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

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

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

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Thyroid Cancer: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84096-2 1. Thyroid Cancer-Popular works. I. Title.

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

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

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

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

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

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON THYROID CANCER .................................................................................... 3 Overview........................................................................................................................................ 3 Federally Funded Research on Thyroid Cancer ............................................................................. 3 E-Journals: PubMed Central ....................................................................................................... 23 The National Library of Medicine: PubMed ................................................................................ 23 CHAPTER 2. NUTRITION AND THYROID CANCER .......................................................................... 71 Overview...................................................................................................................................... 71 Finding Nutrition Studies on Thyroid Cancer ............................................................................ 71 Federal Resources on Nutrition ................................................................................................... 78 Additional Web Resources ........................................................................................................... 79 CHAPTER 3. ALTERNATIVE MEDICINE AND THYROID CANCER .................................................... 81 Overview...................................................................................................................................... 81 National Center for Complementary and Alternative Medicine.................................................. 81 Additional Web Resources ........................................................................................................... 95 General References ....................................................................................................................... 95 CHAPTER 4. CLINICAL TRIALS AND THYROID CANCER ................................................................. 97 Overview...................................................................................................................................... 97 Recent Trials on Thyroid Cancer ................................................................................................. 97 Keeping Current on Clinical Trials ............................................................................................. 99 CHAPTER 5. PATENTS ON THYROID CANCER ............................................................................... 101 Overview.................................................................................................................................... 101 Patents on Thyroid Cancer ........................................................................................................ 101 Patent Applications on Thyroid Cancer..................................................................................... 102 Keeping Current ........................................................................................................................ 105 CHAPTER 6. BOOKS ON THYROID CANCER .................................................................................. 107 Overview.................................................................................................................................... 107 Book Summaries: Online Booksellers......................................................................................... 107 The National Library of Medicine Book Index ........................................................................... 109 Chapters on Thyroid Cancer ...................................................................................................... 110 CHAPTER 7. MULTIMEDIA ON THYROID CANCER ........................................................................ 113 Overview.................................................................................................................................... 113 Bibliography: Multimedia on Thyroid Cancer ........................................................................... 113 CHAPTER 8. PERIODICALS AND NEWS ON THYROID CANCER ..................................................... 115 Overview.................................................................................................................................... 115 News Services and Press Releases.............................................................................................. 115 Academic Periodicals covering Thyroid Cancer......................................................................... 119 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 121 Overview.................................................................................................................................... 121 U.S. Pharmacopeia..................................................................................................................... 121 Commercial Databases ............................................................................................................... 122 Researching Orphan Drugs ....................................................................................................... 123 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 127 Overview.................................................................................................................................... 127 NIH Guidelines.......................................................................................................................... 127 NIH Databases........................................................................................................................... 129 Other Commercial Databases..................................................................................................... 131 APPENDIX B. PATIENT RESOURCES ............................................................................................... 133 Overview.................................................................................................................................... 133 Patient Guideline Sources.......................................................................................................... 133 Finding Associations.................................................................................................................. 139

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APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 141 Overview.................................................................................................................................... 141 Preparation................................................................................................................................. 141 Finding a Local Medical Library................................................................................................ 141 Medical Libraries in the U.S. and Canada ................................................................................. 141 ONLINE GLOSSARIES................................................................................................................ 147 Online Dictionary Directories ................................................................................................... 149 THYROID CANCER DICTIONARY ......................................................................................... 151 INDEX .............................................................................................................................................. 199

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

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

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

Federally Funded Research on Thyroid Cancer The U.S. Government supports a variety of research studies relating to thyroid cancer. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to thyroid cancer. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore thyroid cancer. The following is typical of the type of information found when searching the CRISP database for thyroid cancer: •

Project Title: CHARACTERIZATION OF T(2;3)(Q12;P25) IN THYROID CANCER Principal Investigator & Institution: Kroll, Todd G.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 15-JUN-1999; Project End 30-JUN-2001 Summary: Thyroid nodules are common in the adult human population. Many are benign but some are cancers with varying degrees of malignant potential. Clinical

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

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assessment cannot stratify individual thyroid nodules into definite benign, premalignant, or malignant categories. Pre-operative pathologic classification is imprecise because thyroid follicular hyperplasias, adenomas, and carcinomas have overlapping morphologic features. As a result, the majority of thyroid nodules resected at surgery are benign. We hypothesize that investigations into the pathogenesis of thyroid follicular neoplasms will elucidate their basic biology, improve diagnosis, identify reliable prognosticators, and reduce the need for thyroid surgeries. t(2;3)(q12;p25) has been identified in 8 of 11 human thyroid follicular carcinomas using cytogenetic and fluorescence in situ hybridization (FISH) analyses. t(2;3)(q12;p25) appears specific for follicular carcinoma in that it was absent from 12 papillary carcinomas, 21 follicular adenomas, and 12 multi-nodular hyperplasias lacked t(2;3)(q12;p25) analyzed by FISH. We hypothesize that t(2;3)(q12;p25) results in formation of a novel human oncogene that we propose to characterize and determine whether it is a marker identifying patients with malignant and pre-malignant follicular thyroid nodules. The t(2;3)(q12;p25) oncogene will be localized by physical mapping with YAC- and BAC-FISH of both breakpoints. Fusion oncogene cDNAs will be isolated with BACs and verified by: (1) their ability to hybridize to DNA spanning the translocation breakpoint(s), (2) identification of genomic DNA rearrangements and unique mRNA transcripts in follicular carcinoma tissue, and (3) direct nucleotide sequencing. In vitro systems will be established to characterize oncogene transforming activity, and the utility of the oncogene in diagnosis and classification of thyroid follicular neoplasms will be evaluated in histologic and cytologic pathology specimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZATION OF THE 10Q22-23 CANDIDATE TUMOR SUPPRESSOR IN BREAST CANCER Principal Investigator & Institution: Parsons, Ramon; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001 Summary: Recently, a candidate tumor suppressor gene, PTEN, has been identified on human chromosome 10q23 that is mutated in sporadic cancers of the brain, breast, and prostate. Germline mutations of the PTEN gene are observed in Cowden disease, an inherited predisposition in breast and thyroid cancer. Analysis of the codon sequence of PTEN has revealed a tyrosine phosphatase/dual specificity phosphatase domain. The phosphatase domain sits within a large domain homologous to tensin and auxilin. Mutations have been observed within the phosphatase domain and non-overlapping portions of the tensin domain. The carboxy-terminal half of the codon sequence has no significant homology to other genes; nevertheless, it is a target for mutations as well. Thus, it represents a potential functional domain of unknown significance. The first specific aim will attempt to identify the frequency of PTEN inactivation in brain and breast tumors. Tumor DNA paired with normal DNA samples will be analyzed for PTEN mutations in exonic sequences. Homozygous deletions of exons will be investigated using a variety of techniques, including Southern blotting, PCR, with polymorphic markers within and surrounding the gene, and fluorescent in situ hybridization (FISH). The potential inactivation of PTEN expression through methylation will be explored. Finally, tumors at different phases of development will be tested for alterations. The second specific aim is to characterize the PTEN protein. Both polyclonal and monoclonal antibodies will be developed. These antibodies will be utilized to identify the location of PTEN in cells, normal tissues, and tumors. PTEN will be expressed as a fusion protein in e. coli, purified, and tested for phosphatase activity.

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Mutants of PTEN found in people will be expressed to determine their effects on phosphatase activity. Finding proteins that specifically interact with the phosphatase or other domains of the protein will be a high priority. Approaches to find such proteins include co-immunoprecipitation, two-hybrid analysis, and affinity purification. The third aim is to determine the physiological function of PTEN and uncover its mechanisms of tumor suppressor. To identify the role of PTEN in normal and tumor development, the gene will be mutated in the germline of mice. As an alternative approach, tumor cell lines mutated for PTEN will be complemented with the wild type gene. Phenotypes to be tested include cell proliferation and tumorigenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEMETHYLATION THERAPY OF THYROID CARCINOMA Principal Investigator & Institution: Ain, Kenneth B.; Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2001; Project Start 04-MAY-2000; Project End 31-MAR-2005 Summary: (Applicant's Description) Disseminated dedifferentiated thyroid epithelial carcinoma is a terminal disease with no effective systemic treatment or chemotherapy, as a consequence of the loss of the ability to concentrate iodide, rendering it unable to be treated with radioactive iodide. Our translational research efforts aim to restore the therapeutic effectiveness of radioiodine for systemic therapy. Iodide uptake depends upon expression of the human sodium-iodide membrane symporter (hNIS). Chemical agents, differentiation inducers and demethylation agents, have been able to restore lost differentiated functions in a wide variety of other tumor types. Our data show that demethylation agents can restore expression of hNIS mRNA in dedifferentiated human thyroid cancer cell lines and restore iodide uptake. We have shown that this is likely consequent to demethylation of CpG islands of the hNIS gene promoter (or the promoters of thyroid-specific transcription factors) in tumor samples. For this reason, we hypothesize that methylation-induced loss of hNIS gene transcription is reversible by chemical therapy with demethylating agents or differentiation inducers. Such therapy should enable radioiodide treatment of dedifferentiated thyroid cancers. In addition, we have demonstrated that the same mechanism of gene methylation is responsible for loss of expression of E-cadherin, a protein contributing to cell:cell adhesion in human thyroid cancer cells. Restoration of E-cadherin expression may suppress tumor invasion and metastasis, improving the clinical course of thyroid cancer patients. In this way, clinical use of demethylation agents may enhance the effectiveness of therapeutic radioiodine and simultaneously diminish the progression and spread of disease. This proposed patient-oriented research will utilize demethylation agents to restore or enhance radioiodine uptake in thyroid carcinoma metastases of patients previously unresponsive to radioiodine treatment. Pilot trials using known active agents, such as 5-azacytidine, will be supplemented with trials of additional agents defined by cell culture and xenograft studies. Patients with therapeuticallyunresponsive dedifferentiated thyroid cancer metastases are often treated with palliative surgical resection of gross tumor. In such patients, fresh tumor samples will be analyzed for hNIS gene methylation and E-cadherin expression and cultured for cell lines. These analyses and in vitro studies will permit targeting of specific agents to individual patients for the purposes of both radioiodine therapy and modulation of tumor progression. Such patient-oriented research will proceed in the context of active mentorship in thyroid oncology and translational research centered on Oncology fellows. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ESTABLISH OF POST CHERNOBYL NIS THYROID BANKS Principal Investigator & Institution: Thomas, Geraldine A.; University of Cambridge Cambridge, England Cambridge, Timing: Fiscal Year 2001; Project Start 17-JUL-2000; Project End 10-SEP-2002 Summary: (Applicant's Description) This project will form an internationally supported collaborative research resource for many groups working on the problems of thyroid cancer which has followed the Chernobyl accident. It is designed to promote collaboration and avoid competition in the use of limited and very valued resources. The four funding organizations involved in the project are the National Institute of Health of the USA, the European Commission, the World Health Organization and the Sasakawa Memorial Health Foundation of Japan. The basis of the project is a collaborative approach to the collection of the tissue from cases of thyroid cancer in the areas around Chernobyl with simultaneous collection of blood samples and basic clinical information. The project has several aims (a) to ensure that the best possible diagnostic service is given to patients, (b) to provide a diagnosis agreed by internationally recognized pathologists. This diagnosis will be made available to research groups from those countries carrying out molecular biological, therapeutic, epidemiological and other studies. (c) to ensure that specimens of thyroid cancer are properly described and sampled, and that materials are available for appropriate research studies (frozen tissue, fixed tissue sections, extracted DNA/RNA and blood samples, together with relevant information), through a protocol agreed by the research organizations involved. The project will provide a valuable research tool for future researchers interested in the mechanism of radiation tumourigenesis of the thyroid following irradiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EXPLOITATION OF RET INHIBITORS FOR TREATMENT OF THYROID CANCER Principal Investigator & Institution: Nelkin, Barry D.; Associate Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 12-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Activation of the RET tyrosine kinase is involved in approximately 50% of cases of medullary thyroid carcinoma (MTC) and 20-25% of cases of papillary thyroid carcinoma (PTC). For medullary thyroid carcinoma, there is no effective therapy other than surgery. In this proposal, we will develop therapeutic approaches for MTC and PTC, based on inhibition of RET. We have shown that the indolecarbazole compunds of CEP-701 and CEP-751 inhibit RET and induce apoptosis in MTC cells in culture. Focusing mainly on MTC, this proposal will develop this observation, toward effective therapy for these diseases in humans. The effect of CEP701 and CEP-751 on inhibition of RET activity and MTC growth will be evaluated in an animal model of human MTC. Combination therapy, using CEP-701 or DEP-751 and a conventional cytotoxic agent, will be examined. A library of tyrosine kinase inhibitors, structurally similar to CEP-701 and CEP-751, will be screened for more effective RET inhibitors. Correlative markers will be identified for RET inhibition, based on downstream effectors of RET signal transduction pathways. Immunological assays for these markers will be developed for future use in assessing the efficacy of RET inhibition in clinical settings. The effect of RET inhibition by CEP-701, CEP-751, or other compounds on several forms of RET commonly activated in MTC and PTC will be

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examined. In addition, the effect of RET inhibition therapy will be examined in tumors arising in the natural thyroid setting, in transgenic models of MTC and PTC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL PROTEOGENOMICS OF MITOCHONDRIA Principal Investigator & Institution: Oefner, Peter J.; Associate Director; Biochemistry; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): One hundred and two clinical phenotypes have been associated with mutations in a quarter of the known 406 nuclear-encoded human mitochondrial proteins. Estimated 500-600 nuclear encoded mitochondrial proteins await identification. The physiological mechanisms operating in mitochondria are highly conserved among eukaryotes. Hence, insights gained into the function of mitochondrial proteins in yeast can be correlated to their orthologues in human that are involved in health and disease. Using single-gene yeast deletion mutants, 265 novel proteins with a respiratory deficiency have been identified. By blasting these proteins against an expressed sequence tag library and, consequently, correlating them to mapped putative mitochondrial disorders, candidate genes could be identified for such mitochondrial disorders as optic atrophy 4, Moebius syndrome 2, Friedreich ataxia 2, and thyroid cancer with cell oxyphilia. As a follow-up, a complementary study of mitochondrial function at the transcriptional and translational level is proposed. Using Fourier transform ion cyclotron resonance mass spectrometry of tryptic digests of isolated yeast mitochondria, accurate mass tags for yeast nuclear encoded mitochondrial proteins will be obtained with the goal to identify all mitochondria located proteins. High-density DNA array expression analysis of proteins identified by gene deletion and the proteomics project will be used to identify pathway specific mRNA signature profiles, which can be used to group unclassified genes into an operational network. Thirty-two yeast deletion strains involved in the function of the respiratory chain, amino acid metabolism, heme biosyntesis, and membrane transport were selected under the criteria of their quantitative deletion phenotype and a human orthologue involved in a mitochondrial disorder. In addition, to study more subtle alterations of cellular and mitochondrial function, experiments using the yeast deletion collection on several iron and thiamin conditions are proposed. Further, mRNA signature profiling will be conducted on human cell lines established from patients with mitochondriopathies. These cell lines are related to yeast, 19 have a known gene mutation and a yeast orthologue involved in the similar pathway and partially found with a respiratory deficiency. In a pilot project, a library of accurate mass tags for human mitochondrial proteins will be generated for the characterization of human cell lines derived from patients with known or putative mitochondriopathies. The concordance of protein data with those obtained by means of human mRNA expression arrays and the functional genomic findings from yeast will be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GCRC MASS SPECTROMETRY CORE FACILITY SUPPLEMENT Principal Investigator & Institution: Burnett, John C.; Professor of Medicine & Physiology Direc; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2003; Project Start 01-DEC-1976; Project End 30-NOV-2004 Summary: (provided by applicant): This is a revised supplemental application to bring a proteomic analytical facility to our Biomedical Mass Spectrometry Core Laboratory so as

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to facilitate clinical research in the post-genome era. The investigators request support to expand our shared instrument facility by adding a state-of-the-art mass spectrometer ion-trap to perform protein profile analysis in conjunction with functional and gene array analysis. This new system with high throughput and capability for proteomic analysis will enhance the research efforts of several human researchers. This proposal deals with human studies conducted in the MC GCRC from nine NIH-supported investigators (total 20 NIH grants including two program projects representing support from NIDDK, NIA, NIHL, and NCI). These investigators represent a wide range of disciplines endocrinology, metabolism, aging, nutrition, transplantation biology, vascular biology and cancer. The proposals are: 1) Dr. K. S. Nair (PI) investigates (I) the effect of insulin and amino acids on hepatic and muscle protein profiles and (ii) age and exercise effects on muscle protein and gene transcript profiles. 2) Dr. R. Rizza investigates whether the circulatory proteins differentially regulated by insulin and glucose in Type II diabetics and non-diabetic people. 3) Dr. J. Levine investigates the effect of experimental weight gain on changes in adipocyte protein expression. 4) Drs. B. L. Riggs and S. Khosla investigate the effect of estrogen deficiency on protein expression in bone marrow. 5) Drs. D. Jelinek and N. Kay investigate the protein and gene expression profiling in multiple myeloma and (three cell leukemia. 6) Dr. M. Joyner investigates the protein and gene transcript profiles in microvasculature in people who are non-responsive to nitric oxide stimulants and compare with the responder. 7) Dr. M. Stegall investigates the protein profiling in kidney samples of people with chronic allograft nephropathy. 8) Dr. M. Jensen investigates the differential of proteins and gene transcripts profile in abdominal and gluteal fat cells. 9) Drs. N. Eberhardt and B. McIver investigate the proteins and gene transcripts differentially expressed in thyroid cancer tissues and normal thyroid tissue. The facility is well supported by NIH (through GCRC as well as program projects) and Mayo Foundation for maintenance and supplies. Highly qualified mass spectrometry technicians are available and the investigator has longstanding experience in using biomedical mass spectrometry for protein studies. The addition of new mass spectrometers and personnel will allow our facility to advance our program to identify new proteins and the altered expression of proteins in diseased states and in response to physiological stimuli. The results from the proposed studies are expected to make major contributions to our understanding of molecular mechanisms of various diseases and the aging process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY OF PROSTATE CANCER USING RADIOIODINE Principal Investigator & Institution: Morris, John C.; Associate Professor & Chair; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 31-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Prostate cancer is the second leading cause of cancer death of American men. Metastatic prostate cancer is considered essentially incurable. In marked contrast, thyroid cancers can be effectively treated and, at times, cured even when widespread metastasis is present, because of the ability of the cells to concentrate iodine, making therapy with radioactive iodine possible and effective. The studies described in this proposal are aimed at transferring the gene for the thyroidal sodiumiodide symporter (NIS), the structure that is responsible for iodide trapping by thyroid cells, into prostate cancer cells. In addition, the potential role of this transfer as a means of gene therapy for metastatic prostate cancer is examined. The studies involve targeting expression of the NIS gene using prostate specific promoters in order to achieve prostate specific gene expression. Our preliminary studies have demonstrated the feasibility of

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this gene transfer in vitro and in vivo, in that high level and prostate specific iodide uptake has been established in LNCaP cell tumors in mice and those tumors have been successfully treated with 131I. The experiments outlined in this proposal will further examine the feasibility and efficacy of NIS gene transfer in vivo using mouse models, mechanisms of maximizing NIS protein expression and activity, and the cell killing effect of 131I in these models in vitro and in vivo. Further, our studies will examine the immune response within immunocompetent host mice following radioiodine killing of NIS transfected murine prostate tumors and the influence of that response upon the appearance and progression of native prostate cancer in transgenic mice (TRAMP), which naturally develop prostate cancer. Finally the proposal describes a phase I/II clinical trial of adenoviral mediated NIS gene transfer in patients with recurrent prostate cancer. Our studies, will serve to examine the potential of NIS gene transfer to prostate cancer as a method of therapy of metastatic disease and are the first so described. In addition, successful demonstration of radioiodine effect in our prostate cancer model will serve to stimulate interest in NIS as a therapeutic gene for other cancer types. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENERAL CLINICAL RESEARCH CENTER Principal Investigator & Institution: Boat, Thomas F.; Director; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001; Project Start 30-DEC-1993; Project End 30-NOV-2001 Summary: This is a proposal for the renewal of a multi-categorical General Clinical Research Center at the Children's and University Hospitals. Major areas of research include: 1. Pediatric Liver Disease. Studies are defining the pathophysiology and treatment of new inborn errors of bile acid metabolism and peroxisomal disorders and the pathogenesis of bone disease and growth failure in cholestatic liver disease. 2. Bone Health. Studies will examine the effect of maternal age during lactation on bone demineralization and the value of progestins in ameliorating the loss. Studies will evaluate the role of calcium supplementation on bone accretion in prepubertal children, the role of exercise in bone accretion in preschoolers and the pathogenesis and management of bone disease in juvenile rheumatoid arthritis. 3. Cancer. Using resources available through a proposed Tissue Procurement Facility supported by the GCRC, basic science and clinical investigators will obtain tumors for investigations of the cell biology and molecular mechanisms of malignancies. Studies will investigate thyroid cancer, neural tumors, breast cancer, and the APC and Bloom's Syndrome genes. 4. Gaucher Disease. Despite the availability of enzyme research for Gaucher Disease, disability from bone disease persists. Studies will evaluate the potential value of bisphosphonates as an adjunct to enzyme replacement for the treatment of bone disease in Gaucher Disease. 5. Cystic Fibrosis. Studies are defining the safety of a replicationdeficient recombinant adenovirus construct to deliver the CF transmembrane conductance gene to the nasal epithelium. 6. Cholesterol Synthesis. Studies are evaluating the potential effect of the cholesterol content in breast milk or infant formulae and cholesterol synthesis rates to determine if early exposure to cholesterol in the human infant may have an "imprinting" effect on cholesterol synthesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTRATHECAL CANCER THERAPY USING I131 NAI Principal Investigator & Institution: Wong, Franklin C.; Associate Professor, Nuclear Medicine An; Nuclear Medicine; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030

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Timing: Fiscal Year 2001; Project Start 04-SEP-2001; Project End 31-MAY-2003 Summary: Leptomeningeal metastasis (LM) is a difficult management problem of patients with various types of cancers. If left untreated, it is invariably fatal. There is essentially no effective treatment. Serious untoward effects are associated with current therapies including neural-axis irradiation and/or intrathecal chemotherapy. The former is limited by radiotoxicity to the underlying nervous tissues while the latter, by intrathecal breakdown and poor penetration of the meninges to reach the tumors. On the other hand, the locoregional use of radiopharmaceuticals such as beta-emitters with millimeter ranges may overcome such hurdles. Beta emission from iodine-131 has a limited range of 2-3 mm that is not impeded by diffusion. It will deliver large radiation to the tumors in the CSF and meninges while sparing the cerebral cortices and the spinal cord. Others using tumor-specific I-131 labeled anti-tenascin monoclonal antibodies have found partial therapeutic success but encountered hematotoxicity. Since hematotoxicity from I-131 compounds has been correlated with total body exposure and labeled antibodies are known to be retained in the body for days, exclusion of the antibody moiety may enhance excretion of unnecessary radiopharmaceuticals and decrease hematotoxicity to allow higher initial dosage for better efficacy. This study aims to determine the regional distribution, dosimetry, potential toxicity and efficacy of intrathecal I-131 sodium iodide (NaI). It is a widely available radiopharmaceutical for effective thyroid cancer therapy. Our preliminary modeling results have found sufficient dosimetry to treat tumor cells in the CSF and meninges, while sparing the underlying brain and spinal cord. This Phase I study will measure the whole-body, organ and regional dosimetry of intrathecally injected I- 131 NaI to correlate with potential efficacy and side effects including thyrotoxicity, hematotoxicity and neurotoxicity. Five to six groups of 3 patients will be studied according to the IRBapproved protocol ID98- 331. In brief, study patients will undergo intrathecal injection of I-131 NaI, followed by blood and urine collection and scintigraphic imaging at determined intervals for pharmacokinetics and dosimetry. Eradication of tumor cells in the CSF will be the primary indicator of efficacy. The CSF cytology, MRI, thyroid, hematology and neuropsychology profiles and neurological status will be followed up to 6 months and contrasted with dosages and dosimetry to determine a reliable set of parameters for further studies. At the end of the study period, our team shall have generated a sufficient set of data to determine whether it is worthwhile to pursue a phase II clinical trial of intrathecal I-131 NaI for the treatment of LM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPY

LEVOTHYROXINE:

TRIIODOTHYRONINE

COMBINATION

Principal Investigator & Institution: Jonklaas, Jacqueliine; Medicine; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2002; Project Start 15-MAY-2002; Project End 30-APR-2007 Summary: (provided by applicant): The objective of this project is to determine what combination of thyroid hormones provides optimum replacement therapy for hypothyroidism. There are two circulating thyroid hormones, thyroxine and triiodothyronine, and standard thyroid hormone replacement consists of synthetic thyroxine (levothyroxine) alone. Although levothyroxine is converted into triiodothyronine in the circulation, triiodothyronine levels achieved may not be equal to those seen with intact thyroid function. Therefore, the overall hypothesis of this project is that levothyroxine replacement results in a subtle deficiency of triiodothyronine and provides incomplete treatment for hypothyroidism. The initial hypothesis to be tested in

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11

this project is whether, within individual patients, standard replacement with levothyroxine results in lower serum levels of triiodothyronine than those seen while the thyroid gland is functioning. Participants will be euthyroid individuals scheduled for thyroidectomy for benign nodular disease or thyroid cancer. Serum triiodothyronine levels prior to thyroid surgery will be compared with those after thyroidectomy, to determine if levothyroxine replacement results in lower, sub-physiologic triiodothyronine levels. Another hypothesis of this project is that a panel of genes can be identified whose expression level is reflective of thyroid status. Complimentary (c) DNA array technology will be used to develop a gene panel whose expression is regulated by thyroid hormone. This gene panel will be included in the biochemical markers used to assess thyroid status. The third hypothesis is that levothyroxinetriiodothyronine combination will provide superior treatment of hypothyroidism. Biochemical, physiologic and psychologic indices of thyroid status will be compared during combination therapy with several ratios of levothyroxine and triiodothyronine to indices during treatment with levothyroxine alone. The regimens will be compared to determine if the one that most closely reproduces the triiodothyronine levels seen with intact thyroid function, also has the most favorable impact on thyroid status. The final hypothesis of this project is that sustained release triiodothyronine is superior to commercially available triiodothyronine. Because of its short half-life, replacement with triiodothyronine leads to fluctuating serum levels. A new sustained release product, which results in steady triiodothyronine levels, will furnish more physiologic replacement. This will be tested against treatment with levothyroxine, and levothyroxine and triiodothyronine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF RET/PTC REARRANGEMENTS IN THYROID CANCER Principal Investigator & Institution: Nikiforov, Yuri E.; Assistant Professor; Pathology and Lab Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (Scanned from the applicant's abstract) Thyroid cancer is the most common form of solid neoplasms known to be associated with radiation exposure. However, the mechanisms of radiation-induced carcinogenesis are not well understood. The high prevalence of rearrangements of the RET gene has been recently found in postChernobyl papillary thyroid carcinomas and in thyroid tumors from patients exposed to therapeutic external radiation. The positions of breakpoints sites in the RET and ELEI genes identified in post-Chemobyl tumors with RETPTC3 rearrangements suggested that these two genes may be aligned across from each other in the nucleus at the time of DNA breaks (Nikiforov et al., Oncogene, 1999). Consistent with this idea, we found that one pair of RET and H4 genes (contributing to RET/PTCI rearrangement) was juxtaposed in 35 percent of inter-phase nuclei of normal thyroid cells. These data suggest that two potentially recombinogenic chromosomal loci may be contiguous to each other in the nucleus predisposing to generation of rearrangement by adjacent double-strand DNA breaks produced by ionizing radiation or other genotoxic agents. The main goal of the current proposal is to explore the role of nuclear architecture and gene proximity in generation of chromosomal rearrangements after radiation exposure. We propose to use two-color FISH and three-dimensional confocal laser-scanning microscopy to determine the frequency of physical proximity of genes, contributing to the major types of RET/PTC rearrangements, in normal human thyroid follicular cells and in other cell lineages. We will establish whether chromosomal organization with

12

Thyroid Cancer

respect to these loci is cell-type specific, age-dependent, or varies with cell cycle stage. Any of these parameters could explain in part the high prevalence of thyroid cancer after irradiation, and the higher susceptibility of children. Then, we will expose cultured cells to different doses of ionizing radiation to test directly the relationship between gene proximity and the frequency of radiation-induced RET/PTC rearrangements in vitro. These studies will extend our understanding of the mechanisms of radiationinduced carcinogenesis in the thyroid gland. In addition, they are likely to have importance for a broad range of chromosomal rearrangements found in cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR CHANGE AND THYROID CANCER RISK AFTER CHERNOBYL Principal Investigator & Institution: Davis, Scott; Professor of Epidemiology; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): This study will investigate the occurrence and molecular characteristics of thyroid cancer in residents of the Bryansk Oblast of the Russian Federation who were up to 50 years of age at the time of exposure to radiation from the Chernobyl Power Station accident on April 26, 1986. The study has three primary purposes: 1) to characterize cases of thyroid cancer according to specific molecular markers of genetic change, and to investigate whether the presence of such markers is associated with individual thyroid radiation dose to the thyroid from the Chernobyl accident; 2) to investigate whether age-at-exposure dependent radiation dose response for thyroid cancer differs between cancers that are positive versus negative for the molecular markers investigated; and 3) to investigate whether the presence of these same molecular markers is associated with clinical outcome. Thyroid cancer cases diagnosed between April 1, 2001 and March 31, 2006 will be identified and the diagnosis confirmed by a panel of expert thyroid pathologists. Controls, equal in number to the cases of thyroid cancer, will be selected among residents in the Bryansk Oblast, without thyroid cancer, individually matched to cases by sex, age, type of settlement and talon. For all cases and controls, the following information will be collected: 1) demographic and health history; 2) details of residential and dietary history; 3) appropriate physical samples to aid dose reconstruction; and 4) a blood sample. Individual radiation dose to the thyroid will be estimated for each case and control. Paraffin embedded tissue or fresh frozen tissue will be obtained for each case to assess tyrosine kinase growth factor and tyrosine kinase receptor expression for purposes of estimating the association between the presence of each of the markers and individual thyroid radiation dose. Clinical history and outcome data will be collected from medical records for investigation of the association between adverse clinical outcome (e.g. recurrence) and individual thyroid radiation dose, patient characteristics, and molecular markers of genetic change. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR MECHANISMS ADENOMA/FOLLICULAR CARCINOMA

DISTINGUISH

FOLLICULAR

Principal Investigator & Institution: Zeiger, Martha A.; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001

Studies

13

Summary: Over 28,000 thyroidectomies are performed in the United States annually for suspected malignancy. However, up to 18,000 of these are benign on permanent histology. This phenomenon is due to the fact that fine needle aspirations (FNA) of the thyroid that are suspicious for malignancy ultimately turn out to represent a benign process in 60% of cases. Because of this phenomenon we chose to examine follicular neoplasms of the thyroid for molecular markers that would distinguish a follicular adenoma from a carcinoma. Up to 40 follicular neoplasms of the thyroid were screened by microsatellite polymorphism analysis that might distinguish the two. Although there was no difference between follicular adenomas and follicular carcinomas, Hijrthle cell neoplasms of the thyroid appeared to have greater loss of heterozygosity on chromosomes 1q and 2p that could distinguish Hijrthle cell adenomas from Hijrthle cell carcinomas. These abnormalities could also be demonstrated on FNA samples with 100% sensitivity and 75% specificity; a potential dramatic improvement over what can now be accomplished by cytology. Because Hiirthle cell neoplasms of the thyroid represent a very small percentage of thyroid carcinomas that still left the clinical dilemma of distinguishing follicular adenomas from carcinomas as well as lesions that were suspicious for papillary thyroid carcinoma. We, therefore, examined follicular neoplasms and lesions that were suspicious for papillary cancer for telomerase activity. We found that 100% of follicular carcinomas and 67% of papillary thyroid cancer have a positive telomerase activity. As a result of this above work, we are prospectively collecting FNA samples from patients who have suspicious lesions on thyroid cytology. The collaborating institutions include the University of Pittsburgh and Mayo Clinic at Jacksonville. To date we have collected 127 samples and are currently examining the use of telomerase as a marker to distinguish benign from malignant. Should we be able to accomplish this and apply it to FNA then theoretically this technique could result in the obviation of up to 18,000 thyroidectomies performed annually in this country. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR PATHOPHYSIOLOGY OF THYROID CELL GROWTH Principal Investigator & Institution: Fagin, James A.; Professor; Internal Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-AUG-1989; Project End 30-JUN-2005 Summary: (Adapted from the Investigator's Abstract): This grant application proposes to study the mechanism through which the RET/PTC oncogenes induce papillary thyroid cancer. While the mechanism of RET activation of cell signaling pathways has been evaluated in a variety of cells, almost nothing is known about its signaling pathways in the thyroid, where it is normally expressed. Considering that RET is intimately involved in carcinogenesis, both for differentiated thyroid tumors and medullary thyroid tumors, this study has a very sensible goal. In particular, the applicant will study the effects of RET/PTC on cell cycle control and genomic stability, evaluate signaling of RET/PTC through the RAS pathway and via PLC-gamma and determine the role of PKC-epsilon in thyroid cell transformation in vivo. RET/PTC rearrangements (four or more) are unique to papillary thyroid carcinoma, and RET/PTC3 is especially prevalent in cancers arising in children exposed to radiation in Chernobyl. RET/PTC appears to be a specific initiating event in tumorigenesis, although presumably with additional mutational change. The translocations forming the RET/PTC oncogene appear to be through chromosomal exchange at specific break points, and it is suggested that these are because the sites of exchange are next to each other during interphase. RET/PTC is believed to be constitutively activated, and that phosphorylation at position 586 allows binding to the membrane and interaction with

14

Thyroid Cancer

SHC, allowing it to transduce signals through RAS. Subsequent steps in the pathway may involve MAP kinase, or possibly phospholipase C-gamma. Studies on H-RAS have shown that it, when constitutively expressed, can act possibly through MAP kinases to cause abnormal mitosis. Activation of PLC-gamma can cause activation of PKC-epsilon, and this may possibly be involved in apoptosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR-GENETIC ANALYSIS OF 3P14 GENOMIC STABILITY Principal Investigator & Institution: Drabkin, Harry A.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 14-AUG-1998; Project End 30-APR-2002 Summary: (Adapted from the Investigator's Abstract): The hereditary renal carcinoma 3;8 translocation has been the source of considerable interest among cancer geneticists and a long-term goal of this laboratory. The pattern of disease is one of classic hereditary cancer with autosomal dominant inheritance, multifocal early onset renal cancer and less frequently, thyroid cancer. The investigators were the first to clone the 3p14 translocation breakpoint. Their subsequent investigations identified homozygous deletions in various carcinoma cell lines involving a region approximately 150 kb telomeric to the t(3;8) breakpoint. This region coincides with FRA3B, the most inducible fragile site in the genome. Whether or not the deletions involving FRA3B result solely from genomic instability, or are biologically selected, is an important question, given the high frequency of 3p loss in a variety of malignant diseases. While Ohta et al. identified a 3p14 gene, FHIT, spanning the 3;8 breakpoint, its role as a tumor suppressor has been seriously questioned. The investigators have discovered that the 3;8 translocation results in a fusion transcript between a novel gene, TRC8, and FHIT. The TRC8 gene is suggested to be a membrane receptor with partial similarity to Drosophila patched, the human homologue of which is responsible for the hereditary basal cell carcinoma syndrome. With regard to the distinct 3p14 deletion region, the investigators have obtained evidence for additional non-FHIT transcripts and have identified a cell line, CC19, with ongoing spontaneous deletions in FRA3B which exhibit tumorigenic differences. This system provides an ideal model to investigate the tumorigenic role of FHIT and other putative genes. The investigators propose, therefore, two main areas of investigation: 1) The further characterization of TRC8 including a mutational analysis of renal and thyroid carcinomas; development of antibodies for the subcellular localization of normal and rearranged products; transfection experiments to functionally characterize the TRC8, TRC8-FHIT and FHIT-TRC8 products. 2) To clarify the role of 3p14 deletions in cancer, they will examine the tumorigenesis of CC19 subclones with and without deletions affecting FHIT exons. If consistent correlations between deletions and tumorigenic variation can be obtained, they will perform transfection experiments with FHIT to confirm this activity. If non-FHIT coding regions are suggested to have tumor suppressor activity they will be further characterized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTEIN KINASE C AND THYROID CELL APOPTOSIS Principal Investigator & Institution: Knauf, Jeffrey A.; Internal Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 30-NOV-2002

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15

Summary: (taken from the application) In 1997, there were an estimated 16,100 new cases of thyroid cancer in the United States. Cancer is not simply a proliferation process, but the manifestation of an imbalance between cell growth and cell death. It is likely that for a tumor clone to progress the apoptotic program must be successfully disabled. In support of this paradigm, we have isolated a chimeric and truncated mutant of PKCepsilon (Tr-PKC-epsilon), the gene for which was amplified and rearranged in a thyroid cancer cell line. When transfected into PCCL3 cells (a well-differentiated rat thyroid cell line) Tr-PKC-epsilon inhibits activation-induced translocation of the wild-type isozyme, resulting in protection of cells from apoptosis. This is accompanied by a marked impairment in p53 stabilization, which may be in part due to elevated levels of MDM2. These findings point to a role for PKC-epsilon in apoptosis signaling pathways in thyroid cells, and suggest that disruptions in PKC-epsilon function may be involved in thyroid tumorigenesis, possibly by altering the cellular response to DNA damage. In support of this we have found that in 75-85% of thyroid carcinomas there were dramatic changes in the level and/or subcellular distribution of PKC-epsilon compared to corresponding normal thyroid tissue. The following Specific Aims are proposed: (1) We will use an inducible expression system to achieve selective activation of either PKCepsilon or the constitutively activated mutant PKC-epsilon-A159F and to determine whether this alone can initiate an apoptotic program, that can be blocked by Tr-PKCepsilon. (2) We will explore whether PKC-epsilon activation interferes with phosphorylation, stabilization, and other post-translational modifications of p53 and MDM-2. (3) We will manipulate the function of the isozyme in thyroid follicular cells of transgenic mice, by targeting expression of either PKC-epsilon, PDK-epsilon-A159F, or the dominant negative inhibitor Tr-PKC-epsilon. Effects on thyroid cell apoptosis in vivo will then be studied in mice exposed to external radiation to the thyroid bed. (4) We will determine if the observed changes in expression and distribution of PKCepsilon in thyroid cancers are due to somatically-acquired structural defects in the PKCepsilon gene, or to epigenetic events. For tumor clones to expand, they must not only exhibit unrestrained stimulation to proliferate, but must also disable essential protection circuits that trigger apoptosis. We propose that PKC-epsilon is part of this defensive strategy, and that this can be subverted during tumorigenesis, or perhaps modulated during adaptive responses such as goiter involution, or thyroid remodeling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RADIATION INDUCED THYROID CANCER Principal Investigator & Institution: Schneider, Arthur B.; Professor of Medicine and Chief; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2001; Project Start 01-APR-1977; Project End 30-JUN-2003 Summary: The major objective of this research proposal is to study radiation- induced thyroid cancer by coordinated clinical, epidemiological and laboratory investigations. The clinical studies are designed to determine the continuing incidence of radiationinduced thyroid cancer and to evaluate methods of diagnosis and medical and surgical approaches to treatment. This will be accomplished by continuing the longitudinal study of patients who received childhood head and neck irradiation for benign conditions at Michael Reese Hospital. Of the 4,296 patients who were so treated 3,058 (71.2 percent) have been located and 1,025 (33.5 percent) have had surgery for thyroid nodules. Among those who have had surgery, 357 (34.8 percent) have had thyroid cancer. The follow-up of this population will continue with the following aims: (1) to determine the continuing incidence of radiation-induced thyroid cancer, (2) to determine if their radiation-induced thyroid cancers have the same age- dependent

16

Thyroid Cancer

worsening prognosis as seen in the general population, and (3) to evaluate the diagnostic methods and treatment methods that have been used. Laboratory studies will focus on the role of serum thyroglobulin in the diagnosis of thyroid tumors. Parallel studies will continue on other radiation-induced tumors, including benign and malignant salivary tumors, neural tumors, parathyroid tumors and others. Together these will provide the information to develop guidelines for the care of persons with a history of radiation. Epidemiological studies will focus on identifying evidence for the existence of heritable radiation susceptibility factors. Patterns of multiple tumors in irradiated individuals and family histories of cancer will be analyzed. Specimens of neoplasms from previous surgery will be used to study specific oncogenes as markers of and as participants in radiation-induced neoplastic transformation. These studies will focus on rearrangements of the ret protooncogene in thyroid neoplasms and the NF2 tumor suppressor gene in neural tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RADIATION INDUCED THYROID CANCER Principal Investigator & Institution: Weier, Heinz-Ulrich G.; Staff Scientist; Structural Biology Division; University of Calif-Lawrenc Berkeley Lab Lawrence Berkeley National Laboratory Berkeley, Ca 94720 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 29-SEP-2003 Summary: (From Abstract) In 1986, an accident at the nuclear power plant in Chernobyl, USSR, led to the release of high levels of radioisotopes. Ten years later, the incidence of childhood papillary thyroid cancer (chPTC) near Chernobyl had risen by 2 orders of magnitude, most likely as a consequence of increased exposure to ionizing radiation. The routes and mechanisms by which radiation generated these additional thyroid cancers remain mysterious. Eight years ago, we began to archive thyroid tumor tissues from patients who underwent thyroidectomy near the site of the power plant, among them 214 specimens from children. Several tumors from this collection aberrantly expressed ret tyrosine kinase transcripts due to a ret/PTC1 or ret/PTC3 chromosomal rearrangements on chromosome 10. However, many other chPTC tumors have phenotypes not attributable to aberrant ret expression. Moreover, even within a retpositive chPTC tumor, not all cells express ret or contain a rearranged chromosome 10. We hypothesize that these other classes of tumors may inappropriately express a different oncogene or have lost function of a tumor suppressor as a result of chromosomal rearrangements and that knowledge of the kind of genetic alterations leading to chPTC may facilitate the early detection and staging of tumors as well as provide guidance for therapeutic intervention. To test this hypothesis, we propose to map the sites of chromosomal breakpoints in 38 cases of radiation-induced chPTC and identify genes with abnormal pattern of expression. We will localize the breakpoints in radiation-induced tumors for which we have metaphase spreads using G-banding results and Spectral Karyotyping. With the breakpoints grossly determined, we will define the targets for positional cloning and prepare breakpoint-spanning YAC contigs and high-resolution physical maps based on co-linear BAC clones. Control groups will be comprised of children who developed thyroid cancer without prior radiation exposure as well as tumors in adult patients who underwent radiotherapy as children or adults. Interphase cell preparations from the control groups will be studied with comparative genomic hybridization and probes specific for candidate loci to detect translocations as well as gene amplifications and deletions. We can then identify genes at the chPTC-specific breakpoints by exon-trapping, direct selection, and DNA sequencing. We will prepare stable cell lines carrying the oncogenic rearrangements for

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17

further characterization and distribution. Finally, we will examine the levels and localization of mRNAs with Northern and in situ hybridization analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF THE SODIUM/IODIDE SYMPORTER IN BREAST Principal Investigator & Institution: Brent, Gregory A.; Professor; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 12-JAN-2001; Project End 31-DEC-2004 Summary: (Adapted from the applicant's abstract) In the lactating mammary gland, iodide is concentrated up to 36-fold in milk compared with the plasma iodide concentration, due to stimulation of the sodium/iodide symporter (NIS). Some hormone-dependent breast cancers also concentrate iodide, up to 7-fold, but iodide uptake in breast cancer must be enhanced to make radioiodine treatment possible, analagous to the TSH stimulation required for uptake of radioiodine into thyroid cancer. All-trans retinoic acid (RA) treatment stimulates iodide uptake, MS mRNA, and MS protein in MCF-7 cells, an estrogen receptor (ER) positive human breast cancer cell line, in a time and dose dependent fashion. No RA-induction of iodide uptake is seen in an ER-negative breast cancer cell line, MDA-MB 231, or a normal breast-derived cell line, MCF-12A. An in vitro clonogenic assay demonstrated selective toxicity of radioiodine following RA stimulation of MCF-7 cells. MCF-12A cells have abundant MS protein, but no functional iodide uptake. MS regulation differs significantly in the breast compared to the thyroid, and differs in normal breast and breast cancer cell lines. We propose to study the regulation of iodide transport in breast cancer cell lines compared to normal breast and thyroid cell lines, with the goals of optimzing iodide uptake and selectively targeting breast cancer cells. Specific aims include: 1. Determine the mechanism of RA-mediated transcriptional regulation of the NIS gene in breast-derived cells utilizing selective retinoid agonists and cell lines with a range of endogenous RAR and RXR expression. 2. To determine the characteristics of NIS protein expression, subcellular localization, and kinetics that are associated with maximal function of NIS in breast-derived cell lines and those features that distinguish functional iodide uptake among cell lines that express NIS protein. 3. Utilize an in vitro model to optimize RAstimulated radiation-mediated cell killing in breast cancer cells. 4. Develop in vivo models to determine the efficacy and specificity of RA-stimulated iodide uptake into breast cancer and determine the influence of enhancers and radiation sensitizers. RA raioiodide uptake may be useful for diagnosis and treatment of some differentiated breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RHENIUM-188 THERAPY OF NIS-EXPRESSING BREAST TUMORS Principal Investigator & Institution: Dadachova, Ekaterina; Nuclear Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Breast cancer remains the major cause of cancer death in women in the developed world. Novel therapeutic modalities are needed for those patients in whom chemotherapy, hormonal treatment and external radiation therapy are not effective. Recently a new molecular target has been identified in 80% of mammary cancers in humans but not in normal/healthy breast tissue - mammary gland sodium/iodide symporter (mgNIS) which may open a new avenue in treatment of breast cancer with radioactive iodine 131-I. However, in the absence of prolonged

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Thyroid Cancer

biological retention of 131-I in NIS-expressing mammary tumors an isotope with shorter physical half-life and superior to 131-I decay properties, which can be transported by NIS may provide a better therapeutic option. We have recently showed that the powerful beta-emitter 188-Rhenium (188-Re) which has therapeutically useful emissions superior to those of 131-I, is also transported by NIS and will deliver several times higher radiation dose to the tumor in comparison with 131-I. We hypothesize that 188Re will be more efficient than 131-I in elimination of NIS-expressing breast tumors in mice. We also hypothesize that the combination of dose fractionation/normal organ protection will increase 188-Re tumodcidal effect while decreasing the radiation dose to normal organs. To test these hypotheses we will start with evaluation of 188-Re and 131I cell-killing impact on NIS-expressing cells of thyroid in normal mice under the conditions of suppressed organification. We will perform comparative 188-Re and 131-I therapy of xenografted breast tumors in nude mice including dose escalation and maximum tolerated dose determination. We will employ the combination of dose fractionation/stomach protection to protect the stomach from radiation. We wilt also perform comprehensive dosimetry calculations for future therapy of NIS-expressing breast cancers in humans. The Specific Aims of the project are: Aim 1 To compare cellkilling potential of 188-Rhenium versus 131-Iodine in NIS-expressing tissue in vivo using thyroid in healthy mice as a target organ. Aim 2 To evaluate the feasibility of using 188-REO4- as a tumoricidal agent in NtS-expressing breast cancer tumors in mice. The proposed research will provide data on interaction of a novel molecular cancer target - mgNiS with non-iodine therapeutic radioisotope and on its potential to eradicate breast tumors. The long-term goal of this research is to contribute to the development of a novel cost-effective radionuclide therapy for treatment of breast cancer and, possibly, for other NIS-expressing cancers such as thyroid cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE TUMORIGENESIS

OF

THE

CNC

GENE

IN

DEVELOPMENT

AND

Principal Investigator & Institution: Kirschner, Lawrence S.; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 21-MAR-2003; Project End 28-FEB-2005 Summary: (Adapted from applicant's description): Carney Complex (CNC) is an autosomal dominant tumor syndrome that is best classified as a novel form of multiple endocrine neoplasia. In this application, Dr. Lawrence S. Kirschner proposes to isolate the genetic defect causing CNC and to begin the functional study of the encoded protein product. In the first portion of this study, a positional cloning strategy will be undertaken to isolate the genetic lesion responsible for CNC. 24 families with CNC have been collected, and a candidate region on chromosome 2pl6 has been defined by genetic recombination analysis. A yeast and bacterial artificial chromosome (YAC and BAG, respectively)-based contig of this area will be constructed and utilized to map expressed sequences into the minimal candidate region. Those mRNA sequences falling in the candidate interval will be cloned and screened for mutations using denaturing high performance liquid chromatography (D-HPLC) analysis. Once the CNC gene is identified, this information will be used to generate transgenic mice lacking the CNC gene, and the effects of this mutation during fetal development, especially of the endocrine system, will be examined. At the same time, mutations in the CNC gene will be sought in CNC associated sporadic tumors, such as cardiac myxomas, benign and malignant adrenal tumors, and thyroid cancers. The long-term goal of this project is to identify the role that the CNC gene product plays in the normal development of the

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endocrine and other systems, as well as the role that the mutated gene plays in tumorigenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SIGNALING PATHWAYS IN MEDULLARY THYROID CANCER Principal Investigator & Institution: Chen, Herbert; Chief, Endocrine Surgery; Surgery; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from the calcitonin-producing thyroid C-cells and accounts for 3-5% of cases of thyroid cancer. Besides surgery, there are limited curative and palliative treatments available to patients with MTC, emphasizing the need for development of other forms of therapy. We have shown that over-expression of raf-1 markedly suppresses cellular growth and induces differentiation of human MTC cells in vitro. We have also shown that these raf-1 effects can be mediated through leukemia inhibitory factor (LIF), a soluble cytokine currently in clinical use for central nervous system disorders. However, the role of raf-1 and LIF in modulating MTC growth and differentiation in vivo has not been explored. In this proposal we will further characterize the downstream events required for raf-1-mediated MTC growth suppression and differentiation. Secondly, we will determine if raf-1 activation can inhibit in vivo MTC tumor growth in a mouse model of metastatic MTC. These studies should determine if modulation of the raf-1 signaling pathway, either by direct activation or through LIF signaling, could play a potential role in the management of patients with metastatic MTC. Because LIF has been already utilized in human subjects for treatment of central nervous system disorders, if our animal data validates our in vitro observations, clinical trials with LIF in patients with metastatic MTC could happen in the near future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SIMPLIFIED LOW IODINE DIET FOR I 131 RADIOIODINE DIAGNOSTIC IMAGING Principal Investigator & Institution: Lee, Stephanie; New England Medical Center Hospitals 750 Washington St Boston, Ma 021111533 Timing: Fiscal Year 2001 Summary: Radioactive iodine is used for the diagnosis of distant and local metastases of thyroid cancer and therapy of thyrotoxicosis and thyroid cancer. Because of the high iodine content of the American diet, the efficacy of radioiodine is diminished unless that patient is placed on a strict low iodine diet. This diet which consists of freshly prepared meals and homemade breads and pastas is nearly impossible to follow with the American dietary habits of eating in restaurants and using convenience foods. After review of the iodine content of currently available foods, the objective of this study is to develop and test a convenient and palatable out-patient diet to decrease iodine intake and excretion to less than 50mcg/24hrs in normal volunteers and patients undergoing routine radioactive iodine diagnostic scanning or therapy for thyrotoxicosis and thyroid cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SPORE IN HEAD AND NECK CANCER Principal Investigator & Institution: Sidransky, David; Associate Professor; Otolaryn & Head & Neck Surgery; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 12-SEP-2002; Project End 31-MAY-2007 Summary: (provided by applicant): This application for continuation of the Specialized Program of Research Excellence (SPORE) in Head and Neck Cancer at The Johns Hopkins University School of Medicine supports a highly interactive, multidisciplinary, and interinstitutional program. Five research projects, three cores, a career development and a research developmental program are proposed to carry out our translational research in head and neck cancer. Research Project #1 - Molecular Screening and Risk Prediction of HNSC. - Co- Investigators, William Westra (basic) and Wayne Koch (clinic). Research Project #2 - Tumor Suppressor Gene Promoter Hypermethylation for Detection of Head and Neck Cancer - Co-Investigators, David Sidransky (basic) and Joseph Califano (clinic). Research Project #3 - HPV Vaccine Therapy and Correlates of Response in Head and Neck Squamous Cell Carcinomas (HNSC) - Co-investigators, TC Wu & Keerti Shah (basic) and Maura Gillison (clinic). Research Project #4 - Combined Modalidty Treatment of Head and Neck Cancer Evaluating Inhibitors of the EGFR/TK Pathway - Co-Investigators, Edward Ratovitski & Manuel Hidalgo (basic) and Arlene Forastiere (clinic). Research Project #5 - Exploitation of RET Inhibitors for Treatment of Thyroid Cancer - Co-Investigators, Barry Nelkin (basic) and Doug Ball (clinic). The cores support the research programs (Core #1 - Pathology/Tissue Core, Dr. Westra; and Core #2 - Administrative/Clinical Core (Drs. Sidransky & Forastiere), Core #3 Biostatistics and Bioinformatics Core (Dr. Goodman). The Career Development Program (Dr.Forastiere) aids the emergence of new investigators and the Research Developmental Program (Dr. David Sidransky) provides rapid funding of innovative directions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURAL CHARACTERIZATION OF GLYCOPROTEINS USING MS Principal Investigator & Institution: Desaire, Heather; University of Kansas Lawrence Lawrence, Ks 66045 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: The glycoprotein hormones to be studied are used as diagnostic markers, for pregnancy and tumors, and as pharmaceuticals, for the treatment of infertility and thyroid cancer. Thus, a reliable method to characterize these proteins, particularly when they are used for medicinal purposes, is paramount in order to assure medication is safe and effective. Current techniques used to study these compounds are time-consuming. Furthermore, they often do not provide sufficient information about the point of attachment, of the carbohydrate to the protein, or sufficient information about the heterogeneity of the carbohydrates. We propose to overcome these problems by analyzing intact glycopeptides using tandem mass spectrometry. By developing mass spectrometric methods of characterizing the carbohydrates, while they remain attached to the protein, the origin of carbohydrate attachment will be unambiguous. Our approach will utilize tools developed for analyzing carbohydrates that are not linked to proteins; however we will tailor these techniques to accommodate the peptide fragments linked to the reducing end of the oligosaccharides. After demonstrating our technique will be successful on a purified glycopeptide, we will develop the appropriate

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separation strategies required to use our technology in characterizing a glycoprotein that has multiple glycosylation sites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE MAMMARY GLAND SODIUM/IODIDE SYMPORTER (MGNIS) Principal Investigator & Institution: Carrasco, Nancy; Professor; Pharmacology; Yeshiva University 500 W 185Th St New York, Ny 10033

Molecular

Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The Na symporter (NIS) is a plasma membrane protein that mediates active I- transport in the thyroid and other tissues, including salivary glands, gastric mucosa, and lactating mammary glands (MG). NIS is regulated differently in each tissue. NIS-mediated I- transport in the thyroid is the first step in thyroid hormone biosynthesis. Endogenous functional expression of NIS in thyroid cancer is the foundation for the single most effective and most side effect-free anticancerous targeted radiation therapy available, i.e. radioiodide therapy, which has been successfully used in thyroid cancer for over 60 years. Our group isolated the cDNA encoding NIS and generated anti-NIS Abs. We have characterized thyroid NIS and its regulation. Mammary gland NIS (mgNIS) mediates active I- transport in lactating mammary cells, from which I- is passively translocated via a different transporter to the milk. mgNIS is expressed in lactating (but not in non-lactating) MG. mgNIS is regulated by estrogen, prolactin, and oxytocin. Mammary adenocarcinomas in transgenic mice display mgNIS-mediated active I- uptake. The only two cancers in which endogenous functional NIS is expressed are thyroid cancer and breast cancer. Over 80% of human breast cancers express mgNIS, but it is still unknown in what percentage of these NIS is functional. Normal non-lactating human breast samples do not express mgNIS. The endogenous expression of NIS in breast cancer provides an immense advantage over other cancers, into some of which NIS has been ectopically expressed by virus-mediated gene transfer. To characterize mgNIS in mammary cells and ascertain its potential value in breast cancer diagnosis and treatment, we propose: 1. a) To characterize the regulation of mgNIS in mammary cell lines; b) to investigate the effects of systemic and local regulatory factors on the expression of mgNIS in vivo; c) to determine whether low temperature and chemical chaperones promote targeting of mgNIS to the plasma membrane; d) to complement our understanding of I- translocation in the lactating mammary gland by assessing the role of putative apical I- transporters. 2) To develop a radioiodide therapeutic protocol and assess its effectiveness in the treatment of adenocarcinomas in animal models. 3) To ascertain, in fine needle aspirates from both human primary breast tumors and metastases, the functional expression of mgNIS and its possible correlation with other breast cancer parameters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THYROID NEEDLE BIOPSY--ITS DIAGNOSTIC USEFULNESS IN THYROID CANCER Principal Investigator & Institution: Lopresti J.; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TUMOR SUPPRESSORS AND DIFFERENTIATED THYROID CANCER Principal Investigator & Institution: Eberhardt, Norman L.; Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001; Project Start 05-JAN-1999; Project End 31-DEC-2002 Summary: Thyroid malignancies, the most common endocrine cancer, account for >17,000 new cases and 1,200 cancer deaths per year in the U.S. The bulk (70-95%) of these neoplasms are primary thyroid carcinomas of follicular cell origin, including differentiated papillary (PTC) and follicular (FTC), and undifferentiated anaplastic thyroid cancers. In the U.S. incidence rates are PTC > FTC >> anaplastic carcinomas, while morbidity/mortality rates associated with these cancers are anaplastic carcinomas >> FTC >PTC. Evidence for progression from benign follicular adenoma (Fa) > FTC has been observed, while PTC appears to arise de novo. While numerous studies have attempted to define the molecular genetics of differentiated thyroid cancer, virtually all of these studies have suffered from lack of significant specimen numbers, insufficient pathological criteria, or both. We have shown extensive evidence for frequent loss of heterozygosity (LOH) on chromosomes 3p, 10q, 13q and 17p in FTC , but not FA or PTC, suggesting that tumor suppressor genes (TSGs) may be involved in the genesis of FTC. Known TSGs mapping near regions of LOH on chromosomes 3p (VHL and FHIT) and 17p (p53) do not appear to be involved, since mutations of these sequences are rare in FTC. Thus as yet undefined TSGs appears to be involved in the genesis of FTC. In the current studies we will perform a detail molecular genetic study of at least 30 specimen/tumor type of a well defined and stratified population of thyroid cancers, in which extensive clinical records are available. Tumor types will include PTC (grades 1,2 and 3), FTC (minimally and widely invasive, oxyphilic and non-oxyphilic carcinomas) and FA. With this population of tumors we will: (i) perform a comprehensive LOH analysis of all chromosomes arms at a resolution of approximately 10 cM, (ii) refine mapping of regions of significant LOH at a resolution of less than or qual to 2 cM, (iii) analyze candidate TSGs that resides within the refine map locations and (iv) clone potential tumor suppressor genes that reside in locations for which no known TSG candidates have been identified. The molecular genetic profiles will be correlated with the clinical records to assess the significance of the genetic changes on morbidity and mortality. These studies will offer one of the first comprehensive analyses of LOH in any well defined tumor population that can be reconciled with the clinical record and will provide detailed insight into the pathogenesis of thyroid cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: USE OF RECOMBINANT HUMAN THYROID STIMULATING HORMONE IN A THYROID CANCER PT Principal Investigator & Institution: Burge, Mark R.; Assistant Professor; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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

Identification of rapid turnover transcripts overexpressed in thyroid tumors and thyroid cancer cell lines: use of a targeted differential RNA display method to select for mRNA subsets. by Gonsky R, Knauf JA, Elisei R, Wang JW, Su S, Fagin JA.; 1997 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146961

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Increased expression of AP2 and Sp1 transcription factors in human thyroid tumors: a role in NIS expression regulation? by Chiefari E, Brunetti A, Arturi F, Bidart JM, Russo D, Schlumberger M, Filetti S.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139985

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

3 4

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

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A case of pulmonary metastatic thyroid cancer complicated with Graves' disease. Author(s): Suzuki K, Nakagawa O, Aizawa Y. Source: Endocrine Journal. 2001 April; 48(2): 175-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11456264&dopt=Abstract

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A case of thyroid cancer involving the trachea: treatment by partial tracheal resection and repair with a latissimus dorsi musculocutaneous flap. Author(s): Shigemitsu K, Naomoto Y, Haisa M, Yamatsuji T, Noguchi H, Kataoka M, Kamikawa Y, Tanaka N. Source: Japanese Journal of Clinical Oncology. 2000 May; 30(5): 235-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10857502&dopt=Abstract

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A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: confirmation of linkage to TCO1. Author(s): Bevan S, Pal T, Greenberg CR, Green H, Wixey J, Bignell G, Narod SA, Foulkes WD, Stratton MR, Houlston RS. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 August; 86(8): 3701-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11502798&dopt=Abstract

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A new therapeutic approach in medullary thyroid cancer treatment: inhibition of oncogenic RET signaling by adenoviral vector-mediated expression of a dominantnegative RET mutant. Author(s): Drosten M, Frilling A, Stiewe T, Putzer BM. Source: Surgery. 2002 December; 132(6): 991-7; Discussion 997. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490846&dopt=Abstract

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A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. Author(s): Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R, Pezzino V, Belfiore A. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 January; 87(1): 24554. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11788654&dopt=Abstract

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A pooled analysis of case-control studies of thyroid cancer. VI. Fish and shellfish consumption. Author(s): Bosetti C, Kolonel L, Negri E, Ron E, Franceschi S, Dal Maso L, Galanti MR, Mark SD, Preston-Martin S, McTiernan A, Land C, Jin F, Wingren G, Hallquist A, Glattre E, Lund E, Levi F, Linos D, La Vecchia C. Source: Cancer Causes & Control : Ccc. 2001 May; 12(4): 375-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11456234&dopt=Abstract

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A pooled analysis of case-control studies of thyroid cancer. VII. Cruciferous and other vegetables (International). Author(s): Bosetti C, Negri E, Kolonel L, Ron E, Franceschi S, Preston-Martin S, McTiernan A, Dal Maso L, Mark SD, Mabuchi K, Land C, Jin F, Wingren G, Galanti MR, Hallquist A, Glattre E, Lund E, Levi F, Linos D, La Vecchia C. Source: Cancer Causes & Control : Ccc. 2002 October; 13(8): 765-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420956&dopt=Abstract

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A report of six cases of familial papillary thyroid cancer. Author(s): Orsenigo E, Beretta E, Gini P, Verrecchia F, Invernizzi L, Fiorina P, Di Carlo V. Source: European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2003 March; 29(2): 185-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633563&dopt=Abstract

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A thyroid-specific far-upstream enhancer in the human sodium/iodide symporter gene requires Pax-8 binding and cyclic adenosine 3',5'-monophosphate response element-like sequence binding proteins for full activity and is differentially regulated in normal and thyroid cancer cells. Author(s): Taki K, Kogai T, Kanamoto Y, Hershman JM, Brent GA. Source: Molecular Endocrinology (Baltimore, Md.). 2002 October; 16(10): 2266-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12351692&dopt=Abstract

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Aberrant localization of beta-catenin correlates with overexpression of its target gene in human papillary thyroid cancer. Author(s): Ishigaki K, Namba H, Nakashima M, Nakayama T, Mitsutake N, Hayashi T, Maeda S, Ichinose M, Kanematsu T, Yamashita S. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 July; 87(7): 3433-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12107263&dopt=Abstract

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Ablation of thyroid residues with 30 mCi (131)I: a comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal. Author(s): Pacini F, Molinaro E, Castagna MG, Lippi F, Ceccarelli C, Agate L, Elisei R, Pinchera A. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 September; 87(9): 4063-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12213846&dopt=Abstract

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An audit of management of differentiated thyroid cancer in specialist and nonspecialist clinic settings. Author(s): Kumar H, Daykin J, Holder R, Watkinson JC, Sheppard MC, Franklyn JA. Source: Clinical Endocrinology. 2001 June; 54(6): 719-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11422105&dopt=Abstract

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Analysis of Tg transcripts by real-time RT-PCR in the blood of thyroid cancer patients. Author(s): Savagner F, Rodien P, Reynier P, Rohmer V, Bigorgne JC, Malthiery Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 February; 87(2): 635-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836297&dopt=Abstract

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Analysis of thyroid cancer data from the Ukraine after 'Chernobyl' using a twomutation carcinogenesis model. Author(s): Leenhouts HP, Brugmans MJ, Chadwick KH. Source: Radiation and Environmental Biophysics. 2000 June; 39(2): 89-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10929377&dopt=Abstract

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Anaplastic thyroid cancer evolved from papillary carcinoma: demonstration of anaplastic transformation by means of the inter-simple sequence repeat polymerase chain reaction. Author(s): Wiseman SM, Loree TR, Hicks WL Jr, Rigual NR, Winston JS, Tan D, Anderson GR, Stoler DL. Source: Archives of Otolaryngology--Head & Neck Surgery. 2003 January; 129(1): 96100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525202&dopt=Abstract

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Anaplastic thyroid cancer. Author(s): Pasieka JL. Source: Current Opinion in Oncology. 2003 January; 15(1): 78-83. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490766&dopt=Abstract

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Anatomical distribution and sclerotic activity of bone metastases from thyroid cancer assessed with F-18 sodium fluoride positron emission tomography. Author(s): Schirrmeister H, Buck A, Guhlmann A, Reske SN. Source: Thyroid : Official Journal of the American Thyroid Association. 2001 July; 11(7): 677-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11484897&dopt=Abstract

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Antisense hTERT inhibits thyroid cancer cell growth. Author(s): Teng L, Specht MC, Barden CB, Fahey TJ 3rd. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 March; 88(3): 13626. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629130&dopt=Abstract

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Appearance of antithyroglobulin antibodies as the sole sign of metastatic lymph nodes in a patient operated on for papillary thyroid cancer: a case report. Author(s): Tumino S, Belfiore A. Source: Thyroid : Official Journal of the American Thyroid Association. 2000 May; 10(5): 431-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10884191&dopt=Abstract

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Are posttherapy radioiodine scans informative and do they influence subsequent therapy of patients with differentiated thyroid cancer? Author(s): Fatourechi V, Hay ID, Mullan BP, Wiseman GA, Eghbali-Fatourechi GZ, Thorson LM, Gorman CA. Source: Thyroid : Official Journal of the American Thyroid Association. 2000 July; 10(7): 573-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10958309&dopt=Abstract

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Balancing demands of cancer surveillance among survivors of thyroid cancer. Author(s): Dow KH, Ferrell BR, Anello C. Source: Cancer Practice. 1997 September-October; 5(5): 289-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9341351&dopt=Abstract

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Benign thyroid disease and dietary factors in thyroid cancer: a case-control study in Kuwait. Author(s): Memon A, Varghese A, Suresh A. Source: British Journal of Cancer. 2002 June 5; 86(11): 1745-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12087461&dopt=Abstract

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Bilateral cervical lymph node metastases in well-differentiated thyroid cancer. Author(s): Noguchi M, Kumaki T, Taniya T, Miyazaki I. Source: Archives of Surgery (Chicago, Ill. : 1960). 1990 June; 125(6): 804-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2346381&dopt=Abstract

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Binding of a human monoclonal antithyroglobulin antibody to cultured human thyroid cancer cells. Author(s): Misaki T, Alam MS, Sakahara H, Kasagi K, Konishi J. Source: Ann Nucl Med. 1997 May; 11(2): 81-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9212886&dopt=Abstract

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Biodistribution and dosimetric study in medullary thyroid cancer xenograft using bispecific antibody and iodine-125-labeled bivalent hapten. Author(s): Hosono M, Hosono MN, Kraeber-Bodere F, Devys A, Thedrez P, Fiche M, Gautherot E, Barbet J, Chatal JF. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1998 September; 39(9): 1608-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9744353&dopt=Abstract

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Biologic basis for the treatment of microscopic, occult well-differentiated thyroid cancer. Author(s): Furlan JC, Bedard Y, Rosen IB. Source: Surgery. 2001 December; 130(6): 1050-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11742337&dopt=Abstract

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Biologic dosimetry in thyroid cancer patients after repeated treatments with iodine131. Author(s): M'Kacher R, Schlumberger M, Legal JD, Violot D, Beron-Gaillard N, Gaussen A, Parmentier C. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1998 May; 39(5): 825-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9591584&dopt=Abstract

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Biphasic effects of thyrotropin on invasion and growth of papillary and follicular thyroid cancer in vitro. Author(s): Hoelting T, Tezelman S, Siperstein AE, Duh QY, Clark OH. Source: Thyroid : Official Journal of the American Thyroid Association. 1995 February; 5(1): 35-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7787431&dopt=Abstract

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Bispecific antibody and bivalent hapten radioimmunotherapy in CEA-producing medullary thyroid cancer xenograft. Author(s): Kraeber-Bodere F, Faibre-Chauvet A, Sai-Maurel C, Gautherot E, Fiche M, Campion L, Le Boterff J, Barbet J, Chatal JF, Thedrez P. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1999 January; 40(1): 198-204. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9935077&dopt=Abstract

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Bone changes in pre- and postmenopausal women with thyroid cancer on levothyroxine therapy: evolution of axial and appendicular bone mass. Author(s): Jodar E, Begona Lopez M, Garcia L, Rigopoulou D, Martinez G, Hawkins F. Source: Osteoporosis International : a Journal Established As Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the Usa. 1998; 8(4): 311-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10024900&dopt=Abstract

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Bone mineral density in medullary thyroid cancer. Author(s): Chen JJ, La France ND. Source: The New England Journal of Medicine. 1988 February 25; 318(8): 517-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3340134&dopt=Abstract

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Bone mineral density in well-differentiated thyroid cancer patients treated with suppressive thyroxine: a systematic overview of the literature. Author(s): Quan ML, Pasieka JL, Rorstad O. Source: Journal of Surgical Oncology. 2002 January; 79(1): 62-9; Discussion 69-70. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11754378&dopt=Abstract

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Both class I and class II HLA antigens are thyroid cancer susceptibility factors. Author(s): Rigopoulou D, Martinez-Laso J, Martinez-Tello F, Alcaide JF, Benmamar D, Hawkins F, Arnaiz-Villena A. Source: Tissue Antigens. 1994 May; 43(5): 281-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7940496&dopt=Abstract

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Brachiocephalic vein thrombus of papillary thyroid cancer: report of a case. Author(s): Koike E, Yamashita H, Watanabe S, Yamashita H, Noguchi S. Source: Surgery Today. 2002; 32(1): 59-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11871819&dopt=Abstract

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Brain metastasis from differentiated thyroid cancer in patients treated with radioiodine for bone and lung lesions. Author(s): Misaki T, Iwata M, Kasagi K, Konishi J. Source: Ann Nucl Med. 2000 April; 14(2): 111-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10830528&dopt=Abstract

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Breast uptake of iodine-131 mimicking lung metastases in a thyroid cancer patient with a pituitary tumour. Author(s): Kao PF, Chang HY, Tsai MF, Lin KJ, Tzen KY, Chang CN. Source: The British Journal of Radiology. 2001 April; 74(880): 378-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11387158&dopt=Abstract

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Bronchoscopic diagnosis of thyroid cancer with laryngotracheal invasion. Author(s): Koike E, Yamashita H, Noguchi S, Yamashita H, Ohshima A, Watanabe S, Uchino S, Takatsu K, Nishii R. Source: Archives of Surgery (Chicago, Ill. : 1960). 2001 October; 136(10): 1185-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11585513&dopt=Abstract

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Cardiovascular safety of acute recombinant human thyrotropin administration to patients monitored for differentiated thyroid cancer. Author(s): Biondi B, Palmieri EA, Pagano L, Klain M, Scherillo G, Salvatore M, Fenzi G, Lombardi G, Fazio S. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 January; 88(1): 2114. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519854&dopt=Abstract

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Case-control study of female thyroid cancer--menstrual, reproductive and hormonal factors. Author(s): Zivaljevic V, Vlajinac H, Jankovic R, Marinkovic J, Dzodic R, Sipeti Grujii S, Paunovic I, Diklic A, Zivaljevic B. Source: European Journal of Cancer Prevention : the Official Journal of the European Cancer Prevention Organisation (Ecp). 2003 February; 12(1): 63-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548112&dopt=Abstract

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Characterization of a thyroid hormone-mediated short-loop feedback control of TSH receptor gene in an anaplastic human thyroid cancer cell line. Author(s): Chen ST, Lin JD, Lin KH. Source: The Journal of Endocrinology. 2002 November; 175(2): 459-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12429043&dopt=Abstract

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Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. Author(s): Behe M, Behr TM. Source: Biopolymers. 2002; 66(6): 399-418. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12658727&dopt=Abstract

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Cigarette smoking and the risk of thyroid cancer. Author(s): Kreiger N, Parkes R. Source: European Journal of Cancer (Oxford, England : 1990). 2000 October; 36(15): 196973. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11000579&dopt=Abstract

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Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Author(s): Simon D, Korber C, Krausch M, Segering J, Groth P, Gorges R, Grunwald F, Muller-Gartner HW, Schmutzler C, Kohrle J, Roher HD, Reiners C. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2002 June; 29(6): 775-82. Epub 2002 March 13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12029551&dopt=Abstract

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Clinical review 156: Recombinant human thyrotropin and thyroid cancer management. Author(s): Robbins RJ, Robbins AK. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 May; 88(5): 1933-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727936&dopt=Abstract

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Clinical review 158: Beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer. Author(s): Braga-Basaria M, Ringel MD. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 May; 88(5): 1947-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727938&dopt=Abstract

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Clinico-pathological features of thyroid cancer as observed in five referral hospitals in Iran--a review of 1177 cases. Author(s): Larijani B, Aghakhani S, Khajeh-Dini H, Baradar-Jalili R. Source: Acta Oncologica (Stockholm, Sweden). 2003; 42(4): 334-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899505&dopt=Abstract

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Coexisting Hashimoto's thyroiditis with differentiated thyroid cancer and benign thyroid diseases: indications for thyroidectomy. Author(s): Pisanu A, Piu S, Cois A, Uccheddu A. Source: Chir Ital. 2003 May-June; 55(3): 365-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12872571&dopt=Abstract

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Combined positron emission tomography/computed tomography imaging of recurrent thyroid cancer. Author(s): Zimmer LA, McCook B, Meltzer C, Fukui M, Bascom D, Snyderman C, Townsend DW, Johnson JT. Source: Otolaryngology and Head and Neck Surgery. 2003 February; 128(2): 178-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12601311&dopt=Abstract

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Coming of age: recombinant human thyroid-stimulating hormone as a preparation for (131)i therapy in thyroid cancer. Author(s): Robbins RJ, Pentlow KS. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 July; 44(7): 1069-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12843222&dopt=Abstract

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Comparison of documented and recalled histories of exposure to diagnostic x-rays in case-control studies of thyroid cancer. Author(s): Berrington de Gonzalez A, Ekbom A, Glass AG, Galanti MR, Grimelius L, Allison MJ, Inskip PD. Source: American Journal of Epidemiology. 2003 April 1; 157(7): 652-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672685&dopt=Abstract

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Complications of neck dissection for thyroid cancer. Author(s): Cheah WK, Arici C, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Source: World Journal of Surgery. 2002 August; 26(8): 1013-6. Epub 2002 June 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12045861&dopt=Abstract

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Concomitant hyperparathyroidism and nonmedullary thyroid cancer, with a review of the literature. Author(s): Leitha T, Staudenherz A. Source: Clinical Nuclear Medicine. 2003 February; 28(2): 113-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12544127&dopt=Abstract

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Contralateral papillary thyroid cancer-high incidence in therapeutic completion thyroidectomy. Author(s): Gemsenjager E, Heitz PU. Source: Thyroid : Official Journal of the American Thyroid Association. 2002 April; 12(4): 345-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12034063&dopt=Abstract

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Contribution of an Anti-CEA Fab' scan in the detection of medullary thyroid cancer. Author(s): Malamitsi J, Kosmidis PA, Papadopoulos S, Petounis A, Linos DA. Source: Clinical Nuclear Medicine. 2002 June; 27(6): 447-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12045444&dopt=Abstract

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Current national health insurance policies for thyroid cancer prophylactic surgery in the United States. Author(s): Dackiw AP, Kuerer HM, Clark OH. Source: World Journal of Surgery. 2002 August; 26(8): 903-6. Epub 2002 June 06. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12045864&dopt=Abstract

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Current therapy for childhood thyroid cancer: optimal surgery and the legacy of king pyrrhus. Author(s): Ringel MD, Levine MA. Source: Annals of Surgical Oncology : the Official Journal of the Society of Surgical Oncology. 2003 January-February; 10(1): 4-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12513952&dopt=Abstract

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CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells. Author(s): Hwang JH, Hwang JH, Chung HK, Kim DW, Hwang ES, Suh JM, Kim H, You KH, Kwon OY, Ro HK, Jo DY, Shong M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 January; 88(1): 40816. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519884&dopt=Abstract

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Detection of hepatic metastasis from medullary thyroid cancer with Tc-99m-MIBI scintigraphy in a patient with Sipple's syndrome. Author(s): Sato S, Okumura Y, Tamizu A, Maki K, Akaki S, Takeda Y, Kanazawa S, Hiraki Y. Source: Ann Nucl Med. 2001 October; 15(5): 443-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11758951&dopt=Abstract

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Detection of sentinel lymph nodes in patients with papillary thyroid cancer. Author(s): Takami H, Sasaki K, Ikeda Y, Tajima G, Kameyama K. Source: Asian J Surg. 2003 July; 26(3): 145-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12925288&dopt=Abstract

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Determination of galectin-3 messenger ribonucleic Acid overexpression in papillary thyroid cancer by quantitative reverse transcription-polymerase chain reaction. Author(s): Bernet VJ, Anderson J, Vaishnav Y, Solomon B, Adair CF, Saji M, Burman KD, Burch HB, Ringel MD. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 October; 87(10): 4792-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12364475&dopt=Abstract

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Diabetes and infarcted papillary thyroid cancer. Author(s): Haddad FH, Malkawi OM, Omari AA, Izzat AS, Khassrof HM, Faiad LM, Okla AL, Jamil AN. Source: Saudi Med J. 2002 April; 23(4): 467-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11953778&dopt=Abstract

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Diagnosis and treatment of medullary thyroid cancer. Author(s): Modigliani E, Franc B, Niccoli-sire P. Source: Bailliere's Best Practice & Research. Clinical Endocrinology & Metabolism. 2000 December; 14(4): 631-49. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11289739&dopt=Abstract

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Diagnosis of thyroid cancer and cytogenetics. Author(s): Antonaci A, Boncompagni A, De Capoa A, Consorti F, Giovannone G, Mardente S, Vietri F. Source: Tumori. 2001 July-August; 87(4): S46-8. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11693821&dopt=Abstract

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Diagnostic 131-iodine whole-body scan may be avoided in thyroid cancer patients who have undetectable stimulated serum Tg levels after initial treatment. Author(s): Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 April; 87(4): 1499501. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11932271&dopt=Abstract

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Diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography in the follow-up of papillary or follicular thyroid cancer. Author(s): Hooft L, Hoekstra OS, Deville W, Lips P, Teule GJ, Boers M, van Tulder MW. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 August; 86(8): 3779-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11502811&dopt=Abstract

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Diagnostic changes as a reason for the increase in papillary thyroid cancer incidence in Geneva, Switzerland. Author(s): Verkooijen HM, Fioretta G, Pache JC, Franceschi S, Raymond L, Schubert H, Bouchardy C. Source: Cancer Causes & Control : Ccc. 2003 February; 14(1): 13-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12708720&dopt=Abstract

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Diagnostic dilemma: papillary thyroid cancer with psammomatous calcifications. Author(s): Gooding GA. Source: The American Journal of Medicine. 2001 April 15; 110(6): 496, 503. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11379568&dopt=Abstract

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Diagnostic value of high-resolution B-mode and power-mode sonography in the follow-up of thyroid cancer. Author(s): Gorges R, Eising EG, Fotescu D, Renzing-Kohler K, Frilling A, Schmid KW, Bockisch A, Dirsch O. Source: European Journal of Ultrasound : Official Journal of the European Federation of Societies for Ultrasound in Medicine and Biology. 2003 February; 16(3): 191-206. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12573788&dopt=Abstract

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Differentiated thyroid cancer in children and adolescents. Author(s): Giuffrida D, Scollo C, Pellegriti G, Lavenia G, Iurato MP, Pezzin V, Belfiore A. Source: J Endocrinol Invest. 2002 January; 25(1): 18-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11883862&dopt=Abstract

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Differentiated thyroid cancer presenting as distant metastases. Author(s): Mishra A, Mishra SK, Das BK, Pradhan PK. Source: The European Journal of Surgery = Acta Chirurgica. 2002; 168(5): 305-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12375614&dopt=Abstract

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Differentiated thyroid cancer: “complete” rational approach. Author(s): Kebebew E, Clark OH. Source: World Journal of Surgery. 2000 August; 24(8): 942-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10865038&dopt=Abstract

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Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases. A report from the Surgical Discipline Committee of the Children's Cancer Group. Author(s): La Quaglia MP, Black T, Holcomb GW 3rd, Sklar C, Azizkhan RG, Haase GM, Newman KD. Source: Journal of Pediatric Surgery. 2000 June; 35(6): 955-9; Discussion 960. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10873043&dopt=Abstract

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Differentiated thyroid cancer: determinants of disease progression in patients