Department of Obstetrics and Gynaecology, Northern General Hospital, Sheffield University, Sheffield, UK

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1 Ovarian Cancer 3

2 Helene Harris

3 Ovarian Cancer 3 Edited by Frank Sharp Department of Obstetrics and Gynaecology, Northern General Hospital, Sheffield University, Sheffield, UK Peter Mason The Samaritan Hospital for Women, St Mary's Hospital Medical School, London, UK Tony Blackett Department of Obstetrics and Gynaecology Northern General Hospital, Sheffield University, Sheffield, UK, and Jonathan Berek Division of Gynecologic Oncology UCLA School of Medicine, Los Angeles, USA CHAPMAN & HALL MEDICAL London Glasgow Weinheim. New York Tokyo Melbourne' Madras

4 Published by Chapman & Hall, 2-6 Boundary Row, London SE1 8HN, UK Chapman & Hall, 2-6 Boundary Row, London SE1 8HN, UK Blackie Academic & Professional, Wester Cleddens Road, Bishopbriggs, Glasgow G64 2NZ, UK Chapman & Hall GmbH, Pappelallee 3, Weinheim, Germany Chapman & Hall USA, One Penn Plaza, 41st Floor, New York NY 10119, USA Chapman & Hall Japan, ITP-Japan, Kyowa Building, 3F, 2-2-1, Hirakawacho, Chiyoda-ku, Tokyo 102, Japan Chapman & Hall Australia, Thomas Nelson Australia, 102 Dodds Street, South Melbourne, Victoria 3205, Australia Chapman & Hall India, R. Seshdri, 32 Second Main Road, CIT East, Madras , India First edition Chapman & Hall Softcover reprint of the hardcover 1st edition 1995 Typeset in 10/12 pt Palatino by EXPO Holdings, Malaysia. ISBN ISBN (ebook) / Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the UK Copyright Designs and Patents Act, 1988, this publication may not be reproduced, stored, or transmitted, in any form or by any means, without the prior permission in writing of the publishers, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publishers at the London address printed on this page. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in the book and cannot accept any legal responsibility or liability for any error or omissions that may be made. A catalogue record for this book is available from the British Library Library of Congress Catalog Card Number: ~ Printed on acid-free text paper, manufactured in accordance with ANSI/NISO Z (Permanence of Paper).

5 Contents List of contributors Preface Helene Harris Memorial Trust Introduction ix xvii xix Part One GENETICS OF OVARIAN CANCER 1 The genetic epidemiology of ovarian cancer 3 D.F. Easton, D. Ford, F.E. Matthews and J. Peto 2 Genetic epidemiology of familial ovarian cancer in Utah 13 D.E. Goldgar, K. Rowe, CM. Lewis, M. McDonald, K. Gholami, L. Cannon-Albright and M. Skolnick 3 Isolating tumour suppressor genes relevant to ovarian carcinoma - the role of loss of heterozygosity 23 W.o. Foulkes and J. Trowsdale 4 The BRCA1 gene in sporadic breast and ovarian cancer 39 D.M. Black and E. Solomon 5 Allele losses on chromosome 17 in ovarian tumours 45 CM. Steel, D.M. Eccles, L. Gruber, M. Wallace, A. Lessels, J.M. Morsman, H. Gabra, R.CF. Leonard and B.B. Cohen 6 Cloning and molecular characterization of monoclonal antibody-defined ovarian tumour antigens 53 I.G. Campbell, w.o. Foulkes, T.A. Jones, L.G. Poels and J. Trowsdale 7 New insights into the genetics of human ovarian epithelial tumor development 61 S. Zweizig, J. Zheng, M. Wan, T.M. Kim, M. Velicescu, J. Gosewehr and L. Dubeau Part Two TUMOUR BIOLOGY 8 Molecular and biological factors in the pathogenesis of ovarian cancer 77 J.S. Berek and o. Martfnez-Maza 9 Cytokines and ovarian cancer 89 M.S. Naylor, F. Burke and F.R. Balkwill 10 Growth factors and receptors in ovarian cancer 99 R. Leake, A. Barber, O. Owens, S. Langdon and B. Miller 11 Cell growth regulation in ovarian cancer: tyrosine kinases, tyrosine phosphatases and tumour necrosis factor-a 109 R.C Bast Jr, J. Wiener, S. Kassim, S. Wu, CM. Boyer, K. De Sombre, J.A. Hurteau, G. Rodriguez, G.B. Mills and A. Berchuck v

6 Contents 12 TNF, LT AND IL-l natural inhibitors (soluble receptors and receptor antagonists) in women with ovarian cancer 115 G. Granger, T. Gantanaga, R Burger, E. Grosen, M. Berman and P. DiSaia 13 Activation of human ovarian cancer cells: role of lipid factors in ascitic fluid 121 Y. Xu and G.B. Mills Part Three EARLY OVARIAN CANCER AND BORDERLINE TUMOURS 14 Update on early ovarian cancer and cancer developing in benign ovarian tumors 139 RE. Scully, D.A. Bell and G.M. Abu-Jawdeh 15 Spontaneous transformation of the ovarian surface epithelium and the biology of ovarian cancer 145 H. Salazar, A.K. Godwin, L.A. Getts, J.R Testa, M. Daly, N. Rosenblum, M. Hogan, RF. Ozols and T.e. Hamilton 16 Human ovarian surface epithelium: growth patterns and differentiation 157 N. Auersperg, S.L. Maines-Bandiera and P.A. Kruk 17 Management of low malignant potential ovarian tumors 171 W.R. Robinson 18 Cellular DNA content: the most important prognostic factor in patients with borderline tumors of the ovary. Can it prevent overtreatment? 181 J. Kaern, e.g. Trope, V. Abeler and E.O. Pettersen 19 Complementary and coordinate markers for detection of epithelial ovarian cancers 189 Re. Bast Jr, F. Xu, RP. Woolas, Y. Yu, M. Conaway, K. O'Briant, L. Daly, D.H. Oram, A. Berchuck, D.L. Clarke-Pearson, J.T. Soper, G. Rodriguez and I.J. Jacobs Part Four CHEMOTHERAPY, RADIOTHERAPY AND ETHICS 20 Chemotherapy options in ovarian carcinoma - a dose intensity perspective 195 L. Levin 21 Drug resistance in ovarian cancer and potential for its reversal 203 T.e. Hamilton, S. W. Johnson, A.K. Godwin, M.A. Bookman, P.J. O'Dwyer, K. Hamaguchi, K. Jackson and RF. Ozols 22 Taxol and Taxotere: new drugs of interest in the treatment of advanced ovarian cancer 215 M.J. Piccart 23 The European-Canadian study of pac1itaxel in ovarian cancer. High vs low dose; long vs short infusion 225 K.D. Swenerton and E.A. Eisenhauer 24 Intraperitoneal recombinant interferon-gamma in ovarian cancer patients with residual disease at second look laparotomy 231 E. Pujade-Lauraine, J.P. Guastalla, N. Colombo, E. Francois, P. Fumoleau, A. Monnier, M.A. Nooy, L. Mignot, R Bugat, e.m.d. Oliveira, M. Mousseau, G. Netter, F. Maloisel, S. Larbaoui, P. Devillier and M. Brandely vi

7 Contents 25 Matrix metalloproteinases and their role in ovarian cancer B. Davies, M.S. Naylor and F.R. Balkwill 26 Signal transduction therapy: a new paradigm E.e. Kohn 27 Radiotherapy as salvage or consolidation therapy in advanced epithelial ovarian cancer C.M. Thomas 28 Ethical decision making in the care of seriously ill and dying patients. Theory and practice E.f. Latimer Part Five IMMUNOTHERAPY AND GENE THERAPY 29 Overcoming drug resistance of ovarian carcinoma cell lines by treatment with combination of TNF-a/anti-Fas antibody and chemotherapeutic drugs or toxins 295 B. Bonavida, J.T. Safrit, H. Morimoto, Y. Mizutani, S. Yonehara and J.S. Berek 30 Potential for immunotherapy: PEM as a target antigen 305 J. Taylor-Papadimitriou, N. Peat, J. Burchell, P. Beverley and M. Smith 31 Ovarian tumour reactive cytotoxic T lymphocytes can recognize peptide determinants on polymorphic epithelial mucins Muc e.c. Ioannides, B. Fisk, K.R. Jerome, B. Chesak, T. Irimura, R.S. Freedman, J.T. Wharton and O.f. Finn 32 Use of bifunctional monoclonal antibodies for retargeting human lymphocytes against ovarian carcinoma cells 331 M.I. Colnaghi 33 Active specific immunotherapy (ASI). An immunological approach to ovarian cancer treatment 339 CD. MacLean and B.M. Longenecker 34 Antibody targeting of ovarian cancer: recombinant single-chain fragments and the role of internalization 347 M.A. Bookman, B.J. Giantonio and J. Schultz 35 Carcinoembryonic antigen (CEA) promoter directed tissue specific gene expression in CEA expressing tumour cells 357 D.F. Via, J.M. DiMaio, K.R. Berend, P.B. Jordan and H.K. Lyerly Part Six CONCLUSIONS AND RECOMMENDATIONS Conclusions and recommendations 369 Index 381 vii

8 Contributors v. Abeler Dept of Pathology, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway G.M. Abu-Jawdeh Dept of Pathology, Beth Israel Hospital, Boston, MA 02215, USA N. Auersperg Dept of Anatomy, University of British Columbia, 2177 Westbrook Mall, Vancouver, British Columbia V6T lz3, Canada F.R. Balkwill Inn Fields, London WC2A 3PX, UK A. Barber Dept of Biochemistry, University of Glasgow, Glasgow G12 8QQ, Scotland R.C. BastJr Division of Medicine, Box 092, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA D.A. Bell Dept of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA A. Berchuck Dept of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA J.S. Berek Professor and Vice-Chair, Chief of Gynecology and Gynecologic Oncology, UCLA School of Medicine, The Jonsson Comprehensive Cancer Center, Los Angeles, CA , USA K.R. Berend Duke University Medical Center, Durham, NC 27710, USA M. Berman Dept of Obstetrics and Gynecology, Clinical Cancer Center, University of California, Irvine Medical Center, Orange, CA, USA P.Beverley ICRF Tumour Immunology, Courtauld Institute of Biochemistry (UCH), 91 Riding House St., London WIP 8BT, UK D.M. Black Beatson Institute for Cancer Research, Garscube Estate, Switchback Rd, Bearsden, Glasgow G61 lbd, UK B. Bonavida Dept of Microbiology and Immunology, UCLA School of Medicine, University of California, Le Conte Avenue, Los Angeles, CA 90024, USA ix

9 Contributors M.A. Bookman Avenue, Philadelphia, P A 19111, USA CM. Boyer Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA M. Brandely Roussel-Uelaf, Romainville, France R. Bugat Purpan Hospital, Toulouse, France J. Burchell Inn Fields, London, WC2A 3PX, UK R. Burger Dept of Obstetrics and Gynecology, Clinical Cancer Center, University of California, Irvine Medical Center, Orange, CA, USA F. Burke Inn Fields, London WC2A 3PX, UK I.G. Campbell of University of Southampton, Dept Obstetrics and Gynaecology, Princess Anne Hospital, Southampton, UK L. Cannon-Albright Dept of Internal Medicine, University of Utah, 420 Chip eta Way, Salt Lake City, UT 84108, USA B. Chesak Dept of Gynecologic Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA D. Clarke-Pearson Dept of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA B.B. Cohen MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland M.1. Colnaghi Division of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian I, Milan, Italy N. Colombo San Gerardo Hospital, Monza, Italy M.Conaway Dept of Community and Family Medicine, Duke University Medical Center, Durham NC 27710, USA L. Daly Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA M. Daly Avenue, Philadelphia, P A 19111, USA B. Davies Inn Fields, London WC2A 3PX, UK K. De Sombre Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA P. Devillier Roussel-Uelaf, Romainville, France J.M. DiMaio Dept of Surgery, Box 3551, Duke University Medical Center, Durham, NC 27710, USA P. DiSaia Dept of Obstetrics and Gynecology, Clinical Cancer Center, University of California, Irvine Medical Center, Orange, CA, USA x

10 L. Dubeau Dept of Pathology, Kenneth Norris Jr Comprehensive Cancer Center, 1441 Eastlake A venue, Los Angeles, CA 90033, USA D.F. Easton Institute of Cancer Research, 15 Cotswold Rd, Belmont, Surrey, UK D.M. Eccles CRC Genetic Epidemiology Research Group, \ Dept of Child Health, University of L.A. Getts Southampton, Southampton, UK E.A. Eisenhauer NCIC Clinical Trials Group, Queen's University, Barrie St., Kingston, Ontario K7L 3N6, Canada O.J. Finn Dept of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Contributors P. Fumoleau Centre Rene Gauducheau, Nantes, France H. Gabra ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, Scotland T. Gatanaga Dept of Molecular Biology and Biochemistry, University of California, Irvine, CA K. Gholami Dept of Medical Informatics, University of Utah, 420 Chipeta Way, Salt Lake City, UT 84108, USA B.J. Giantonio B. Fisk Dept of Gynecologic Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA D. Ford Institute of Cancer Research, 15 Cotswold Rd, Belmont, Surrey, UK W.D. Foulkes Division of Medical Genetics, McGill University, Montreal General Hospital, 1650 Avenue Cedar, Montreal, Quebec, H3G la4, Canada E. Francois Centre Fran<;ois Lacassagne, Nice, France R.S. Freedman Dept of Gynecologic Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA A.K.Godwin D.E. Goldgar Dept of Medical Informatics, University of Utah, 420 Chipeta Way, Salt Lake City, UT 84108, USA J. Gosewehr Dept of Gynecologic Oncology, Kenneth Norris Jr Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA G. Granger Dept of Molecular Biochemistry, University of California, Irvine, CA , USA E. Grosen Dept of Obstetrics and Gynecology, Clinical Cancer Center, University of California, Irvine Medical Center, Orange, CA, USA xi

11 Contributors L. Gruber MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland J.P. Guastalla Centre Leon Berard, Lyon, France K. Hamaguchi T.e. Hamilton M.Hogan J.A. Hurteau Dept of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA e.g. Ioannides Dept of Gynecologic Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA T.lrimura Dept of Tumor Biology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA K. Jackson I. Jacobs Dept of Obstetrics and Gynaecology, Rosie Maternity Hospital, Cambridge CB2 2SW, UK K.R. Jerome Dept of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, P A 15213, USA xii S.W. Johnson Avenue, Philadelphia, P A 19111, USA T.A. Jones Inn Fields, London WC2A 3PX, UK P.B. Jordan Dept of Surgery, Box 3551, Duke University Medical Center, Durham, NC 27710, USA J. Kaern Dept of Gynecology, Norwegian Radium Hospital, Montebello, N-031O Oslo, Norway S. Kassim Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA T.M.Kim Dept of Pathology, Kenneth Norris Jr Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA E.e. Kohn Laboratory of Pathology, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA P.A.Kruk Gerontology Research Center, Laboratory of Molecular Genetics, 4940 Eastern Avenue, Baltimore, MD 21224, USA S.Langdon ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, Scotland S. Larbaoui Roussel-Ucla, Romainville, France E.J. Latimer Palliative Care Program, Henderson General Hospital, 711 Concession St East, Hamilton, Ontario L8V IC3, Canada

12 Contributors R. Leake Dept of Biochemistry, University of Glasgow, Glasgow G12 8QQ, Scotland R.CF. Leonard ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, Scotland A. Lessels Dept of Pathology, Western General Hospital, Edinburgh, Scotland L. Levin London Regional Cancer Center, 790 Commissioners Rd East, London, Ontario N6A 4L6, Canada CM. Lewis Dept of Medical Informatics, University of Utah, 420 Chip eta Way, Salt Lake City, UT 84108, USA B.M. Longenecker Dept of Immunology, Faculty of Medicine, University of Alberta T6G 2H7, Canada U.K. Lyerly Dept of Surgery, Box 3551, Duke University Medical Center, Durham, NC 27710, USA G.D. MacLean Medical Oncology Unit, Cross Cancer Institute, University Avenue, Edmonton, Alberta T6G 1Z3, Canada S.L. Maines-Bandiera Dept of Anatomy, University of British Colombia, 2177 Westbrook Mall, Vancouver, British Colombia T6G lz3, Canada F. Maloisel Centre Paul Strauss, Strasbourg, France o. Martinez-Maza Dept of Microbiology and Immunology, UCLA Medical School, Los Angeles, USA F.E. Matthews Institute of Cancer Research, 15 Cotswold Rd, Belmont, Surrey, UK M.McDonald Dept of Medical Informatics, University of Utah, 420 Chipeta Way, Salt Lake City, UT 84108, USA L. Mignot Foch Hospital, Suresnes, France B. Miller ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, Scotland G.B. Mills Oncology Research, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada Y. Mizutani Department of Urology, Faculty of Medicine, Kyoto University, Kyoto 606, Japan A.Monnier A. Boulloche Hospital, Montbeliard, France H.Morimoto Mayo Clinic Scottsdale, S.c. Johnson Medical Research Building, East Shea Blvd., Scottsdale, AZ 85259, USA J.M. Morsman Dept of Obstetrics and Gynecology, Plymouth General Hospital, Devon, UK M.Mousseau La Tronche Hospital, Grenoble, France M.S. Naylor Institute of Cancer Research, Haddow Laboratories, South Surrey, SM2 5NG, UK M.A. Nooy Academisch Ziekenhuis, Leiden, Netherlands xiii

13 Contributors G. Netter Clinique Courlancy, Reims, France K. O'Briant Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA P.J. O'Dwyer Avenue, Philadelphia, P A 19111, USA CM.D. Oliveira Coimbra Hospital, Coimbra, Portugal D.Oram Dept of Obstetrics and Gynaecology, University of London Hospital, London, UK O.Owens Dept of Biochemistry, University of Glasgow, Glasgow G12 8QQ, Scotland R.F. Ozols N. Peat Inn Fields, London WC2A 3PX, UK J. Peto Institute of Cancer Research, 15 Cotswold Rd, Belmont, Surrey, UK E.O. Pettersen Dept of Tissue Culture, Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway M.J. Piccart Institut Jules Bordet, Rue Heger-Bordet I, Brussels 1000, Belgium L.G. Poels Dept of Cell Biology and Histology, Catholic University of Nijmegen, 6500 HB Nijmegen, Netherlands xiv E. Pujade-Lauraine Hotel Dieu Hospital, Paris, France W.R. Robinson Dept of Obstetrics and Gynecology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA G. Rodriguez Dept of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA N. Rosenblum K. Rowe Dept of Medical Informatics, University of Utah, 420 Chipeta Way, Salt Lake City, UT 84108, USA J.T. Safrit Aaron Diamond AIDS Research Center, 455 First Avenue, 7th Floor, New York, NY 10016, USA H. Salazar J. Schultz Avenue, Philadelphia, P A 19111, USA R.E. Scully Dept of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA M. Skolnick Dept of Medical Informatics, University of Utah, 420 Chipeta Way, Salt Lake City, UT 84108, USA M. Smith Inn Fields, London WC2A 3PX, UK

14 Contributors E. Solomon Inn Fields, London WC2A 3PX, UK J. Soper Dept of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA e.m. Steel MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland K.D. Swenerton BC Cancer Agency, Vancouver Clinic, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada J. Taylor-Papadimitriou Inn Fields, London WC2A 3PX, UK J. Taylor Wharton Dept of Gynecologic Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA J.R. Testa G.M. Thomas Division of Radiation Oncology, Toronto Bayview Regional Cancer Center, 2075 Bayview Avenue, Toronto, Ontario M4N 3MJ, Canada e.g. Trope Dept of Gynecologic Oncology, Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway J. Trowsdale Inn Fields, London WC2A 3PX, UK M. Velicescu Dept of Pathology, Kenneth Norris Jr Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA D.F. Via Dept of Surgery, Box 3551, Duke University Medical Center, Durham, NC 27710, USA M. Wallace MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland M. Wan Dept of Pathology, Kenneth Norris Jr Comprehensive Cancer Center, 1441 Eastlake A venue, Los Angeles, CA 90033, USA J. Wiener Dept of Obstetrics and Gynaecology, Duke University Medical Center, Durham, NC 27710, USA R. Woolas Dept of Obstetrics and Gynaecology, Northern General Hospital, Sheffield, UK S. Wu Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA F.J.Xu Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA Y.Xu Oncology Hospital, Canada Research, Toronto General Toronto, Ontario M5G 2C4, S. Yonehara Biotechnology Institute, Tokyo Metropolitan Institute of Medical Sciences, Tokyo, Japan xv

15 Contributors Y.Yu Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA J. Zheng Dept of Pathology, Kenneth Norris Jr Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA s. Zweizig Dept of Gynecologic Oncology, Kenneth Norris Jr Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA xvi

16 Preface The Helene Harris Memorial Trust has become recognized as providing one of the most important international fora for the presentation of research in ovarian cancer. Four biennial meetings have taken place, the most recent of which was held between May 11-14, 1993, in Toronto, Canada. This forum has grown in stature from its inception in 1987 and has brought together interdisciplinary clinical and scientific researchers from around the world who are endeavouring to perform 'cutting edge' studies in the field. The assembled group of prestigious investigators met on this occasion to present their data, to exchange ideas, and to arrange collaborations with the goal of developing new means of detection, treatment and cure of ovarian cancer. The incentive for the establishment of the Trust and its international forum was the premature loss through ovarian cancer of Helene Harris, the wife of Mr John Harris. Mr Harris and the Trustees looked for a meaningful way to honour the memory of Helene and to advance the noble cause of gaining an increase in the scientific knowledge of the subject. For those of us who spend most of our waking hours assisting patients and their families who are devastated by this disease, the Trust's generosity provides inspiration, hope and the opportunity for their practical application in a unique professional forum. The excitement and enthusiasm of the scholars who have met to discuss their research on ovarian cancer is remarkable. New levels of knowledge in many aspects of the basic sciences and their clinical application have been reached during the past several years, and the Trust has made an important contribution to this achievement. Over the years, the meetings have become more innovative in their approach to the subject, as the participants have extended themselves in this special collaboration and debate. Whereas the programme of the very first Trust Forum contained only one brief session on the biology of ovarian cancer, the results of the most recent forum, contained herein, fully reflect the burgeoning biological research now influencing clinical practice. Most notably, research inquiries have developed a greater emphasis on the molecular genetics of ovarian cancer. These efforts have engendered presentations that help to focus our attention on the most fundamental methods of achieving control of aberrant ovarian growth. The programme has fostered interdisciplinary international research, as well as improved understanding of the genetics and inheritance of familial susceptibility to ovarian cancer and this, in turn, has led to considerable co-operative research into molecular control of the disease. Collating the research information and translating it into a form that can be applied in the clinic for the welfare of the patient is a critical part of the work of the Trust. This book XVll

17 Preface summarizes the topics covered in the Fourth Helene Harris Memorial Trust Biennial International Forum on Ovarian Cancer together with its conclusions and recommendations. The book also documents the Trust's commitment to support the finest efforts of all of those who are combating this disease. Frank Sharp, Sheffield Peter Mason, London Tony Blackett, Sheffield Jonathan Berek, Los Angeles xviii

18 Helene Harris Memorial Trust Introduction The Helene Harris Memorial Trust was formed in 1986 to promote communication, discussion and research into ovarian cancer on an international scale. The dialogue between scientists and clinicians covering all departments of the work has proved to be a most successful innovation. It is pleasing to note that parallel bodies using a similar format are now being set up for other types of cancer. This is the third book published for the H. H. M. T. on ovarian cancer by Chapman & Hall; they have produced yet another fine volume and I would like to express my gratitude on behalf of the H. H. M. T. The three books in the series taken together represent the largest body of work on research and current treatment of ovarian cancer available anywhere in the world and I believe that scientists, clinicians, hospitals and medical schools will find them invaluable. I would like to thank our editors, Professor Frank Sharp, Mr Peter Mason, Professor Jonathan Berek and Dr Anthony Blackett for their dedicated work which has provided a volume which will prove indispensable to everyone involved in the latest treatment and research into ovarian cancer. My thanks also to our many distinguished contributors who have voluntarily donated the presentations from which this book is compiled. A further debt of gratitude is owed to Mrs Shirley Claff and Mrs Geraldine Presland for their fine efforts in administering, liaising and transcribing the work of our varied contributors from many countries. I would also like to extend my appreciation to the Toronto Group in Academic Gynaecological Oncology and Dr Denny DePetrillo, who were our hosts for the Toronto Forum. Toronto has been in the forefront of the research work and the latest clinical practice for ovarian cancer and it was a privilege to hold our 4th Forum in Toronto and enjoy the strong input into the work and the fine cooperation of Dr DePetrillo and his colleagues. J.E. Harris xix

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