This volume represents a series of papers presented at the Second International Workshop on HPV Immunology held at the University of Cambridge July 5-7 1993. This Workshop and its predecessor held in Amsterdam in May 1992 were two of the major activities of the European Concerted Action "Immunology of Human Papillomavirus and Vaccine Development." The Concerted Action (CA) was supported by grants from the Commission of the European Communities (EC), the French Association for Cancer Research (ARC) and the European Association for Medical Research (EAMR). Twenty two laboratories throughout Europe and Scandinavia were members of the CA, the objectives of which were to develop collaborations, implement scientific exchanges and co-operate in a collective effort to develop vaccination strategies for HPV. HPV's are ubiquitous pathogens and evidence which has been accumulated over the past decade leaves little doubt that infection with certain HPV types (the so called "oncogenic HPV's" 16, 18 and their relatives) is the major risk factor in the development of cancer of the uterine cervix in women. Since an infectious agent, a virus, is implicated as the main aetiologic factor in this disease, the possibility is raised that if one could prevent HPV infection or treat established infections this would be an effective anti-cancer strategy against what is the commonest cancer in women worldwide."

Chronic obstructive pulmonary disease (COPD) ranges amongst the commonest diseases in the world. The relentless progression of the disease causes a pressing need for a better understanding of and therapies for COPD. This volume provides state-of-the-art information on the pathophysiology of COPD including an outlook on new therapies. It is of interest to researchers and clinicians in academia as well as in the pharmaceutical industry.

VEGF and Cancer is a comprehensive and up to date review of current knowledge on the role of vascular endothelial growth factor (VEGF) in cancer. Key Features: -Discussion of VEGF as potent angiogenic factor and its role in tumor angiogenesis, -Review of the biology, molecular properties and regulation of VEGF, -Discussion of the role of VEGF in a range of different tumor types, both solid tumors and haematological cancers, -Review of the therapeutic potential of different approaches to block VEGF, -Review of recent evidence that in addition to its role as an endothelial cell mitogen, VEGF may also be an autocrine growth factor for tumor cells, regulating survival and invasion. This book is aimed at scientists new to angiogenesis and VEGF biology and provides new information for established researchers and scientists. It will also be a useful text for clinicians interested in anti-angiogenic therapy for treatment of human cancers.

From the preface: "Pathologists are responsible for the interpretation of tissue samples removed for the purpose of establishing a diagnosis. This textbook has been conceived and arranged in a manner that facilitates the task of arriving at a diagnosis through the evaluation of tissues removed from patients afflicted with neurological complaints. The portion of the diagnostic work-up that is purely "clinical", such as the history of the disease and the results of the physical examination are entirely beyond the scope of this textbook...Extensive descriptions of disease processes, which are available in most of the references cited, have been omitted in favor of relatively detailed descriptions and abundant illustrations of the histologic abnormalities that, as a group, constitute a diagnostic entity."

Reproduction is, it would appear, a very simple biological event: the result of an act of love. In actual fact, it has always been, and still continues to be, one of the most complex, yet at the same time, most fascinating, problems, with which Science has ever been engaged. Physiopathology of human reproduction has always made use of investigations of a morphological nature, perhaps on account of the need to "see inside" the reproductive apparatus or within the gonads themselves in order to better understand how they function. Observation of spermatozoa practically coincided with the discovery of the microscope, and histological study of the testis and ovary was, for a very long time, the only means available with which to closely follow the evolution of gametes destined to their meeting. Improvement of techniques resulting from the evolution of endocrinology of reproduction has only apparently put aside morphological techniques, whilst at the same time there has been a gradual development of ultrastructural techniques, on the one hand, and, on the other, macroscopic diagnostic systems through images.

It is well known that estrogen is "somehow a protective hormone for various age-related disorders. This book provides a solid knowledge of estrogen s neuroprotective activities in the brain with a special emphasis on neurodegenerative disorders such as Alzheimer s Disease. The focus is (1) to describe the biochemical, molecular, and cellular basis of the protective activity of estrogen and (2) to transfer this knowledge into the hospitals by discussing preventive and therapeutic approaches such as estrogen replacement therapy for post-menopausal women. Besides up-to-date information on estrogen and the brain, this book explains in a highly understandable manner molecular and cellular techniques by which basic data have been collected. The reader, which may include the professional specialist as well as the interested non-specialist, will also gain insight into the scientific transfer process of knowledge from basic science to the clinical situation and therefore "from bench to bed ."

This year marks the tenth anniversary of the International Symposium on Medical Virology. In the Foreword to the book of the 1980 Symposium, we stated, "However, the challenges still lying ahead are more numerous than our past accomplishments". Little did we know at the time, that within a few years the spread of human immunodeficiency virus type I was going to occur. This worldwide epidemic has, like no other disease in recent history, awakened the scientific community and the public at large. It is a reminder to all of us that regardless of our vast technical advances, Nature provides such great opportunity for biological diversity, that it will always be one step ahead of our scientific knowledge. Although our understanding of virology, molecular biology and immunology have increased by leaps and bounds over the last decade, we are still at the point of being unable to effectively control the spread of this viral infection. We hope that our Symposium this year has helped researchers to come together and exchange' ideas, so that our growing knowledge of viral infections will help produce better approaches to control them. Luis M. de la Maza Irvine, California Ellena M. Peterson March, 1991 v ACKNO~EDGEMENTS It would be impossible to single out all those individuals who helped us make this Symposium a reality, however, we would like to take this oppor tunity to express our appreciation for their efforts.

This book is based upon a series of papers originally presented at a NATO Advanced Studies Workshop of the same title held at the study Center HI Cappuccini," a converted monastery in San Miniato, a small village located between Pisa and Florence, Italy, in October 1991. Authors were asked to submit their completed chapters by the following February; these were then scanned onto computer disks, edited and returned to the authors for final revision, and updating, with a final deadline of February 1993. The authors were encouraged to make whatever modifications they wanted, especially regarding updating their chapters, with an eye to making the final product both comprehensive and current. In this we succeeded beyond our expectations, with most chapters extensively altered and many completely re-written and significantly expanded. Thus, although the original meeting was held in 1991, the chapters in this volume may be regarded as current from at least February, 1993, with some of the final updated revisions received as late as July, 1993. This book, as agreed in our original contract, has been delivered to the publisher "camera-ready. " This means that all of the scanning, editing, proofing and typesetting were done here, by the office of the Department of Dermatology at the New Jersey Medical School. We essentially produced the book, which the publisher, for the most part, then photocopied. This has been an enormous burden, borne mainly by my colleague in this division, Robert A.

The first Symposium on ~iammary Pathology organized by the International Society against Breast Cancer was held in Paris on December 3-7, 1979. The programme was divided into sections with morning lectures on current topics in mammary pathology given by invited speakers, followed by discussions, and, in the afternoon, emphasis on practical work, such as slide seminars, technical explanations of tissue and cell preparations for histology, cytology, electron microscopy and tissue culture work. The morning sessions were held at the Racing Club of France, 5 rue Eble, 75007 Paris and the organizers of the meeting wish to thank the RCF andits President, Mr. R. Menard for their kindness and generous help in the arrangement of the symposium. The afternoon workshops too~ place at the Institut de Pathologie et de Cytologie Appliquee {Director Professor J. de Brux) , rue des BeIles Feuilles, Paris XVI, with the help of staff members from this Institute. The editors of the Proceedings of the Symposium wish to thank the contributors for their help in providing manuscripts for publication and for complying with the instructions given by the editors and the Plenum p;ubli- shing Company. Financial supports providea by the Ligue Nationale Fran9aise contre le Cancer and the FEGEFLUC are gratefully acknowledged. It is hoped that the present volume will provide stimuli for future work on clinical and basic research in mammary pathology.

The study of atherosclerosis centered since the first decade of the present century on etiology and pathogenesis. In fact, the studies of the military academy of medicine in St. Petersburg have opened the way of inducing atherosclerosis in animals. Pathogenesis of atheroma has been studied since then in humans and animals naturally prone to the development of the disease and by a variety of dietary and other procedures. The various experimental studies allowed science to evaluate the relative importance of different factors (genetic, dietary, hormonal, pharmacological. mechanical, circulatory, etc.) in atherogenesis. Epidemiological studies as well as biochemical plasma lipid and lipoprotein estimations coupled with light microscopic, histo chemical and electron microscopic investigations decreased the gap between observations on the human and experimental animal research. The enormous literature covering this field allows the intelligent reader to formulate a comprehensive concept regarding etiological factors and pathogenesis of atherosclerosis. Its impact on pre ventive and curative medicine was however limited in scope."

For more than 35 years the Swiss Society of Neuropathology has organiseditstraditionalInternationalWinterMeeting.Themainaimofthis venue is to bring together neuropathologists and clinicians as well as neuroscientistsinterestedindiseasemechanisms.TheXVIIIthInternational WinterMeeting washeld inMarch 2000 in St. Moritz, Switzerland. The topicofthe2000Meetingwas"NeuropathologyandGeneticsofDementia." Aprogrammeofinvitedplenarylecturesofhigheducationalvalueaswellas platform andposterpresentations given by manyparticipantscoveredthe broadspectrumofdementingdisorders.Encouragedbythehighstandardof the meeting, and probably also influenced by the advent of a new Millenniumwedecided, togetherwithKluwerAcademiclPlenumPublishers, topublishtheProceedingsofthe2000Meetinginthepresentbook. The increaseofthe agedpopulation challenges social and health care systemsinindustrializedsocieties.Maintenanceofhealthandautonomyinto oldage isakeyfactor, andtheautonomyandindependenceofoldpersons crucially depend on mental health. However, neurodegenerative disorders accompanied bydementiaaffect 5-10%ofindividualsoverthe ageof65, and for the age group between 65 and 95 the prevalence of cognitive dysfunction doubles every 5 years. With this challenge in mind, Rossor discusses the clinical syndrome of dementia which encompasses an enormousvarietyofunderlyingdisorders. Over the last few years it has become apparent that many neurodegenerative disorders are characterised by protein misfolding and aberrant polymerization and may therefore be viewed as "aggregation proteopathies." Among them a substantial subsetofdementing disorders, either with or without motor dysfunction, are characterised by abundant v VI Preface neuronaland/orglialaccumulationofhyperphosphorylatedtauprotein.The molecular parametersofthese "tauopathies" are reviewed by Delacourte. Therecentdiscoverythatmutationsofthetaugenearecausativeforfamilial formsoffrontotemporaldementiaandParkinsonism(FTDP-17)broughtthe "taupathway"and the"tauopathies"tothecentrestage.Thisextraordinary breakthroughwillbecoveredbySpillantiniandGoedert.Thereisincreasing evidence that argyrophilic grain disease is much more frequent in older patients than previously thought. Tolnay et al. are reviewing recent contributionstothepathologyofthislate-onsetdementingdisorderinwhich ofamyloidbetadeposits, isalmost taupathology, inthealmosttotalabsence exclusivelyrestricted to the limbic lobe and the amygdala. Schultzet al. report an intriguing age-related progression of neuronal and glial tau pathologyinbaboonsthusrenderingthe baboonapotentialprimatemodel forage-relatedhuman"tauopathies." Gotzetal. introducetransgenicmice expressingmutated human tau as valuable animal models for reproducing formationofneuro-andglialfibrillarylesions.

This volume is divided into three sections. Section I deals with factors that regulate the development and maturation of T cells and B cells and lymphocyte traffic. The significance of C-kit, Bcl-6, IL-7, and Vav in the development of T and B lymphocytes is discussed. A role of lymphotoxins and VAP-I in trafficking of leucocytes is reviewed. Finally, the trafficking and homing characteristics of T cell and B cell subsets, and the regulation of these processes during the immune response, is presented. Section II discusses various aspects of naive and memory T cell biology, including clonal expansion, reprogramming of genes including those encoding cytokines and cytotoxic granules, changes in the expression of cell surface proteins involved in cell-cell adhesion, homing of naive and memory T cells, the role of MHC and cytokines in the maintenance of naive and memory T cells, and the characterization and differentiation of virus-specific memory T cell heterogeneity in mice and humans. Novel methods of visualization of immune cells and immune systems are reviewed in Section III.

The purpose of this book-the fourth volume of a series on Can cer Markers-is intended to provide an updated "status report" on today's use of cancer markers in the diagnosis and monitoring of can cer, with an emphasis on cancer markers detected in the serum. It has been 7 years since the publication of the last volume in this series. The 1980, 1982, and 1985 volumes covered the development of cancer markers, not only in their roles of unraveling the basic biology of can cer, but also as increasingly important players in the management of patients with cancer. During the last 7 years we have seen the applica tion of a number of markers identified by monoclonal antibodies, as well as the beginnings of the use of genetic markers defined by mo lecular probes. Measurements of oncogenes in tissues or cells prom ise many applications for the future, but as yet, these genes have not shown to be useful as serum markers of cancer. The commercial interest in serum markers for cancer, particu larly for the diagnosis and monitoring of tumor patients, is indicated in Chapter 24 by Owen, where the total worldwide market for cancer markers is projected to increase from $148 million in 1988 to $232 million in 1993. The degree of research interest in cancer markers is reflected in the fact that in 1988 a separate category for tumor mark ers was added to Index Medicus.

The discovery of the human T cell leukemia virus type I in the late 1970s heralded a new era in retrovirology. For the first time, it was demonstrated that a retrovirus could play a role in the development of a human disease, in this case adult T cell leukemia (ATL). Several years later, the acquired immunodeficiency syndrome (AIDS) epidemic began, and it was dem- strated that a retrovirus, originally designated the human T cell lymp- tropic virus type 3, was the causal agent of this syndrome. This virus, later named the human immunodeficiency virus type 1 (HIV-1), has since been extensively studied in terms of its pathogenesis as well as its ability to elicit immune responses. In that time, a tremendous amount of information has been obtained about the virus. Although recent drug regimens have been useful in significantly lowering viral loads and perhaps maintaining an asymptomatic state among individuals infected with HIV-1, an established "cure" for AIDS eludes us. In addition, the effective drug therapies are very expensive, and are not available to infected people in the third world, where greater than 90% of new infections occur. Furthermore, the development of viral resistance against the drug therapies is an additional concern. Despite extensive study, no effective vaccine has been developed. One of the problems in developing an effective vaccine against HIV-1 is the ability of the virus, particularly in the immunogenic envelop glycoprotein, to undergo amino acid hypervariability.

The title of this monograph, Brain Tumor Research and Therapy, is the name of the Conference itself, which had its inaugural meeting in the United States in 1975 andhas since progressed to the international scale. In Japan, the first conference ofits kind was organized by Dr. Takao Hoshino and me and was held at Nikko in 1980, hence its name, the Nikko Conference on Brain Tumor Research and Therapy. Though it started as a small, closed meeting, the conference has grown considerably, and in 1992 it was reorganized as the Japanese Conference on Brain Tumor Research and Therapy and was opened to all neurosurgeons and neuropathologists interested in the study of brain tumor problems and who are participating in this field. The main purpose of the Conference on Brain Tumor Research and Therapy is the candid and informed discussion of the most up-to-date developments in basic re search and clinical treatment of brain tumors. The 3rd Japanese Conference on Brain Tumor Research and Therapy was held at Nasu (Tochigi Prefecture), Japan, in No vember 1994. It was a great honor to welcome many distinguished guests from over seas who kindly attended each session and made valuable contributions.

The past 20 years have seen a surge of research into colorectal cancer, which is a reflection of the need to improve our methods of treating patients suffering from this increasingly common form of cancer. Greater knowledge of the basic mechanisms involved in colorectal carcinogenesis is an essential prerequisite to improvements in cancer prevention. In this volume the editors have brought together an impressive list of experts to cover the epidemiology, pathophysiology, morphology and basis for new diagnostic and therapeutic approaches to early detection and prevention. This broad scientific approach provides the reader with up-to-date review of our current state of knowl edge of colorectal carcinogenesis and indicates how this information can be used to generate more research and create new opportunities for diagnosis and treatment. This is a book of knowledge and ideas, some of them still at the stage of theoretical interest, but others with practical potential for the care of patients. I recommend it to those who have a research interest in colorectal carcinogenesis, as well as to readers who wish to know just how far medical scientists have progressed in their efforts to achieve the ideal of cancer prevention."

This two-volume work contains the full text of the oral and poster presentations and the general discussion at the round table discussion of the Second International Conference on Alzheimer's and Parkinson's Diseases: Basic and Therapeutic Strategies, held at the Kyoto Park Hotel in Kyoto, Japan, on November 6-10, 1989. The First Conference was held at the Aviya Sonesta Hotel in Eilat, Israel, on March 24-27, 1985. , The record of this First Conference was published by Plenum Press in 1986 as Volume 29 in Advances in Behavioral Biology, under the title "Alzheimer's and Parkinson's Diseases: Strategies for Research and Development." We are happy that the comprehensive texts of the oral and poster presentations of the Second Conference could again be published within the framework of this series. Since the First Conference in 1985, rapid progress has been made in both basic and therapeutic aspects of these diseases. About 700 scientists from allover the world participated in the Second Conference, and 300 papers were presented in oral and poster sessions. Many people and organizations have helped to organize this multi disciplinary international conference and hence have contributed to the scientific quality of these two volumes. We thank the members of the organizing committee, the organizations that provided financial support, and the contributing scientists for their enthusiastic participation.

Practicing specialists in pathology, laboratory medicine, and obstetrics comprehensively summarize the latest scientific findings and their experiences in the use and interpretation of laboratory testing in patients who are pregnant or experiencing recurrent pregnancy loss. Topics of interest include the effects of normal physiological changes on test results, test selection for diagnosis, changes in reference ranges, monitoring the pregnant patient, new technologies, and the limitations of laboratory testing. The authors not only clearly explain currently used test methods and technologies for the nontechnical reader, but also provide comprehensive details for laboratory professionals. The comprehensive appendix that compiles published normal reference ranges by first, second, and third trimester consttitutes an excellent resource for professionals caring for pregnant women.

This two-volume work contains the full text of the oral and poster presentations and the general discussion at the round table discussion of the Second International Conference on Alzheimer's and Parkinson's Diseases: Basic and Therapeutic Strategies, held at the Kyoto Park Hotel in Kyoto, Japan, on November 6-10, 1989. The First Conference was held at the Aviya Sonesta Hotel in Eilat, Israel, on March 24-27, 1985. The record of this First Conference was published by Plenum Press in 1986 as Volume 29 in Advances in Behavioral Biology, under the title "Alzheimer's and Parkinson's Diseases: Strategies for Research and Development." We are happy that the comprehensive texts of the oral and poster presentations of the Second Conference could again be published within the framework of this series. Since the First Conference in 1985, rapid progress has been made in both basic and 'therapeutic aspects of these diseases. About 700 scientists from allover the world participated in the Second Conference, and 300 papers were presented in oral and poster sessions. Many people and organizations have helped to organize this multi disciplinary international conference and hence have contributed to the scientific quality of these two volumes. We thank the members of the organizing committee, the organizations that provided financial support, and the contributing scientists for their enthusiastic participation. These two volumes follow the same publishing philosophy as the volume derived from the First Conference. They span a broad spectrum of topics and bridge preclinical and clinical concepts related to these diseases.

The Italian Study Group on Cardiomyopathies organized in Florence in April 1997, eight years after the first successful meeting, the second international symposium devoted to "Advances in Cardiomyopathies". In these years exceptional progress has been made in the field of heart muscle diseases, in clinical research as well as in molecular biology, molec- ular genetics., pathophysiology and treatment. Many of these advances were presented and discussed in Florence by a distinguished team of international experts. Hypertrophic cardiomyopathy was addressed in ten papers; in the first one Seidman reported the results obtained by the use of molecular genetic tech- niques which showed that hypertrophic cardiomyopathy is a heterogeneous disorder caused by different mutations of different genes and discussed the clinical role and significance of genetic testing. Original data regarding the natural history and prognosis of symptomatic patients were obtained in the Italian multicentric study (Cecchi, Lazzeroni), while Baroldi discussed the clinico-pathologic spectrum of the disease in severely symptomatic patients treated with heart transplantation. Sudden death in the young (Basso), the identification and management of high risk patients (Elliott), the clinical importance and the problems of detec- tion of ischemia (Camici) were deeply discussed as well as the indications and results of different types of treatment: medical, surgical, DDD pacing (Spirito, Betocchi, Schoendube).

Ataxia-telangiectasia or A-T is a fatal progressive neurological disease of children. The symptoms indicate disruptions in the development of such diverse body parts as cerebellum, thymus and chromosomes. The patients are unduly sensitive to ionizing radiation, immunodeficient, and a third of them develops cancer. All of this stems from defects of a single gene. Provided here is an up-to-date review of all important work in thefield. A wide spectrum of topics is covered, namely genetics, chromosome 11 mapping, radiobiology, complementation, heterozygote identification, clinical variants, biochemistry, and treatment of A-T.

As an addition to the European postgraduate training system for young neurosurgeons, we began to publish in 1974 this series of Advances and Technical Standards in Neurosurgery which was later sponsored by the European Association of Neurosurgical Societies. This series was first discussed in 1972 at a combined meeting of the Italian and German Neurosurgical Societies in Taormina, the founding fathers of the series being Jean Brihaye, Bernard Pertuiset, Fritz Loew and Hugo Krayenbuhl. Thus were established the principles of European co operation which have been born from the European spirit, flourished in the European Association, and have been associated throughout with this senes. The fact that the English language is now the international medium for communication at European scientific conferences is a great asset in terms of mutual understanding. Therefore we have decided to publish all contri butions in English, regardless of the native language of the authors. All contributions are submitted to the entire editorial board before publication of any volume for scrutiny and suggestions for revision. Our series is not intended to compete with the publications of original scientific papers in other neurosurgical journals. Our intention is, rather, to present fields of neurosurgery and related areas in which important recent advances have been made. The contributions are written by specialists in the given fields and constitute the first part of each volume.

As an addition to the European postgraduate training system for young neurosurgeons we began to publish in 1974 this series of Advances and Technical Standards in Neurosurgery which was later sponsored by the European Association of Neurosurgical Societies. This series was first discussed in 1972 at a combined meeting of the Italian and German Neurosurgical Societies in Taormina, the founding fathers of the series being Jean Brihaye, Bernard Pertuiset, Fritz Loew and Hugo Krayenbiihl. Thus were established the principles of European co operation which have been born from the European spirit, flourished in the European Association, and have throughout been associated with this series. The fact that the English language is well on the way to becoming the international medium at European scientific conferences is a great asset in terms of mutual understanding. Therefore we have decided to publish all contributions in English, regardless of the native language of the authors. All contributions are submitted to the entire editorial board before publi cation of any volume. Our series is not intended to compete with the publications of original scientific papers in other neurosurgical journals. Our intention is, rather, to present fields of neurosurgery and related areas in which important recent advances have been made. The contributions are written by specialists in the given fields and constitute the first part of each volume.

The Nato Advanced Study Institute on Humoral Immunity in Neurological Diseases became possible thanks to the active help of many people. I will not mention our colleagues at the neuroche- mical laboratory of the Born-Bunge Foundation : it was our common job. But I wish to thank : - the Nato and Dr. Kester for their aid, support and gene- rosity, - the Belgian Ministry of Foreign Affairs and Secretary-ge- neral Mr. Grandry for their help and assistance in esta- blishing valuable contacts with many foreign countries, - the Belgian Ministry of Culture for their grant, - the National Fund for Scientific Research and the Belgian Society of Neurology for their financial support. Substantial help came from the Universitaire Instelling Ant- werpen : not only financiall~ but by allowing members of their staff to assist us 'in many ways. The Belgian Friends of the Weizmann Institute and the Belgian Medical Care for Israel helped invite some participants, and many firms made a contribution to our organization. To all of them our warmest thanks.

Atlas of Selective Lymphadenectomy for Melanoma, Breast Cancer and Colon Cancer emphasizes a multidisciplinary approach combining the experiences of a nuclear medicine physician, surgeon, and pathologist. This is an important reference also for researchers and clinicians who want to become familiar with sentinel lymph node mapping. The underlying thesis in solid tumor biology is that metastasis in general starts in an orderly progression with lymphatic spread first to the sentinel lymph node (SLN) in the nearest lymph node basin. Therefore, the logical approach is to harvest that specific SLN for thorough analysis.