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

MYELOFIBROSIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

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

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Myelofibrosis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00735-5 1. Myelofibrosis-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on myelofibrosis. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON MYELOFIBROSIS ........................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Myelofibrosis................................................................................. 4 The National Library of Medicine: PubMed .................................................................................. 7 CHAPTER 2. NUTRITION AND MYELOFIBROSIS............................................................................... 53 Overview...................................................................................................................................... 53 Finding Nutrition Studies on Myelofibrosis................................................................................ 53 Federal Resources on Nutrition ................................................................................................... 55 Additional Web Resources ........................................................................................................... 55 CHAPTER 3. ALTERNATIVE MEDICINE AND MYELOFIBROSIS ........................................................ 57 Overview...................................................................................................................................... 57 National Center for Complementary and Alternative Medicine.................................................. 57 Additional Web Resources ........................................................................................................... 61 General References ....................................................................................................................... 62 CHAPTER 4. BOOKS ON MYELOFIBROSIS ......................................................................................... 63 Overview...................................................................................................................................... 63 Book Summaries: Online Booksellers........................................................................................... 63 CHAPTER 5. PERIODICALS AND NEWS ON MYELOFIBROSIS ........................................................... 65 Overview...................................................................................................................................... 65 News Services and Press Releases................................................................................................ 65 Academic Periodicals covering Myelofibrosis .............................................................................. 66 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 71 Overview...................................................................................................................................... 71 NIH Guidelines............................................................................................................................ 71 NIH Databases............................................................................................................................. 73 Other Commercial Databases....................................................................................................... 75 APPENDIX B. PATIENT RESOURCES ................................................................................................. 77 Overview...................................................................................................................................... 77 Patient Guideline Sources............................................................................................................ 77 Finding Associations.................................................................................................................... 79 APPENDIX C. FINDING MEDICAL LIBRARIES .................................................................................. 81 Overview...................................................................................................................................... 81 Preparation................................................................................................................................... 81 Finding a Local Medical Library.................................................................................................. 81 Medical Libraries in the U.S. and Canada ................................................................................... 81 ONLINE GLOSSARIES.................................................................................................................. 87 Online Dictionary Directories ..................................................................................................... 87 MYELOFIBROSIS DICTIONARY................................................................................................ 89 INDEX .............................................................................................................................................. 125

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with myelofibrosis is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about myelofibrosis, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to myelofibrosis, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on myelofibrosis. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to myelofibrosis, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on myelofibrosis. The Editors

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

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

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

Practice Guidelines for Liver Biopsy Source: Canadian Journal of Gastroenterology. 14(6): 481-482. June 2000. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: Histological assessment of the liver by using biopsy remains important in the diagnosis and follow up of acute and chronic hepatic (liver) disease. This article offers practice guidelines for liver biopsy, as established by the Canadian Association of Gastroenterology (CAG). Liver biopsies may be obtained blind, i.e., by clinical estimation of organ location; by using radiological guidance with computerized tomography or ultrasound; via the transvenous (through the jugular or femoral veins) route in patients with contraindications to percutaneous (through the skin) biopsy; or

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via direct vision, surgically or laparoscopically in certain situations. The authors list the indications for liver biopsy and note that the prebiopsy workup of a patient should include informed consent, including an explanation of the risks of the procedure and the laboratory test results that can be obtained from the biopsy. Postbiopsy management should include a recording by the physician performing the biopsy of how many 'passes' were made, any medications administered, and any apparent complications. Contraindications to percutaneous liver biopsy include an uncooperative patient, impaired coagulation, severe uncorrected anemia, significant ascites, infection in the path of the needle, suspected extrahepatic biliary obstruction of high grade, cholangitis, echinococcal cysts, no safe unobstructed access route to biopsy, leukemia and myelofibrosis, and uremia. The authors conclude that with strict attention to the indications and contraindications, liver biopsy can be regarded as a safe and useful procedure. 2 references.

Federally Funded Research on Myelofibrosis The U.S. Government supports a variety of research studies relating to myelofibrosis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to myelofibrosis. 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 myelofibrosis. The following is typical of the type of information found when searching the CRISP database for myelofibrosis: •

Project Title: APOPTOSIS IN MYELOFIBROSIS WITH MYELOID METAPLASIA Principal Investigator & Institution: Mesa, Ruben A.; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Myelofibrosis with myeloid metaplasia is a clonal hematopoietic stem cell disorder that results in progressive cytopenias, splenomegaly, blastic transformation, and death. No broadly applicable therapy is available. The pathogenetic mechanism of MMM is currently unknown. A defect in the normal process of apoptosis has been demonstrated in the related myeloproliferative disorders of chronic myeloid leukemia and polycythemia vera. We have shown that apoptosis (spontaneous, serum deprivation, and TNF-alpha induced) is quantitively diminished in the granulocytes of patients with MMM. We have also observed that erythroid precursors from MMM patients can be grown in vitro in the absence of the prerequisite cytokine erythropoietin. Cytokine independent growth has been characterized in

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

Studies

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polycythemia Vera to arise from over-expression of Bcl-XL (an anti-apoptotic member of the Bcl-2 family). We believe the diminished apoptosis we have observed in MMM may be linked to cytokine hypersensitivity and, potentially, to the anti-apoptotic pathways of Bcl-2 or the Akt pathway. We hypothesize that apoptosis is dysregulated in granulocytes in MMM, and this is a reflection of the corresponding defect in the aberrant clone. In this grant application we propose to: 1.Compare baseline levels of apoptotic proteins and regulators across the spectrum of MMM patients and controls. Baseline levels of apoptotic proteins (caspases), and regulators (lAP's, Bcl-2 family members) will be assessed across a spectrum of MMM patients and normal controls. 2. Evaluate the regulation of caspase activation in MMM neutrophils subjected to apoptotic stimuli through both cellular and cell free systems. Isolated neutrophils from MMM patients and controls will be subjected to various apoptotic stimuli to delineate which pathway of apoptosis is aberrantly regulated. Subsequent experiments will use both immunoblotting and a cytosol caspase activation assay to determine which caspases and regulators are responsible for the apoptotic defect seen in MMM neutrophils. 3. Evaluate the role of the phosphatidylinositol 3- kinase pathway on cytokine independent growth in myeloid progenitors in MMM. Cytokine independent growth of myeloid colonies will be confirmed across a spectrum of MMM patients. Subsequent experiments will delineate the role of the phosphatidylinositol-3 kinase pathway in both apoptosis resistance and cytokine independent colony growth. Successful accomplishments of these goals will provide the scientific basis for targeted anti-myeloproliferative therapy for the treatment of patients suffering from MMM and potentially related chronic myeloid disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEOMIC STUDY OF MEGAKARYOCYTE TRANSCRIPTIONAL CONTROL Principal Investigator & Institution: Cantor, Alan B.; Leader, Biostatistics and Informatics Co; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Megakaryocytes are large polyploid bone marrow cells that play essential roles in hemostasis through the generation of platelets. Disorders of megakaryocyte proliferation and development, including megakaryoblastic leukemia, myelofibrosis, essential thrombocythemia, and megakaryoblastic thrombocytopenia are associated with high morbidity and mortality in humans. While much is known about platelet biology and the cytokine regulation of megakaryopoiesis, the transcriptional regulation of megakaryocyte development and growth is incompletely understood. Prior work has shown that the zinc finger transcription factor GATA-1 plays an essential role in both of these processes. Deficiency of GATA-1 leads to marked hyperproliferation and impaired maturation of megakaryocytes, and causes progressive myelofibrosis in mice. Mutations that result in an amino terminal truncation of GATA-1 are highly associated with megakaryoblastic leukemia in patients with Down syndrome. Preliminary studies using gel filtration chromatography indicate that GATA-1 participates in at least two stable multiprotein complexes of about 360 and 230 kDa in the L8057 murine megakaryocytic cell line (molecular mass of GATA-1 alone is 48 kDa). This proposal utilizes a proteomic approach to identify the components of these complexes and test the following hypotheses: (1) the formation of stable multiprotein complexes containing GATA-1 is functionally important in controlling megakaryocytespecific gene expression and growth control; (2) the composition of GATA-1 containing complexes changes during megakaryocyte differentiation, (3) distinct GATA-1

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containing complexes exist in megakaryocyte versus erythroid cells, and (4) amino terminal truncation mutations of GATA-1 associated with megakaryoblastic leukemia result in altered multiprotein complex formation and/or activity. A novel method employing metabolic biotin tagging followed by avidin affinity chromatography will be used to isolate GATA-1 containing complexes. Components will be identified by LC/MS/MS mass spectrometry and database search. Results will be validated by coimmunoprecipitation and gel shift assays in primary megakaryocytes. Finally, the functional significance of identified components will be assessed by stable RNAi gene silencing in induced L8057 cells. The results of this study should provide new insights into the transcriptional regulation of megakaryopoiesis, and possibly new therapeutic targets for disorders of megakaryocyte proliferation and development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STEM CELL RESCUE AFTER BONE MARROW CURETTAGE FOR TREATMENT OF AMM Principal Investigator & Institution: Silver, Richard T.; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRANSPLANTS FOR MYELODYSPLASIA AND MYELOFIBROSIS Principal Investigator & Institution: Deeg, H Joachim.; Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002 Summary: Hematopoietic stem cell transplantation (HSCT) is currently the only therapeutic modality with curative potential in patients with myelodysplastic syndromes (MDS). Relapse (in advanced MS), regimen- related toxicity (RRT) and nonrelapse-mortality (MRS) have remained causes of treatment failure. RRT increases with age, a concern in MDS patients with a median age at diagnosis of 65-70 years. Patients with myelofibrosis (MF) frequently are in a similar age range and have limited therapeutic options. The long-term goal of this project is to improve outcome with HSCT in patients with MDS and MF. To reduce NRM, new regimens with reduced to improve outcome with HSCT in patients with MDS and MF. To reduce NRM, new regimens with reduced toxicity for related or unrelated transplants will be developed. Specifically, 1) patients with "less advanced" MDS will receive busulfan (BU) targeted to plasma levels of 800-900 ng/mL plus cyclophosphamide (CY), g-CSF mobilized peripheral blood stem cells (PBSC), and post-grafting methotrexate (MTX) and cyclosporine (CSP); 2) patients with "advanced" MDS will be treated with either a) targeted BU (800-900 ng/mL) plus fludarabine, G-CSF mobilized blood stem cells (PBSC), and post-grafting methotrexate (MTX) and cyclosporine (CSP); 2) patients with "advanced" MDS will be treated with either a) targeted BU (800- 900 NG/mL) plus fludaribine, G-CSF mobilized PBSC, and MTX/CSP (patients 65 years old; CD33+;