Rogers DW, Pritchard J. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1984 July; 2(7): 742-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=6539811&dopt=Abstract

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Advanced neuroblastoma: results of two treatment programs including sequential hemibody irradiation. Author(s): Lombardi F, Rottoli L, Gianni C, Gandola L, Lattuada A, Fossati-Bellani F, Gasparini M. Source: International Journal of Radiation Oncology, Biology, Physics. 1989 September; 17(3): 485-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=2674076&dopt=Abstract

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Aggressive surgery combined with intensive chemotherapy improves survival in poor-risk neuroblastoma. Author(s): Haase GM, O'Leary MC, Ramsay NK, Romansky SG, Stram DO, Seeger RC, Hammond GD. Source: Journal of Pediatric Surgery. 1991 September; 26(9): 1119-23; Discussion 1123-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1941492&dopt=Abstract

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Allergic reactions to teniposide in patients with neuroblastoma and lymphoid malignancies. Author(s): Hayes FA, Abromowitch M, Green AA. Source: Cancer Treat Rep. 1985 April; 69(4): 439-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3857970&dopt=Abstract

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Altered irinotecan and SN-38 disposition after intravenous and oral administration of irinotecan in mice bearing human neuroblastoma xenografts. Author(s): Zamboni WC, Houghton PJ, Thompson J, Cheshire PJ, Hanna SK, Richmond LB, Lou X, Stewart CF.

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Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1998 February; 4(2): 455-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9516936&dopt=Abstract ·

Aluminum uptake by neuroblastoma cells. Author(s): Shi B, Haug A. Source: Journal of Neurochemistry. 1990 August; 55(2): 551-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=2115072&dopt=Abstract

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An open-label, multicentre, randomised phase 2 study of recombinant human granulocyte colony-stimulating factor (filgrastim) as an adjunct to combination chemotherapy in paediatric patients with metastatic neuroblastoma. Author(s): Michon JM, Hartmann O, Bouffet E, Meresse V, Coze C, Rubie H, Bordigoni P, Cattiaux E, Ward N, Bernard JL, Lemerle J, Zucker JM, Philip T. Source: European Journal of Cancer (Oxford, England : 1990). 1998 June; 34(7): 1063-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9849455&dopt=Abstract

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Anti-apoptotic effect of trans-resveratrol on paclitaxel-induced apoptosis in the human neuroblastoma SH-SY5Y cell line. Author(s): Nicolini G, Rigolio R, Miloso M, Bertelli AA, Tredici G. Source: Neuroscience Letters. 2001 April 13; 302(1): 41-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11278107&dopt=Abstract

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Antiproliferative effect of the garlic compound S-allyl cysteine on human neuroblastoma cells in vitro. Author(s): Welch C, Wuarin L, Sidell N. Source: Cancer Letters. 1992 April 30; 63(3): 211-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1349504&dopt=Abstract

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ASK1 resistant neuroblastoma is deficient in activation of p38 kinase. Author(s): Arvidsson Y, Hamazaki TS, Ichijo H, Funa K.

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Source: Cell Death and Differentiation. 2001 October; 8(10): 1029-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11598801&dopt=Abstract ·

Atrial natriuretic peptide binds to ANP-R1 receptors in neuroblastoma cells or is degraded extracellularly at the Ser-Phe bond. Author(s): Delporte C, Poloczek P, Tastenoy M, Winand J, Christophe J. Source: European Journal of Pharmacology. 1992 November 2; 227(3): 247-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1335413&dopt=Abstract

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Autologous bone marrow transplantation for stage IV neuroblastoma: the role of soybean agglutinin purging. Author(s): Kapelushnik J, Nagler A, Or R, Naparstek E, Cividalli G, Aker M, Mehta J, Mumcuoglu M, Slavin S. Source: Transplantation Proceedings. 1993 June; 25(3): 2375-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8516934&dopt=Abstract

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Autologous bone marrow transplantation for very bad prognosis neuroblastoma. Author(s): Philip T, Biron P, Philip I, Favrot M, Bernard JL, Zucker JM, Lutz B, Plouvier E, Rebattu P, Carton M, et al. Source: Prog Clin Biol Res. 1985; 175: 569-86. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3887433&dopt=Abstract

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Avascular necrosis of bone in neuroblastoma treated with combination chemotherapy. Author(s): Ishii E, Yoshida N, Miyazaki S. Source: European Journal of Pediatrics. 1984 December; 143(2): 152-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=6519114&dopt=Abstract

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Ayurvedic (science of life) agents induce differentiation in murine neuroblastoma cells in culture. Author(s): Prasad KN, Edwards-Prasad J, Kentroti S, Brodie C, Vernadakis A.

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Source: Neuropharmacology. 1992 June; 31(6): 599-607. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1357573&dopt=Abstract ·

Basic fibroblast growth factor induces proteolysis of secreted and cell membrane-associated insulin-like growth factor binding protein-2 in human neuroblastoma cells. Author(s): Russo VC, Rekaris G, Baker NL, Bach LA, Werther GA. Source: Endocrinology. 1999 July; 140(7): 3082-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10385400&dopt=Abstract

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Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Author(s): Dole M, Nunez G, Merchant AK, Maybaum J, Rode CK, Bloch CA, Castle VP. Source: Cancer Research. 1994 June 15; 54(12): 3253-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8205548&dopt=Abstract

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Bcl-xL is expressed in neuroblastoma cells and modulates chemotherapy-induced apoptosis. Author(s): Dole MG, Jasty R, Cooper MJ, Thompson CB, Nunez G, Castle VP. Source: Cancer Research. 1995 June 15; 55(12): 2576-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7780971&dopt=Abstract

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Betulinic acid induces apoptosis in human neuroblastoma cell lines. Author(s): Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM. Source: European Journal of Cancer (Oxford, England : 1990). 1997 October; 33(12): 2007-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9516843&dopt=Abstract

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Binding partners for the myelin-associated glycoprotein of N2A neuroblastoma cells. Author(s): Strenge K, Schauer R, Kelm S. Source: Febs Letters. 1999 February 5; 444(1): 59-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10037148&dopt=Abstract

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BIRICODAR (VX-710; Incel): an effective chemosensitizer in neuroblastoma. Author(s): Yanagisawa T, Newman A, Coley H, Renshaw J, Pinkerton CR, Pritchard-Jones K. Source: British Journal of Cancer. 1999 June; 80(8): 1190-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10376971&dopt=Abstract

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Bovine seminal ribonuclease exerts selective cytotoxicity toward neuroblastoma cells both sensitive and resistant to chemotherapeutic drugs. Author(s): Cinatl J Jr, Cinatl J, Kotchetkov R, Matousek J, Woodcock BG, Koehl U, Vogel JU, Kornhuber B, Schwabe D. Source: Anticancer Res. 2000 March-April; 20(2A): 853-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10810366&dopt=Abstract

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Brain-derived neurotrophic factor protects neuroblastoma cells from vinblastine toxicity. Author(s): Scala S, Wosikowski K, Giannakakou P, Valle P, Biedler JL, Spengler BA, Lucarelli E, Bates SE, Thiele CJ. Source: Cancer Research. 1996 August 15; 56(16): 3737-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8706017&dopt=Abstract

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Ca2+/calmodulin mediated pathways regulate the uptake of L-DOPA in mouse neuroblastoma neuro 2A cells. Author(s): Sampaio-Maia B, Soares-da-Silva P. Source: Life Sciences. 2000 November 17; 67(26): 3209-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11191628&dopt=Abstract

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Calcium independence of phosphoinositide hydrolysis-induced increase in cyclic AMP accumulation in SK-N-SH human neuroblastoma cells. Author(s): Baumgold J, Paek R, Fiskum G. Source: Journal of Neurochemistry. 1992 May; 58(5): 1754-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1313853&dopt=Abstract

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Carboplatin activity in cisplatin treated neuroblastoma. Author(s): Lewis IJ, Stevens MC, Pearson AD, Pinkerton CR, Barnes JM.

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Source: Prog Clin Biol Res. 1991; 366: 553-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=2068173&dopt=Abstract ·

Characterization of an insulin-like growth factor binding protein-5 protease produced by rat articular chondrocytes and a neuroblastoma cell line. Author(s): Matsumoto T, Gargosky SE, Kelley K, Rosenfeld RG. Source: Growth Regul. 1996 September; 6(3): 185-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8894652&dopt=Abstract

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Chemoimmunotherapy in conjunction with surgery: strategies for management of murine neuroblastoma. Author(s): Leonard MP, Gearhart JP, Jeffs RD. Source: Journal of Pediatric Surgery. 1991 October; 26(10): 1224-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1779333&dopt=Abstract

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Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. Author(s): Cheung NV, Heller G. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1991 June; 9(6): 1050-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=2033419&dopt=Abstract

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Chemotherapy for advanced esthesioneuroblastoma: the Mayo Clinic experience. Author(s): McElroy EA Jr, Buckner JC, Lewis JE. Source: Neurosurgery. 1998 May; 42(5): 1023-7; Discussion 1027-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9588546&dopt=Abstract

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Cisplatin, vinblastine, and bleomycin (CVB) therapy for relapsed disseminated neuroblastoma. Author(s): Bostrom B, Woods WG, Ramsay NK, Krivit W, Levine P, Nesbit ME Jr.

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Source: Cancer Treat Rep. 1984 September; 68(9): 1157-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=6206945&dopt=Abstract ·

Cis-platinum (CDDP) plus etoposide (VP-16-213) and treatment of disseminated neuroblastoma. Author(s): Helson L. Source: Anticancer Res. 1986 November-December; 6(6): 1337-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3813490&dopt=Abstract

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Clinical experience with radiation enhancement by hyperbaric oxygen in children with recurrent neuroblastoma stage IV. Author(s): Voute PA, van der Kleij AJ, De Kraker J, Hoefnagel CA, Tielvan Buul MM, Van Gennip H. Source: European Journal of Cancer (Oxford, England : 1990). 1995; 31A(4): 596-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7576976&dopt=Abstract

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Combination chemotherapy with ifosfamide and etoposide is effective in the treatment of central nervous system metastasis of childhood neuroblastoma. Author(s): Watts RG. Source: Cancer. 1992 June 15; 69(12): 3012-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1591695&dopt=Abstract

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Combined continuous infusion etoposide with high-dose cyclophosphamide for refractory neuroblastoma: a phase II study from the Societe Francaise d'Oncologie Pediatrique. Author(s): Meresse V, Vassal G, Michon J, De Cervens C, Courbon B, Rubie H, Perel Y, Landman J, Chastagnier P, De Valck C, et al. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 1993 April; 11(4): 630-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8478658&dopt=Abstract

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Comparison of melatonin versus vitamin C on oxidative stress and antioxidant enzyme activity in Alzheimer's disease induced by okadaic acid in neuroblastoma cells.

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Author(s): Montilla-Lopez P, Munoz-Agueda MC, Feijoo Lopez M, Munoz-Castaneda JR, Bujalance-Arenas I, Tunez-Finana I. Source: European Journal of Pharmacology. 2002 September 20; 451(3): 237-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=12242084&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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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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

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drkoop.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

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

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·

Herbs and Supplements Betula Alternative names: Birch; Betula sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Hyperlink: http://www.herbmed.org/ Gamma-Linolenic Acid (GLA) Source: Integrative Medicine Communications; www.onemedicine.com Hyperlink: http://www.drkoop.com/interactivemedicine/ConsSupplements/G ammaLinolenicAcidGLAcs.html GLA Source: Integrative Medicine Communications; www.onemedicine.com Hyperlink: http://www.drkoop.com/interactivemedicine/ConsSupplements/G ammaLinolenicAcidGLAcs.html Sambucus Alternative names: Black Elderberry; Sambucus nigra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Hyperlink: http://www.herbmed.org/

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General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at: 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

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· 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 The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Bleomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Chemosensitizer: A drug that makes tumor cells more sensitive to the effects of chemotherapy. [NIH] Chondrocytes: cartilage. [NIH]

Cartilage cells. They make the structural components of

Cysteine: A thiol-containing non-essential amino acid that is oxidized to form CYSTINE. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU]

Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Hydrolysis: A chemical reaction that uses water to break down a compound. [NIH]

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Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH]

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] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Nausea: An unpleasant sensation, vaguely referred to the epigastrium and abdomen, and often culminating in vomiting. [EU] Neuropharmacology: The branch of pharmacology dealing especially with the action of drugs upon various parts of the nervous system. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Platinum: A metal that is an important component of some anticancer drugs, such as cisplatin and carboplatin. [NIH] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH]

Thiotepa: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]

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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 neuroblastoma. 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 neuroblastoma may be given different recommendations. Some recommendations may be directly related to neuroblastoma, 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 neuroblastoma. We will then show you how to find studies dedicated specifically to nutrition and neuroblastoma.

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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.

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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.

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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.

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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.

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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.

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Vitamin B2, also known as riboflavin, is important for the nervous system and muscles, but is also involved in the release of proteins from

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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

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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.

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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.

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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.

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Vitamin D helps the body absorb calcium which strengthens bones and teeth; food sources for vitamin D include oily fish and dairy products.

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Vitamin E can help protect certain organs and tissues from various degenerative diseases; food sources for vitamin E include margarine, vegetables, eggs, and fish.

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Vitamin K is essential for bone formation and blood clotting; common food sources for vitamin K include leafy green vegetables.

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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.

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·

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:172 ·

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.

172

Adapted from the FDA: http://www.fda.gov/fdac/special/foodlabel/dvs.html.

Researching Nutrition 273

·

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?173 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.”174 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.175 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. 174 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]. 175 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.” 173

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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 Neuroblastoma 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.176 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.

176

Researching Nutrition 275

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 “neuroblastoma” (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 “neuroblastoma” (or a synonym): ·

13-cis-retinoic acid (NSC 122758) in the treatment of children with metastatic neuroblastoma unresponsive to conventional chemotherapy: report from the Childrens Cancer Study Group. Author(s): Harbor/UCLA Medical Center, Torrance. Source: Finklestein, J Z Krailo, M D Lenarsky, C Ladisch, S Blair, G K Reynolds, C P Sitarz, A L Hammond, G D Med-Pediatr-Oncol. 1992; 20(4): 307-11 0098-1532

·

13-cis-retinoic acid-induced eosinophilia following autologous bone marrow transplantation for neuroblastoma. Author(s): Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA. Source: Degar, B A Harrington, R D Rappeport, J M Woolfrey, A E MedPediatr-Oncol. 1999 April; 32(4): 308-10 0098-1532

·

1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine. Author(s): Groningen Utrecht Institute for Drug Exploration, Department of Pediatric Oncology, Beatrix Children's Hospital, The Netherlands. Source: Sietsma, H Veldman, R J Kolk, D Ausema, B Nijhof, W Kamps, W Vellenga, E Kok, J W Clin-Cancer-Res. 2000 March; 6(3): 942-8 1078-0432

·

6-Hydroxydopamine toxicity towards human SH-SY5Y dopaminergic neuroblastoma cells: independent of mitochondrial energy metabolism. Author(s): Department of Neurology, University of Ulm Medical School, Federal Republic of Germany. [email protected] Source: Storch, A Kaftan, A Burkhardt, K Schwarz, J J-Neural-Transm. 2000; 107(3): 281-93

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·

A phase I trial of high-dose carboplatin and etoposide with autologous marrow support for treatment of stage D neuroblastoma in first remission: use of marker genes to investigate the biology of marrow reconstitution and the mechanism of relapse. Source: Anonymous Hum-Gene-Ther. 1991 Fall; 2(3): 257-72 1043-0342

·

A PKCbeta isoform mediates phorbol ester-induced activation of Erk1/2 and expression of neuronal differentiation genes in neuroblastoma cells. Author(s): Lund University, Molecular Medicine, Malmo University Hospital, 205 02 Malmo, Sweden Source: Troller, U Zeidman, R Svensson, K Larsson, C FEBS-Lett. 2001 November 9; 508(1): 126-30 0014-5793

·

A role for inwardly rectifying K+ channels in differentiation of NG10815 neuroblastoma x glioma cells. Author(s): Center for Bio/Molecular Science and Engineering, Naval Research Laboratory, Washington, DC 20375, USA. Source: Pancrazio, J J Ma, W Grant, G M Shaffer, K M Kao, W Y Liu, Q Y Manos, P Barker, J L Stenger, D A J-Neurobiol. 1999 March; 38(4): 466-74 0022-3034

·

A single center experience with bone marrow transplantation for high risk neuroblastoma. Author(s): Coordination Center EBMT Registry, Lyon, France. Source: Ladenstein, R Lasset, C Bouffet, E Brunat Mentigny, M Biron, P Philip, I Chauvin, F Philip, T Bone-Marrow-Transplant. 1991; 7 Suppl 293 0268-3369

·

A single hamster PrP amino acid blocks conversion to proteaseresistant Prp in scrapie-infected mouse neuroblastoma cells. Source: Priola, S.A. Chesebro, B. J-virol. Washington, D.C.: American Society for Microbiology. December 1995. volume 69 (12) page 7754-7758. 0022-538X

·

A study of thiotepa, etoposide and fractionated total body irradiation as a preparative regimen prior to bone marrow transplantation for poor prognosis patients with neuroblastoma. Author(s): Bone Marrow Transplant Program, Miami Children's Hospital, FL, USA. Source: Kamani, N August, C S Bunin, N Leahey, A Bayever, E Goldwein, J Zusman, J Evans, A E Angio, G D Bone-Marrow-Transplant. 1996 June; 17(6): 911-6 0268-3369

Researching Nutrition 277

·

Arachidonate release and c-fos expression in various models of hypoxia and hypoxia-hypoglycemia in retinoic acid differentiated neuroblastoma cells. Author(s): Institute of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133, Milan, Italy Source: Petroni, A Papini, N Blasevich, M Rise, P Galli, C Neurochem-Int. 2002 March; 40(3): 255-60 0197-0186

·

ASK1 resistant neuroblastoma is deficient in activation of p38 kinase. Author(s): Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, Goteborg University, Box 420, SE-405 30 Gothenburg, Sweden. [email protected] Source: Arvidsson, Y Hamazaki, T S Ichijo, H Funa, K Cell-Death-Differ. 2001 October; 8(10): 1029-37 1350-9047

·

Bioavailability and dose-dependent anti-tumour effects of 9-cis retinoic acid on human neuroblastoma xenografts in rat. Author(s): Childhood Cancer Research Unit, Dept of Women's and Children's Health, Karolinska Institutet, Karolinska Hospital, Stockholm, S-171 76, Sweden Source: Ponthan, F Kogner, P Bjellerup, P Klevenvall, L Hassan, M Br-JCancer. 2001 December; 85(12): 2004-9 0007-0920

·

Calcium protects differentiating neuroblastoma cells during 50 Hz electromagnetic radiation. Author(s): Dipartimento di Fisiologia e Biochimica Generali, I(a) Universita di Milano, I-20133 Milano, Italy. Source: Tonini, R Baroni, M D Masala, E Micheletti, M Ferroni, A Mazzanti, M Biophys-J. 2001 November; 81(5): 2580-9 0006-3495

·

Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. Author(s): Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, TN 38105, USA. Source: Teitz, Tal Wei, Tie Liu, Dong Valentine, Virginia Valentine, Marcus Grenet, Jose Lahti, Jill M Kidd, Vincent J Oncogene. 2002 Mar 14; 21(12): 1848-58 0950-9232

·

Chromosomal localization of amplified N-myc in neuroblastoma cells using a biotinylated probe. Author(s): University of Melbourne, Department of Medicine, Fitzroy, Victoria, Australia. Source: Rudduck, C Lukeis, R E McRobert, T L Chow, C W Garson, O M Cancer-Genet-Cytogenet. 1992 January; 58(1): 55-9 0165-4608

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·

Combined continuous infusion etoposide with high-dose cyclophosphamide for refractory neuroblastoma: a phase II study from the Societe Francaise d'Oncologie Pediatrique. Author(s): Service de Pediatrie, Institut Gustave-Roussy, Villejuif, France. Source: Meresse, V Vassal, G Michon, J De Cervens, C Courbon, B Rubie, H Perel, Y Landman, J Chastagnier, P De Valck, C et al. J-Clin-Oncol. 1993 April; 11(4): 630-7 0732-183X

·

Common fragile sites and human cancer. A study on lymphocytes from neuroblastoma patients. Author(s): Department of Public Health and Cellular Biology, 2nd University of Rome, Italy. Source: Vernole, P Tedeschi, B Caporossi, D Nicoletti, B Cancer-GenetCytogenet. 1988 November; 36(1): 13-23 0165-4608

·

Coordinated use of sequentially escalated cyclophosphamide and cellcycle-specific chemotherapy (N4SE protocol) for advanced neuroblastoma: experience with 100 patients. Author(s): Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York. Source: Kushner, B H Helson, L J-Clin-Oncol. 1987 November; 5(11): 1746-51 0732-183X

·

Cytotoxic actions of the heavy metal chelator TPEN on NG108-15 neuroblastoma-glioma cells. Author(s): Neurotoxicology Branch, Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. [email protected] Source: Adler, M Shafer, H Hamilton, T Petrali, J P Neurotoxicology. 1999 August; 20(4): 571-82 0161-813X

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

Researching Nutrition 279

·

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

·

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/

·

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

·

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

·

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

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

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

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

·

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

·

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: Bioavailability: The degree to which a drug or other substance becomes

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available to the target tissue after administration. [EU] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Eosinophilia: The formation and accumulation of an abnormally large number of eosinophils in the blood. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [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]

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] 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 281

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.177

177

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

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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):178 ·

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

·

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

·

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

·

California: Gateway Health Library (Sutter Gould Medical Foundation)

·

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

178

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

Finding Medical Libraries 283

·

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

·

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

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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/

·

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/

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

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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

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

·

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre), http://www.deerlodge.mb.ca/library/libraryservices.shtml

Finding Medical Libraries 285

·

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

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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center), http://www.saintpatrick.org/chi/librarydetail.php3?ID=41

286 Neuroblastoma

·

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

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·

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

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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

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

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

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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

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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/

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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.179

179Adapted

from Consumer Bill of Rights and Responsibilities: http://www.hcqualitycommission.gov/press/cbor.html#head1.

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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

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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

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·

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.

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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.180

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.”181 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. 181 Adapted from http://www.hcqualitycommission.gov/press/cbor.html#head1. 180

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·

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.182 The U.S. Department of Labor, in particular, recommends ten ways to make your health benefits choices work best for your family.183 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. 183 Adapted from the Department of Labor: http://www.dol.gov/dol/pwba/public/pubs/health/top10-text.html. 182

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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.

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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.

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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 Care184 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 184

Adapted from the NCI: http://cis.nci.nih.gov/fact/8_3.htm.

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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.

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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.

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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.185 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:186 ·

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. 186 You can access this information at: http://www.nlm.nih.gov/medlineplus/healthsystem.html. 185

Your Child’s Rights and Insurance 301

·

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

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APPENDIX F. TALKING WITH YOUR CHILD ABOUT CANCER Overview187 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.

187

Adapted from the NCI: http://www.cancer.gov/CancerInformation/youngpeople.

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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

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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.

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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.

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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 -

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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

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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.

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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 neuroblastoma and keep them on file. The NIH, in particular, suggests that parents of children with neuroblastoma visit the following Web sites in the ADAM Medical Encyclopedia:

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·

Basic Guidelines for Neuroblastoma Neuroblastoma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001408.htm

·

Signs & Symptoms for Neuroblastoma Abdomen, swollen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003122.htm Abdominal mass Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003274.htm Alopecia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003246.htm Anemia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000560.htm Ataxia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003198.htm Bone pain or tenderness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003180.htm Depression Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Diarrhea Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003126.htm

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Difficulty breathing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003075.htm Dysphagia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003115.htm Enlarged abdomen Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003122.htm Excessive tiredness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Eye movements, uncontrollable Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003037.htm Fatigue Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Fever Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm Flushed, red skin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003241.htm Hearing loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003044.htm Heterochromia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003319.htm

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High blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003082.htm Irritability Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003214.htm Loss of movement Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003190.htm Malaise Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003089.htm Movement, uncoordinated Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003198.htm Nystagmus Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003037.htm Pale skin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003244.htm Paralysis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003190.htm Profuse sweating Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003218.htm Rapid pulse Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm

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Stress Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Tachycardia Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003077.htm Tiredness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003088.htm Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm ·

Diagnostics and Tests for Neuroblastoma Biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003416.htm Blood pressure Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003398.htm Bone marrow aspiration Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003658.htm Bone marrow biopsy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003934.htm Bone scan Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003833.htm Catecholamines - blood Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003561.htm

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Catecholamines - urine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003613.htm CBC Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm Chest X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm Creatinine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003475.htm CT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm Ferritin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003490.htm Heart rate Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003399.htm LDH Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003471.htm MRI Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm Platelet count Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003647.htm

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SGOT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003472.htm SGPT Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003473.htm Uric acid Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003476.htm VIP Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003508.htm X-ray Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm ·

Background Topics for Neuroblastoma Benign Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002236.htm Cancer - support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002166.htm Chemotherapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002324.htm Chronic Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002312.htm Metastasis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002260.htm

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Palpation Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002284.htm Radiation therapy Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001918.htm Support group Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002150.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

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NEUROBLASTOMA 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. Abdomen: The part of the body that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] ACTH: Adrenocorticotropic hormone. [EU] Adenocarcinoma: Cancer that begins in cells that line certain internal organs and that have glandular (secretory) properties. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]

Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Aetiology: Study of the causes of disease. [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Alopecia: Baldness; absence of the hair from skin areas where it normally is present. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Analog:

In chemistry, a substance that is similar, but not identical, to

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another. [NIH] Anaplastic: A term used to describe cancer cells that divide rapidly and bear little or no resemblance to normal cells. [NIH] Anemia: A condition in which the number of red blood cells is below normal. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiosarcoma: A type of cancer that begins in the lining of blood vessels. [NIH]

Anoikis: Apoptosis triggered by loss of contact with the extracellular matrix. [NIH] Antiangiogenic: vessels. [NIH]

Having to do with reducing the growth of new blood

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] Antineoplastons: Substances isolated from normal human blood and urine being tested as a type of treatment for some tumors and AIDS. [NIH] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Aphidicolin: An antiviral antibiotic produced by Cephalosporium aphidicola and other fungi. It inhibits the growth of eukaryotic cells and certain animal viruses by selectively inhibiting the cellular replication of DNA polymerase II or the viral-induced DNA polymerases. The drug may be useful for controlling excessive cell proliferation in patients with cancer, psoriasis or other dermatitis with little or no adverse effect upon nonmultiplying cells. [NIH] Apoptosis: A normal series of events in a cell that leads to its death. [NIH] Aspirate: Fluid withdrawn from a lump, often a cyst, or a nipple. [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]

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Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astrocytoma: A tumor that begins in the brain or spinal cord in small, starshaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Loss of muscle coordination. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Barium: An element of the alkaline earth group of metals. It has an atomic symbol Ba, atomic number 56, and atomic weight 138. All of its acid-soluble salts are poisonous. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [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] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] 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] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Bleomycin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. [NIH] Bone marrow aspiration: The removal of a small sample of bone marrow (usually from the hip) through a needle for examination under a microscope. [NIH]

Bone marrow biopsy: The removal of a sample of tissue from the bone marrow with a needle for examination under a microscope. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Borrelia:

A genus of gram-negative, anaerobic, helical bacteria, various

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species of which produce relapsing fever in man and other animals. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Calcium: A mineral found in teeth, bones, and other body tissues. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] 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] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH] Cardiotoxicity: Toxicity that affects the heart. [NIH] Catecholamines: A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [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] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] 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

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uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Charities: Social welfare organizations with programs designed to assist individuals in times of need. [NIH] Chemoprotective: A quality of some drugs used in cancer treatment. Chemoprotective agents protect healthy tissue from the toxic effects of anticancer drugs. [NIH] Chemosensitizer: A drug that makes tumor cells more sensitive to the effects of chemotherapy. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [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] Cholinergic: Resembling acetylcholine in pharmacological stimulated by or releasing acetylcholine or a related compound. [EU] Chondrocytes: cartilage. [NIH]

action;

Cartilage cells. They make the structural components of

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] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An anticancer drug that belongs to the family of drugs called platinum compounds. [NIH] CNS: Central nervous system. The brain and spinal cord. [NIH] Collagen: A fibrous protein found in cartilage and other connective tissue. [NIH]

Colloids:

Two-phase systems in which one is uniformly dispersed in

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another as particles small enough so they cannot be filtered or will not settle out. The dispersing or continuous phase or medium envelops the particles of the discontinuous phase. All three states of matter can form colloids among each other. [NIH] Colonoscope: A thin, lighted tube used to examine the inside of the colon. [NIH]

Colorectal: Having to do with the colon or the rectum. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contralateral: Having to do with the opposite side of the body. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniopharyngioma: A benign brain tumor that may be considered malignant because it can damage the hypothalamus, the area of the brain that controls body temperature, hunger, and thirst. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Criterion: A standard by which something may be judged. [EU] Curative: Tending to overcome disease and promote recovery. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytotoxic: Cell-killing. [NIH] Dacarbazine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Dexrazoxane: A drug used to protect the heart from the toxic effects of anthracycline drugs such as doxorubicin. It belongs to the family of drugs

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called chemoprotective agents. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diploidy: The chromosomal constitution of somatic cells, in which each type of chromosome is represented twice. Symbol: 2N or 2X. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [EU]

Distention: The state of being distended or enlarged; the act of distending. [EU]

Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH] Doxorubicin: An anticancer drug that belongs to the family of drugs called antitumor antibiotics. It is an anthracycline. [NIH] Dronabinol: A synthetic pill form of delta-9-tetrahydrocannabinol (THC), an active ingredient in marijuana that is used to treat nausea and vomiting associated with cancer chemotherapy. [NIH] Dysphagia: Difficulty in swallowing. [EU] Dystonia: Disordered tonicity of muscle. [EU] Ecchymosis: A small haemorrhagic spot, larger than a petechia, in the skin or mucous membrane forming a nonelevated, rounded or irregular, blue or purplish patch. [EU] Electroporation: A technique in which electric pulses of intensity in kilovolts per centimeter and of microsecond-to-millisecond duration cause a temporary loss of the semipermeability of cell membranes, thus leading to ion leakage, escape of metabolites, and increased uptake by cells of drugs, molecular probes, and DNA. Some applications of electroporation include introduction of plasmids or foreign DNA into living cells for transfection, fusion of cells to prepare hybridomas, and insertion of proteins into cell membranes. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endothelium: The layer of epithelial cells that lines the cavities of the heart and of the blood and lymph vessels, and the serous cavities of the body, originating from the mesoderm. [EU]

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Enema: The injection of a liquid through the anus into the large bowel. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Eosinophilia: The formation and accumulation of an abnormally large number of eosinophils in the blood. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] 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] 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] Extracellular: Outside a cell or cells. [EU] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH] Fenretinide: A drug being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibroma: A benign tumor of fibrous or fully developed connective tissue. [NIH]

Fibrosarcoma: A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Flagellin: A protein with a molecular weight of 40,000 isolated from bacterial flagella. At appropriate pH and salt concentration, three flagellin monomers can spontaneously reaggregate to form structures which appear identical to intact flagella. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and

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emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Gadolinium: Gadolinium. An element of the rare earth family of metals. It has the atomic symbol Gd, atomic number 64, and atomic weight 157.25. Its oxide is used in the control rods of some nuclear reactors. [NIH] Gallium: A rare, metallic element designated by the symbol, Ga, atomic number 31, and atomic weight 69.72. [NIH] Ganglioneuroblastoma: A moderately malignant neoplasm composed of primitive neuroectodermal cells dispersed in myxomatous or fibrous stroma intermixed with mature ganglion cells. It may undergo transformation into a neuroblastoma. It arises from the sympathetic trunk or less frequently from the adrenal medulla, cerebral cortex, and other locations. Cervical ganglioneuroblastomas may be associated with horner syndrome and the tumor may occasionally secrete vasoactive intestinal peptide, resulting in chronic diarrhea. [NIH] Gastric: Having to do with the stomach. [NIH] 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] 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] Glutamine: An amino acid used in nutrition therapy. It is also being studied for the treatment of diarrhea caused by radiation therapy to the pelvis. [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] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granuloma: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious

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agents. [NIH] Hemangiopericytoma: A type of cancer involving blood vessels and soft tissue. [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] 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] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Heparin: A drug that helps prevent blood clots from forming. It belongs to the family of drugs called anticoagulants (blood thinners). [NIH] Hepatic: Refers to the liver. [NIH] Hepatoblastoma: A type of liver tumor that occurs in infants and children. [NIH]

Hepatomegaly: Enlargement of the liver. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [NIH] Hydrogen: Hydrogen. The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolysis: A chemical reaction that uses water to break down a compound. [NIH] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperplasia: An abnormal increase in the number of cells in an organ or

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tissue. [NIH] Hypertension: Abnormally high blood pressure. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] 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] Immunity: The condition of being immune; the protection against infectious disease conferred either by the immune response generated by immunization or previous infection or by other nonimmunologic factors (innate i.). [EU] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressive: responses. [NIH]

Describes the ability to lower immune system

Immunotherapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also called biological therapy or biological response modifier (BRM) therapy. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A response of redness, swelling, pain, and a feeling of heat in certain areas which is meant to protect tissues affected by injury or disease. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Inoperable: Not suitable to be operated upon. [EU] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH]

Insulin: A hormone made by the islet cells of the pancreas. Insulin controls

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the amount of sugar in the blood by moving it into the cells, where it can be used by the body for energy. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and -gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Intracellular: Inside a cell. [NIH] Intravenous: IV. Into a vein. [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]

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] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isotretinoin: A drug that belongs to the family of drugs called retinoids. It is used in the treatment of acne and psoriasis and is being studied in cancer prevention. Also called 13-cis retinoic acid. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Laparotomy: A surgical incision made in the wall of the abdomen. [NIH] Leiomyoma: A benign smooth-muscle tumor, usually in the uterus or gastrointestinal tract. Also called fibroid. [NIH] Leiomyosarcoma: A tumor of the muscles in the uterus, abdomen, or pelvis. [NIH]

Lesion: An area of abnormal tissue change. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] LH: A small glycoprotein hormone secreted by the anterior pituitary. LH plays an important role in controlling ovulation and in controlling secretion of hormones by the ovaries and testes. [NIH] Lipoma: A benign tumor composed of fat cells. [NIH] Liposarcoma: A rare cancer of the fat cells. [NIH] Liposomal: A drug preparation that contains the active drug in very tiny fat particles. This fat-encapsulated drug is absorbed better, and its distribution

Glossary 331

to the tumor site is improved. [NIH] Liposome: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. [EU] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5-lipoxygenase, arachidonate 12lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Lithium: Lithium. An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] 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] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: Cancer that arises in cells of the lymphatic system. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Malaise: A vague feeling of bodily discomfort. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Mammogram: An x-ray of the breast. [NIH] 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]

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Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [NIH] 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] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Cells in the skin that produce and contain the pigment called melanin. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melphalan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Meningeal: Refers to the meninges, the tissue covering the brain and spinal cord. [NIH] Meningioma: A type of tumor that occurs in the meninges, the membranes that cover and protect the brain and spinal cord. Meningiomas usually grow slowly. [NIH] Mesna: A drug that helps protect the kidneys and bladder from the toxic effects of anticancer drugs such as ifosfamide and cyclophosphamide. [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] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Metoclopramide: A drug that prevents or reduces nausea and vomiting. [NIH]

Microbiology: The study of microorganisms such as fungi, bacteria, algae,

Glossary 333

archaea, and viruses. [NIH] Microgram: A unit of mass (weight) of the metric system, being onemillionth of a gram (10-6 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Milligram: A measure of weight. A milligram is approximately 450,000times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Mime: Facial expression. (NOT: mimicry = adaptation for survival in which an organism takes on the semblance another organism or a non-living object.) [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] 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] MRI: Magnetic resonance imaging (mag-NET-ik REZ-o- nans IM-a-jing). A procedure in which a magnet linked to a computer is used to create detailed pictures of areas inside the body. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myositis: Inflammation of a voluntary muscle. [EU] 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] Neoplasm: A new growth of benign or malignant tissue. [NIH] Nephrectomy: Surgery to remove a kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes, and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor but not the entire kidney. [NIH] Nephroblastoma: A malignant kidney tumor made up of three cell types: blastemal, stromal, and epithelial, but not all present in every case. [NIH] Neural: 1. pertaining to a nerve or to the nerves. 2. situated in the region of

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the spinal axis, as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH]

Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuroma: A tumor that arises in nerve cells. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neuropharmacology: The branch of pharmacology dealing especially with the action of drugs upon various parts of the nervous system. [NIH] Neurosurgeon: A doctor who specializes in surgery on the brain, spine, and other parts of the nervous system. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neutrophil: 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] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nonmetastatic: Cancer that has not spread from the primary (original) site to other sites in the body. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic

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sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nystagmus: An involuntary, rapid, rhythmic movement of the eyeball, which may be horizontal, vertical, rotatory, or mixed, i.e., of two varieties. [EU]

Occult: Obscure; concealed from observation, difficult to understand. [EU] Oligodendroglioma: A rare, slow-growing tumor that begins in brain cells called oligodendrocytes, which provide support and nourishment for cells that transmit nerve impulses. Also called oligodendroglial tumor. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] 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] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Otorhinolaryngology: That branch of medicine concerned with medical and surgical treatment of the head and neck, including the ears, nose and throat. [EU]

Overdose: 1. to administer an excessive dose. 2. an excessive dose. [EU] Paclitaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [NIH] Palliative: 1. affording relief, but not cure. 2. an alleviating medicine. [EU] Palpation: Examination by pressing on the surface of the body to feel the organs or tissues underneath. [NIH] Pancytopenia: Deficiency of all cell elements of the blood; aplastic anaemia. [EU]

Paralysis: Loss of ability to move all or part of the body. [NIH] Pathologist: A doctor who identifies diseases by studying cells and tissues under a microscope. [NIH]

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Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periorbital: Situated around the orbit, or eye socket. [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]

Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasmapheresis: The process of separating certain cells from the plasma in the blood by a machine; only the cells are returned to the person. Plasmapheresis can be used to remove excess antibodies from the blood. [NIH] Platelet Count: A count of the number of platelets per unit volume in a sample of venous blood. [NIH] Platinum: A metal that is an important component of some anticancer drugs, such as cisplatin and carboplatin. [NIH] Plexus: A network or tangle; a general term for a network of lymphatic vessels, nerves, or veins. [EU] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Potassium: A metallic element that is important in body functions such as regulation of blood pressure and of water content in cells, transmission of

Glossary 337

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 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] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proptosis: Forward projection or displacement especially of the eyeball : exophthalmos. [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] 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] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH]

Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Radioactive: Giving off radiation. [NIH] Radioactivity: The quality of emitting or the emission of corpuscular or electromagnetic radiations consequent to nuclear disintegration, a natural

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property of all chemical elements of atomic number above 83, and possible of induction in all other known elements. [EU] Radiography: The making of film records (radiographs) of internal structures of the body by passage of x-rays or gamma rays through the body to act on specially sensitized film. [EU] Radiolabeled: Any compound that has been joined with a radioactive substance. [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] Rebeccamycin: An anticancer drug that belongs to the family of drugs called antineoplastic antibiotics. [NIH] 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] 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] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [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]

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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 pigmented, whereas the inner nine layers are transparent. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retrobulbar: Behind the pons. [EU] Retrospective: Looking back at events that have already taken place. [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] Sarcoma: A cancer of the bone, cartilage, fat, muscle, blood vessels or other connective or supportive tissue. [NIH] Sargramostim: A colony-stimulating factor that stimulates the production of blood cells, especially platelets, during chemotherapy. It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called GM-CSF. [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] Scrapie: A fatal disease of the nervous system in sheep and goats, characterized by pruritus, debility, and locomotor incoordination. It is caused by proteinaceous infectious particles called prions. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. the process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. any substance produced by secretion. [EU] Selenium: An essential dietary mineral. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sigmoidoscope: A thin, lighted tube used to view the inside of the colon. [NIH]

Sigmoidoscopy: Inspection of the lower colon using a thin, lighted tube

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called a sigmoidoscope. Samples of tissue or cells may be collected for examination under a microscope. Also called proctosigmoidoscopy. [NIH] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] 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] 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] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stomach: An organ that is part of the digestive system. It helps in the digestion of food by mixing it with digestive juices and churning it into a thin liquid. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Subcutaneous: Beneath the skin. [NIH] Supratentorial: Located in the upper part of the brain. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU]

Systemic: Affecting the entire body. [NIH] Tachycardia: Excessive rapidity in the action of the heart; the term is usually applied to a heart rate above 100 per minute and may be qualified as atrial, junctional (nodal), or ventricular, and as paroxysmal. [EU]

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Technetium: The first artificially produced element and a radioactive fission product of uranium. The stablest isotope has a mass number 99 and is used diagnostically as a radioactive imaging agent. Technetium has the atomic symbol Tc, atomic number 43, and atomic weight 98.91. [NIH] Telomerase: Essential ribonucleoprotein reverse transcriptase that adds telomeric DNA to the ends of eukaryotic chromosomes. Telomerase appears to be repressed in normal human somatic tissues but reactivated in cancer, and thus may be necessary for malignant transformation. EC 2.7.7.-. [NIH] Teniposide: An anticancer drug that is a podophyllotoxin derivative and belongs to the family of drugs called mitotic inhibitors. [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] Thermography: Measurement of the regional temperature of the body or an organ by infrared sensing devices, based on self-emanating infrared radiation. [NIH] Thermoregulation: Heat regulation. [EU] Thiotepa: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Thoracic: Having to do with the chest. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tomography: A series of detailed pictures of areas inside the body; the pictures are created by a computer linked to an x-ray machine. [NIH] 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] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Transplantation: person. [NIH]

The replacement of an organ with one from another

Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and

342 Neuroblastoma

other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumour: 1. swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. a new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ultrasonography: A procedure in which sound waves (called ultrasound) are bounced off tissues and the echoes are converted to a picture (sonogram). [NIH]

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] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] 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] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vertebral: Of or pertaining to a vertebra. [EU] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vinorelbine: 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] Xenograft: The cells of one species transplanted to another species. [NIH]

Glossary 343

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

·

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

·

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

·

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

·

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

·

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

·

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

·

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

344 Neuroblastoma

·

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

·

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

·

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

·

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 345

INDEX A Abdomen .......11, 26, 170, 184, 220, 268, 313, 322, 330, 331, 333, 336 Adenocarcinoma..................103, 268, 334 Adenovirus...........................................256 Adjuvant...........................14, 15, 190, 192 Adolescence ..52, 126, 145, 176, 319, 336 Adrenergic .............................................62 Aetiology..............................................127 Algorithms............................................114 Allogeneic ..............................................14 Analog .............................................62, 76 Anaplastic ..........................61, 74, 75, 127 Anemia ..............11, 30, 52, 135, 177, 341 Angiogenesis .......107, 113, 119, 145, 320 Angiosarcoma..............................103, 167 Anoikis .................................................119 Antiangiogenic .....................................133 Antibody......58, 62, 67, 69, 70, 75, 93, 94, 106, 116, 124, 150, 201, 206, 320, 329, 332 Antigens.................................93, 115, 320 Antioxidant...........................................263 Aphidicolin ...........................................141 Apoptosis ....107, 110, 112, 116, 119, 130, 131, 137, 143, 258, 260 Aspirate .......................................179, 187 Assay...................................116, 137, 182 Astrocytoma.................61, 74, 75, 94, 327 Asymptomatic ......................183, 185, 204 Ataxia...........................................177, 177 Autologous......14, 71, 106, 188, 194, 198, 199, 200, 201, 203, 205, 206, 208, 209, 275, 276 B Barium .................................................166 Benign ....94, 95, 109, 112, 167, 170, 171, 324, 326, 330, 333, 339 Bereavement .........................................39 Bilateral........................................184, 186 Biochemical .................................109, 164 Biopsy.......12, 14, 25, 179, 180, 184, 187, 192, 315, 321 Biosynthesis ................................109, 111 Bleomycin ............................................262 Bowel ....... 170, 171, 191, 193, 197, 204, 220, 322, 326, 340 C Calcium........................267, 271, 272, 322 Calmodulin...........................................261 Capsules..............................................273

Carbohydrate ...................... 108, 225, 272 Carboplatin... 65, 188, 194, 197, 200, 202, 205, 206, 207, 206, 208, 209, 268, 276, 336 Carcinogen.......................................... 104 Carcinogenic ................................. 97, 340 Carcinoma........... 102, 169, 268, 322, 334 Cardiotoxicity ........................................ 79 Catecholamines .......................... 178, 179 Catheter ................................................ 74 Ceramide ............................ 108, 116, 119 Cerebellar ........................................... 177 Cerebral ................ 26, 126, 222, 327, 337 Cervical ..... 4, 38, 52, 102, 160, 161, 165, 322 Cervix.................................... 52, 166, 322 Chemoprotective................... 94, 113, 325 Chemosensitizer ................................. 261 Cholera ............................................... 132 Cholesterol.............. 79, 97, 270, 272, 340 Cholinergic .......................... 151, 162, 334 Chondrocytes...................................... 262 Choroid ........................................... 59, 60 Chromosome ..... 107, 114, 126, 142, 156, 181, 220, 325 Chronic.................... 26, 79, 216, 291, 327 Cisplatin ..... 140, 179, 188, 193, 194, 195, 196, 198, 200, 201, 203, 205, 208, 209, 255, 257, 261, 268, 336 Collagen.............................. 119, 148, 326 Colloids ............................... 109, 147, 324 Colonoscope ....................................... 166 Colorectal............................ 102, 160, 161 Conjugated.......................... 109, 116, 129 Contamination..................................... 160 Contralateral ....................................... 186 Cranial......................................... 115, 206 Craniopharyngioma ........................ 74, 75 Creatinine.................................... 187, 190 Criterion .............................................. 178 Curative......................... 40, 176, 280, 334 Cyclic .......................... 162, 261, 267, 322 Cyclophosphamide .. 66, 78, 95, 188, 190, 191, 193, 194, 195, 196, 197, 200, 202, 205, 206, 207, 208, 209, 263, 278, 332 Cysteine .............................................. 258 Cytotoxic ............................. 106, 115, 116 D Degenerative ...................................... 271 Dexrazoxane......................................... 72 Diarrhea .......... 11, 26, 148, 177, 270, 327

346 Neuroblastoma

Diploidy................................................199 Disposition ...........................................257 Distention.............................................177 Docetaxel.........................................71, 73 Doxorubicin...66, 71, 78, 79, 94, 179, 188, 193, 194, 195, 196, 197, 200, 201, 202, 205, 207, 208, 209, 324 Dystonia...............................................125 E Electroporation ....................106, 147, 325 Encapsulated...................79, 95, 167, 330 Endogenous ........................................119 Endothelium.........................................119 Enema .................................................166 Enzyme.......139, 149, 152, 253, 256, 263, 331, 337 Eosinophilia .........................................275 Epidemiological ...................................104 Epidermal ............................................128 Erythroleukemia...................................108 Etoposide....... 66, 69, 188, 193, 194, 195, 196, 197, 200, 202, 205, 207, 208, 209, 263, 276, 278 Exogenous...................106, 147, 325, 326 Extracellular.........................106, 148, 326 F Fenretinide...................................116, 143 Ferritin .................................181, 191, 193 Fibroblasts ...........................................113 Fibroma ...............................................167 Fibrosarcoma.......................................167 Filgrastim .......................................66, 258 Flagellin .......................................148, 326 Fluorescence .......................116, 148, 327 Folate...................................................141 G Gadolinium ............................................74 Ganglioneuroblastoma ........133, 183, 256 Gastric .................................................160 Gastrointestinal.....27, 170, 185, 191, 193, 197, 204, 330, 340 Genitourinary .......185, 191, 193, 197, 204 Gland ....11, 152, 153, 221, 280, 333, 337, 339, 341 Glioblastoma....................................74, 75 Glutamine ............................................132 Grade...................114, 148, 191, 193, 327 Granulocyte ...........94, 139, 255, 258, 326 Granuloma...........................................167 H Hemangiopericytoma...........................167 Hemophilia.............................................30 Hemorrhage...........................52, 185, 337 Heparin ............................................72, 74 Hepatoblastoma ..................................104 Hepatomegaly .............................185, 203

Herpes ........................................ 148, 328 Homogeneous .................................... 108 Hybridization ............................... 128, 142 Hydrogen .... 146, 149, 151, 322, 328, 333 Hydrolysis ........................................... 261 Hyperbaric........................... 263, 268, 328 Hyperplasia ......................................... 167 Hypertension....................................... 177 Hypoglycemia ..................................... 277 Hypoxia ............................... 113, 142, 277 I Ifosfamide .... 95, 188, 194, 198, 200, 203, 205, 208, 209, 263, 332 Immunity ............................................. 122 Immunoglobulin .................................... 77 Immunohistochemistry................ 119, 178 Immunology .......................... 25, 115, 319 Immunosuppressive.... 108, 148, 178, 327 Immunotherapy........... 106, 115, 116, 136 Infiltration ............................................ 186 Inflammation . 77, 162, 171, 245, 320, 337 Infusion . 97, 139, 149, 263, 278, 329, 341 Inoperable ........................................... 253 Insulin.......................... 128, 141, 260, 262 Interferon............................. 116, 149, 330 Intracellular ................................. 119, 141 Intravenous ........... 14, 149, 178, 257, 329 Iodine .................................................... 75 Ipsilateral............................. 186, 194, 196 Irinotecan ............................................ 257 Ischemia.............. 185, 191, 193, 197, 204 Isotretinoin ............................................ 67 K Kinetics ....................................... 109, 173 L Laparotomy......................................... 166 Leiomyoma ......................................... 167 Leiomyosarcoma ................................ 167 Lesion ........... 25, 150, 170, 321, 327, 331 Leukemia ...................... 30, 103, 104, 216 Lipoma ................................................ 167 Liposarcoma ....................................... 167 Liposomal.............................................. 79 Liposome .............................................. 79 Lipoxygenase...................................... 143 Lithium ................................ 164, 170, 331 Liver ...... 11, 13, 25, 26, 57, 71, 73, 103, 113, 148, 177, 184, 187, 221, 272, 280, 319, 328, 331, 339 Localization ..... 109, 116, 117, 149, 277, 329 Lumbar................................................ 184 Lymph ...... 11, 13, 52, 147, 179, 184, 186, 187, 188, 190, 191, 192, 194, 194, 195, 196, 221, 268, 322, 325, 332, 333 Lymphocyte......................... 106, 150, 332

Index 347

Lymphoid .............................................257 Lymphoma.............61, 103, 105, 127, 216 M Macrophage.................................139, 255 Malignancy ..................................109, 114 Mammogram .......................................165 Mammography...............................37, 165 Mediastinum ........................................256 Medulloblastoma ...........59, 60, 61, 74, 75 Melanin ................139, 150, 153, 332, 342 Melanocytes ..........................95, 118, 332 Melanoma.....58, 102, 108, 118, 161, 206, 216 Melphalan ......................................68, 201 Membrane ....94, 111, 116, 127, 152, 170, 220, 260, 323, 325, 333, 339 Meningeal ............................................206 Meningioma .....................................74, 75 Metabolite ....................................189, 273 Metastasis ....95, 113, 117, 129, 143, 177, 184, 194, 206, 208, 263, 332 Microscopy ..................................116, 178 Milligram ......................187, 190, 221, 333 Mitosis .................................................183 Molecular ......97, 108, 109, 112, 114, 115, 128, 147, 148, 152, 181, 210, 213, 215, 267, 322, 324, 325, 326, 337, 342 Molecule ...... 26, 106, 109, 138, 150, 333, 338 Mucosa ................152, 167, 170, 333, 337 Myelin ..................................................260 Myositis................................................167 N Nausea ........................245, 252, 325, 332 Necrosis.......................................116, 259 Neoplasm ..........4, 26, 115, 157, 327, 342 Nephrectomy .......................195, 221, 333 Nephroblastoma ..................................135 Neural ....... 107, 111, 118, 127, 138, 167, 177, 178 Neuroendocrine ...........................118, 144 Neuroma..............................................167 Neuronal ......................113, 130, 178, 276 Neuropeptide .......................................109 Neurotoxin ...........................................129 Neutrophil ............................................116 Niacin...................................................271 Nicotine................................................133 Nonmetastatic......................179, 187, 192 Non-small cell lung cancer ..................253 Norepinephrine ................62, 93, 178, 319 O Occult ..........................................118, 166 Oligodendroglioma ....................61, 74, 75 Oncogene ...112, 129, 151, 180, 203, 204, 216, 335

Oncologist ..................................... 52, 335 Oncology.. 18, 32, 50, 128, 162, 164, 176, 303 Oncology nurse................................... 303 Osteosarcoma .......................... 58, 71, 73 Overdose ............................................ 271 P Paclitaxel....................................... 73, 258 Paediatric .................................... 162, 258 Palliative................................................ 40 Pancytopenia ...................................... 177 Paralysis ....................................... 11, 177 Pediatrics ............................................ 182 Pelvis .... 11, 148, 170, 221, 327, 330, 331 Peptide....... 26, 109, 110, 121, 129, 142, 143, 152, 177, 259, 327, 337 Periorbital............................................ 177 Pharmacologic .................... 109, 153, 341 Phenotype... 109, 112, 114, 119, 151, 336 Phosphorous....................................... 272 Phosphorus................................. 280, 336 Physiologic... 26, 118, 146, 151, 321, 336, 338 Plasma ........ 116, 152, 221, 222, 336, 338 Plasmapheresis .................................. 178 Platinum ................ 93, 147, 263, 322, 323 Plexus ............................................. 59, 60 Posterior................................ 94, 184, 323 Postnatal ............................................. 104 Potassium ................................... 133, 272 Preclinical............................ 110, 139, 237 Precursor .................................... 153, 342 Prenatal...... 103, 104, 166, 177, 190, 192, 193 Progression.... 16, 71, 107, 117, 160, 181, 205, 206, 208, 262 Progressive ........... 16, 157, 206, 208, 342 Prolactin .............................................. 142 Prostate...... 102, 160, 161, 166, 216, 247, 253 Protease...................................... 262, 276 Proteins ....... 52, 106, 109, 147, 148, 151, 152, 153, 238, 270, 272, 325, 328, 333, 336, 339 Proximal .............................................. 107 Psychomotor ....................................... 177 Psychotherapy .................................... 247 Punishment ................................. 304, 306 Pyogenic ............................................. 167 R Radioactive ...... 72, 75, 96, 143, 149, 222, 321, 328, 338, 341 Radioactivity.......................................... 72 Radiography ....................................... 184 Radiolabeled ................................. 75, 118

348 Neuroblastoma

Randomized ....... 79, 160, 179, 182, 192, 199, 256 Rebeccamycin .......................................76 Receptor .....106, 128, 134, 139, 141, 142, 162 Recombinant .................................78, 258 Reconstitution..............................201, 276 Rectum ................................103, 147, 324 Recurrence ...16, 189, 191, 205, 206, 207, 208, 209 Refractory .....56, 58, 62, 68, 76, 106, 114, 206, 206, 210, 263, 278 Regimen ...67, 72, 78, 188, 194, 197, 200, 202, 203, 205, 207, 208, 209, 257, 276 Remission....................206, 276, 280, 338 Resected ....... 15, 75, 190, 192, 193, 196, 207, 208 Resection....134, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 203, 204, 205, 207, 209 Retina ..................................131, 280, 339 Retinoblastoma..............60, 103, 104, 216 Retinoid .......................................116, 209 Retrobulbar..........................................177 Retrospective.......................................102 Rhabdomyosarcoma ..60, 71, 73, 78, 104, 164, 167, 178 Riboflavin.............................................270 S Sarcoma ....... 57, 58, 71, 73, 78, 96, 103, 140, 143, 167, 170, 326, 335 Sargramostim ..................................67, 69 Schwannoma.......................................167 Scrapie ........................................124, 276 Screening ...23, 83, 84, 86, 102, 109, 135, 160, 161, 165, 166, 182, 183, 189, 190, 191, 193 Secretion .....106, 149, 153, 177, 330, 339 Selenium..............................................272 Serum ..................178, 179, 181, 222, 338 Sigmoidoscope ....................166, 171, 340 Sigmoidoscopy ....................................166 Somatostatin................................118, 129 Species ....... 25, 116, 126, 146, 153, 221, 319, 322, 333, 340, 342 Spectrum .......................................79, 112

Staging....... 12, 179, 180, 181, 182, 183, 184, 186, 190, 191, 192, 194, 195, 196, 199 Steroid................................................... 77 Stool.................................................... 166 Subcutaneous ....................................... 71 Supratentorial ................................. 59, 60 Symptomatic ...... 103, 178, 185, 189, 191, 194, 197, 202, 204 Synergistic .......................... 120, 152, 337 Systemic ............................................... 14 T Technetium ......................................... 184 Telomerase......................................... 181 Teniposide ...... 179, 193, 195, 196, 200, 201, 257 Thalassemia.......................................... 30 Thermography .................................... 165 Thermoregulation................................ 270 Thiotepa .............................................. 276 Thoracic .......................................... 4, 132 Thyroxine ............................................ 272 Tomography........................................ 184 Topotecan ........................................... 206 Toxicity.... 71, 79, 106, 132, 139, 261, 275 Toxicology................................... 104, 211 Tubulin .......................................... 73, 255 Tumour........................................ 156, 277 Tyrosine .............. 137, 144, 181, 220, 322 U Ultrasonography ......................... 166, 177 Unresectable.... 56, 59, 60, 61, 63, 64, 65, 66, 67, 68, 70, 77, 186, 187, 192, 192, 194, 195, 196, 199 Urinary ........ 178, 179, 182, 189, 220, 327 Urine .. 56, 72, 73, 93, 165, 178, 220, 222, 280, 316, 320, 324, 339, 342 V Vaccine ........................... 25, 71, 139, 319 Vascular ........ 94, 113, 142, 167, 259, 323 Vasoactive ............................ 26, 177, 327 Vertebral ............................................. 186 Vinblastine .............. 73, 97, 261, 262, 342 Vincristine ...... 73, 78, 97, 190, 191, 195, 200, 275, 342 Virus.................................... 126, 139, 256 X Xenograft .................... 110, 113, 118, 129

Index 349

350 Neuroblastoma

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