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

LIVER

TRANSPLANT 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., 1960Liver Transplant: 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: 0-597-84484-4 1. Liver Transplant-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 liver transplant. 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 LIVER TRANSPLANT .................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Liver Transplant ......................................................................... 15 E-Journals: PubMed Central ....................................................................................................... 62 The National Library of Medicine: PubMed ................................................................................ 66 CHAPTER 2. NUTRITION AND LIVER TRANSPLANT ...................................................................... 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Liver Transplant ........................................................................ 115 Federal Resources on Nutrition ................................................................................................. 121 Additional Web Resources ......................................................................................................... 122 CHAPTER 3. DISSERTATIONS ON LIVER TRANSPLANT ................................................................. 123 Overview.................................................................................................................................... 123 Dissertations on Liver Transplant ............................................................................................. 123 Keeping Current ........................................................................................................................ 124 CHAPTER 4. CLINICAL TRIALS AND LIVER TRANSPLANT ............................................................ 125 Overview.................................................................................................................................... 125 Recent Trials on Liver Transplant ............................................................................................. 125 Keeping Current on Clinical Trials ........................................................................................... 129 CHAPTER 5. PATENTS ON LIVER TRANSPLANT ............................................................................ 131 Overview.................................................................................................................................... 131 Patents on Liver Transplant ...................................................................................................... 131 Patent Applications on Liver Transplant .................................................................................. 135 Keeping Current ........................................................................................................................ 136 CHAPTER 6. BOOKS ON LIVER TRANSPLANT ................................................................................ 137 Overview.................................................................................................................................... 137 Book Summaries: Federal Agencies............................................................................................ 137 Book Summaries: Online Booksellers......................................................................................... 139 Chapters on Liver Transplant .................................................................................................... 140 CHAPTER 7. MULTIMEDIA ON LIVER TRANSPLANT ..................................................................... 145 Overview.................................................................................................................................... 145 Video Recordings ....................................................................................................................... 145 CHAPTER 8. PERIODICALS AND NEWS ON LIVER TRANSPLANT .................................................. 147 Overview.................................................................................................................................... 147 News Services and Press Releases.............................................................................................. 147 Newsletters on Liver Transplant ............................................................................................... 151 Newsletter Articles .................................................................................................................... 151 Academic Periodicals covering Liver Transplant....................................................................... 152 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 153 Overview.................................................................................................................................... 153 U.S. Pharmacopeia..................................................................................................................... 153 Commercial Databases ............................................................................................................... 154 Researching Orphan Drugs ....................................................................................................... 154 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 159 Overview.................................................................................................................................... 159 NIH Guidelines.......................................................................................................................... 159 NIH Databases........................................................................................................................... 161 Other Commercial Databases..................................................................................................... 163 APPENDIX B. PATIENT RESOURCES ............................................................................................... 165 Overview.................................................................................................................................... 165

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Patient Guideline Sources.......................................................................................................... 165 Finding Associations.................................................................................................................. 176 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 179 Overview.................................................................................................................................... 179 Preparation................................................................................................................................. 179 Finding a Local Medical Library................................................................................................ 179 Medical Libraries in the U.S. and Canada ................................................................................. 179 ONLINE GLOSSARIES................................................................................................................ 185 Online Dictionary Directories ................................................................................................... 186 LIVER TRANSPLANT DICTIONARY...................................................................................... 187 INDEX .............................................................................................................................................. 253

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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 liver transplant 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 liver transplant, 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 liver transplant, 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 liver transplant. 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 liver transplant, 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 liver transplant. 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 LIVER TRANSPLANT Overview In this chapter, we will show you how to locate peer-reviewed references and studies on liver transplant.

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

Pilot Study of Interferon Alfa and Ribavirin Combination in Liver Transplant Recipients with Recurrent Hepatitis C Source: Hepatology. 36(5): 1253-1258. November 2002. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Although interferon alfa (IFNa) and ribavirin are widely used in the treatment of hepatitis C, their role in the transplant recipient is unclear. This article reports on a pilot study conducted to determine the efficacy and safety of this therapy in transplant recipients with recurrent hepatitis C. Patients at least 6 months posttransplantation were treated with IFNa and ribavirin for 48 weeks followed by ribavirin monotherapy for 24 weeks. The primary end point was sustained virologic

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response, and secondary end points included biochemical, virologic, and histologic responses at the end of combination treatment. Thirty-eight patients initiated therapy, but 16 withdrew due to adverse effects, including 2 with myocardial infarction (heart attack). Median age was 50 years, 74 percent were men, and 91 percent had genotype 1 hepatitis C. On an intention-to-treat basis, 7 patients (18 percent) had a biochemical and 5 patients (13 percent) had a virological response at the end of combination treatment. Inflammatory activity did not change, but fibrosis worsened in virologic nonresponders. Ribavirin maintenance caused a further decrease in serum alanine aminotransferase levels, but hepatitis C virus (HCV) RNA levels increased. Only 2 of the 38 patients (5 percent) had a sustained virologic response. Several patients required treatment with erythropoietin for anemia. The authors conclude that IFN alfa and ribavirin are effective in a small proportion of liver allograft recipients with recurrent hepatitis C. 1 figure. 4 tables. 16 references. •

Medical Problems Occurring After Orthotopic Liver Transplantation Source: Digestive Diseases and Sciences. 42(8): 1666-1674. August 1997. Summary: Common medical problems such as hypertension, hypercholesterolemia, and obesity are seen in long term clinical follow up after liver transplantation. In addition to these problems, specific areas of post transplant dysfunction include: diabetes mellitus, malignancy, bone disease, sexual dysfunction, neurological disease, and recurrence of the primary liver disease. In this article, the authors review these medical problems and discuss the most common etiologies. The incidence of diabetes mellitus ranges from 4 to 20 percent following solid organ transplantation. Immunosuppressive agents contribute to glucose intolerance, hyperlipidemia, and hypertension. These combined comorbidities increase cardiovascular risk. Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis experience up to a 13 percent incidence of colon cancer after transplantation. Lymphomas occur in 1 to 3 percent of patients after transplantation and account for 57 percent of malignancies occurring in adult patients. Atraumatic bone fracture occurs in 22 to 38 percent of patients and neurological complications, including seizures, headache, and neuropathy occur in 19 to 47 percent of patients following liver transplantation. Patients undergoing liver transplantation may experience recurrent of their primary liver disease. In patients not receiving immunoprophylaxis after transplantation for chronic hepatitis B, recurrent hepatitis B is seen in up to 90 percent of patients. Recurrent hepatitis C is seen in the majority of patients; current treatment modalities are inadequate. Recurrence of primary biliary cirrhosis or PSC in the allograft is infrequent. The authors also discuss psychiatric issues, quality of life, and rehabilitation. 3 tables. 36 references. (AA-M).

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Long-Term Follow-Up of the Orthotopic Liver Transplantation Patient Source: Seminars in Liver Disease. 15(2): 173-180. May 1995. Contact: Available from Thieme Medical Publishers, Inc. 381 Park Avenue South, New York, NY 10016. (800) 782-3488. Summary: In this article, the authors highlight aspects of both routine and special needs of patients following liver transplantation. Topics covered include immunosuppression medications; hypertension medications; anti-infective agents; medications for other medical disorders; specialized medications; vaccines; monitoring of immunosuppression; laboratory studies for clinical monitoring; specialized studies; routine physician visits, including a recommended schedule; specialized followup studies; the role of good communication between patient, primary care provider, and

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the transplant center; the needs of daily living, including nutrition, the use of ethanol (alcohol), exercise, return to work, sexual activity, pregnancy, and travel; complications, including headache, hypertension, renal dysfunction, allograft rejection, biliary disorders, opportunistic infection, recurrent disease, and bone disease; and the need for retransplantation. 3 tables. 54 references. (AA-M). •

Hepatitis C and Liver Transplantation Source: Journal of Gastroenterology and Hepatology. 10(4): 471-480. July-August 1995. Summary: In this article, the authors review the interrelationship between hepatitis C virus (HCV) and liver transplantation. HCV is important to the liver transplant recipient for several reasons: chronic HCV infection is a frequent cause of end-stage liver disease; recurrence of HCV after liver transplantation is almost universal; HCV infection in the organ donor or in blood transfusions make acquisition of HCV possible; and liver transplantation for chronic HCV infection represents a major financial burden. The authors discuss the prevalence of hepatitis C in patients undergoing liver transplantation; the natural history of HCV infection following liver transplantation; pathology and pathogenesis; and treatment options. They note that factors that determine why some patients are more susceptible to liver damage than others are currently under study. 4 figures. 1 table. 61 references. (AA-M).

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New Aspects of Heterotopic Liver Transplantation Source: Transplant International. 5(1): 43-50. 1992. Summary: In this article, the history and clinical results of heterotopic liver transplantation (HLT) are reviewed and some special aspects of current research on HLT are highlighted. After a brief review of the history of HLT, the authors discuss aspects of HLT, including the absence of intraoperative fibrinolysis, the stability of hemodynamic parameters during the HLT procedure, the effect of HLT on portal pressure and hypersplenism, the interaction between the two livers in situ, the role of portal blood flow in HLT, the temporary support given by the heterotopic graft in acute liver failure, and the possible role of HLT in inborn errors of hepatic metabolism. 4 figures. 3 tables. 67 references.

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Pediatric Liver Transplantation: Part II: Managing the Long-Term Complications Source: Gastroenterology Nursing. 13(1): 44-53. Summer 1990. Summary: Increasing numbers of children are receiving liver transplants at major centers and returning to their home hospitals for long-term follow-up. This article summarizes the recognition and management of long-term complications in pediatric liver transplant recipients. Emphasis is placed on an understanding of the practical aspects of the pharmacokinetics and toxicity of cyclosporine, the major immunosuppressive drug used in these patients. Common infectious problems, particularly serious viral infections, are reviewed with their unique clinical presentations in this immunocompromised population. Therapeutic alternatives for episodes of acute rejection are offered to facilitate communication with the transplant center and familiarize the local pediatric gastroenterologist and his or her staff with the management issues facing those who take care of these complex patients. 55 references. (AA-M).

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Disease Recurrence After Liver Transplantation: Need We Worry? (editorial) Source: Journal of Gastroenterology and Hepatology. 17(7): 733-736. July 2002. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: It has long been recognized that in patients transplanted for hepatitis B or C related liver disease, recurrence of hepatitis infection in the graft is common and that this may result in serious and progressive liver injury. There are now varying levels of evidence to suggest that most other forms of chronic liver disease also have the potential to recur in the graft. This editorial stresses that it is important for those involved in the care of liver transplant recipients to recognize the possibility of disease recurrence, so that patients may be adequately counseled, liver biochemistry, radiology and histology correctly interpreted, and to ensure that appropriate therapy is instituted. The authors briefly report on recent studies in this area. The authors conclude that is it likely that as the overall results of liver transplantation continue to improve, recurrence of diseases such as primary sclerosing cholangitis, autoimmune hepatitis, and hepatitis C disease will become increasingly recognized as a major cause of late morbidity and mortality. In contrast, the problems of recurrence of hepatitis B and hepatocellular cancer have now largely been overcome, resulting in an increased demand for transplantation for these indications, at a time when overall organ donor rates are falling. This has major implications for both patient selection and donor organ allocation.

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Prophylactic Use of OKT3 in Liver Transplantation: A Review Source: Digestive Diseases and Sciences. 36(10): 1427-1430. October 1991. Summary: Liver rejection in the era of cyclosporine-based immunosuppression is approximately 60-70 percent. About 15-25 percent of liver transplant patients will require hemodialysis following transplantation. These facts argue for a potent, less nephrotoxic immunosuppressive regimen. This review article examines the potential benefits and pitfalls of a prophylactic regimen of OKT3 (orthoclone) as a means to decrease the need for hemodialysis while maintaining potent immunosuppression. The authors stress that a lack of documentation of long-term patient and graft survival, the potential susceptibility to infectious complications, development of sensitization, and cost factors must be weighed against the decreased need for hemodialysis and the control of early rejection episodes. 22 references. (AA).

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Review: Hepatitis B and Liver Transplantation Source: Journal of Gastroenterology and Hepatology. 13(3): 217-223. March 1997. Contact: Available from Blackwell Science Pty Ltd. P.O. Box 378, Carlton, Victoria 3053, Australia. Phone: 61 3 9347 0300; Fax: 61 3 9347 5001; Web site: http://www.blacksci.co.uk. Summary: Liver transplantation in hepatitis B virus (HBV) infected patients is very commonly followed by recurrence of infection in the transplanted liver. This review article focuses on new strategies for the prevention and treatment of disease recurrence after transplantation. Most recipients with HBV recurrence will develop chronic hepatitis that follows a more aggressive course than is seen in nonimmunocompromised subjects; this frequently results in graft failure. The presence of hepatitis B e antigen or significant levels of HBV-DNA in the serum is highly predictive of recurrence and this has led to the view that patients, whose serum is positive for these conventional markers

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of replication, should be excluded from transplantation. The key to improving the results of transplantation in patients with HBV infection lies in the development of effective strategies to prevent reinfection. High dose anti-HBs immunoglobulin is effective in patients who are coinfected with hepatitis D, those transplanted for fulminant hepatitis, and cirrhotic patients who have very low levels of viral replication prior to transplantation. Unfortunately, immunoprophylaxis does not seem to influence the outcome in those patients with higher levels of replication. There are several new orally active nucleoside analogues that are potent inhibitors of hepatitis B replication that may be effective for both the prevention and treatment of recurrent disease. The most promising are lamivudine and famciclovir. Both agents have been extensively evaluated in animal models of HBV and have been shown to rapidly suppress viral replication. The author concludes that the initial experience with these agents in liver transplant recipients has been promising and a number of studies are currently under way to determine whether these drugs, used alone or in combination with immunoprophylaxis, are able to prevent recurrence in those patients at highest risk of posttransplant HBV recurrence. 1 table. 59 references. (AA-M). •

Resource Utilization in Liver Transplantation: Effects of Patient Characteristics and Clinical Practice Source: JAMA. Journal of the American Medical Association. 281(15): 1381-1386. April 21, 1999. Summary: Liver transplantation is among the most costly of medical services, yet few studies have addressed the relationship between the resources used for this procedure and specific patient characteristics and clinical practices. This article reports on a study to assess the relationship between pretransplant patient characteristics and clinical practices on the one hand and hospital resource utilization on the other. The prospective cohort included 711 patients who received single organ liver transplants, were at least 16 years old, and had nonfulminant liver disease. The main outcome measure was a standardized resource utilization derived from a database created by matching all services to a single price list. Higher adjusted resource utilization was associated with a donor age of 60 or older; a recipient age of 60 or older; alcoholic liver disease; ChildPugh class C; care in the intensive care unit at time of transplant; death in the hospital; and multiple liver transplants during the index hospitalization. Adjusted length of stay and resource utilization also differed significantly among transplant centers. The authors conclude that clinical, economic, and ethical dilemmas in liver transplantation are highlighted by these findings. Recipients who were older, had alcoholic liver disease, or were severely ill were the most expensive to treat; this suggests that organ allocation criteria may affect transplant costs. Clinical practices and resource utilization varied considerably among transplant centers. The authors note that methods to reduce variation in practice patterns, such as clinical guidelines, might lower costs while maintaining quality of care. 1 figure. 2 tables. 29 references.

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Liver Transplantation for Viral Hepatitis: Current Status Source: American Journal of Gastroenterology. 87(4): 409-418. April 1992. Summary: Liver transplantation is now considered a definitive therapy for end-stage liver disease and has been playing an increasingly important role in the management of fulminant hepatic failure. This article reviews the current status of liver transplantation used for this indication. The authors note that, with the advent of effective immunosuppression and improved surgical techniques, high survival rates can be expected for most transplanted patients. It has become apparent, however, that

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transplantation for patients with viral hepatitis is associated with some unique problems because of the propensity for viral reinfection of the grafted liver. Patients with actively replicating hepatitis B viral infection before transplantation appear to be the most likely to experience clinically significant recurrent hepatitis after transplantation. Recurrent hepatitis D (delta) and hepatitis C appear to be relatively less serious in the transplanted liver. Interventions to prevent or treat this graft reinfection have thus far met with limited success. The authors call for further studies to define more precisely which patients with viral hepatitis are likely to do poorly after liver transplantation, and to develop strategies to treating recurring hepatitis in transplant recipients. 3 tables. 57 references. (AA-M). •

Liver Transplantation: What the Non-Hepatologist Should Know Source: Practical Gastroenterology. 25(4): 42, 47-48, 50, 52, 54, 56-58, 60, 62, 64, 66. April 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: Over the last two decades, liver transplantation (LT) has been transformed from an experimental procedure with uncertain outcome to a safe and reliable treatment for hepatic failure that has dramatically changed the natural history of liver diseases. This article familiarizes health care providers (who are not liver specialists) with the present indications for liver transplantation and care of patients undergoing this procedure. More than 3,000 LTs are performed each year in the United States; the number is limited only by the shortage of donor organs. The 5 year survival rate after LT is up to 80 percent in the most successful centers and LT is the only reasonable option for individuals with end stage liver disease. However, because of the reduced number of available organs and the long waiting times on transplant lists, the selection and timing of patient referral to a transplant center is crucial. Equally important is the long term medical followup of individuals with liver transplants. The goals should be to prevent and to recognize at the earliest opportunity any complications that can be managed appropriately. For all this to occur, all the medical personnel involved in the care of an individual with liver disease must be familiar with the option of LT as well as with the pathophysiology of liver failure, its clinical recognition and management. The authors conclude with a discussion of the side effects of immunosuppression, noting that these adverse drug events are common medical problems in allograft recipients. These complications include hypertension (high blood pressure), diabetes mellitus, renal dysfunction (kidney failure), infection (usually by an opportunistic organism), and new onset neoplasia, including cancer. 2 figures. 10 tables. 30 references.

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Nutrition Support for Liver Transplant Patients Source: Nutrition and the M.D. 17(3): 3-4. March 1991. Summary: Patients facing liver transplantation are often in a poor nutritional state. Hepatic failure causes fluid and sodium retention, may be associated with protein intolerance, and usually causes poor appetite. This article reports on a recent study that investigated the effects of nutrition support for at least a week after liver transplantation in 28 hypoalbuminemic cirrhotic patients. The patients were randomly assigned to one of three postoperative regimens: no nutritional support, other than isotonic intravenous glucose solutions; a standard total parenteral nutrition (TPN) formula; or an isocaloric, isonitrogenous TPN formula enriched with branched-chain amino acids. Both TPN groups were weaned from respirators more rapidly, and thus left the intensive care unit

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earlier. The researchers concluded that specialized branched-chain formula may not be necessary to achieve benefits from TPN in liver transplant patients. •

Features of Recurrent Primary Sclerosing Cholangitis in Two Consecutive Liver Allografts After Liver Transplantation Source: Journal of Clinical Gastroenterology. 32(2): 151-154. February 2001. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: Primary sclerosing cholangitis (PSC) is a disease of unknown etiology (cause) that is characterized by inflammation and fibrosis (scarring) of the biliary tree, which results in stricture formation and, eventually, in liver failure. Recurrence of PSC after liver transplantation is very uncommon. The true incidence of recurrence is unknown, mainly because of the difficulty in differentiating ischemic strictures from that of recurrent disease. PSC and ischemic strictures have identical histopathologic and cholangiographic (a type of diagnostic test) features. In this article, the authors report the case of a young man who had recurrence of PSC in two allografts (transplants) and also report their experience with 32 patients who had liver transplantation for PSC. Six patients (18 percent) had evidence of non anastomotic strictures and, of these, only one patient (reported here) had unequivocal evidence of true recurrence. The strictures in the other five patients happened because of ischemia (lack of blood flow to the organ involved). The authors conclude that the recurrence of the disease in two allografts in an immunosuppressed patient (taking drugs to avoid rejection of the transplant), in the absence of ischemia, chronic rejection, or any known pathogen, raises the question of the role of an unidentified infectious agent in the cause of PSC. 2 figures. 2 tables. 14 references.

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Should Alcoholics Compete Equally for Liver Transplantation? Source: JAMA. Journal of the American Medical Association. 265(10): 1295-1298. March 13, 1991. Summary: The circumstances of liver transplantation are unique among organ transplantation because of the scarcity of donor livers and the predominance of one disease, alcohol-related end-stage liver disease, as the principal cause of liver failure. The authors of this article propose that patients who develop end-stage liver disease through no fault of their own should have higher priority for receiving a liver transplant than those whose end-stage liver disease results from failure to obtain treatment for alcoholism. This proposal is based on considerations of fairness, and on whether public support for liver transplantation can be maintained if patients with alcohol-related end-stage liver disease receive more than half the available donor livers. The authors conclude that since not all can live, priorities must be established for the use of scarce health care resources. 43 references. (AA).

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NIDDK Liver Transplantation Database Source: Liver Transplantation and Surgery. 3(1): 10-22. January 1997. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Summary: The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database was established to prospectively investigate questions related to the experience of patients evaluated for and undergoing liver

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transplantation. This article presents the study design, methods, and quality of data collection, along with some of the overall results. An initial 4 year planning phase was used to develop data collection instruments and quality control procedures for assessing transplantation, liver donors, and the recipients course before and after surgery. During the 1990-1995 implementation phase, three clinical centers refined the data collection instruments and enrolled and followed consecutive liver transplant candidates who agreed to be included in the protocol. The database contains more than 49,000 data forms from 1,563 candidates, 1,002 donors, and 916 transplant recipients followed up to 5 years after transplantation. Overall, 95 percent of protocol forms were completed. The database includes uniformly defined histology results of liver biopsies performed per protocol or for complications throughout followup. In addition, the database maintains an inventory of available sera for the serum bank. All test results of studies performed on the sera are added to the database. Of the 1,563 patients evaluated, 59 percent were deemed eligible for liver transplantation. Of the others who were too well or had contraindications, 15 percent became eligible later. Characteristics of patients in this study were generally comparable to those of patients nationally. The authors conclude that the NIDDK Liver Transplantation Database has yielded comprehensive, high quality data and is a rich resource for extensive analysis about many important clinical aspects of liver transplantation. 5 figures. 2 tables. 10 references. (AA). •

Survey of Liver Transplantation from Living Adult Donors in the United States Source: New England Journal of Medicine. NEJM. 348(9): 818-825. February 27, 2003. Summary: The transplantation of the right lobe of a liver from a living adult donor into an adult recipient has been performed increasingly frequently in the United States. Although the use of grafts from living donors is standard practice in transplantation in children, their use in adults remains controversial. This article reports on a study that used a 24 item questionnaire, sent to all liver transplantation programs in the U.S., to collect data on the indications, evaluation, and outcomes of the use of liver transplantation from a living donor. Questionnaires were returned by 84 of the 122 programs (69 percent) describing the results of 449 adult-to-adult transplantations of partial livers from living donors that were performed in 42 centers. A total of 45 percent of potential donors who were evaluated eventually donated a lobe of their liver; 99 percent of these donors were genetically or emotionally related to the recipient. Complications in the donor were more frequent in the centers performing the fewest transplantations from living donors in adults and included biliary complications requiring intervention (6.0 percent), reoperation (4.5 percent), and death (in one donor). Among the recipients, 1.6 percent did not meet criteria for receipt of a cadaveric transplant; cancer, retransplantation, and acute liver failure were uncommon indications for transplantation from a living donor. Biliary complications occurred in 22.0 percent of recipient, and vascular complications occurred in 9.8 percent. The authors conclude that adult-to-adult liver transplantation from a living donor is increasingly performed in the United States but is concentrated in a few large-volume centers. Mortality among donors is low, but complications in the donor are relatively common. 2 figures. 3 tables. 26 references.

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Oral Management of the Patient with End-Stage Liver Disease and the Liver Transplant Patient Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 86(1): 55-64. July 1998.

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Contact: Available from Mosby, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-3318. (800) 453-4351 or (314) 453-4351. Summary: This article addresses the oral management of the patient with end stage liver disease and the liver transplant patient. The authors emphasize that the patient with end stage liver disease, who is in need of a liver transplant, should have a pretransplant dental evaluation. Such a patient faces lifelong immunosuppression with an increased risk of infection. The article discusses both the need for control of oral diseases before liver transplantation and guidelines for oral care in the immediately postoperative and long term transplant patient. Specific indications for antibiotic prophylaxis and antibiotic regimens are presented; in addition, the adverse reactions and side effects of immunosuppressant drugs are discussed. The authors review pertinent drug interactions related to the dental management of patients with end stage liver disease, and present specific management recommendations. Specific drugs covered include cyclosporine, FK 506, prednisone, monoclonal antibody (OKT3), azathioprine, antilymphocyte globulin (ATG), morphine, codeine, nonsteroidal antiinflammatory drugs (NSAIDs), sedatives and anxiolytic drugs, local anesthetics, barbiturates, and propofol. 5 tables. 95 references. (AA-M). •

Dialysis in Liver Failure and Liver Transplantation Source: Transplantation Proceedings. 25(2): 1740. April 1993. Summary: This article briefly reports on a study designed to define the long-term survival of liver transplant candidates and recipients who also require dialysis and to determine the factors important in predicting outcome. From May 1988 to June 1989, 141 patients with liver failure or liver transplant recipients required hemodialysis at the University of Pittsburgh. Eighty-eight patients received liver transplants; of these, 3 were dialyzed before transplantation, 7 were receiving dialysis at the time of transplantation, and 78 were dialyzed after transplantation. Actuarial patient survival was 51 percent after 18 months in the transplanted group. The authors summarize that acute renal failure after liver transplantation typically occurs in the setting of multiorgan failure and is associated with high mortality rates. They note that the leading cause of renal failure was ischemic acute tubular necrosis and not hepatorenal syndrome or nephrotoxic immunosuppressants. 5 references.

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Dental Treatment of a Prospective Recipient of a Liver Transplant: A Case Report Source: Journal of Clinical Pediatric Dentistry. 23(1): 75-78. 1998. Contact: Available from Journal of Clinical Pediatric Dentistry. P.O. Box 830259, Birmingham, AL 35283-0259. (800) 633-4931 or (205) 991-1177. Fax (205) 995-1588. Website: www.pediatricdentistry.com. Summary: This article describes a protocol to treat a carious (dental cavities) condition in a young girl scheduled to receive a liver transplantation. The child's teeth with serious caries were filled with amalgam. Those teeth with pulp exposure were extracted. To stop bleeding, sutures and a surgical splint with a periodontal pack were used. All procedures were performed as rapidly as possible to minimize stress. Antibiotics were used sparingly. The major goal of dental intervention, before and after liver transplantation, is the prevention of bacteremia from an oral source that could lead to systemic infection. The authors conclude that by improving the oral health of transplant recipients, the chances that the transplanted liver will become infected are much reduced, increasing the likelihood of a successful surgical outcome for the transplant. The child described in the case received her liver transplant more than two years ago,

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maintained effective oral hygiene procedures, and is still alive and well. 5 figures. 14 references. •

Hepatitis B Infection and Liver Transplantation Source: Canadian Journal of Gastroenterology. 11(5): 462-468. July-August 1997. Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Summary: This article discusses liver transplantation in patients with hepatitis B. Patients with chronic hepatitis B virus (HBV) infection have historically high rates of allograft reinfection from extrahepatic (outside the liver) reservoirs of HBV, with worse long term outcome compared with that of transplant recipients without HBV infection. As a result, chronic HBV infection has been considered a contraindication for transplantation. However, prophylaxis against HBV recurrence, in the form of passive immunization with high dose hepatitis B hyperimmunoglobulin and the antiviral agent lamivudine, has recently been demonstrated to decrease the risk of reinfection. The author summarizes past experience and current status of HBV infection and transplantation, with emphasis on the issues surrounding prophylaxis. The author concludes that with appropriate prophylaxis, liver transplantation can be a viable proposition for patients with HBV infection. The main obstacles to high dose HBIG prophylaxis are the continued availability of the product, practicality of administration, and the cost and long term duration of treatment. 2 tables. 60 references. (AA-M).

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Dental Treatment of the Liver Transplant Patient Source: Oral Surgery, Oral Medicine, Oral Pathology. 73(4): 419-426. April 1992. Summary: This article first reviews the history and current status of human liver transplantation. The authors present the complications and side effects of the agents used for immunosuppression. The dental treatment of patients before and after liver transplantation is discussed in detail. 8 tables. 22 references. (AA-M).

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Review of Liver Transplantation for the Dentist and Guidelines for Dental Management Source: SCD. Special Care in Dentistry. 13(2): 74-80. March-April 1993. Summary: This article provides a review of liver transplantation for the dentist. The authors present information on the indications for liver transplant, the selection process, the surgery itself, and the mechanism and implications of immunosuppression. In addition, the authors discuss dental considerations and present protocols for the dental management of patients pre-and posttransplantation. They note that the major goal of dental intervention, before and after liver transplantation, is the prevention of bacteremia from an oral source that could lead to systemic infection. In addition, pretransplant medical conditions of concern to the dentist include poor drug metabolism, bleeding disorders, poor wound healing, and an inability to metabolize swallowed blood. Post-transplant dental treatment must take into consideration immunosuppressive drugs and the potential for infections. 6 tables. 39 references. (AAM).

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Outcomes Following Liver Transplantation for Patients with Alcohol-Versus Nonalcohol-Induced Liver Disease Source: Canadian Journal of Gastroenterology. 14(10): 851-855. November 2000.

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Contact: Available from Pulsus Group, Inc. 2902 South Sheridan Way, Oakville, Ontario, Canada L6J 7L6. Fax (905) 829-4799. E-mail: [email protected]. Summary: This article reports on a study undertaken to document and compare the outcomes of adult patients who received liver transplants for alcohol and nonalcohol induced liver diseases. These patients also attended a liver transplantation followup clinic in an urban, nontransplantation center at a time when no formal alcohol abuse program for transplant candidates or recipients was offered. The study population included 10 alcoholic patients and 48 nonalcoholic patients followed for an average of 41 months (range 5 to 79 months) and 46 months (range 2 to 116 months), respectively. Primary outcome variables included rates of recidivism (going back to drinking), duration of abstinence after transplantation, and compliance with posttransplant medical followup visits. Secondary outcome variables included time to discharge after transplantation, episodes of graft rejection, liver and renal biochemical abnormalities, diabetes, hypertension, sepsis, strictures, complications unrelated to transplantation, and changes in psychosocial status. Significant differences were found with respect to a higher incidence of recidivism (50 percent for alcoholic patients compared with 2 percent for nonalcoholic patients), a shorter period of abstinence after transplantation (mean of 14.7 months for alcoholic patients compared with a mean of 26.3 months for nonalcoholic patients), and more missed office visits (2.7 for alcoholic patients compared with 1.0 for nonalcoholic patients) in the alcoholic group. The alcoholic group also had a lower incidence of rejection episodes, but higher rates of posttransplantation diabetes, more nontrasplantation related complications, and higher serum creatinine but lower bilirubin and cyclosporine A levels. Marital separations were also more common in the alcoholic group. The authors conclude that, in the absence of formal alcohol abuse programs, the posttransplantation outcome in alcoholic patients generally does not compare well with that of patients who undergo transplantation for nonalcoholic related liver diseases. 3 tables. 13 references. •

Current Concepts in Pediatric Liver Transplant Source: Seminars in Liver Disease. 18(3): 295-307. 1998. Contact: Available from Thieme Medical Publishers, Inc. 333 Seventh Avenue, New York, NY 10001. (212) 760-0888. Fax (212) 947-1112. Website: www.thieme.com. Summary: This article reviews orthotopic liver transplantation, a procedure that has significantly improved the survival rate of children with end stage liver disease. Efforts to correct abnormalities existing prior to transplantation, coupled with improved surgical techniques and immunosuppression have led to better quality of life and 1 year survival rates approaching 90 percent in many centers. Despite this success, the expanding waiting list has driven the development of surgical techniques to expand the donor pool. Building on the success of reduced size transplantation, split liver and living donor transplantation are now suitable alternatives, especially when used in candidates with satisfactory clinical stability. In the postoperative period, infectious complications represent an important cause of morbidity and mortality. Although antimicrobial regimens are effective in the immediate postoperative phase, acquisition of viral infections represents a major concern, particularly in the young liver recipient. Early detection and development of new antiviral agents are likely to decrease occurrence of posttransplant proliferative disorders and optimize long term outcomes. 4 figures. 6 tables. 70 references. (AA).

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Liver Transplantation: Current Status and Novel Approaches to Liver Replacement Source: Gastroenterology. 120(3): 749-762. February 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: This article reviews the current status and novel approaches to liver replacement. The author contends that the major challenge currently facing liver transplantation is the performance of a greater number of liver transplants, which has been fueled by the large and growing disparity between the increasing number of qualified patients listed for transplantation and the relatively static number of available cadaver donor organs. In the past 2 years, approximately 4,500 liver transplants have been performed annually, with 1 year survival rates in the 85 to 90 percent range, while the waiting list has expanded as of November 2000 to more than 16,000 patients, resulting in an increasing death rate among listed patients. In the short term, there will continue to be a major focus on more effective use of available cadaver donor organs to balance the competing principles of justice (patients with most urgent need for transplant and lower probability of posttransplant survival) and medical utility (patients with less urgent need for transplant and higher odds of postoperative survival). Over the long term, there will be an increasing application of novel approaches to liver replacement including cadaver split liver transplantation and adult living donor liver transplantation and possibly, in the more distant future, xenotransplantation (using organs from other mammals) and hepatocyte transplantation. The treatment, and ideally the prevention, of recurrent disease after liver transplantation, notably chronic hepatitis C, is a major priority to optimize the use of liver grafts. Finally, improved immunosuppressive strategies, including movement toward minimal immunosuppression and steroid withdrawal and the development of safer and more effective drugs, is another important factor that has the potential to increase the success of liver transplantation. 2 figures. 11 tables. 104 references.

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Nutrition Considerations in Liver Transplantation Source: Topics in Clinical Nutrition. 7(3): 24-33. June 1992. Summary: This article reviews the nutritional considerations in liver transplantation. Topics include the types of liver disease that may require transplantation as a therapeutic option; nutrition assessment of the orthotopic liver transplant (OLT) patient; short-term posttransplant nutrition problems and requirements; and long-term nutrition treatment, problems, and needs. The article concludes with a detailed case study of a patient that illustrates the difficult nutrition needs of an OLT patient and an unusual complication (Stevens-Johnson syndrome).

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Alcoholics and Liver Transplantation Source: JAMA. Journal of the American Medical Association. 265(10): 1299-1301. March 13, 1991. Summary: Two arguments underlie a widespread unwillingness to consider patients with alcoholic cirrhosis of the liver as candidates for transplantation. First, alcoholics are considered by some to be morally blameworthy and their condition is believed to be the result of their own misconduct; this disqualifies alcoholics in unavoidable competition for organs with others who are equally sick but blameless. Second, because of their habits, it is believed that alcoholics will not exhibit satisfactory rates of survival after transplantation; good stewardship of a scarce lifesaving resource therefore requires that

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alcoholics not be considered for liver transplantation. This article carefully analyzes these arguments and proves them to be defective. The authors conclude that there is not good moral or medical reason for categorically precluding alcoholics as candidates for liver transplantation. 19 references. (AA-M).

Federally Funded Research on Liver Transplant The U.S. Government supports a variety of research studies relating to liver transplant. 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 liver transplant. 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 liver transplant. The following is typical of the type of information found when searching the CRISP database for liver transplant: •

Project Title: A GENERALIZED MODEL FOR POST-TRANSPLANT SURVIVAL Principal Investigator & Institution: Chang, Chung-Chou H.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) The applicant's long-term career goal is to become an independent investigator in analytical methodologies for clinical and health services research. She will dedicate her career to conducting quantitative studies and promoting the proper use of analytical methodologies in these research areas. This career development award will provide her with initial support for achieving her career goals. There are three goals for her career development over the next five years. First, she will develop a general survival regression model that is more encompassing than any of the semi-parametric regression models currently used in the analysis of liver transplantation data. The proposed research will result in less restrictive assumptions and provide a systematic way of constructing survival models in liver transplantation studies. The products of the research include a new model that can be used to provide estimates on post-transplant survival, which in turn can be used to estimate the optimal timing for liver transplantation. Her second objective is to develop expertise in clinical applications of survival analysis for patient-oriented research. The third goal is to become an educator to clinical researchers in analytical methodologies. While many other questions are also important in the area of transplantation (such as which organ allocation method is optimal and what is the appropriate time to list a patient for transplant), many of the clinically related questions require accurate and clinically relevant predictions of survival. The proposed research will focus on: Aim 1:

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

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Development of a general survival regression model. Aim 2: Development of diagnostic procedures for the general survival regression model. Aim 3: Assessment of the impact of different survival models on the prognosis in liver transplantation. The proposed general survival model that reduces to both the additive and multiplicative model as special cases. Moreover, the covariate effect on hazard in this model can be either constant or time-varying. Estimation of the model parameters will through the penalized log-partial likelihood with double penalty terms. Inference on the effect of any given covariate will also be assessed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACCESS OF BLACK PATIENTS TO LIVER TRANSPLANTATION Principal Investigator & Institution: Reid, Andrea E.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 29-SEP-2005 Summary: (adapted from the application) Orthotopic liver transplantation is the treatment of choice for selected patients with end-stage liver disease (ESLD). Unfortunately, liver allografts are a scarce resource. The disparity between the supply and demand for donor livers creates a potential for bias in the selection of organ recipients and the allocation of available organs. There is evidence that liver transplants are less available to blacks that to whites, despite a higher burden of ESLD, and higher rates of death from ESLD among blacks. Several small studies have suggested that barriers do exist for black patients with ESLD, but these barriers have not been defined. The overall goal of this grant is to determine what and where the barriers to transplantation are for black patients with ESLD. We will examine two components of the pre-transplant process in this study. We will focus on the referral process from the physician to the transplant center, and on patient perceptions of liver transplantation and the transplantation process. The specific aims of our study are: 1) To compare the referral rates for liver transplant evaluation and the overall clinical outcome in black and white patients with ESLD who were treated at three urban hospitals in Boston between 1994 and 1998, and 2) To determine if there are racial differences in knowledge and preferences about liver transplantation among patients with chronic liver disease. We will perform a retrospective cohort study of black and white patients with ESLD to determine if there are different rates of referral for liver transplant based on race. We will examine the clinical, financial, social, socioeconomic, and demographic factors that influence the rates of referral for liver transplant evaluation for these populations. We will also test the hypothesis that patient knowledge, attitudes and preferences about liver transplantation vary according to race and may influence the willingness of patients with ESLD to accept a liver transplant. To accomplish this, we will conduct a survey of a racially diverse group of patients with chronic liver disease. We will develop an appropriate instrument during the course of this grant, validate and pre-test it, then administer it to our study cohort. Advanced-level coursework in clinical epidemiology, biostatistics, survey development, and outcomes will also be a critical element of this project. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADLDT: AN OPPORTUNITY TO EXPAND THE NATIONAL DONOR POOL Principal Investigator & Institution: Busuttil, Ronald W.; Surgery; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024

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Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant):The overall objective of this proposal is to establish a Clinical Research Consortium to define the outcomes of ALDLT. We propose the following specific aims to fully evaluate the impact of ALDLT: 1. Core Study: Establish a Donor and Recipient Core Information Database for Adult LDLT and Non-ALDLT Patients Hypothesis: ALDLT short-term survival outcomes, but not complication rates, are equivalent to whole cadaveric and SLT transplantation. We and others, achieved excellent short-tem survival outcomes of ALDLT, despite a high rate of recipient complications, in non-urgent patients. To fully evaluate the benefits of ALDLT, the technique will be applied to both urgent and non-urgent recipients, and compare its outcomes to three sets of patient cohorts that include: a) whole organ recipients, b) cadaveric SLT recipients, and c) candidates who ultimately do not receive a transplant. The living donor section will compare living donors and potential donors who do not undergo donation. Primary endpoints define survival outcomes and complication rates in donors and recipients at 1, 2 and 3 years posttransplantation. This will elucidate the efficacy of ALDLT as compared to whole cadaveric, SLT, and control (untransplanted) patients in the entire spectrum of recipients' status, and determine if ALDLT is justified when compared to the natural history of non-transplanted non-urgent controls. Secondary endpoints assess the impact of technical variations on postoperative recovery, liver regeneration postdonation, impact of living donation on the cadaveric donor pool, and defines donor exclusion criteria.2. Clinical Research Protocol for Recipient Outcome: Determine the impact of ALDLT on Posttransplant HCV Recurrence in Transplant Recipients Hypothesis: ALDLT may be accompanied by accelerated recurrence of HCV versus whole cadaveric liver transplantation. Rapid and severe HCV recurrence observed, at our center, in ALDLT recipients compared to whole organ transplant patients, may offset the benefits of early transplantation with living donors. This protocol compares the time to histological recurrence of HCV in ALDLT and whole organ graft recipients at 6 months, 1, 2, and 3 years posttransplantation. The effects on patient and graft survival and the correlation between the degree of histological disease and HCV RNA levels are investigated by our secondary endpoints.3. Clinical Research Protocol for Donor Outcome: Determine Health-Related Quality of Life Outcomes and Resource Utilization of Adult Living Donation Hypothesis: HRQL of living donors is impacted in the short-, but not, the long-term and the HRQL of ALDLT recipients may be enhanced following ALDLT. HRQL in both donors and recipients will be compared before ALDLT and at 6 and 12 months posttransplantation through generic and diseasespecific instruments. Additionally, health utility index assessments and evaluation of health care resource utilization will be conducted. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT LIVE DONOR LIVER TRANSPLANT-A COMPARATIVE ANALYSIS Principal Investigator & Institution: Abecassis, Michael; Associate Professor of Surgery; Surgery; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant):The shortage of available cadaver organs has prompted the transplant community to consider living donor liver transplantation (LDLT) as an effective alternative to cadaveric liver transplantation (CLT). The potential limitations of LDLT consist primarily of 1) the potential risk to an otherwise healthy donor, and 2) the uncertainty regarding graft and patient outcomes for LDLT as compared to CLT. The core project of this proposal will compare outcomes for recipients

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of LDLT to those of CLT, while addressing the potential complications to living donors. In addition, we propose to analyze two separate issues. First, we will evaluate donor hepatic steatosis in both LDLT and CLT. We will compare novel non-invasive measurements of steatosis in living donors with the current gold standard, a liver biopsy. We will compare the results of transplanting steatotic livers from living and cadaveric donors, assessing graft and patient outcomes in both groups. We will also evaluate the role of hepatic steatosis on liver regeneration in both the living donor and recipient. We hypothesize that outcome of transplantation in steatotic livers of LDLT is superior to results obtained in steatotic CLT recipients. This first aim will help design a decision algorithm for the use of steatotic livers in both CLT and LDLT while validating non-invasive measurements of hepatic steatosis. Second, we propose to address the potential role for LDLT in the multimodal management of hepatocellular carcinoma (HCC). Given the lack of randomized trials and large case series, this issue has been recently addressed in studies utilizing decision-modeling analysis. This second aim will provide clinical data to validate these studies, and will compare CLT, with its inherent waiting times, to LDLT, a strategy that theoretically eliminates waiting times. We hypothesize that the outcome of transplantation of HCC in LDLT is superior to results obtained with CLT. In the aggregate, these studies will define the efficacy of LDLT in the US, while a focus on both a donor issue (hepatic steatosis) and a recipient issue (the special problem of HCC) will help delineate the potential advantages of LDLT over CLT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT TO ADULT LDLT COHORT STUDY Principal Investigator & Institution: Shaked, Abraham; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant):The aim of this proposal is to demonstrate that the group of physicians and scientists at the Liver Transplant Program of the University of Pennsylvania has the interest, infrastructure and resources to participate in the Living Donor Liver Transplantation (LDLT) Cohort Study among adults awaiting transplantation. Progress in the care of patients suffering from end stage liver disease has been hampered by the limited availability of donor organs for transplantation. Adult to adult LDLT is expected to significantly expand the donor pool and provide numerous organs to be transplanted into designated recipients. The initial results are encouraging, however, there are many questions related to donor and recipient outcomes and whether better management of these patients can improve these results.A prospective mutli-center study of LDLT in the adult setting is expected to: 1. Collect and analyze data that will assist in the establishment of reliable criteria for donor selection, examine operative techniques that are associated with the best short and long term outcomes, and recommend methods for long-term follow up of the donor's physical and psychosocial well being. 2. Determine recipient outcomes when compared to the cadaveric setting and study whether results are affected by preoperative selection and preparation, operative techniques, and the interrelationship between regeneration and immune response. 3. Study the effects of LDLT on clinical practice and socioeconomic issues in transplantation. Success in addressing these problems through a national collaborative network will depend on the scientific and operational performance of the centers involved in the consortium. The Penn Transplant center is committed to participate in these collaborative efforts, and contribute to the research efforts that are aimed at better understanding of medical and surgical issues of LDLT.Our proposal is

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divided into three sections. Section one: A description of the resources and participation of the team of physicians at Penn Transplant Center. Section two: A description and strategy for the development of a comprehensive database. Section three: Two research proposals describing a four year research effort to identify: a. the interrelationship between the regenerative process, graft function, alloimmune response. and b. the biopsychosocial impact of LDLT on donors and recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION Principal Investigator & Institution: Fisher, Robert A.; Surgery; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant):Over the past decade a growing shortage of donated organs has greatly increased the number of patients who have developed complications of end-stage cirrhosis including hepatocellular carcinoma (HCC) and the mortality for patients awaiting liver transplantation (LT). Living donor liver transplantation (LDLT) was conceived as a way to increase the availability of donated organs and was initiated in infants and children more than a decade ago. Controlled trials demonstrated the safety and efficacy of this procedure. Recently, LDLT has been adapted for the adult. Since then patients, their families and the transplant community have embraced this procedure despite reports of donor morbidity, mortality and early reports that recipients may have increased post-operative complications and reduced survival compared to CADLT. The specific aims of the LDLT cohort study is to define the short and long term risks of morbidity and mortality for the adult donor and to determine the efficacy of this procedure for the adult recipient compared to patients undergoing LT with a cadaveric liver (CADLT). Individuals interested in becoming living donors will be asked to participate in this study. Those who are selected and undergo the surgical procedure will be followed at periodic intervals to define the long term morbidity and mortality of the procedure. Individuals not selected as living donors will be matched to the actual donors 2:1 by age, race and gender and also followed prospectively as a donor control group. Individuals being evaluated for LT will be asked if they would be interested in undergoing LDLT. Those patients who identify an acceptable donor and undergo LDLT will be followed prospectively at periodic intervals to define the short and long term morbidity and mortality associated with this procedure. Those patients who are unable to identify a living donor will be matched to an actual LDLT recipient 2:1 by age, race, gender, disease etiology and severity of liver disease (MELD score). These patients will act as the recipient control group and will and be followed prospectively before and after they undergo CADLT. Ancillary studies accompanying the main trial will specifically evaluate the ability of LDLT to improve the long term outcome of patients with HCC and to evaluate the effects of donation and LDLT on hepatic histology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION COHOR* Principal Investigator & Institution: Emond, Jean C.; Surgery; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant): Living donor liver transplantation (LDLT) has been widely accepted for the transplantation of children with excellent results in the recipient,

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and a track record of donor safety that approaches renal donation. In the face of a progressive scarcity of cadaver donors, LDLT has been extended to adults and proliferated rapidly over the last 4 years. This operation requires a more extensive hepatectomy and thus an increased risk to the donor which has not been adequately quantified. The combination of uncertain donor risk and unregulated proliferation has led to cries of alarm in both the scientific literature and the lay press. The current study will provide a structured response to these concerns and an opportunity to address fascinating biological questions inherent to this procedure. Our interest in LDLT spans nearly two decades across a broad range of surgical and medical issues. The liver transplant program in our center was constituted from the outset with the expectation that LDLT would be a significant proportion of our transplants because of the enormous waiting list in New York State. Currently LDLT accounts for nearly 1/3 of adult transplants in our center; we will perform 30 this year with continued anticipated growth in the next 5 years. Our team is broadly constituted and exceptionally capable of addressing a range of issues pertaining to structured health assessment of donor outcomes, medical indications and application of LDLT as well as surgical and biological questions. We have particular strength in epidemiology, virology, and immunology, in addition to transplant hepatology and surgery. While we recognize that a broad range of surgical questions will need to be addressed, we find two issues specific to LDLT related to the central theme of regeneration of the allograft most compelling; first, the pathophysiology and possible treatment of failure of regeneration in the recipient, ie. "small-for-size syndrome", and second, the risk of early and more severe recurrence of hepatitis C in a regenerating liver graft. The central theme of regeneration pervades LDLT, and likely hinges on inflammatory injury. Our collaborative partners, Charles Rice of the New York-Presbyterian Center for the Study of Hepatitis C and Manikkan Suthanthiran in the Transplantation Medicine program position us to test our hypotheses using novel techniques for the assessment of inflammatory cytokines and viral reinfection on the cellular level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION COHORT Principal Investigator & Institution: Freise, Chris; Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant): Cadaveric liver transplantation is recognized as the optimal therapy for end stage liver disease, with marked improvement in results over the last two decades. With the increasing success of this treatment, the demand for suitable donor organs has also risen, resulting in a large discrepancy between the number of transplantable organs and the number of patients waiting. This imbalance has led to the development of living donor liver transplantation (LDLT) as an additional method to increase organ supply. The exact indications for this procedure as well as long-term results and potential impact on the healthy donor are questions that remain unanswered. These issues form the basis for this research protocol, which proposes a longitudinal cohort study of live donor liver transplant recipients and their donors across eight transplant centers with an extended period of follow-up. The aims of this cohort study will be the formation of a core database containing information collected pre-transplant, intraoperatively and post-transplant. At least 250 living liver donor/recipient pairs and an equal or greater number of cadaveric recipients will be followed for a minimum of two years to provide critically needed information on the

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safety and efficacy of living donor liver transplantation, the potential impact on disease progression and recurrence, and ultimately to better define the specific role of living donor liver transplantation in the management of end stage liver disease.In addition to core data collection, this cohort study will offer an opportunity to address specific research questions unique to the setting of LDLT. The first project focuses on patients with hepatitis C, the most common indication for transplantation in the U.S. The kinetics of recurrent hepatitis C viral load post-transplantation will be compared in living donor and matched cadaveric recipients, and the effect of pre-transplant interferon treatment on the tempo and severity of recurrence evaluated. The second project focuses on optimization of pain control in living donors, comparing the use of preemptive thoracic epidural catheter analgesia delivery with patient controlled intravenous analgesia, and using pain scores and quality of life instruments to evaluate the impact of these treatments on long and short-term outcomes.We anticipate that the study will provide the necessary information to aid physicians in the counseling of patients regarding transplant options, and help prospective donors and recipients to better understand the risks and benefits of the procedure. Additionally, the information gained through this cohort study can be expected to impact the entire living donor transplantation procedure itself, by identifying factors that can be modified pre-transplantation, intraoperativiely, and post-transplantation to improve donor and recipient outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL, INOS UPREGULATION, LEAKY GUT & LIVER DISEASE Principal Investigator & Institution: Keshavarzian, Ali; Professor of Pharmacology & Molecular Bi; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): Clinically significant alcoholic (A) liver damage (LD), secondary to a hepatic necroinflammatory cascade (HNIC), occurs only in a subset of alcoholics. Hence, factors other than ethanol (E) must be involved. Hypothesis: The key cofactor for ALD is a breakdown of gut barrier integrity ("leaky gut") due to chronic E use, which allows intestinal endotoxin to reach the liver & initiate a HNIC; this leakiness is due to cytoskeletal instability caused by oxidation of cytoskeletal proteins which is elicited by E-induced gut iNOS upregulation & nitric oxide (NO) overproduction. We found: 1} in man, gut leakiness in alcoholics with LD but not in those without LD or in nonalcoholics with LD; 2} in rats, E-induced leaky gut is associated with LD; reversal of gut leakiness attenuates LD; 3} in intestinal monolayers, E-induced iNOS upregulation causes cytoskeletal & barrier disruption. We will continue to use this successful translational approach (monolayers, rats & man) to test our current hypotheses. Aims: (1) To see if, in a larger sample, a leaky gut: a) occurs only in alcoholics with LD & precedes cirrhosis b) persists during abstinence & after liver transplant for ALD, c) correlates quantitatively with LD severity, d) is associated with NO overproduction & HNIC, e) is more pronounced in females. We predict that gut leakiness (excess urinary lactulose, mannitol & sucralose levels after oral sugar load): i) is seen only in alcoholics with LD, precedes cirrhosis; ii) correlates with severity of LD (clinical parameters, liver enzymes); iii) is associated with NO overproduction (gut mucosal NO), serum endotoxin & HNIC (high neopterin/cytokines). (2) To see if, in rats, prevention of E-induced leaky gut also prevents E-induced LD & if a hyperactive, NO pathway is involved. We predict that in E-fed rats with LD: i) leaky gut, endotoxemia, HNIC, upregulation of intestinal iNOS, NO overproduction & oxidation of actin & tubulin occurs; ii) preventing gut leakiness (by oats, iNOS inhibitors or Arginine) prevents LD. (3) To see, using monolayers of wild type ((inhibitors) &

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transfected cells, if E-induced iNOS upregulation & its consequences (assessed by cytoskeletal oxidation/disarray & barrier disruption) are mediated by NF-kappaB activation. We predict i) E activates NF-kappaB by degrading IkappaBalpha; ii) preventing NF-kappaB activation prevents E-induced iNOS upregulation & its consequences. Significance: Showing that ALD requires a leaky gut, & that NO & cytoskeletal pathways are involved, could 1) identify drinkers at risk for LD (sugar test); 2) lead to therapies to prevent LD in those drinkers unable to abstain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANDIDATES

ALCOHOLISM

TREATMENT

IN

LIVER

TRANSPLANT

Principal Investigator & Institution: Weinrieb, Robert M.; Assistant Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 22-SEP-1999; Project End 31-AUG-2004 Summary: Alcoholism is the most common root cause of end stage liver disease in the United States. By the time cirrhosis with liver failure is diagnosed, there are often no viable alternatives to liver transplantation even for the then-abstinent alcoholic. Liver transplant surgery is costly and donor organs are scarce. Once selected for transplant, patients typically wait two years for an organ and must remain "medically and psychologically stable". Data from our studies indicate that 15 percent of listed alcoholic liver transplant candidates admit drinking - and we believe this may be an underestimate. Further, studies have shown that cirrhotic alcoholics who continue to drink have high rates of mortality. Once listed, alcoholic patients are typically referred off-site for alcohol treatment or to AA meetings. But, our research has shown that greater than 50 percent of alcoholic patients who received liver transplants never attended formal substance abuse treatment or AA. Based on the data from these pilot efforts and from the larger literature on promising therapies for alcohol dependence, we plan to test a modified and expanded version of Motivational Enhancement Therapy (MET) combined with case management techniques (STD-MET), for use in the treatment of alcoholics awaiting liver transplant. We will test this integrated alcohol treatment in a randomized controlled design comparing two samples of 100 listed alcoholic liver transplant patients, each receiving supplemental treatments for their alcoholism over a six month period while listed. Both groups will receive standard referral to AA and community treatment. One group will receive on-site, integrated STD-MET while the second group will receive an equal number of sessions, on-site, viewing alcohol educational videos (STD-VID). Hypotheses: 1.During the pre-transplant "wait list" period - patients receiving STD-MET will show better engagement into the liver transplant regimen, reduced drinking and better general function than patients assigned to (STD-VID). STD-MET group will show: a) greater compliance with appointments and medical regimen - measured by standard measures of attendance, medical status, recall and understanding of their medication regimen, b) more awareness and acceptance of alcohol, smoking and/or other drug problems - measured by the (SOCRATES) stage of change, c) more attendance at standard off-site alcohol treatment programs and AA meetings - measured by standard checks on treatment attendance as well as TSR from subjects and collaterals, d) greater and more lasting reductions in drinking, cigarette and other drug use - measured by urine screens, breathalyzer, self-report and collateral TLFB measures, e) lower levels of depression and anxiety - measured by the BDI, BAI and the ASI psychiatric scale every three months, f) less mortality and morbidity prior to organ transplant - than the STD-VID group. 2. For patients who ultimately receive a liver transplant - STD-MET patients will show better general recovery than patients assigned

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to the alcohol education video series STD-VID. The STD-MET will show: a) fewer complications during during hospitalization measured by standard surgical records, b) better general function at one- month post hospital discharge-measured by standard medical evaluation and ASI than the STD-VID group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APOPTOSIS IN TRANSPLANTATION Principal Investigator & Institution: Krams, Sheri M.; Associate Professor; Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: (adapted from applicant's abstract): Apoptosis is a highly regulated program of cell death. Recent studies suggest that apoptosis is an important mechanism of tissue injury in allograft rejection. The hypothesis to be tested is that apoptosis has a dual role in the allograft, a deleterious role is a mechanism of graft cell damage and a beneficial role involving elimination of alloreactive cells. The overall goal of this project is to modulate apoptosis during organ transplantation so as to inhibit death of graft associated cells and to promote deletion of infiltrating host reactive cells. An integrated series of studies utilizing well defined animal models of orthotopic liver transplantation and small intestinal transplantation are proposed. In Specific Aim 1 the mechanisms responsible for apoptotic graft damage during allograft rejection will be defined. RNase protection assays, and competitive reverse transcriptase polymerase chain reaction will be utilized to determine the cellular and soluble initiators as well as the signaling pathways which culminate in irreversible cell damage and death. Further studies will utilize functional assays to examine the proteolytic cleavage of caspases during graft rejection. Specific peptide inhibitors of caspase activation will be administered to allograft recipients to disrupt the apoptotic pathway and graft damage. The investigators have previously determined that CD8+ cells are not essential for allograft rejection or graft cell apoptosis. The apoptotic pathways that function independent of CD8 cells will therefore be elucidated and modulated in Specific Aim 2. In Specific Aim 3 they will examine the role of apoptosis in inducing allograft tolerance. Recently, they have determined that depletion of the majority of host CD4+ T cells results in abundant apoptosis of graft infiltrating cells with minimal allograft damage and rejection. The cellular and biochemical mechanisms by which infiltrating lymphocytes are deleted will be examined using this model. Furthermore, the impact of conventional immunosuppressives and the deletion of alloreactive host lymphocytes will be studied. Definition and characterization of apoptotic pathways in organ transplantation will lead to novel therapeutics to enhance graft survival and eliminate alloreactive cells while preserving the host immune response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIORAD ASPERGILLOSIS

GALACTOMANNAN

EIA

FOR

DIAGNOSIS

OF

Principal Investigator & Institution: Marr, Kieren A.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 29-FEB-2008 Summary: (provided by applicant): The Bio-Rad galactomannan enzyme immunoassay (GM EIA) will soon be submitted to the FDA for approval as an aid to diagnose aspergillosis, a frequent cause of infectious death in immunosuppressed patients. Our preliminary studies suggest that the assay may also be used as a screening test to enable

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Liver Transplant

early diagnoses; however, the optimal cut-offs for positivity have not been determined. Defining cut-offs to optimize performance is critical for patients who have different manifestations of infection (endobronchial vs. invasive), such as in solid organ transplant recipients, and in children, who appear to have frequent false-positive results. The studies proposed in this project will define parameters to use the GM EIA in multiple different patient populations, using clinical samples obtained from a large ongoing FHCRC longitudinal protocol in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients, and samples obtained from multicenter trials sponsored by the NIH. Aim 1 will define parameters for use of the GM EIA as an early diagnostic test for aspergillosis in adult allogeneic HSCT patients. Studies will be performed to determine the lower limit of GM detection, identify clinical factors that impact levels of circulating GM, and to determine the role of GM EIA applied to non-blood fluids (bronchoalveolar lavage fluid and urine). Aim 2 will define appropriate cut-offs for positivity and characterize performance of the GM EIA as a diagnostic assay for aspergillosis in high-risk solid organ transplant recipients. To do this, longitudinal sample collection will be performed in a protocol conducted as a companion to an ongoing CDC-sponsored multicenter surveillance study. Aim 3 will define parameters for use of the GM EIA as an early diagnostic test for aspergillosis in neutropenic children. To determine the appropriate cut-offs for positivity in children, GM EIAs will be performed on serial sera obtained from children at high risk for aspergillosis after treatment with induction chemotherapy for AML, and after cord blood transplant. Companion protocols will be performed to collect sera as part of ongoing multicenter studies performed by the Children' s Oncology Group and the NHLBI Cord Blood Transplantation Study. Studies will be performed to determine if false-positivity of the GM EIA in children corresponds with gut translocation of GM during periods of mucositis, by measuring surrogate markers for GI integrity in a case-control study. This project is enabled by the cooperative activities of FHCRC investigators, Bio-Rad Laboratories, and several multicenter networks supported by the CDC, NIAID, and NHLBI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BOUND SOLUTE DIALYSIS Principal Investigator & Institution: Patzer, John F.; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-APR-2007 Summary: (provided by applicant): The American Liver Foundation estimates that one in ten people has some form of liver disease and that 26,000 people die each year from liver disease. In the year 2000, 18,137 people were listed for liver transplantation, only 4,934 cadaveric donor liver transplants were made, and 1,636 patients died while awaiting transplant. A medical need for a treatment modality that can "bridge" patients to transplant or slow or reverse the progression of liver disease clearly exists. Even better would be a new standard of care treatment that can be easily employed by any hospital at early stages (Parson's encephalopathy grade 1 and 2) of liver failure that would retard or prevent progression to acute liver failure that requires OLTx. Bound solute dialysis (BSD), practiced heuristically by the MARS and Biologic-DT approaches, offers the potential of a new standard of care treatment modality. Improvements in such heuristic practice require a theoretical approach that encompasses the underlying thermodynamics and transport phenomena. Such an analysis indicates that BSD is both more robust and more easily employed than expected from the heuristic approaches practiced here-to-fore. Experimental observations follow the theoretical predictions. The

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objective of this research proposal is to expend upon the preliminary studies in order to define what is necessary to bring BSD to the status of an easily employed standard of care treatment for liver disease that can be practiced with minimal requirements by any hospital or clinic. This will be accomplished by expanding the theoretical approach to encompass other forms of BSD, experimental validation of modeling predictions, development of an animal model of chronic liver failure, and preclinical evaluation of the various modes of BSD with the animal model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPREHENSIVE FOLLOW-UP OF LIVING DONORS Principal Investigator & Institution: Matas, Arthur J.; Professor; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: The aims of this project are to definitively determine the long-term risks associated with kidney donation and the short- and long-term risk of liver donation. These represent 2 separate situations: a) living kidney donation has been done for the last 4 decades and the short-term risks have been well-defined. But (previous retrospective) long-term studies have suffered from inability to contact all the donors. In some of these studies, it has been shown that some donors have hypertension, proteinuria, and renal dysfunction. And it is know that some donors have developed ESRD. Yet, because follow-up is incomplete, it is unclear whether the risk to the donor exceeds that of the general population. We plan a long-term study, in which we maintain regular contact with the kidney donors, to determine: the risk of developing hypertension, albuminuria, and renal dysfunction (and any progression should they develop). We will also determine the incidence of type 2 diabetes and study whether nephropathy occurs more rapidly in the uninephrectomized donor. And we will study the impact of postdonation proteinuria on cardiovascular risk. Living donor (especially right lobe) liver transplantation is a relatively new innovation. There are few short-term and no long-term follow-up studies. We plan a long-term study, in which we maintain regular contact with the donors to determine both short- and long-term term consequences of living donor liver transplantation. Both of these follow-up studies are necessary to be able to provide accurate information to prospective donors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CLINICAL AND TRANSLATIONAL RESEARCH Principal Investigator & Institution: Peters, Marion G.; Professor; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAY-2007 Summary: (provided by the applicant) The Core Facility provides Liver Center investigators with biostatistical consultation, data analysis, interpretation, and assistance in writing up statistical methods and results; serum samples, peripheral blood mononuclear cells and liver specimens from patients with liver disease and limited clinical data from these patients. Investigation of liver disease transcends many disciplines from adult hepatology to pediatrics, from surgery to radiology to pathology, from basic immunology to clinical virology to epidemiology. Liver Center investigators have been studying questions related not only to liver transplantation and antiviral therapy but also to biliary disease, variceal bleeding, cost effectiveness and quality of life. The Core has been able to provide support for a broad range of investigations into hepatobiliary diseases and normal hepatic metabolism, and to serve as a regional and

26

Liver Transplant

national resource for clinical research in viral hepatitis and transplant. Finally, the Core has been instrumental in bringing together a group of investigators focused on liver cancer, who now have applied for expanded funding in this area, through the NCI SPORE mechanism. The Core provides comprehensive assistance to investigators at all stages of study development and execution, including assistance with study design, database construction, statistical analysis, and manuscript writing. By removing the inertial barriers to entering clinical research, it plays a major role in the productivity and career development of UCSF trainees and junior faculty while also assisting more senior investigators with established research programs. The extensive collection of serum and tissue samples has been made available to, and utilized extensively by, Liver Center members and, on a limited basis, by non-Center investigators at other academic institutions. The diversity and number of specimens available through the Core provides a scarce and unique human resource for those engaged in clinical and translational research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--HUMAN LIVER AND TISSUE BANKS Principal Investigator & Institution: Thummel, Kenneth E.; Professor; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 06-AUG-2003; Project End 31-JUL-2008 Summary: HUMAN LIVER AND INTESTINE BANKS: The PPG Core has been obtaining human tissue for use in research since 1986. This occurred initially through a collaboration with Dr. Craig Eddy, in the Department of Surgery at UWMC, and later through a collaboration with a past Core co-investigator, Dr. James Perkins, Director of Transplantation in the Division of Transplant Surgery. In addition, the procurement of tissue occurred with the assistance and consent of the regional Organ Procurement Agency, formerly the Northwest Organ Procurement Agency and now LifeCenter Northwest. Protocols for the acquisition and safe handling of human tissue have been approved by the University of Washington Human Subjects Review Committee. As of September 2002, a total of 71 human livers and 64 human intestines have been collected. Approximately half of the livers were rejected for transplantation, the other half were obtained either before the establishment of the liver transplant program (before 1991) or represent waste tissue from split liver transplants in a pediatric population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYTOGAM TO PREVENT EBV INFECTION IN PED LIVER TRANSPLANT Principal Investigator & Institution: Burroughs, Margaret; Mount Sinai School of Medicine of Cuny New York, Ny 10029 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CYTOKINES AND LIVER TRANSPLANTATION Principal Investigator & Institution: Martinez, Olivia M.; Associate Professor; Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JUL-1993; Project End 30-NOV-2003

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Summary: The long term goal of this project is to understand the role of cytokines in the cellular and molecular mechanisms of liver allograft rejection. During the previous funding period the in situ cytokine profile during human liver allograft rejection was characterized for the first time. The findings indicate that human allograft rejection does not conform to the Th1/Th2 paradigm. Elucidation of the intragraft cytokine profile led to the identification of cellular effector pathways that are operative in human allografts. Furthermore, a novel T cell subset that expresses CD30 and is the primary source of IL-5 and IFN-gamma produced in response to alloantigen has been identified. The hypothesis to be tested is that CD30 expression identifies a population of alloreactive, cytokine-producing T cells that promote graft rejection. In the first specific aim the development, regulation, and function of alloreactive CD30+ T cells will be characterized. Alloactivated CD30+ T cells obtained by fluorescence activated cell sorting and single cell cloning will be utilized to define the cytokine profile of CD4+CD30+ and CD8+CD30+ cells. CD30+ T cells will be added to mixed leukocyte cultures to determine their ability to regulate allospecific proliferative responses, cytotoxic T cell development, and antibody production. Antibody blocking and transfection strategies will define the contribution of the co- stimulatory molecules B7-1 and B7-2 to the development of CD30 cells. The influence of immunosuppression and the form of alloantigen on the development of CD30 T cells will be determined. Aim 2 will characterize the function of the CD30 molecule. The hypothesis to be tested is that CD30 ligation engages the cytokine gene expression program in alloactivated T cells. CD30+ T cells will be stimulated with agonistic anti-CD30 mAbs and the effect on cytokine gene and protein expression will be determined. Transfection experiments will examine the link between CD30 signaling and cytokine gene promoter activity. Truncation mutants of the CD30 molecule will identify the intracellular regions necessary for induction of cytokine gene expression. Aim 3 will define the role of CD30+ T cells in allograft rejection utilizing a rat orthotopic liver transplant model. The development and function of alloreactive CD30 cells during graft rejection will be assessed by immunohistochemical staining and by isolation and characterization of CD30+ T cells from rejecting allografts. CD30+ T cells will be depleted by antibodybased approaches, including immunotoxins, and the impact on the cellular and molecular pathways of graft rejection will be assessed. The contribution of CD30+ T cells to graft rejection will be directly determined in an adoptive transfer model. We anticipate elucidation of the function of CD30+ cells and their role in liver allograft rejection. Identification and characterization of an alloreactive immunoregulatory subset with discrete phenotypic markers would enhance the development of therapeutic strategies to achieve specific immunosuppression in organ allograft recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETECTION AND CTL THERAPY OF PTLD AFTER LIVER TRANSPLANT Principal Investigator & Institution: Goss, John A.; Surgery; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2005 Summary: (provided by applicant): Despite advances in medical and gene therapy, orthotopic liver transplantation remains the only definitive therapeutic option for children with end-stage liver disease and certain metabolic disorders. Recent advances in pre-, intra-and early post-transplant care have resulted in a dramatic improvement in survival of the pediatric liver transplant patient. The broad long-range goal of our research program is directed at enhancing the patients' long-term survival. Our primary

28

Liver Transplant

focus relates to obligate life-long immunosuppression, with its inherent complications including severe infection and development of cancer. These two complications come together in a single disease, Epstein-Barr Virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD). EBV, a latent human lymphotrophic herpes virus infects and immortalizes human B cells. Primary infection usually occurs via salivary exchange and results in a mild, self-limiting illness (infectious mononucleosis) followed by life-long EBV-specific T cell controlled EBV latency. T-cell based immunosuppression prevents allograft rejection, however, it also suppresses cytotoxic T lymphocyte (CTL) function generating an environment in which EBV-infected B cells can proliferate. Patients receiving life-long T cell based immunosuppression have an increased risk of developing PTLD due to their inability to produce normal immunoregulatory responses. Studies have suggested that EBV load and maintenance of host immunoregulation may be an important indicator of PTLD development. This disease is particularly devastating to the pediatric patient as its incidence is at least 4-fold greater than in the adult liver transplant-patient population. In fact, PTLD is the number one cause of death following pediatric liver transplantation. At this time, there is no definitive method of prospectively detecting, diagnosing, or treating PTLD, and current treatment protocols place the liver allograft and patient at risk. Therefore, a diagnostic tool that is both sensitive and specific, and a treatment strategy with low toxicity are greatly needed to decrease the morbidity and mortality suffered by the pediatric liver transplant patient with PTLD. The investigation proposed herein involves studies that will support our hypothesis that the combination of a persistently elevated EBV load in the setting of a diminished immune response to EBV will be an early risk indicator associated with PTLD development, and that pre-emptive treatment utilizing autologous adoptive EBV-specific CTL immunotherapy will provide a low toxicity treatment option. The specific experimental goals proposed include: Specific Aim 1: To identify pediatric liver transplant recipients with persistently high EBV levels who fail to mount an adequate immune response to EBV, and Specific Aim 2: To determine if infusions of autologous EBV-specific CTL lines are safe, increase immunity to EBV and reduce viral burden in pediatric liver transplant recipients. We plan to serially follow our pediatric liver transplant recipients monthly following transplantation with real time quantitative DNA analysis for EBV load and antiviral immunity via EBV-specific ELISPOT assays. In patients found to have persistently high loads of EBV and a diminished level of EBV-specific immunity, despite minimization of T-cell based immunosuppressive medications, EBV-specific CTLs will be generated and administered in a phase 1 dose escalation study. These studies represent a phase 1 trial to determine the relevance of EBV load and EBV-specific immune responses following liver transplantation. In addition, these studies will determine the safety and ability of autologous adoptive EBV-specific CTL immunotherapy to enhance EBV-specific immunocompetency. The data from our proposed study will provide the database for the development of future larger multi-centered trials to determine the utility of this adoptive immunotherapeutic regimen Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF A NOVEL BIOARTIFICIAL LIVER Principal Investigator & Institution: Rozga, Jacek; Arbios Technologies, Inc. 2331 Buckingham Ln Los Angeles, Ca 90077 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 30-NOV-2003 Summary: ARBIOS developed a novel hybrid bioartificial live r(HyBAL) to treat patients with liver failure of various etiologies. In the absence of any other alternative,

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29

such patients must receive a liver transplant or endure prolonged hospitalization. In treating acute liver failure it is critical to provide whole liver functions. It is believed that liver support at this level of complexity requires utilization of viable isolated liver cells. Our own argument, which dates back to the development of our first-generate bioartificial liver, is that a truly effective system should be a hybrid one, i.e., it should combine liver cell therapy and detoxification using sorbents (e.g., activated charcoal, exchange resin). The HYBAL is the first liver assist system in which these two functions are integrated in a single molecule. Depending on the cause of liver disease, severity of illness and deficiency of specific liver functions, these modes of therapy can be provided individually, simultaneously or sequentially. In addition, the HYBAL's basic commercially available kidney dialysis platform represents a major improvement in efficiency with a concomitant reduction in cost and complexity compared to other existing systems. The goal of this proposal is to validate the HyBAL concept. The prototype HyBAL devices will utilize matrix-anchored rat or pig hepatocytes and sorbents (charcoal and exchange resin particles). They will e perfused for 8 hours with plasma removed with pigs with surgically-induced fulminant hepatic failure(FHF). Changes in plasma levels of ammonia, urea, bilirubin and other liver-specific parameters will be monitored. In addition, the HyBAL will be challenged with exogenous ammonium chloride, galactose and lidocaine. In vivo, he ability of HyBAL to support pigs with FHF will be examined. In both experimental settings, HyBAL devices from which either cell therapy or sorbents have been omitted, will be tested to determine the respective role of cell and sorption therapy in the overall HyBAL performance. PROPOSED COMMERCIAL APPLICATIONS: The National Center for Health Statistics (NCHS) reported that in 1999, over 250,000 patients underwent 340,000 hospitalizations due to acute liver failure; 43,000 patients died (7th leading cause of death). Based on these data, NCHS estimates that more than 200,000 liver support treatments are needed annually in the U.S. lone to keep liver failure patients alive until an organ becomes available for transplantation or the native liver recovers from injury ($1.5-billion market). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DFMO PREVENTION STUDY (2B) IN ORGAN TRANSPLANT SUBJECTS Principal Investigator & Institution: Bailey, Howard H.; Assistant Professor of Medicine; Human Oncology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Skin cancer is the most common malignancy encountered in the US. While most occurrences of non-melanoma skin cancer can be successfully treated, the growing number of cases and the increased virulence of the malignancy in certain populations make it a significant societal risk. An example of a population at increased risk based on incidence and virulence is organ transplant recipients (OTR), a growing subset of our population due to increased graft survival and numbers of graft recipients. In most series, the incidence of skin cancers in OTR has been > 50% by 20 years post-graft. Initiators and promoters of skin epithelial tumor formation have long been observed to cause increased levels of polyamines and their rate-limiting biosynthetic enzyme ornithine decarboxylase (ODC). Conversely, compounds that decrease ODC activity inhibit skin tumor formation. Difluoromethylornithine (DFMO) is a specific inhibitor of ODC and has been observed to significantly reduce tumor formation secondary to many different initiators and promoters. Past and ongoing

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chemoprevention studies of DFMO at the UW and other institutions have revealed significant inhibition in ODC activity and polyamine levels in target tissues at relatively nontoxic doses. Due to concerns about chronic immunosuppressants, like cyclosporine, interfering with the ability to adequately measure promoter-induced ODC activity in skin samples and DFMO effects upon graft survival, an initial phase I pilot study of 0.5 and 1.0 g/day of DFMO in OTR was performed. It revealed that 28 days of 0.5 g/day of DFMO significantly inhibited TPA-induced ODC activity and decreased polyamine (putrescine) levels in skin samples of OTR without toxicity.Prior to pursuing a large phase III study of DFMO in OTR, we propose to perform a phase 2b randomized study of 0.5g/day of DFMO versus placebo for one year in OTR at high risk for skin cancer. The primary endpoint would be a greater than 50% reduction in TPA-induced ODC activity in skin samples for one year. Secondary endpoints will be a 50% decrease in skin putrescine and decreased development of skin lesions (actinic keratoses and carcinomas) for one year. Additional parameters include: toxicity assessment including audio grams for ototoxicity, graft status, compliance, and DFMO and immunosuppressant levels.The importance of assessing the biochemical and potential toxic effects of DFMO in OTR, a population at considerable risk of skin cancer, is magnified further by the increased incidence of multiple malignancies in OTR and the importance of ODC induction in many types of tissue carcinogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG TREATMENT FOR TRANSPLANT CANDIDATES Principal Investigator & Institution: Haller, Deborah L.; Associate Professor; St. Luke'sRoosevelt Inst for Hlth Scis Health Sciences New York, Ny 10019 Timing: Fiscal Year 2003; Project Start 10-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): This application proposes a Stage I project targeting substance abusers with end-stage liver or renal disease who are seeking organ transplant. The proposed research is perfectly suited to a Stage I study because substance abuse: (1) causes/exacerbates both liver and renal disease; (2) has a negative impact on transplant outcomes; and (3) poses a barrier to obtaining life-prolonging surgery. At present, no empirically validated treatment exists for organ transplant candidates with co-occurring addiction; in addition, no RCT of any validated substance abuse intervention has been conducted in pre-transplant candidates. Lack of relevant substance abuse services for this population is further worsened because organ transplant patients have difficulty assimilating into community drug treatment programs. Together, these factors suggest the need for a "tailored" intervention. The proposed approach will allow us to develop and pilot test a homebased (telephone) intervention on a small number of pre-transplant patients to determine if it is sufficiently promising to warrant further evaluation in a Stage II clinical trial. It is hoped that the proposed treatment will result in increased: (1) readiness to change drug use behavior; (2) abstinence, both pre- and post-transplant; (3) treatment adherence; (4) behavioral health; and (4) psychological status/Quality of Life (QOL). Longer term medical outcomes of interest include: (1) being listed for transplant; (2) receiving a transplant; (3) morbidity (e.g., rejection episodes); and (4) mortality. The Transplant & Addiction Program (TAP) is a 12- session telephone intervention that uses motivational interviewing (MI) as its therapeutic platform, supplemented by CBT exercises, health education and contracting. TAP emphasizing abstinence, disease management, and adherence, while de-emphasizing confrontation, labeling, and telling the patient what to do. Because it is home-based, the intervention will be accessible to patients who live far away from their chosen transplant center or who are too ill to attend drug treatment in

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the community. Following the development and piloting of TAP and adherence/competence scales, 20 subjects will be randomized to TAP + TAU and 20 to TAU alone. For this study, TAU consists of medical management by a designated transplant team (internist, RN transplant coordinator, surgeon, and medical social worker) who will adhere to the research protocol. Subjects will be evaluated at baseline, upon completion of treatment (wk. 12) and at 3 and 6- month follow-up points. Hair analysis, BAL, urine (plasma for those no longer making urine) and collateral reports will serve as the dependent measures of substance use. The medical team will provide information regarding medical status and service utilization to the research team on a monthly basis until such time as the subject dies, is administratively discharged from the program, or the study ends. The focus during the extended follow-up period will be on secondary end-points (i.e., medical outcomes) as well as relapse. If the proposed behavioral intervention proves to be efficacious, we will next propose a Stage II study that will likely involve several transplant centers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: END-STAGE LIVER DISEASE/PREVALENCE & TREATMENT VARIATION Principal Investigator & Institution: Bryce, Cindy L.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-AUG-2005 Summary: (adapted from the application) The primary purpose of this proposal is to provide the applicant with means and structure for achieving two goals. The immediate goal is to evaluate the effect of gender, race and income on access to liver transplant services. The long-term goal is to gain independence as a health services researcher by developing methodological expertise in decision sciences and multivariate statistical modeling and research expertise in organ transplantation and health policy evaluation. The applicant will obtain further instruction in computer simulation, geographic information systems, and advanced statistical analysis; in addition, she will receive clinical education to better understand the liver transplantation process and overall delivery of patient care. This training will be provided through formal coursework, directed readings, seminars and conferences, a clinical preceptorship, and research. Most activities will take place at the University of Pittsburgh's School of Medicine, Graduate School of Public Health, and Center for Research on Health Care. The applicant's research project evaluates the role of gender, race, and income in determining access to liver transplantation and explaining variation in liver transplant rates. To date, most studies on access to transplantation have focused on renal transplant services; few researchers have studied hepatic transplantation because of serious data limitations. Whereas the federal government maintains a comprehensive database of persons with renal disease from the time they receive dialysis, there is no centralized, population-based registry for persons with end-stage liver disease (ESLD). Most information on ESLD patients is collected on liver transplant candidates by the United Network for Organ Sharing. The hypothesis of this project is that demographic and economic factors significantly affect early access to transplant services, namely referral rates to transplant centers and listing rates by transplant centers. To address this issue, better information is needed. Therefore, the project will satisfy two aims: (1) develop and validate a population-based methodology for identifying and tracking a cohort of "transplant potential" patients with ESLD; and (2) estimate the effect of gender, race and income on movement through the transplantation process. This project will collect new information on patients with ESLD and combine it with existing data

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resources made available through The Optimal Timing of Liver Transplantation Project (AHCPR, R01 HS09694-02). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENGINEERING ASPECTS OF LIVER SUPPORT SYSTEMS Principal Investigator & Institution: Clemens, Mark G.; Professor and Chair; Biology; University of North Carolina Charlotte Office of Research Services Charlotte, Nc 282230001 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): In spite of many advances in liver transplant surgery, an increasing number of patients with terminal liver disease are dying while awaiting transplants. Consequently, further advances in the storage of donor livers, as well as alternative replacement options and mechanisms for supporting liver function while awaiting a donor liver are needed. A very promising area of research and development is in the development of engineered solutions to the problems of liver support for either natural donor organs or bioartificial livers. However, efforts undertaken within a single discipline are hampered by the complexity of both the engineering and biological aspects of such projects. This proposal constitutes a partnership between bioengineers, biologists and a liver transplant surgeon with the goal of combining their expertise to devise improved methods of liver support via bioartificial livers and improved preservation of donor livers via machine perfusion preservation (MPP). The partnership encompasses three inter-related projects. The first project focuses on delivery of oxygen and other nutrients to the cells in in vitro systems such as the bioartificial liver. The approach involves the modification of the support matrix to facilitate enhanced mass transport. The second project addresses the hypothesis that improved bioartificial liver function can be attained by providing a more physiological combination of cell types in the support device. Specifically, we will investigate the relationship between Kupffer cells and hepatocytes in maintaining prolonged hepatic-specific function in culture. The final project focuses on development of methods for optimization of microvascular perfusion in machine-perfused livers. This project uses a combination of intravital microscopy and mathematical modeling. In all of the projects, engineering and biological approaches, as well as clinical experience, are combined to address focused, clinically relevant problems. Moreover, the unique environment that supports the partnership will maximize the potential for success in this interdisciplinary approach and provide an avenue for potential clinical application of laboratory advances. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENERATION/EMERGENCE OF VARIANT IN HEPADNAVIRUS INFECTON Principal Investigator & Institution: Summers, Jesse; Professor; Cell Biology and Physiology; University of New Mexico Albuquerque Controller's Office Albuquerque, Nm 87131 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 30-JUN-2005 Summary: The objectives of the proposed research are to understand the mechanisms for the generation and emergence of variants during chronic infection with hepadnaviruses. Variants are thought to be important in the pathogenesis or persistence of HBV infections in humans, and are known to be responsible for the development of drug resistance during antiviral therapy and for infection in vaccinated individuals and

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liver transplant recipients. However, because chronic infection is due to persistent infection at the cellular level, and the liver is a relatively quiescent tissue, it is not clear how variants that are generated during a chronic infection emerge as the dominant species of virus. The research we propose is designed to clarify the mechanisms for emergence of virus strains. Understanding the processes that result in evolution of the virus population in a chronically infected liver requires gaining new fundamental information about the nature of chronic infections; i.e. about how the progeny of the infecting viruses and variants are distributed in the liver, how much viral and cellular turnover occurs during chronic infection, and how virus lineages are segregated in different populations of hepatocytes where selection of individual variants can occur. Because these questions cannot be addressed experimentally in human HBV infections, we will use the duck hepatitis B virus (DHBV) model. DHBV, a member of the hepadnavirus family, closely resembles HBV in virus structure, genome replication, persistence, and tissue tropism. DHBV is the only member of this family of viruses that can be genetically manipulated in vitro and tested conveniently in animal infections. The five specific aims are (1) to measure the spontaneous mutation frequency in a single round of transcription and reverse transcription of the DHBV genome, (2) to determine the nature of mixed infections of the liver at the cellular level, particularly the frequency of doubly and singly infected hepatocytes, cell-to-cell variation in covalently closed circular DNA (cccDNA) copy number, and the effects of liver growth and regeneration on these properties, (3) to measure the dynamic state of in vivo chronic infections, (4) to describe the process of replacement of a cytopathic strain by a noncytopathic reverant in vivo, and (5) to determine the spatial distribution of virus strains in mixed infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HCV QUASISPECIES DYNAMICS AND LIVER TRANSPLANT Principal Investigator & Institution: Vargas, Hugo E.; Associate Professor; Mayo Clinic Coll of Med, Mayo Clinic Az Sc Johnson Research Medical Building Scottsdale, Az 85259 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2005 Summary: (provided by applicant): HCV related cirrhosis is the leading cause of liver transplantation in this country and in Europe. A significant proportion of patients have a rapid recurrence of hepatitis that leads to graft loss and mortality. The dynamic nature of HCV populations could underlie its biology, including immune evasion and persistence. We propose to study the transmission and evolution of HCV quasispecies 65 liver transplantation recipients. Aim 1: Is there a selection of viral variants within quasispecies at the time of transmission? We hypothesize that not all viral variants present in infectious blood are able to establish infection in a susceptible host. Therefore, we will compare the composition of viral quasispecies in all 65 transplant recipients using single-strand conformation polymorphism (SSCP), cloning and sequencing to evaluate changes that correlate with the clinical course. This analysis will be conducted in the highly variable E2 and conserved 5' untranslated (5'UTR) regions. Aim 2: How does the HCV quasispecies distribution evolve over time in the natural course of infection and does it have a prognostic value with respect to outcome? We hypothesize that in OLT recipients infected with HCV, the quasispecies composition evolves in the E2 and 5'UTR regions and these changes correlate with the clinical outcome. Therefore, we will analyze quasispecies complexity, divergence and genetic drift longitudinally using SSCP and heteroduplex mobility assays in all 65 infected recipients. We will correlate quasispecies behavior with clinical outcome of the infection. Aim 3: What is the biological basis of selective transmission and evolution of quasispecies in the E2 and 5'UTR regions? We hypothesize that the selection and evolution of variants within the

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5'UTR quasispecies is related to differences in viral fitness associated to its competence to direct translation. We will clone representative 5'UTR fragments into bicistronic dual luciferase reporter plasmid and we will measure and compare their translation efficiency in vitro. We hypothesize that E2 region quasispecies variants bound by antibodies are less efficient in establishing infection in the graft. Furthermore, we postulate that new viral variants appearing during the infection represent mutants which escape immune detection. We will separate viral variants bound in immunocomplexes from "free" virus and compare the variants using SSCP, cloning and sequencing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATIC DIFFERENTIATION OF CO-CULTURED ES CELLS Principal Investigator & Institution: Fair, Jeffrey H.; Surgery; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 29-SEP-2005 Summary: (provided by applicant): Candidate: The overall objective of this K18 Career Enhancement Award application is to provide the resources for enhanced training for the principal investigator so that he will become an independently funded surgical scientist who will contribute at a national level in stem cell biology leading to new cell therapies for liver disease. The principal investigator has enlisted the ongoing stem cell expertise of the following mentors: Terry Magnuson, PhD, Oliver Smithies, PhD, and Larysa Pevny, PhD, who are experts in stem cell and developmental biology. Retraining is required due to the length of time in the last seven years spent in clinical practice and patient-based research. There is a clear need to retrain in current recombinant DNA practices, advanced PCR analysis, and basic molecular biology in order to make the transition from clinical to basic science research. Environment: UNC-CH has a strong academic tradition and a commitment to training clinical scientists. The School of Medicine has a strong core facility including the Lineberger Cancer Center, the UNC Genomics Lab, the Confocal Microscopy Lab, and the Mouse Histology Facility to support all aspects of the basic stem cell research. Dr. Terry Magnuson, the stem cell mentor for this project, has an extensive track record of scientific success and is committed to the mentoring process necessary to carry this research to its fruition. Research: In this proposal, we will define the characteristics of embryonic stem cells in vitro as they differentiate in the hepatic lineage and co-culture with either embryonic cardiac mesoderm or hepatic progenitors. Our hypothesis is that Hepatic Progenitor (HP) cells signal Embryonic Stem (ES) cells to undergo tissue-restricted differentiation towards hepatocyte lineage in vitro that are capable of organ specific function in vivo. We will then investigate the biologic fate of these cells in vivo using a cellular transplant model of 2/3 partial hepatectomy. Growth factor culture conditions have been used to derive hepatocyte-like cells from ES cultures, but the in vivo function of the cells is unknown, and may be capable of producing malignancy. In addition, experiments in other organ systems suggest that manipulation of cell culture conditions alone is insufficient, but that cell-cell interactions are required in order to reconstruct and restore organ function. Furthermore, MHC expression, essential in the alloimmune response to liver transplants and the induction of tolerance, is not understood in ES cell development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEPATITIS C: STUDIES OF IMMUNITY AND PATHOGENESIS Principal Investigator & Institution: Rice, Charles M.; Professor; Lab/Virology & Infect Diseases; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 30-JUN-2005 Summary: Hepatitis C virus (HCV) is an important cause of chronic liver disease, cirrhosis and hepatocellular carcinoma in most parts of the world. Its fastidious nature and limited host range have made it difficult to study. In this program, four separate groups of investigators join forces to attack the hepatitis C virus from a variety of different but interrelated vantage points. The four groups (PIs H. Greenberg, C. Rise, T. Wright, and M. Kay) have a well-documented history of collaborations in the general areas of hepatitis viruses and bring a pathogenesis and immunity and will range from clinically based investigation to fundamental analysis of the interaction of the HCV genome and the host. By combining resources, reagents and ideas, the program team hopes to advance the state of knowledge concerning HCV pathogenesis. The individual projects in this program are briefly outlined. Dr. Greenberg who is the overall program director, will carry out studies on the class I restricted CD8+ T cell response to HCV in patients with acute and chronic hepatitis and in patients undergoing liver transplant. He will take advantage of several new assay systems (tetramers and intracellular cytokines) to study responses in peripheral blood and the liver and will work closely with Drs. Wright and Kay to carry out these studies. Dr. Wright will continue her longitudinal analysis of two groups of patients: examine the contributions of virologic and immunologic variables to disease progression and will work collaboratively with Drs. Greenberg and Rice to study host immune responses and hepatocyte response to HCV infection. Dr. Kay will continue to develop his murine model for HCV replication. This model involves the engraftment of human hepatocytes on immunodeficient mice treated with antibody to c-met. Once established, Drs. Kay and Wright to study HCV strain variation phenotypes in the grafts. Finally, Dr. Rice will collaborate with Dr. Greenberg to study hepatocytes and other liver cell transcriptional responses to HCV using microarray techniques. These studies will involve cells in culture which express HCV proteins under the control of an inducible promoter, hepatocytes in vivo derived from chimpanzees and humans, and, when feasible, infected hepatocytes engrafted in our mouse model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEPATOTOXICITY CLINICAL RESEARCH NETWORK Principal Investigator & Institution: Davern, Timothy J.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): Hepatotoxicity, or drug-induced liver inury (DILl), is currently the most common cause of fulminant hepatic failure in the United States and the main indication for market withdrawal of drugs and, thus, it is a problem of enormous medical, financial, legal and regulatory importance. Although a vast number of drugs, toxins and alternative medications have the potential to cause hepatotoxcity, severe DILl is a problem of sufficient rarity that a large group of dedicated investigators working in a coordinated effort will be required to better understand the pathogenesis of DILl and develop effective prevention and treatment strategies. This proposal brings together a unique, multi-disciplinary consortium of investigators and resources, concentrated within Northern California but also including sites across the country, with a plan for a participating Clinical Center in the Hepatotoxicity Clinical Research

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Network (HCRN). Our research plan describes, firstly, the establishment of a large multicomponent Clinical Center patient database that would contribute to the proposed multicenter HCRN. The proposed DILl patient informational database, serum, DNA and tissue bank will comprise a prospective cohort derived from several sources, each providing distinct epidemiological facets and research potential. These include the Liver Transplant Programs at UCSF, Stanford University and California Pacific Medical Center, the Tuberculosis Clinics at San Francisco General Hospital, Boston University, Emory University, University of Puerto Rico, and Louisiana Health Sciences Center, and the HIV Clinic at San Francisco General Hospital. At each site, we have developed strategies to identify well-defined cases of toxin-induced liver injury in a prospective manner that will permit careful collection of detailed epidemiological and clinical information, as well as serum, DNA and tissue samples for biochemical, pharmacological and genetic studies. We plan to initially identify patients with potential DILl based on proposed operational diagnostic criteria and then further evaluate cases using a validated causality assessment instrument. Patients classified as having "highly probable" DILl using this instrument will be followed prospectively in order to better define the natural history of DILl. Identification of such DILl-associated polymorphisms is an essential first step in the development of a rational gene-based prevention strategy. We anticipate that our Clinical Center will recruit approximately 120 cases and wellmatched controls from an ethnically and racially diverse patient population to the national HCRN network. We have a well-organized, multi-disciplinary group of physicians, scientists, and research nurses who are dedicated to the success of this Clinical Center and the overall National Hepatoxicity Clinical Research Network. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ICOS-B7H AUTOIMMUNITY

IN

ISLET

TRANSPLANT

REJECTION

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Principal Investigator & Institution: Shapiro, Andrew M.; University of Alberta Edmonton T6g 2E1, Canada Edmonton, Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Recent progress in clinical islet transplantation with the introduction of the 'Edmonton Protocol' has created enthusiasm for this approach as an effective therapy for highly selected patients with unstable forms of Type I diabetes. The therapy, however, is not suitable for patients in the earliest stages of Type I diabetes because of potential risks associated with anti-rejection therapies. While the risk of malignancy and life-threatening infection has been very low in recent clinical series, complications of severe mouth ulceration, elevated cholesterol, hypertension and the need for two or more organ donors to secure insulin independence emphasize the need for further improvements in the safety and efficacy profile of islet transplantation if it is to be more broadly applied in diabetes. Our Laboratory has focused intense efforts in exploring ways to induce minimal immunosuppression or tolerance in mouse models of islet transplantation. Recently, we have found that an antibody directed against the surface inducible co-stimulatory molecule ICOS (12A8) is highly effective in prolonging islet allograft survival beyond 100 days in approximately half of treated mice. The current proposal is designed to further explore blockade of the ICOS-B7h pathway in control of allograft rejection and autoimmune recurrence after islet transplantation in mice. We believe that this promising finding could be further enhanced by rational combination of anti-ICOS therapy with complimentary approaches that have potential for rapid clinical translatability. More specifically, anti-ICOS will be combined with either donor specific transfusion, CTLA4-1g, CD40 blockade, or with the drug FTY720 to

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evaluate its effect in preventing islet allograft rejection. The most promising of these approaches will be further tested in the primary and secondary prevention of spontaneous diabetes in NOD mice. We will explore the immunological mechanisms associated with tolerance phenotypes [mice treated with anti-ICOS based therapies] by donor and third party islet and skin graft rechallenge, by thymectomy, or by following the fate of donor-specific T cells in TCR-transgenic models. Furthermore, in vitro coculture assays and adoptive transfer studies, in addition to islet-kidney graft retransplantation experiments will be conducted to search for regulatory T cell activity. We will also study our clinical islet transplant patients by flow cytometry and TaqMan quantitative PCR for ICOS expression in peripheral blood and in graft biopsies. We will correlate clinical outcomes with ICOS expression to determine if ICOS monitoring might be a useful tool for prediction of clinical course. If these initial studies show promise, we would plan to further explore anti-ICOS therapies in primate models of islet transplantation within the context of an extended future proposal, with a view to ultimate testing in clinical islet transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNE PATHOGENESIS OF HEPATITIS C VIRUS--HUMAN MODEL Principal Investigator & Institution: Wright, Teresa L.; Professor of Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002 Summary: This proposal is focused on the identification of predictors of disease progression in hepatitis C (HCV) infection. We will examine the influence of the immune response on the natural history in two cohorts; immune compromised liver transplant patients and immune competent patients with HCV. Our primary hypothesis is that fibrosis progression is accelerated by immune suppression. Our secondary hypothesis is that type of immune suppression and ethnicity contribute to fibrosis progression. We will use databases of patients who have undergone liver transplantation and immune competent patients who have undergone liver biopsy, databases which include clinical, demographic, biochemical and histological data as well as information regarding risk exposures and alcohol consumption. All liver biopsies have been graded and staged for the degree of inflammation and fibrosis respectively. Serum is available from the majority. Initial analysis of 284 liver transplant recipients showed that post-transplantation fibrosis progression was linear but variable, and was independently associated with year of transplantation, non-Caucasian ethnicity, number of steroid boluses and HCV RNA level at transplantation. Since the explanation of these associations was not apparent, we expanded the transplantation databases in order to identify precisely predictors of disease progression. We will also measure variables including ethnicity in fibrosis progression in immune competent patients. In most studies of natural history, the duration of HCV infection is estimated retrospectively from time of presumed first risk exposure. Through modeling timing of exposures, we will develop an approach to assign accurately time of initial infection. We will also investigate the association between genetic diversity in the envelope and NS3 genes and disease progression. Finally, we will collect lymphocytes from HCV- infected patients for future analysis of the association between genetic markers and disease progression. These cohorts will provide lymphocytes to Dr. Greenberg to measure HCVspecific CTL response and HCV variants to Dr. Kay to measure pathogenicity of HCV in an animal model. Elucidation of the mechanisms by which HCV causes disease is essential for the identification of those at risk for serious consequences.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVING DRUG ABUSE TREATMENT PLANNING CRITERIA Principal Investigator & Institution: Gastfriend, David R.; Director; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 30-JUN-2005 Summary: Improving Drug Abuse Treatment Planning Criteria: This K-24 Mid- Career Investigator Award will provide an intense phase of career development and mentoring in drug abuse health services research. The research goal is to develop criteria for determining treatment quality and appropriateness, parameters that become increasingly important as clinical management changes focus on cost reduction to costeffectiveness. The specific aims are to apply the ASAM PPC algorithms to 4 additional data sets that complement the ASAM Study sample, to extend our knowledge of the 1) concurrent validity and 2) predictive validity of the ASAM PPC and 3) to improve it. These cohorts include: non-treatment seekers, outpatient treatment seekers, hospitalized liver transplant candidates and opiate anesthesia detoxification candidates. This is an efficient opportunity to study all levels of care described by the ASAM Criteria, without the cost/effort of devising controlled, prospective trials. The hypotheses are that the ASAM PPC: H1) will show baseline between-group differences that are useful for disease staging, H2) will demonstrate predictive validity for clinical and utilization outcomes, and H3) will yield some dimensional constructs, decision rules and scoring thresholds that do not initially meet validity criteria but, with revision and iterative reanalysis, can achieve significance. The results will facilitate future controlled trials via RO1 applications. The Mentoring Plan will focus on Post-residency Fellows in Addiction Psychiatry (3 per year), and also incorporate post- doctoral trainees in health services research and dissertation students in health policy. Mentoring will occur through trainees' participation in the research projects that are planned in each of the four naturalistic convenience samples (for whom complete data are already gathered or are substantially underway). Validation work is required for each of the 6 ASAM PPC assessment dimensions, for each level of care, and within sub-populations. This range of research needs offers a rich matrix of opportunities for a group of trainees and junior investigators in patient-oriented research. Over the next five years, the candidate seeks to: a) move to full-time effort in research and research mentoring, b) increase the depth of his own skills in psychometrics, health economics and data analysis through specific trainings, c) increase his ability to incorporate advanced modeling approaches through collaborations with statistical and health economics experts, and to d) increase his efforts at dissemination, both through publication of results in the scientific literature and through a generation of junior investigators who will acquire the fascination and skills to advance this new area of patient- oriented research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIVER EXPRESSED MHC ANTIGENS Principal Investigator & Institution: Stroynowski, Iwona T.; Associate Professor; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: Mammalian liver has been long known to exhibit properties of immunologically privileged tissue: it expresses low levels of surface class I MHC antigens on parenchymal hepatocytes and induces donor-specific allotolerance in MHC mismatched transplant recipients. The suppressed display of surface class I MHC

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proteins is paradoxical in view of the high constitutive transcription of H-2K, D genes in mice and HLA-A, -B, -C in human, and in view of the liver s ability to clear intracellular hepatic pathogens via CTL-mediated, class I-restricted immune responses. This application seeks to define a full set of class I genes expressed in hepatocytes of normal, cytokine treated (IFNgamma, TNFalpha) and pathogen (Listeria monocytogens, recombinant adenovirus used for liver gene therapy) infected mice and to explore the role of class I antigen processing pathway in their expression. We will restrict our studies to C57BL/6 mice and its H-2Kb,Db-deficient mutant, which will serve to optimize the conditions for detection of rare class Ib products. The results of the proposed research will provide information about the heterogeneity of distince class Ib proteins expressed in parenchymal tissue of liver. Furthermore, the studies of the regulated expression of the components of class I antigen- processing machinery in liver cells will contribute to the understanding of the mechanisms involved in class Imediated responses against model hepatotrophic pathogens. This knowledge is relevant for clinical research addressing liver transplantation, opportunistic infections of liver and liver gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVER REGENERATION AS A MODEL FOR ANGIOGENESIS Principal Investigator & Institution: Stolz, Donna B.; Assistant Professor; Cell Biology and Physiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 15-AUG-1998; Project End 30-NOV-2008 Summary: (provided by applicant): Angiogenesis is the process whereby new blood vessels sprout from existing vessels and requires that the specialized resident cells lining the vasculature, the endothelial cells (ECs), proliferate, migrate and differentiate spatially and temporally in response to specific signals. Vasculogenesis, on the other hand, has only recently emerged as an alternative mechanism of blood vessel growth in adult tissues and is the result of homing and engraftment of circulating EC precursors (ECPs) of bone marrow origin to areas of neovascularization. Both events are known to occur within the liver vasculature under very different conditions of growth, injury and repair, but the extent of each and the mechanisms by which they proceed in each case is completely unknown. The overall goal of this proposal is to determine the specific growth factor signaling events that induce angiogenic versus vasculogenic blood vessel growth in the context of liver and determine the subsequent microenvironmental milieu that induces EPC recruitment and/or differentiation of the liver-specific sinusoidal endothelial cell (SEC) fenestrated morphotype. Two paradigms of clinically-relevant liver repair allow us to spatially and temporally detail the growth factor signaling events and evaluate sinusoidal ultrastructure and liver-specific SEC function in the rat. AIM I: Growth factor and microenvironmental interactions will be examined at the sinusoidal surface following 70% partial hepatectomy (PHx) since there is initially extensive hepatocyte proliferation in the absence of EC proliferation until 96 hr postPHx, resulting in avascular hepatic foci. Subsequent proliferation and infiltration of the SEC into these avascular parenchymal clusters and reestablishment of the normal hepatic architecture provides a well-timed model for evaluating physiological angiogenesis. AIM II: Angiogenic and vasculogenic events will be examined concurrently using an allogeneic liver transplant model (dual cross strain and female to male transplants, non-GFP to GFP rats) to ascertain the source of SEC (host vs. graft) and determine extent of recipient and donor involvement in SEC engraftment and/or proliferation. Prior to transplantation, livers are stored under cold, ischemic conditions

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for 18 h, and upon transplantation (warm reperfusion), a majority of the SEC slough off immediately from the sinusoidal surface. Remarkably, within 24 hr, the SEC lining has nearly completely repopulated at least partially from ECPs, but microvascular remodeling, morphological and functional modification occurs over subsequent days. Comparative analysis of these two systems will elucidate both similar and dissimilar growth factor signaling mechanisms and the role of the microenvironment that control these events and potentially lead to optimization of therapies that will reflect the specific requirements for injury based liver neovascularization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVER TRANSPLANTATION: THE ROLE OF DENDRITIC CELLS Principal Investigator & Institution: Thomson, Angus W.; Professor; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 30-NOV-2005 Summary: (adapted from the applicant's abstract): The precise role of donor dendritic cells in the inherent tolerogenicity of hepatic allografts remains unresolved. We have shown, however, that poorly stimulatory, immature liver dendritic cells, or dendritic cells whose co-stimulatory function is blocked, can strikingly enhance activationinduced death in allogeneic T cells. Moreover, infusion of such immature donor dendritic cells plus co-stimulatory blockade augments apoptotic death of host immunoreactive T cells and markedly enhances graft survival. These data support our hypothesis that liver dendritic cells have potential to promote the development of tolerance in allogeneic recipients by mediating the apoptotic death of allospecific T cells. Aim 1 is to elucidate the role of apoptosis in the outcome of liver dendritic cellallogeneic T cells interactions and the factors that influence this activity. These studies will test whether myeloid and lymphoid dendritic cells exhibit functional differences in their interaction with T cells and whether they have equal potential to mediate apoptosis in activated T cells and whether Th1 and Th2 cells are equally susceptible. The role of critical co-stimulatory pathways and of IL-2 in the regulation of T cell death will be examined. Aim 2 will ascertain the death regulatory pathways that may determine T cell apoptosis by liver dendritic cells. Contribution of the Fas pathway and the role of TNF families, in particular TRAIL, will be examined. Cell survival factors and death resistance molecules will also be examined for the possible differential resistance of Th1/Th2 subsets to dendritic cell induced death. Aim 3 studies will examine the ability of liver dendritic cells to delete alloreactive cells in vivo and will examine factors that modulate this activity. These studies will involve quantitative assessment of proliferation and apoptosis of CD4 and CD8 T cells in vivo. The impact of blockade of specific co-stimulaory pathways and whether antigen specific T cells are deleted selectively will be ascertained. Finally, Aim 4 studies will assess and maximize the therapeutic potential of liver dendritic cell induced alloantigen-specific T cell apoptosis in organ transplant recipients. In these clinically-relevant studies, emphasis will be placed on targeting specific costimulatory pathways, including use of novel blocking agents. The results will provide new insight into how liver dendritic cells can modulate survival of alloreactive T cells, and determine the potential of donor dendritic cells to delete allospecific T cells to facilitate transplant tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIVER-INDUCED ACTIVATED T CELL DEATH Principal Investigator & Institution: Qian, Shiguang; Associate Professor; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

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Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 30-JUN-2005 Summary: (provided by applicant): Hepatic tolerance was initially demonstrated by spontaneous acceptance of liver allografts in pigs, and subsequently in rats and mice. In humans, rejection of liver transplants is a common occurrence, which is, however, easy to control. There are well-documented cases in which liver grafts survive for years after discontinuation of immunosuppressive therapy. Vulnerability of livers to chronic infection (hepatitis and parasitic infection) and cancerous metastasis has also been attributed to the tolerogenic properties of the liver. The involved mechanisms are unclear. Accumulating data have demonstrated however, that hepatic tolerance is associated with activated T cell apoptosis probably via differentiation of T regulatory cells. These observations support our hypothesis that the liver has the potential to promote apoptotic death of activated antigen-specific T cells, and generate T regulatory activity. The overall goal of this proposal is to yield insights into the underlying mechanisms using T cell receptor (TCR) transgenic mice. There are four Specific Aims. In Specific Aim 1, we will characterize the responses of both CD4+ and CD8+ TCR transgenic T cells to the antigens that are exclusively expressed in the liver. The use of this system will also allow us to precisely test whether tolerance towards the antigen expressed in the liver is local or systemic, and whether it involves attenuation of affector or effector arms of the immune response (Specific Aim 1). The nature of antigen presenting cells (APC) in the liver is another area that has mostly been investigated in vitro, but little has virtually been explored in vivo or ex vivo, despite the suggested central role of these cells in regulating tolerance induction. Thus, we will characterize the behavior, antigen-presenting capacity of liver APC and interaction with T cells (Specific Aim 2). In Specific Aim 3 and 4, we will ascertain the mechanisms of two key events occurring in hepatic tolerance: activated T cell apoptosis and T regulatory cell differentiation, both of which are believed to be crucial in induction of peripheral immune tolerance. We will determine how the liver induces activated T cell death (Specific Aim 3), and the role of T regulatory activity in hepatic tolerance (Specific Aim 4). We believe that these focused relevant studies will provide better understanding of liver immunity and facilitate novel therapeutic strategies to combat chronic liver diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVING DONOR LIVER TRANSPLANT DATA COORDINATING CENTER Principal Investigator & Institution: Merion, Robert M.; Surgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 21-AUG-2002; Project End 31-JUL-2009 Summary: (provided by applicant):We propose to develop and maintain a Data Coordinating Center (DCC) to support the Adult to Adult Living Donor Liver Transplantation (AALDLT) Cohort Study including a Specimen Core Facility. The proposed AALDLT DCC will be comprised of multidisciplinary expertise in liver transplantation, biostatistics, epidemiology, clinical trials, and data management. We will develop a secure, integrated Internet-based data entry and data management system to support data and specimen acquisition. The AALDLT DCC will coordinate the design and implementation of the AALDLT cohort study and clinical protocols and will provide support in the relevant content areas to the Steering Committee and the NIDDK in its effort to accomplish the primary goal of conducting a longitudinal study of the recipients and donor outcomes in AALDLT. The DCC will accomplish the foregoing goals through the implementation of the following specific aims: 1. Design,

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Liver Transplant

organize, implement and coordinate a secure electronic, centralized web-based distributed data entry system for the participating transplant centers (TCs) 2. Establish a secure data management and archival system for the AALDLT cohort study, clinical protocols and substudies 3. Develop comprehensive, valid data collection instruments4. Establish a high standard, quality-assured central repository for biological specimens acquired from AALDLT donors, recipients, and controls5. Perform methodologically rigorous analyses of AALDLT data 6. Facilitate the presentation, dissemination and publication of the results of the AALDLT study. 7. Organize, schedule and manage the meetings, conferencing and communication of the Steering Committees, subcommittees, the DSMB and the central laboratories involved in the AALDLT study. 8. Provide timely and effective communication among the NIDDK project officer and project scientists, DCC, and participating TCs regarding all aspects of the AALDLT study to ensure the fulfillment of the programs scientific goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVING DONOR LIVER TRANSPLANTATION COHORT STUDY Principal Investigator & Institution: Berg, Carl Lansing.; Associate Professor of Medicine; Internal Medicine; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-AUG-2009 Summary: (provided by applicant):As the disparity between number of potential liver transplant recipients and available cadaveric organs has widened, novel approaches have been developed to permit the successful transplantation of the largest possible number of patients with end-stage liver disease. The most promising of these strategies has involved the application of adult to adult living donor liver transplantation (LDLT). More than fifteen U.S. transplant centers have now utilized LDLT as a standard method for liver replacement. Despite the increasingly widespread application of this approach, considerable heterogeneity exists between centers regarding donor and recipient evaluation as well as the surgical techniques employed. Moreover, information is lacking regarding outcomes of this procedure for both donor and recipient, no data available to identify donors or recipients who may benefit most (or least) from this procedure, and no data to determine whether using LDLT is a cost-effective strategy. In this setting, we propose to participate as a transplant center (TC) in the LDLT Clinical Research Consortium. In this role, we propose to participate in the development of a prospective comprehensive data base and information core that will permit the dissection of the factors which lead to favorable, or unfavorable, outcomes in LDLT as compared to standard cadaveric transplantation. The existing UVA STRANDS database will permit retrospective collection of data from LDLT and cadaveric transplants performed over the last 5 years. In addition, the TC proposes to build on its institutional strengths to lead two clinical research protocols. The first protocol will develop a Cost Utility Decision Analysis using the Adult to Adult Living Donor Liver Transplantation Cohort. This research will yield a valid decision analysis model that can be used in a general patient population to better define subpopulations that would benefit from LDLT as opposed to cadaveric liver transplant. Costs and utilities to the health care system and the patients involved will be clarified for use in patient counseling, medical decision-making, and policy formulation. The second clinical research proposal will examine the outcomes of LDLT in patients infected with hepatitis C and compare these outcomes to cadaveric controls. Mechanisms that contribute to rapid allograft infection and injury will be examined including hepatocyte infection, rates of viral replication and kinetics of serum viral clearance.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LONG TERM FOLLOW UP OF THE NIDDK LTD Principal Investigator & Institution: Detre, Katherine M.; Professor; Epidemiology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-AUG-2004 Summary: (Adapted from Investigator's abstract) The NIDDK Liver Transplantation Database (LTD) is a multicenter registry of more than 1500 consecutive candidates for liver transplantation (LT), recruited between 1990 and 1994, by three major liver transplant centers in the United States. As such, it is the only scientifically designed and implemented multicenter study from which the recent experience of a large cohort of LT candidates and recipients in this country can be rigorously analyzed. The effort to build this detailed and high quality resource was carried out under a 7-year NIDDK contract which ends in December 1997. Valuable information collected in this study includes clinical and laboratory data collected by protocol and at a time of events, and it is enriched with protocol biopsies from a high proportion of recipients, a bank of serial serum specimens, and a virtual tissue bank. Since the current contract only provided for follow-up of 3 years on average, the range of topics that could be investigated, using this comprehensive data base, is limited. The current plan is to continue the follow-up of the cohort of transplant recipients for another 5 years through the next phase of the posttransplantation period, when recurrence of the original disease and long-term adverse effects of immunosuppression and re-transplantation are most likely to occur. Thus, the Coordinating Center, with the support of the investigators of the three LTD clinical centers, will be able to obtain complete follow-up for an average of 10 years (8-12 years) to observe the information recorded in the study before, during an dafter transplantation. The proposed effort is expected to yield results of great scientific and clinical importance which could directly influence future transplant candidate selection and post-transplantation patient management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM(S) OF ALCOHOL-INDUCED LIVER GRAFT FAILURE Principal Investigator & Institution: Lemasters, John J.; Cell and Developmental Biology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-AUG-1992; Project End 28-FEB-2006 Summary: (provided by applicant) Transplantation of fatty livers is a major problem since many of them fail when used as donor organs. Because the source of liver grafts is largely accident victims who use alcohol, the relationship between fatty liver and graft failure needs to be understood to expand the pool of donor organs. Therefore, the goals of this project are to elucidate mechanisms involved in the failure of fatty livers and to develop strategies to prevent graft failure. Studies with chemicals are often not specific making interpretation difficult therefore. we will use mice with specific genetic deletions to test unique hypotheses about the source of free radicals and the role of endotoxin and TNFa in mechanisms of liver graft failure. Our first goal to be achieved in Aim 1 will be to optimize liver transplantation in knockout mice using treatments and techniques which are routine in this laboratory for rats. Recently, we have established liver transplantation here in the mouse. Survival and non-survival conditions will be established in the mouse, validating it as a useful model for mechanistic studies. Next, we will use knockout mice to provide unequivocal evidence for or against the

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Liver Transplant

hypothesis that endotoxin and TNFa play a critical role in failure of fatty grafts. To test this hypothesis, CD-14 knockout and TNF receptor I (TNFRI) knockout mice and appropriate wild-type controls will be treated with ethanol in Aim 2. The time course of survival, transaminase release and bile production will be observed after transplantation. NFKB (a pivotal transcription factor), TNFa and ICAM-1 will be measured at appropriate times after transplantation. We expect that deletion of CD-14 and TNFRI will improve survival of marginal livers. In Aim 3, the source of free radicals will be identified. Mitochondria in hepatocytes and NADPH oxidase in Kupffer cells are two potential sources of free radicals. Accordingly, knockouts of p47Phox, a required subunit of NADPH oxidase, and transgenic mice over expressing mitochondrial MnSOD will be given ethanol and livers will be transplanted under non-survival conditions. We expect that NADPH oxidase deficiency will prevent free radical production and reduce ethanol-induced primary non-function after liver transplantation. Depending on the results of Aims 2 & 3, targeted therapies such as ebselen, an antioxidant and anti-inflammatory drug, soluble TNFa receptor, and a novel endotoxin antagonist, E5331, will be evaluated in Aim 4. Taken together, we expect that by using the knockout approach these studies will provide solid evidence supporting the roles of endotoxin, free radicals, NFKB and TNFa in primary graft non-function in fatty livers. This work will develop mechanism-based strategies to increase the use of marginal fatty livers for transplantation in the clinic and save lives. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ISCHEMIA REPERFUSION INJURY IN THE LIVER Principal Investigator & Institution: Engelhardt, John F.; Associate Professor; Anatomy and Cell Biology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 31-AUG-2005 Summary: Orthotopic liver transplantation is a common therapy for many acquired and inherited disorders. Liver damage caused by ischemia and reoxygenation (termed ischemia/reperfusion or I/R) has been proposed to substantially contribute to the initial poor function (IPF) of transplanted livers, acute rejection, and graft failure. Central mediators of I/R injury in the liver are reactive oxygen species (ROS) generated during reperfusion with oxygenated blood. Of the multiple forms of ROS potentially generated during reperfusion, O2-, H2O2, and OH will be addressed in the proposed studies. These ROS can cause direct damage to cellular proteins, lipids, and DNA, or they can act as intracellular second messengers to activate and/or inhibit signal transduction pathways that determine cell fates by altering the expression patterns of stress response genes. Central to the goals of this grant are to determine: 1) Which ROS are pathophysiologically important in I/R damage, 2) How do ROS lead to activation of AP1 and NFkB signal transduction pathways following liver I/R, 3) In which subcellular compartments (i.e., nucleus, mitochondria, endoplasmic reticulum, or cytoplasm) do these ROS act to alter the activity of AP-1 and NFkB signal transduction pathways, and 4) Is activation of AP-1 and NFkB beneficial or detrimental to the liver following I/R injury. Several model systems will be used to address these questions including: 1) Recombinant adenoviral vectors to modulate the cellular redox state and inhibit/activate specific signal transduction pathways, 2) transgenic knockout mice deficient in certain signal transduction components, 3) partial lobar, liver I/R mouse model, and 4) a syngeneic rat liver transplant model. Preliminary data has demonstrated that ectopic expression of MnSOD using reombinant adenovirus protects the liver from warm I/R injury and concordantly reduces AP-1 and NFkB activation.

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The mechanisms of NFkB activation appear to involve redox mediated tyrosine phosphorylation of 1kBalpha. The hypothesis that subcellular compartmentalized ROS are important in mechanisms of liver I/;R injury is supported by the fact that ectopic expression of Cu/ZnSOD does not protect the liver from I/R damage. Based on our findings that OH radicals and AP-1 activation are increased in Cu/ZnSOD but not MnSOD or LacZ expression livers, and inhibition of Rac1 pathways by expression of the dominant inhibitor N17Rac1 also activates AP-1, one novel focus of our mechanistic studies on AP-1 activating following I/R injury will involve Rac1/PI3-kinase /PKK/GSK modulation of c-Jun phosphorylation. Recombinant adenoviral mutants for the proteins in this signal transduction pathway will be used to dissect its importance. Using recombinant expressing dominant inhibitors and transgenic knockout mice to block either AP-1 and NFkB activation, we will attempt to determine the importance of each of these pathways in mediating both acute hepatic toxicity and subacute inflammatory responses following I/R injury. In the last phase of this proposal, studies will be aimed at determining the relevance of findings in our mouse partial lobar warm I/R model to the rat liver transplant model of cold ischemia. In summary, this proposal will provide experimental and mechanistic paradigms for linking ROS formation in the liver following I/R injury to both acute damage and subsequent inflammation. Moreover, these studies may provide clinically relevant gene therapy approaches for minimizing organ damage following transplantation, which may ultimately increase the graft survival in orthotopic liver transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MMP-9 MEDIATES CEREBRAL EDEMA IN FULMINANT LIVER FAILURE Principal Investigator & Institution: Nguyen, Justin H.; Mayo Clinic Coll of Med, Jacksonville Mayo Clinic Jacksonville Jacksonville, Fl 322243899 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): Fulminant hepatic failure (FHF) is a life-threatening disease. The definitive treatment for FHF is a liver transplant. Unfortunately, 35% of all FHF patients and 62% of nonacetaminophen-induced FHF patients die within 48 hours after reaching stage 3 or 4 coma, while awaiting a transplant. Increasing this narrow therapeutic window would provide substantially more opportunities for these patients to be transplanted. One of the primary causes of death in these individuals is cerebral edema. The mechanisms responsible for cerebral edema in these FHF patients are poorly understood. Recent evidence from other laboratories has shown that matrix metalloproteinase-9 (MMP-9) may play a pivotal role in the development of cerebral edema in other disease states. For example, treatment with either MMP-9 synthetic inhibitors or anti-MMP-9 monoclonal antibodies has been shown to result in a significant reduction in the size of cerebral infarcts. Further, studies using MMP-9 knockout mice have shown a significant attenuation in cerebral edema following either cerebral ischemic or traumatic events. Based on these data we hypothesize that MMP-9 plays a critical role in the development of cerebral edema following FHF. Significant support for this hypothesis has come from two observations made in our laboratory. First, both proMMP-9 and MMP-9 are elevated in the sera of FHF patients and in rats with experimentally induced FHF. Second, in a pilot study, we have shown that treatment with an MMP-9 inhibitor (GM6001) results in an approximate 30% reduction in cerebral edema in rats with experimentally induced FHF. In this application, we specifically propose to: 1. To further determine if inhibition of MMP-9 by the MMP synthetic inhibitor GM6001 attenuates cerebral edema in rats with experimentally

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induced FHF. 2. To determine whether cerebral edema is attenuated in MMP-9 knockout mice following experimentally induced FHF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODELS FOR OPTIMAL LIVER TRANSPLANT OUTCOMES Principal Investigator & Institution: Dickson, E R.; Mary Lowell Leary Professor of Medicine; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002; Project Start 15-JAN-1986; Project End 30-NOV-2006 Summary: Orthotopic liver transplantation (OLT) is now a well- established means of restoring health in patients with end stage liver disease. Our long-term objective is to provide evidence- based information to help optimize the outcome of OLT, which is relevant not only at the individual physician and patient level, but also at the health policy level. Building on our achievements from the previous program period and data collaboration from a network of academic transplant centers, we propose to study the three most important issues that face liver transplantation in the United States today. In specific aim 1, we will prospectively validate the Model for End-stage Liver Disease (MELD) in current OLT candidates. The MELD scale, a liver disease severity index developed by this program, has recently been adopted by the United Network for Organ Sharing (UNOS) as the national liver allocation system for OLT. Our central hypothesis is that the addition of further variables to the model will not materially improve the model, except in patients with hepatocellular carcinoma, in whom the risk of tumor progression needs to be considered in addition to the severity of underlying liver disease. In specific aim 2, we will identify determinants of the outcome of recurrent hepatitis C following OLT. OLT recipients with hepatitis C, the most common indication for the procedure today, have shorter survival and poorer quality of life. Our hypothesis is that pretransplant alcohol consumption and post-transplant obesity affect the rate of progression of recurrent hepatitis C and thus, the outcome. In specific aim 3, we will study the cardiovascular morbidity in long-term survivors following OLT. Based on the number of patients and length of follow-up available in our database, we will identify traditional (e.g., diabetes, hypertension, and hyperlipidemia) and transplant-specific (e.g., cytomegalovirus infection and liver disease diagnosis) risk factors that are associated with cardiovascular complications. The results of these studies will provide relevant information not only to clinicians in practice, but also transplantation policy makers. The feasibility of the proposed projects is supported by the extensive experience and track record of this program in creating and maintaining a large, multicenter, liver transplant database and strong statistical expertise. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOUSE MODEL FOR HCV INFECTION Principal Investigator & Institution: Kay, Mark A.; Professor; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002 Summary: The study of HCV infection, replication and development of new therapeutics has been hampered by the lack of a small animal model permissive to infection and replication. We have recently found a means to maintain human hepatocytes in mice for at least 5 months. We have demonstrated that these animals are susceptible to human hepatocytes in mice for at least 5 months We have demonstrated that these animals are susceptible to HBV/HDV infection/replication. We will now attempt to infect these mice with HCV. The goal of this proposal is two-fold. We plan to

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improve upon the human hepatocyte xenotransplant model by changing the transplantation strategies so that we can implant a larger number of cells. Moreover, we will characterize the implant by histological methods and gene expression profiles using microarray technologies to determine the similarity between the implanted cells and normal liver. We will then determine if this chimeric mouse is able to undergo HCV infection/replication. We will do this by implanting human hepatocytes isolated from HCV infected individuals, infection of normal hepatocytes ex vivo and in vivo with high titer HCV stocks, and infusion of an infectious RNA derived from a single clone. We will follow the animals for HCV infection by quantitating serum HCV RNA titers over time. Ultimately, we will combine the best transplant model with the best method for HCV infection to determine the highest possible HCV titer that can be achieved in mice. When we are successful, this animal model will be used for numerous studies. These include: gene therapy approaches to reduce or eliminate HCV infection, proliferation of quasispecies, viral pathogenicity, and the importance of the immune response in infection and pathogenicity. The development of a small animal model of HCV infection will be invaluable in our advancement for better knowledge and treatment of this devastating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYCOPHENOLATE TRANSPLANT RECIPIENTS

MOFETIL

IN

ORTHOTOPIC

LIVER

Principal Investigator & Institution: Dupuis, Robert; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYCOPHENOLATEMOFETIL IN POST LIVER TRANSPLANT RENAL IMPAIRMENT Principal Investigator & Institution: Pinson, C Wright.; Professor & Vice-Chairman Surgery; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NITRIC OXIDE IN PLASMA & RED CELLS--HEMODYNAMIC CHANGES IN LIVER TRANSPLANT Principal Investigator & Institution: Textor, S C.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2002 Summary: The overall hypothesis behind these studies is that reversal of the vasodilation of end-stage liver disease (ESLD) and the transition to vasoconstriction of post-transplant hypertension is closely related to alterations in endothelial generation of nitric oxide, which will be reflected by changes in levels and compartmental distribution of NO in plasma and red cells. To accomplish this objective, we wish to examine: Specific Aim No. 1. Changes in plasma and RBC NO during spontaneous variations in blood pressure and peripheral resistance during a 24-hour period in patients with ESLD and four months after liver transplantation. Our hypothesis is that plasma NO levels

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and partitioning between plasma and RBC will vary in parallel with circadian changes in wall stress induced by changes in arterial pressure. Specific Aim No. 2. Changes in plasma and RBC NO induced during infusion of excess substrate (L-arginine), which normally leads to systemic and renal vasodilation. Our hypothesis is that L-arginine excess will increase plasma NO levels in ESLD subjects, but will fail to do so in patients with impaired endothelial function, i.e. hypertension after liver transplantation. Specific aim No. 3: Changes in vasoconstrictor and vasodilator systems affecting blood flow and perfusion, specifically endothelin, prostacyclin and the renin-angiotensin system in relation to changes in plasma and RBC NO. Our hypothesis is that vasodilator effects of NO will be counterbalanced by greater activation of vasoconstrictor systems in ESLD as compared with post-transplant hypertensive patients with impaired endothelialdependent mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OLD AGE, LIFE EXTENSION, AND GERIATRICS Principal Investigator & Institution: Kaufman, Sharon R.; Professor; Institute for Health and Aging; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): The goal of this 4-year qualitative anthropological study is to investigate first, how physicians, patients age 70 and over and their families make decisions regarding the use of three groups of life-extending medical procedures (cardiac bypass, angioplasty and stent; kidney and liver transplant; and renal dialysis) and how they each respond to those procedures; and second, to identify socio-cultural issues of relevance to physicians and to society regarding the growing use of lifeextending medical procedures on elderly patients. This will be an empirical, ethnographic study based on the collection of data by in-depth interviews with physicians, patients and their families, and by participant-observation of support groups for cardiac and transplant patients and of physician-patient discussions where lifeextending procedures are discussed. There are 4 specific aims:1) to provide a descriptive account of physician, patient, and family understandings of relationships among changing conceptions of old age, health in late life and expectations about life-extending medical care; 2) to learn how physicians in different specialties are extending the lives of their elderly patients and the values underlying their decisions; 3) to learn the structural and cultural constraints on their choices for life-extending procedures; and 4) to describe patient and family choices, knowledge and values. Coding-based qualitative data analysis will be used: cross-sectional comparison, thematic analysis, case studies, and frequencies of response. The interpretive goal is to examine in detail the social, structural and medical practices and values brought to bear on the extension of life at progressively older ages. This will be the first research that comprehensively addresses medical and lay decision-making surrounding life-extending medical procedures for older persons, and the responses and experiences of physicians, patients and families to those procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ORAL HEALTH OUTCOMES IN PEDIATRIC TRANSPLANT RECIPIENTS Principal Investigator & Institution: Shiboski, Caroline H.; Assistant Professor; Stomatology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747

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Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-MAY-2005 Summary: (provided by applicant): We propose to conduct a study to explore specific oral health outcomes in relation to new generation immunosuppressants in a population of pediatric renal transplant recipients (RTRs) and liver transplant recipients (LTRs) at UCSF. Oral health outcomes of interest include mucosal diseases (e.g., candidiasis, hairy leukoplakia, ulcers, warts, lip carcinoma, non-Hodgkin's lymphoma, and Kaposi's sarcoma (KS), gingival enlargement (GE), and dental needs. The principal investigator of the proposed study is a recipient of a K23 award that bears as its central theme the study of oral health outcomes among adult RTRs. Dr. Shiboski also received a small amount of pilot funds to study utilization of dental care among medically compromised children. As part of this pilot project she has been recruiting, and administering oral health questionnaires to pediatric RTRs and LTRs at UCSF. Taking advantage of this developing research infrastructure, the goal of the present application is to request funds to conduct a prospective study among pediatric RTRs and LTRs, exploring specific oral health outcomes by following these children at 6-months intervals over a 2year period. The Specific Aims of the proposed study among pediatric RTRs and LTRs are: a. To estimate the prevalence and incidence of oral mucosal diseases and GE in relation to new immunosuppressive drug regimens, type of transplant, and time since transplant surgery; b. To estimate the prevalence of unmet dental need in relation to socio-demographic variables and time since transplant surgery; c. To collect preliminary data on any potential association between unmet dental needs (e.g., advanced caries, chronic gingival inflammation associated with GE) and history of acute graft rejection episode(s). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORGAN REPLACEMENT TECHNOLOGY ANALYSIS PROJECT (ORTAP) Principal Investigator & Institution: Stahl, James E.; Research Staff; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2007 Summary: There is a severe shortage of cadaveric organs for liver transplant. Critically ill patients compete with one another for the only therapy open to them. Only new supplies of organs or alternative therapies can address this need. The proposed research seeks to develop a model of the liver allocation system to evaluate the costs, effectivenesses and systemic implications of non-cadaveric organ replacement technologies (ORT). Using discrete event simulation (DES), the liver allocation system with and without ORTs will be modeled. DES is a modeling technique that explicitly captures the competition for limited resources, which is central to this problem. We will develop a model to estimate the health and economic effects of introducing new therapies such as tissue-engineered organs, xenotransplants, living-donor partial-liver transplants, and liver dialysis. Outcomes will include costs, quality-adjusted life-years and process measures such as waiting time and resource utilization. The model will also be used to identify performance characteristics required to make ORTs useful alternatives to cadaveric organs and help design future trials by identifying parameters which influence outcome and are not know with certainty. Finally, the model will help estimate the effects of gaming by patients and institutions and help predict the way ORTs will change the decision-making environment. Data from diverse sources such as the Optimal Timing of Liver Transplant project, UNOS and NIDDK and others will be used to derive parameter estimates for the models. Estimates of functionality, longevity, and time to production for ORTs will be derived from the literature and expert opinion.

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The candidate has previously developed and verified a model of the current liver allocation system. This model will be expanded and used to examine the following specific aims: 1) determine the role and cost-effectiveness of organ replacement therapies (ORT) that are functionally equivalent to cadaveric organs; 2) determine the role and cost-effectiveness of ORTs that are temporary or not as effective as cadaveric organ; 3) examine liver allocation policy with/without ORTs from the perspective of game theory and ethics. On completion, this project should contribute to the general knowledge of the liver allocation problem and help policy makers better understand which technologies are the best investments. The research will lay the groundwork for future R01 proposals by the candidate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OUTCOMES TRANSPLANTATION

OF

HEPATITIS

C

FOLLOWING

LIVER

Principal Investigator & Institution: Shakil, A. Obaid.; Associate Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 07-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Hepatitis C is the leading indication for liver transplantation. Patients transplanted for hepatitis C virus (HCV) disease universally develop re-infection of the allograft. The resultant hepatitis has an accelerated course. With the continued shortage of donor organs, it is crucial to develop strategies to promote long-term graft survival. We hypothesize that in the immune suppressed transplant recipient, HCV genetic features play a dominant role in disease progression. The principal goal of this proposal is to determine the impact of HCV genomic variability on the outcome of recurrent hepatitis C in liver allograft recipients. We propose to examine clinical and viral data under three different scenarios to test the hypothesis that an association exists between levels of genetic diversity in HCV and the severity of recurrent hepatitis following transplantation. We will assess the levels of viral diversity prior to and following liver transplantation in a group of individuals from whom samples and clinical outcomes are available. Further, to gain a more clear understanding of changes in viral evolutionary dynamics associated with liver transplantation, we will track viral evolutionary changes at several time points leading to and immediately following transplantation in a small number of individuals. This study will test the presence of a relationship between viral diversity and transplantation outcome, as defined by the severity of hepatitis on allograft biopsy one year following transplantation. It will also reveal changes in viral evolutionary dynamics over a window encompassing liver transplantation. Much of the genetic analyses will be undertaken by Heteroduplex Mobility Assay (HMA). Selected samples that show interesting profiles in HMA will be sequenced and examined by phylogenetic analyses. Clinical evaluation will include recipient and donor demographics, details of immunosuppression and episodes of rejection, and graft and patient survival. Patients will be categorized to have mild or severe disease. The two groups will be compared for differences in clinical and laboratory variables including the HMA score. A statistical model will be created to predict severe disease. If validated such a model will greatly enhance our ability to optimize transplant outcomes. Completing the specific aim of this proposal may also provide valuable information about key aspects of host-viral interactions and the influence of such interactions on disease course. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS AND TREATMENT OF CHRONIC REJECTION Principal Investigator & Institution: Murase, Noriko; Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2003 Summary: (Adapted from the applicant's abstract): This investigation postulates that chronic rejection of allografts is caused by the elimination of donor antigen presenting cells residing in the graft, and that through retention of these cells, promotes low grade stimulation of the recipient s immune system leading to prevention of CR. An animal model as been developed to test this hypothesis. Animals are pretreated with donor bone marrow or a hepatic allograft in concert with Tacrolimus. Donor microchimerism persists for at least 100 days, and then, the animals are challenged with a heterotopic cardiac allograft (CCA). The PI has found that animals previously receiving a liver allograft do not experience CR while those that receive bone marrow do. The hypothesis is advanced that the liver provides the stromal elements for survival of donor hematopoietic stem cells which protect cardiac allografts from CR. In contrast, with animals receiving donor bone marrow, there is induction of a strong Th-1 type cell response due to a loss of microchimerism, which leads to CR. In this project, the PI proposes to study the mechanisms responsible for lymphocyte trafficking and cellular activation, the influence of persistent donor antigen presenting cells on the incidence and intensity of CR and whether maneuvers for augmentation of donor chimerism in human liver transplant patients lowers the severity of CR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PH III: CELLCEPT IMPAIRMENT ON NEORAL

IN

LIVER

TRANSPLANT

W/

RENAL

Principal Investigator & Institution: Clavien, Pierre A.; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACODYNAMIC THRESHOLDS OF IMMUNOSUPPRESSION Principal Investigator & Institution: Sindhi, Rakesh K.; Children's Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 15213

Hosp

Timing: Fiscal Year 2002; Project Start 04-SEP-2001; Project End 31-MAY-2005 Summary: (provided by applicant): Acute rejection or side effects occur in nearly half of all transplant patients receiving immunosuppression. During our studies with regimens of (SRL) sirolimus+cyclosporine/tacrolimus (CsA/TAC), cytokine and costimulatory cell surface proteins (biomarkers), have demonstrated sensitivity to clinically relevant immunosuppressive drug concentrations in mitogen-stimulated peripheral blood lymphocytes (PBL) from normal and transplanted human subjects. Effect: concentration (pharmacodynamic, PD) relationships between biomarkers and drug concentrations also indicate ability to measure single- and multiple-agent effects within combination regiments, and to predict the amount of drug needed to inhibit a certain amount of biomarker, both for patient populations and individuals. However, prior to use as measures of immunosuppressive effect, the amount of biomarker inhibition associated with clinical conditions representing insufficient, excessive and adequate immunosuppression must be known. This may define safe amounts of drugs for

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Liver Transplant

children, who experience a higher incidence of life-threatening complications of immunosuppression such as post-transplant lymphoproliferative disorder. Therefore, the specific aim of this project is to measure biomarker expression during a planned pharmacokinetic (PK) evaluation of a SRL+TAC regimen in 40 children with liver transplants, relate it to amount of drug, and to determine whether the occurrence of acute rejection, side effects and stable post-transplant course can be related to threshold levels of biomarker inhibition or the amount of drug associated with such thresholds. During a sponsored clinical trial of SRL+TAC, our proposal will manage biomarker data as follows: 1. Measure mitogen-stimulated expression of the cytokines IL-2, TNF-alpha and IFN-gamma in T-cells, and of costimulatory proteins CD54 (intercellular adhesion molecule-1), CD86 (B7.2) and CD95 (Fas antigen) in B-cells, and the proliferative response of lymphocytes to donor antigen. This will be performed during PK studies planned in the clinical trial, and additionally, during rejection, side effects, and at 12, and 24 month after transplantiation. 2. PD modeling to predict biomarker thresholds or drug concentrations associated with them, which are related to the occurrence of acute rejection, side effects, and the stable post-transplant course. Potential benefits may include customized regimens in the future, and decreased complications in one-half of the nearly 40,000 new transplant recipients of solid organ and bone marrow grafts, each year. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACOKINETICS OF ABBOTT CYCLOSPORINE FOLLOWING LIVER TRANSPLANT Principal Investigator & Institution: Pruett, Timothy L.; Professor of Surgery; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PREDICTING OUTCOME--ALCOHOLIC LIVER TRANSPLANT PATIENTS Principal Investigator & Institution: Dimartini, Andrea F.; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2004 Summary: APPLICANT'S ABSTRACT: Alcoholic Cirrhosis is the most common reason for liver failure and the largest diagnostic category receiving liver transplantation. However, factors that shape policy, treatment choices, candidate selection, and public options are strongest against this group. Without guidance from rigorous research data, the future for alcohol cirrhotics pursuing transplantation is uncertain. To date, no studies of outcome in alcoholic cirrhotics have used alcohol research measures or models, as proposed herein. In the transplant literature there is a lack of consistency in relapse definitions, timing or methods of follow-up, or use of post-transplant factors to predict alcohol use. This proposed research will expand the primary aim of alcohol research which is to identify and explain the factors that shape alcohol use and its consequences in various populations. To investigate outcome in alcoholic cirrhotics undergoing liver transplantation, expertise in psychiatry, medicine, transplantation, and alcoholism is needed. The applicant, an M.D. board certified in psychiatry, has the basic requisite skills to embark on this line of research. Through five years of clinical work evaluating, treating, and following alcoholic cirrhotic patients pursuing transplantation

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the applicant has developed a high degree of clinical acumen as well as the necessary connections to one of the largest liver transplant teams in the U.S. This Mentored Clinical Scientist Development Award will allow the applicant the opportunity to consolidate clinical skills in conjunction with a structured educational program and mentored research. During the award period, the candidate will conduct a prospective longitudinal study of alcohol use following liver transplantation, while investigating pre-transplant and post-transplant factors hypothesized to influence return to drinking. This research experience will be complemented by career development activities supervised by pioneering researchers in addictions, transplantation, and psychiatric research. The proposed plan is designed to develop the candidate's expertise in: 1) longitudinal study design and analysis; 2) alcohol relapse identification and monitoring; 3) conceptual and analytic modeling of relapse factors; and 4) post-transplant alcohol use outcome, and will give her the necessary skills to become an independent academic researcher in addictions and transplantation research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROTEOMICS AND BIOMARKERS FOR HEPATOCELLULAR CANCER Principal Investigator & Institution: Afdhal, Nezam H.; Associate Professor of Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 25-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Hepatitis C (HCV) is the commonest cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) in the United States. HCC occurs primarily in patients with advanced fibrosis and cirrhosis from HCV. Current screening techniques involve the use of serum alfafetoprotein and liver imaging with ultrasound performed in high risk patients on a 3 to 6 monthly basis. Early detection can improve outcomes with liver transplantation and perhaps non-surgical therapies. However screening is not very effective and many patients present with large tumors or multifocal HCC with a median survival of only 6 months. There is a definite clinical need for better non-invasive biomarkers for HCC which can lead to early detection and treatment. The specific aims of this exploratory R21 proposal are to utilize a proteomic approach to identify novel biomarkers for HCC and then evaluate these biomarkers in a cohort of patients with HCV at high risk for HCC. The initial step will be identification of a matching group of patients with a high risk of HCC and those who have developed HCC during the prospective COPILOT study. The COPILOT study provides a large cohort of patients with HCV and cirrhosis who are randomized to treatment with either low dose PEGylated interferon alfa 2b or colchicine and are followed for 4 years with rigorous clinical screening for HCC. The study is in year 2 and the incidence of HCC is approximately 5%. Serum from these patients prior to and after the development of HCC is stored and will be utilized for proteomic studies. Tissue from normal liver and HCC is available from these patients who have undergone liver transplant. A control disease serum bank from patients with HCC unrelated to HCV is also available at BIDMC. The serum and tissue will be examined by proteomics for identification of novel biomarkers using SELDI-TOF mass spectrometry. Careful clinical characterization and matching will assist in the bioinformatic approach necessary to identify candidate biomarkers. Novel proteins and peptide biomarkers will be sequenced and identified and an ELISA will be developed for any promising candidate biomarkers. The candidate biomarker ELISA will then be validated in the large HCV serum bank at BIDMC of patients with all stages of HCV and those in the COPILOT

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Liver Transplant

trial. These studies may lead to identification of more specific and sensitive biomarkers for HCC in HCV which can then be validated further in prospective clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: QUALITY TRANSPLANTATION

OF

LIFE

IN

CHILDREN

AFTER

LIVER

Principal Investigator & Institution: Alonso, Estella M.; Children's Memorial Hospital (Chicago) Chicago, Il 606143394 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2004 Summary: The long-term goal of this study group is to improve outcome, quality of care, and promote cost-savings for pediatric liver transplant (LT) recipients. The primary objectives of the proposed study are to describe the health-related quality of life (HRQOL) of children who survive liver transplantation (LT) and to examine the impact of disease severity at transplant and the type of graft received (living-donor (LD) or cadaveric) on long-term HRQOL. The study will be conducted at five medical centers selected from the Studies of Pediatric Liver Disease (SPLIT) research network. SPLIT is a consortium of 38 centers in North America, established in 1995 to prospectively collect demographic and clinical outcome data from a large cohort of children receiving LT. Multi-center collaboration is needed to enroll a sufficient sample size to achieve the current study objectives. This is a cross-sectional study that will evaluate 150 children aged 2-18 years at the two-year anniversary of their transplant. Parents of these children will complete Child Health Questionnaire and the Family Assessment Device. These surveys are carefully validated multi-dimensional tools that have been used to test both normative and clinical samples. Data from these surveys will include measures of physical and mental health, role function, social limitations and family function. Patient demographic information and clinical data, both past and present, will be obtained from the SPLIT database and tested as predictors of these domains of HRQOL. Specifically, this project will test the hypothesis that children who have more advanced liver disease at the time of LT have lower HRQOL in long-term follow-up. It will also evaluate whether the LD LT process improves long-term HRQOL and family function as compared to cadaveric transplantation. Assessing the HRQOL of children following transplant is an important aspect of predicting their ongoing needs. HRQOL measures could be used to demonstrate to payers and policy makers the value of those interventions which may not affect traditional clinical outcomes but which may have great impact on patients? overall well being and ability to function in society. Selecting clinical options and interventions that maximize long-term HRQOL would help reduce the burden of care over time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECURRENT HEPATITIS B AFTER LIVER TRANSPLANTATION Principal Investigator & Institution: Lok, Anna S.; Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2008 Summary: Hepatitis B accounts for approximately 5000 deaths/yr in the United States. Early results with orthotopic liver transplantation (OLT) for hepatitis B were poor with recurrence rates of >80% and 2-year mortality rates of 50%. Recent studies found that continuous high dose IV hepatitis B immune globulin (HBIG) can decrease the rate of reinfection to