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Background Cancer is a variety of malignancies generally associated with aging. As the overall health technology and health care delivery improved with the advances made in medicine and science in the United States, the life expectancy of the population also increased. The average life expectancy in the U. S. A. has increased from 49 years at the end of 1900 to 75 years today in 1990 (1-3). The population of 65 years and older that constituted 25. 5 million or 11. 3% of the total U. S. population in 1980(4) has now increased to 31. 1 million or 12. 5% of the population according to the 1990(5) census. As cancer diagnosis and treatment have improved, cancer mortality among patients under 55 has been significantly reduced within recent years •1; however, cancer incidence under 55 is still increasing at about 0. 4% per year (as compared to 1. 0% for all ages or 0. 6% for < 65) according to the 1990 review of the 15 year trends in the Cancer Statistics Review 1973-1987, published by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI). In contrast, both cancer incidence and mortality have been increasing among the population 65 and over•2 at a rate of 1. 4% and 1. 0% respectively per year between 1973-1987(6).

During the past two decades, a significant international research effort has been di­ rected toward understanding the composition and regulation of the preocular tear film. This effort has been motivated by the recognition that the tear film plays an essential role in maintaining corneal and conjunctival integrity, protecting against microbial challenge, and preserving visual acuity. In addition, research has been stimulated by the knowledge that alteration or deficiency of the tear film, which occurs in countless individuals throughout the world, may lead to desiccation of the ocular surface, ulceration and perfo­ ration of the cornea, an increased incidence of infectious disease, and, potentially, pro­ nounced visual disability and blindness. To promote further progress in this field of vision research, the Second International Conference on the Lacrimal Gland, Tear Film and Dry Eye Syndromes: Basic Science and Clinical Relevance was held at the Southampton Princess Resort in Bermuda November 16-19, 1996. This conference was organized and directed by David A. Sullivan, Ph. D., codirected by Darlene A. Dartt, Ph. D., and Michele A. Meneray, Ph. D., and sponsored by the Schepens Eye Research Institute (Boston, MA), an affiliate of Harvard Medical School. The meeting was designed to assess critically the current knowledge and'state of the art'research on the structure and function of lacrimal tissue, tears, and the ocular sur­ face in both health and disease.

The suggestion of Max Knoll that an electron fascinated by the numerous SEM photographs, the wealth of information and the enthusiasm of the microscope could be developed using a fine scanning researchers covering a variety of disciplines. All aspects beam of electrons on a specimen surface and recording the emitted current as a function of the position of the of the female and male genital tract have been covered, beam was launched in 1935. Since then several culminating in the prizewinning award showing the in investigators and clinicians have used this concept to vitro fertilized human egg. develop techniques now known as scanning electron In clinical diagnostics SEM also proved to be a microscopy (SEM) and scanning transmission electron valuable complementary technique, shedding new light microscopy (STEM). The choice to study the female on oncology, the pathogenesis of tubal disease and the reproductive organs was a logical one because cells and maturation process of the placenta. Future research has tissue samples can be sampled relatively easily; still to be accomplished; e.g. quantification of SEM furthermore, these cells and organs are influenced photographs for meaningful and sound biological, continuously by the cyclic production of hormones. scientific and statistical evaluation in diagnostic This atlas demonstrates the state of the art in 1983. gynecology, obstetrics, andrology and oncology.

Over the past decade, techniques have been developed and implemented to observe metabolism noninvasively in localized regions of intact, living experimental animals and humans through the use of magnetic resonance spectroscopy (MRS). At the same time, magnetic resonance imaging (MRI) techniques developed in the 1970s and refined in this decade have been increasingly applied as a powerful clinical tool to probe human anatomy. Because of the unusual metabolic and physiologic characteristics of malignant tissues, oncology has been one of the primary focuses of the application of both MRS and MRI. Although considerable progress has been made in oncologic applications of magnetic resonance (MR), further research is needed to realize the full potential of MR in this area. Consequently, the 21st Annual Detroit Cancer Symposium entitled'Magnetic Resonance in Experimental and Clin­ ical Oncology'was organized to provide a forum for researchers in the field to report the state of the art of MRS and MRI in oncol­ ogy, to discuss future goals for MRS and MRI in oncology, and to define the research needed to meet those goals. The major emphasis of the symposium was on MRS due to both the recent widespread availability of clinical MRS instrumentation and the extensive amount of animal MRS research performed over the past half decade.

This volume contains the proceedings of the First International Conference on Eicosanoids and Other Bioactive Lipids in Cancer and Radiation Injury held in Detroit, Michigan on October 11-14, 1989. The program consisted of 83 oral and 29 poster presentations, 74 of which are included in these proceedings. The major sponsors of the conference were the Armed Forces Radiobiology Research Institute, located in Bethesda, Maryland, the Radiation Oncology Research and Development Center of the Gershenson Radiation Oncology Center, Harper Hospital in Detroit, Michigan, and Schering AG of West Germany. Eighteen other organizations provided additional support. The conference was unique in its attempt to link the eicosanoid and lipid researchers in the radiobiology and cancer disciplines. The diverse roles that eicosanoids and other bioactive lipids play in these biological phenomena including the participation of lipid oxidation in conversion of procarcinogens, positive and negative modulation of tumor growth, immunomodulation, tissue injury, and yet protection and enhancement of cancer therapy, necessitated scientific interaction to sort out and understand these complex and sometimes contradictory observations. The success of this effort is reflected not only through these proceedings, but also through the decision to continue the conference series with a second meeting to be held in Berlin between September 17-21, 1991.

The publication of this volume, which is based upon presentations made to the Third European Symposium on Radiopharmacology at Noordwijkerhout, April 22 - 24, 1982, is indicative of the continued interest in this sub-branch of Nuclear Medicine. The transactions of the first two meetings were published as Progress in Radiopharmacology, Volumes 1 and 2 by Elsevier/North-Holland Bio­ medical Press. We are particularly pleased to have reached an agreement with Martinus Nijhoff Publishers to include Progress in Radiopharmacology 3 in the series Developments in Nuclear Medicine. This not only ensures the continuity of the series but by including it in a series of Nuclear Medical Monographs the availability of the text to more general readers, for background information, is greatly enhanced. As with the previous two volumes each of the three topics has been so treated as to relate the biodistribution of the radiopharmaceuticals to normal and pathophysiological conditions to provide background information for the practising nuclear medical specialist. Special attention has been given to European activities but these have been clearly placed in context in relation to developments from outside Europe. The Third European Symposium on Radiopharmacology was held under the auspices of the European Joint Commitee on Radiopharmaceuticals of the European Nuclear Medicine Society and the Society of Nuclear Medicine Europe. Solco Nuclear, Basle, provided both financial and material support and I would like to thank Dr M. de Schrijver, Mr. I. Waser and Mrs. E. Rufenacht for their continued help and encouragement.

The first symposium of the working group on experimental urology of the German Society of Urology was held in Cologne in 1972. It was meant to be a platform to present and, in particular, to discuss experimental studies developing new diagnostic and therapeutic approaches, and to promote in­ novation in urology in Germany. This plan was well received, and during the last 16 years both the number of participants from other European and overseas countries and the number and quality of presentations have been continuously increasing. At the most recent meeting, held in Aachen in 1988, new data were presented on renal cell cancer, andrology, prostatic cancer and adenoma, bladder cancer, urinary diversion, urodynamics, renal pathophysiology, transplantation and the pathogenesis and treatment of urolithiasis. The present book contains 44 of the 109 papers given at the Aachen meeting, covering both basic and clinical research. It will be of eminent interest to all scientifically minded urologists, oncologists, neurophysiolo­ gists, endocrinologists, and pathologists because it is a synopsis of all the major scientific research currently being conducted in urology in Europe. There are no other books available which offer as comprehensive a cover­ age of recent experimental issues in urology. The aim of the series Inves­ tigative Urology is to demonstrate the continuous development of research in urology and to encourage all colleagues interested in experimental urol­ ogy to continue their important activities and create new international co­ operation.

Prostate cancer is not only the most common genitourinary tumor but, accord­ ing to the tumor registry of Munich, the male tumor with the highest inci­ dence. The wide range of information concerning this important disease has been dealt with comprehensively. In a time when interested urologists can surf in the internet to find an article they are looking for, they usually get lost because of the flood of papers covering the same subject. Furthermore, they are still alone in deciding which scientific contribution to believe and which will serve their patients best. A well-edited book such as this, however, provi­ des quick access to all pertinent questions. These renowned authors have taken on the responsibility of writing a balanced report and producing a sort of a guideline, i. e., a diagnostic or therapeutic standard. The editors are to be congratulated on mastering such a formidable task, bringing together the leading names in prostate cancer to present their views on all the questions one might have about this disease. I trust that this book will serve urologists in practice and their patients well. J. E. Altwein Miinchen Contents Pathology and Molecular Biology of Prostate Cancer 1 Morphogenetic Aspects of Prostate Cancer H. Bonkhoff............................................ 3 2 Cytogenetics of Prostate Cancer L. Bubendorf........................................... 13 3 Molecular Dissection of the Prostate Cancer Genome V. Srikantan, S. Srivastava................................ 25 Diagnosis and Clinical Significance of Prostatic 4 Intraepithelial Neoplasia V. Ravery, L. Boccon-Gibod...............................

Blood vessels of tumors display many structural and functional abnormalities. Their unusual leakiness, potential for rapid growth and remodeling, and expression of distinctive surface molecules mediate the dissemination of tumor cells in the bloodstream and maintain the tumor microenvironment. Like normal blood vessels, they consist of endothelial cells, mural cells and their enveloping basement membrane. Common features, irrespective of their origin, size and growth pattern, are absent hierarchy, formation of large-caliber sinusoidal vessels, markedly heterogeneous density, increased permeability, decreased and abnormal pericyte-endothelial cell adhesion, irregular basement membrane structure, and the incorporation of bone-marrow-derived endothelial progenitor cells in the microvasculature. A number of specific tumor endothelial markers have been identified, as well as chromosomal abnormalities. These markers may be used to deliver drugs specifically and selectively to the tumor microvasculature.

Cell based impedance sensing is becoming a new biophysical and cellular technology in cell based analyses. The technology has been used in investigation of cellular growth and death, cell adhesion and migration, cell invasion and cell-cell interactions, cell toxicity, angiogenesis, cell permeability, signal transduction and cellular behaviour under flow conditions. It is a probe free, highly sensitive, and versatile technology platform. Recent development in the technology has also allowed high throughput, automated analyses. It has been widely explored in chemistry, toxicity, cell biology, cancer biology, and other areas of chemistry, medicinal chemistry, life and medical science. Written by experts in the area of cell impedance sensing, including the Nobel Laureate Dr Ivar Giaever, this books covers the background of electric cell-substrate impedance sensing, their applications in cell based investigations, particularly in the area of cancer biology. This book is the first on thistechnology platform and will be a highly useful reference for molecular and cell biologists, cancer biologists, chemists and biochemists, clinical researchers who work in the areas of cell biology, molecular biology, toxicology, pharmaceutical industry, life science and medical research.

The Twelfth Annual Washington Spring Symposium on Health Sciences attracted over 300 scientists from 20 countries. It was held at the Lisner Auditorium of the George Washington University in Washington, D.C. during June 1-5, 1992. The theme of the meeting was'Growth Factors, Peptides, and Receptors,'and speakers emphasized both basic and clinical research in these areas. The seven plenary sessions emphasized Peptides, Growth Factors, Peptide Receptors, Growth Factor Receptors, Second Messengers, Proliferation, and Clinical Correlations. The chapters in this volume are derived from each of these scientific sessions plus the poster and special sessions. The Abraham White Distinguished Scientist Award was presented to Dr. Solomon H. Snyder for his numerous contributions to the field of neurochemistry. He presented the keynote address'Nitric Oxide: A Novel Neuronal Messenger.'Dr. Snyder discussed the pathway of nitric oxide (NO) synthesis by the enzyme NO synthase. Released NO may be responsible for the neuronal toxicity associated with NMDA, an excitatory amino acid analogue. Dr. Snyder noted that NO may be the first of a new class of transmitters, with carbon monoxide being another candidate. The Distinguished Public Service Award was presented to Senator Fritz Hollings in of his leadership and outstanding achievements in the United States Senate recognition and for his legislative support for biomedical research and education. In the symposium banquet address, Senator Hollings stressed the need for continued support of research to combat serious diseases such as cancer.

During the last few decades, there has been a tremendous improvement in the treatment of cancer. There is evidence that this trend is continuing, based on the achievements re­ sulting from the combined efforts of clinicians and basic re­ search workers. This book is an example of such interaction and collaboration. It was prepared by authors representing both areas of work. Most of the work reported in this book is not merely theoretical, but has been experimentally successfully tested and sometimes applied clinically. This work has, however, not yet been generalized and practiced on a wide scale. Some of the results reported here relate to new aspects and open new horizons for future progress. This book will be of great value for both clinicians and basic research workers. VICC Treatment and Rehabilitation Programme ISMAIL ELSEBAI Chairman Preface The three main approaches to the treatment of cancer are surgery, radiotherapy, and chemotherapy. Today, all malignant neoplasms are managed by one or more of these modalities, with varying success rates depending on the type of tumor, its degree of spread, and the knowl­ edge and skill with which the treatment plan has been designed and executed. In the United States of America and in Europe, approximate­ ly half of all cancer is presently curable, but this has been the case for approximately 20 years.

Starting in 1986, the European School of Oncology has expanded its activities in postgraduate teaching, which consisted mainly of traditional disease-orientated courses, by promoting new educational initiatives. One of these is the cloister seminars, short meetings intended for highly qualified oncologists and dealing with specific, controversial aspects of clinical practice and research. Another is the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on developments and treatment in specific fields of oncology. This series of ESO Monographs was designed with the specific purpose of disseminating the results of the most interesting of the seminars and study groups, and providing concise and updated reviews of the subjects discussed. It wa& decided to keep the layout very simple in order to keep costs to a minimum and make the monographs available in the shortest possible time, thus overcoming a common problem in medical literature: that of the material being outdated even before publication.

Hormonal treatment of malignant diseases has been used for quite some years now, and progress in this field is still being made at a steady pace. The detection of new endocrine feed­ back loops and the availability of new classes of hormonal agents made hormonal intervention with predictable outcome possible. Besides the intellectual challenge of modulating the hormone system, an important aspect of recent research on hormones and cancer is the reduction of treatment-related morbidity achieved with the new hormonal strategies. Thus, controlled intervention in the hypothalamic-gonadotropic axis is increasingly apt to replace surgical removal of the relevant glands, i. e., the pituitary gland or the gonads. In the same way as, for example, aromatase inhibitors are being used as a substitute for adrenalectomy. The concept that secretion of hypothalamic gonadotropin­ releasing hormone (GnRH), pituitary gonadotropins, and sex steroids are regulated via negative and positive feedback loops is based on the pioneering work of Hohlweg and Harris some 40 years ago. In 1971, a breakthrough was achieved with the isolation, structural analysis, and synthesis of the luteinizing hormone releasing hormone (LH-RH), or GnRH as it is now more appropriately termed, since it provokes the secretion of both gonadotropins, LH and FSH, and since then the progress made in this area of research has been remarkable. Both ago­ nists and antagonists of LH-RH have been synthesized and extensively studied in preclinical and clinical settings.

Malignancies originating from the urogenital tract account for about 20% of all solid neoplasias. The various tumor types, including carcinoma of the prostate, transitional cell carcinoma, renal cell carcinoma, and testicular germ cell tumors, differ widely in terms of biological features, in­ cidence and appearance, diagnostic work-up and manage­ ment. It is not surprising that this complexity of urologic oncology with its related problems has increasingly attracted both experimental investigators and clinical experts. Only time will tell whether the achievements that today are con­ sidered· as progress will turn out to be significant contribu­ tions towards the ultimate goal: the cure of the patients'life-threatening diseases with little or no side effects. How­ ever, many innovations and improvements have already taken place in the field of urologic oncology within recent years. The high pace of innovative development requires continuous, thorough, and critical updating of our kowledge so that persisting deficits can be defined: the basic require­ ment for posing new scientific questions. The following examples may serve to illustrate the recent developments and the resulting new problems and questions: Recently, it has become evident that carcinoma of the prostate must be detected earlier to enable us to cure more of the affected patients in the future than currently.

Physicians, biologists and physicists present their recent work in the field of hyperthermia with regard to both its application and its combination with radiation and chemotherapy. Current technical possibilities, clinical management and major aspects of its use for superficial and deep-seated tumors are pointed out. The main topics discussed are: changes of metabolism and microcirculation under heat conditions, the biological interaction of heat with X-rays and several chemotherapeutic agents, and the most recent clinical data from different institutions on the combined application in the treatment of cancer.

The American Cancer Society anticipates that during 1995, 244000 new cases of cancer of the prostate will have been diagnosed in the United States, with 40400 deaths from the disease process. The rapid increase in the actual number of new cases in the United States is directly related to more regularized digital rectal examinations and the more frequent and widespread use of prostate-specific antigen (PSA) screening programs. As a conse­ quence, major controversies have emerged in how best to manage the patient with cancer of the prostate. These include the necessity of PSA screening programs, how to interpret PSA values, what imaging studies are most appropriate for definition of the true extent of the disease process, the value of pretreatment surgical staging of the disease process, and the value of different treatments. The latter encompass a wide range of options: observa­ tion, radical prostatectomy, the Walsh-type prostatectomy procedure, definitive external beam radiation therapy, local interstitial implantation using iodine-125, iridium-l92, or palladium-103, orchiectomy, cryosurgery, hyperthermia, and various antitestosterone agents such as estrogens or LH,RH agonists. The present volume deals with the major parameters of controversy with regard to cancer of the prostate and will enable the reader to acquire a better understanding of the disease and how best it might be managed to achieve an optimal outcome with a minimum of complications.

Significant recent advances in the imaging of the lower urinary tract are comprehensively presented in this handbook. It offers information on both imaging examinations and interventional techniques with all the modern modalities, including MRI and ultrasound. The contributors are all experts in clinical urology; their varying and at times conflicting opinions track the fast-moving pace in the field and demonstrate the complexity of the subject. The approach is disease-oriented, though grouped by anatomic region. Each chapter covers etiology, physiology, pathology, epidemiology, clinical presentations and especially diagnostic imaging, but also the appropriate interventional radiologic techniques for both diagnosis and treatment.

Pancreatic Disease: Towards the Year 2000 provides a clear picture of the current research activity in pancreatic disease and its related basic science. Experts currently contributing to advances in understanding and treatment have provided concise and clear reviews of their subject. Each contribution summarises the relevant literature and describes recent advances whilst highlighting those areas where current research will impinge on clinical practice in the next few years. The reader will find in this book all the latest material related to pancreatic disease, cancer, acute and chronic pancreatitis and a number of other topics including transplantation and the relationship between endocrine and exocrine disease and cystic fibrosis. The book will supplement existing texts and will be of value to practising specialists who deal with pancreatic disease as well as specialist trainees in surgery and medical gastroenterology.

A symposium on benign prostatic hyperplasia is appropriate at a time when new knowledge and new technology are rapidly emerging. As the age of the population has increased and diagnostic methods have improved, the incidence of diseases of the prostate has increased. Benign prostatic hyperplasia (BPH) is the most common benign tumor in men and results in urinary symptoms in the majority of men older than 50 years; furthermore it has in the past necessitated operative intervention in 20%-30% of men who live to the age of 80 years. The relief of obstruction resulting from this benign neoplasm by means of transurethral resection (TURP) or surgical enucleation represented a major advance and helped to establish urology as a major surgical science. Over the years, urologists became more and more proficient with the resectoscope, reducing the need for open surgery, and over time more procedures were done for more modest symptoms. Although unquestionably effective in the relief of bladder outlet obstruction in the majority of men treated, TURP has not been without morbidity. In 1989, the American Urological Association (AUA) reported an 18% im­ mediate postoperative morbidity in its cooperative study of 13 participating institutions evaluating 3885 patients (MEBUST et al. 1989). Included were patients requiring transfusion, those experiencing excessive absorption of irrigating fluids ('TUR syndrome'), those experiencing myocardial arrhythmias, and a few suffer­ ing myocardial infarction.

Hans-Jorg Senn H.-J. Senn (~) Center for Tumor Detection and Prevention, Rorschacherstr. 150, CH-9006 St. Gallen, Switzerland Clinical oncology has centered mainly on developing new strategies and a multitude of new drugs for fighting relapsing and progressive cancer during the last two decades. Furthermore, it has done this with respectable success in quite a number of neoplastic diseases such as acute leukemias and sarcomas in pediatric patients and certain types of aggressive lymphomas, as well as se­ lected solid tumors such as testicular cancer and choriocarcinoma in adult age. Curatively intended adjuvant chemo-and endocrine-therapies of several'main killers'among prevalent cancer types, especially breast and colon can­ cer, have also become successful and health-politically meaningful therapeutic targets [1, 2]. However, the net gain in'cure'of these (mostly pharmacologic) therapeu­ tic approaches has to be realistically judged as having a moderate impact on the cancer problem as a whole, and the mortality rate of the most frequent tu­ mor types, which are prevalent in adult life, has with very few exceptions not been substantially decreased over the past two to three decades. Increasingly, health politicians, epidemiologists, and medical journal editors are asking for alternative strategies of lowering cancer incidence and increasing survival, ventilating new and hitherto mostly neglected areas of research such as pri­ mary and secondary cancer prevention.

Breast and prostate cancers are both hormone-dependent, at least in some stages of their progression. Hormonal manipulation represents an important therapeutic approach. Although most of breast and prostate cancers initially respond to hormone therapy, most tumors reinitiate to growth. Finally, hormone-resistant and metastatic breast and prostate cancers may develop. Thus, the challenge is the dissection of mechanisms by which steroid receptor signaling pathways continue to influence cell growth and invasiveness. Compelling evidence indicates that steroid hormones elicit non-genomic responses in extra-nuclear compartment of target cells. In this cellular location, steroid-coupled receptors rapidly recruit signaling effectors or scaffold proteins and activate multiple pathways leading to proliferation, survival, migration and invasiveness. The immediate challenge is the dissection of key events regulating the steroid response of target tissues to prevent progression and improve treatment of breast and prostate cancers.

Carl Edward Sagan's (1934-1996) one of the famous quotation was “Who are we? We find that we live on an insignificant planet of a humdrum star lost in a galaxy tucked away in some forgotten corner of a universe in which there are far more galaxies than people.“ From past to date, well-known molecules, enzymes, proteins, lipids and carbohydrates are studied in the pathogenesis of several diseases both as a diagnostic/prognostic biomarker and therapeutic agent. The underlying mechanism of unexplained diseases and failure of therapies are frequently studied with well-known biomarkers, but remain unclear in many cases. As Dr. Sagan said other keys are still waiting to be known in some forgotten corner of a body universe, we find strength to propose that one of them can be the growth factor with cytokine activity named “Midkine” This book summarizes the extensive up-to-date literature overeview with the lastest work of experts about midkine in a detailed format that conveys its role as botha pathologic factor and therapeutic agent.

The biology of solid tumor metastasis has been the subject of significant scientific and clinical interest for years and while experimental evidence reveals that metastasis is not solely a random event, very little is known about the biology of metastasis originating from prostate cancer. This is in spite of the fact that the majority of prostate cancer patients die with metastatic lesions to the bone. Progress in understanding this most important aspect of prostate cancer has been hampered by the lack of suitable animal models and an inability to accurately quantify bone metastases and their responses to therapy. Over the past decade, scientists in Japan and the United States have steadily advanced our understanding of the cellular, molecular and immunologic biology of primary and disseminated prostate cancer. It is this body of new information, combined with advances in imaging techniques and prostate cancer tumor markers, that prompted the need for an in-depth assessment of bone metastasis of prostate cancer. Accordingly, on December 12, 1990, a group of basic and clinical investigators from Japan and the United States convened in Gotenba, Japan, to hold the first conference devoted solely to the basic biology and clinical aspects of bone metastases originating from prostate cancer. The cross-fertilization of ideas that was fostered through in-depth discussion of technological advances among various basic and clinical disciplines not only further advanced our understanding of prostate metastases to the bone, but suggested approaches for precise quantitative assessment of these lesions and their treatment.

These proceedings emanate from the Second Prouts Neck Conference on prostate cancer held on October 17-19, 1986, the theme of which was treat­ ment, with focus on current issues and future research that is needed to answer critical questions related to optimal management of the various stages of prostate cancer. The objective was to reveal the most crucial problems impeding progress and to crystallize the combined multidisci­ plinary input generated by the conference into focused concepts or recommendations for presentation to the National Cancer Institute (NCI), with the ultimate intent of targeting research to address the priority issues identified. In organizing the workshop, every effort was made to maintain a multidisciplinary balance among nationally renowned authorities on prostate cancer. Thus, leading surgeons, radiation and medical onco­ logists and biostatisticians were in equal presence. While there were spirited exchanges with careful scrutiny and critique of all data pre­ sented, there was a common belief that the challenge of prostate cancer would be best approached in this multidisciplinary Organ Systems-oriented fashion. During the course of the conference, it became apparent to all present that major nomenclature and procedural barriers have made it generally difficult, and frequently impossible, to compare results of clinical research.

Following the development of gray-scale imaging, real-time scanning, Doppler examination, and high-frequency sonography, endosonography is one of the latest major breakthroughs in the history of diagnostic ultrasound. Although early attempts at inserting ultrasound transducers in natural cavities of the body can be traced back more than two decades, only in the past few years has technology allowed the development and commercialization of effective, easy-to-use endosono­ scopic probes. Because the transducer can be placed in direct contact with or close to lesions, high frequencies (up to ~2 MHz) can be used, yielding cross-sectional images of unsurpassed resolution. The availability of specially designed intracorporeal probes for specific natural cavities that are routinely explored by conventional (optical) endoscopy or palpation has significantly expanded the diagnostic applications of sonography. Transrectal and transvaginal examinations are now performed routinely in many institutions, and virtually all sonographic equipment manufac­ turers have in their line of products at least one endorectal and one endovaginal transducer. Most endosonoscopic probes connect to existing scanners, and for radiology departments, the invest­ ment for transrectal or transvaginal scanning will usually be limited to the purchase of the specific probe. In this book, clinical applications of endosonography (excluding transesophageal echocardio­ graphy) are covered by European and North American experts. Current equipment and techniques of examination are described in detail to help newcomers get started in the field of endosonography.

The study of genitourinary tumors is an area of recent rapid growth both in the understanding of disease processes and in the development of new diagnostic and therapeutic modalities. During rapid growth phases within any field, it is desirable to reflect on the current'state of the art'. It is difficult even for experts in reputed areas of advancement to distinguish true advances from false leads, but it is far more difficult yet for those whose expertise lies in other areas to evaluate important advances. Thus, an objective assessment of evolving areas of investigation in the form of a comprehensive review is of considerable value. we have attempted to provide the reader with an over­ In this volume, view of some of the current areas of investigation in urologic oncology by experts in each area. There often is a tendency for invited papers in books of this nature to lack important critical peer review and therefore, suffer from a lack of objectivity. We have attempted to diminish this problem by the selection of two experts to discuss each subject. We believe that this format has improved the overall quality of the book for two reasons: 1) the know­ ledge of each contributor that his or her work would be reviewed by a peer 2) the fact that contributions by encourages more rigorous scholarship, and two experts, including the individual insights of each, provides a better per­ spective for the reader.

The growth and function of many tissues are influenced by hormones. Therefore it is quite understandable that hormones play a role in the development and treatment of malignant tumors. Numerous publications address this topic; however, the results of many studies are controversial and have not been unequivocally accepted. For nearly 50 years the carcinogenic effect of steroid hormones has been under debate, and their therapeutic value a matter of discussion for equally as long. The present volume concentrates on substantiated data first obtained from the study of tumors developing from hormone­ regulated or hormone-producing tissue, e.g., the thyroid, adrenal glands, prostate, and the female genital tract. Through a joint approach from the field of molecular biology, biochemistry, and histopathology, advances in the management of these tumors have been elaborated. Another exciting example is the endo­ nuclear diagnosis of adrenal tumors. Antihormones, i.e. antian­ drogens or GnRH analogues have proved to be important indeed since they exhibit a destructive effect on prostate carcinomas and breast cancer. Further improvements can be expected in the localization of hormones in tumor tissue by specific antibodies. A special chapter is dedicated to the diffuse endocrine cell system (DECS), the clinical significance of which has mainly become obvious in the gastroenteropancreatic tract.

Where do you begin to look for a recent, authoritative article on the diagnosis or management of a particular malignancy? The few general oncology textbooks are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often preliminary reports on a very limited number of patients. Certain general journals frequently publish good indepth reviews of cancer topics, and published symposium lectures are often the best overviews available. Unfortunately, these reviews and supplements appear spo­ radically, and the reader can never be sure when a topic of special interest will be covered. Cancer Treatment and Research is a series of authoritative volumes which aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, revised frequently to keep the coverage up to date, easily available on a single library shelf or by a single personal subscription. We have approached the problem in the following fashion. First, by dividing the oncology literature into specific subdivisions such as lung cancer, genitourina­ ry cancer, pediatric oncology, etc. Second, by asking eminent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diagnosis, staging, markers, all forms of treatment modalities, basic biology, and more.

The current volume represents the fourth over a period of five years in our series on Advances in the Cellular and Molecular Biology of Breast Cancer. The first three volumes were entitled Breast Cancer: Cellular and Molecular Biology, Regulatory Mechanisms in Breast Cancer, and Genes, Oncogenes, and Hormones, respectively. Throughout this series, we have tried to take a broad look at cutting-edge topics in basic science research into breast cancer. This attempt has resulted in a wide range of subject material, including rodent and human model systems, oncogenes, suppressor genes, growth factors, hormones, tumor-host interactions, and determinants of metastases. Since our last volume, research in breast cancer has continued to proceed at an explosive rate. We hope the current volume will provide the reader with some of the excitement felt by the editors and authors as we begin to understand this all-too-common disease. The first section of this book is devoted to the basic processes of proli­ feration, differentiation, and malignant progression of breast cancer. T.l. Anderson and W.R. Miller lead off with a detailed description of controls on proliferation in the normal human breast and in breast cancer. This chapter strongly emphasizes pathological aspects. The second chapter, by M.R. Stampfer and P. Yaswen, presents a corresponding viewpoint through a presentation of experiments with human mammary epithelial cells in culture. The second section of the book emphasizes the genetic basis for breast cancer onset and malignant progression. Chapter 3, by M.-C. King and S.

These are the Proceedings of the 2nd International Metastasis Congress of the Metastasis Research Society which took place in the town hall (Stadthalle) of Heidelberg, FRG, in September, 1988. This first Metastasis Congress in the FRG was organized in conjunction with the German Association of Cancer Research (SEK) of the German Cancer Society. The congress topic generated tremendous interest and attracted about 400 scientists from 22 countries. Most participants came from Europe, Israel, and the United States. Why did we organize the Metastasis Congress? Only about 50% of all people who develop some form of cancer are curable. Despite improved patient care and increasingly innovative and effective techniques for diagnosing and treating primary cancers, the development of secondary cancer colonies, i. e., metastasis, can not be prevented and is the major cause of death. In the Federal Republic of Germany there are still as many as 160 000 cancer patients per year who succumb to their disease, often after periods of terrible suffering, and this overall figure is not improving. Partly because of the complexity of the process, basic research on metastasis has lagged behind other disciplines such as carcino­ genesis and cancer genetics. Metastasis formation involves the ability of malig­ nant cells to invade adjacent tissue and to penetrate into lymphatic or blood circulatory systems, or both, and to spread to near or distant sites to form new tumor colonies. Meanwhile, research on metastasis is receiving much attention.

More than 25 years ago, when ultrasound diagnostic methods were first intro­ duced into gynecology and obstetrics, few of the pioneers of these techniques sus­ pected what importance sonographic diagnosis was destined to assume. It was soon recognized that the organs of the lesser pelvis could be visualized to much greater advantage by inserting probes into the natural bodily orifices than by abdominal sonography. Full exploitation of the physical properties of ultra­ sound had to wait, as so often in the history of sonography, for technological ad­ vances. Endosonography in the form available to us today combines the advantages of endoscopy and sonography. The next light-reflecting surface, once the limit of en­ doscopy, represents no barrier to ultrasound. A whole range of both diagnostic and therapeutic procedures can be sonographically guided. Blood flow in vessels lying deep in the lesser pelvis can now be measured by means of vaginal duplex sonography.

Androgen Receptors is the most comprehensive and up to date volume on the topic, including discussions of the basic mechanisms of androgen-androgen receptor actions, their roles in the androgen-related diseases, and their potential clinical applications.Key topics covered include: -The discovery and cloning of the androgen receptor; -Androgen receptor coregulators; -Androgen related genes and their consensus DNA response elements; -Basic mechanism of action including functional analyses, cellular localization and phosphorylation studies; -Cross-talk to other signal transduction systems; -The recent connections of androgens to women's diseases, such as osteoporosis and ovarian cancer.This book is of interest to students, basic scientists, and clinicians as both a study guide and reference of research in the androgen field. It could also be used as an advanced level text in endocrinology, urology, OBGYN, or oncology.

Metastases determine malignancy. The main attention so far has been focused upon organ metastases. The molecular mechanisms thereof, while far from being totally elucidated, are increasingly well understood. Modern diagnostic tools now enable detection and precise localization of small lesions. In contrast, our knowl­ edge and diagnostic capabilities regarding metastatic spread to the'lymphatic system are rather limited. However, there have re­ cently been a number of interesting advances. It is the aim of this volume to submit these developments to detailed analysis. The therapeutic relevance of enhanced sensitivity in detection of lymph node metastases has to be considered in the light of in­ creased morbidity versus eventual prognostic improvements by modification of therapy. An interesting concept which might im­ prove diagnostic accuracy while reducing operative morbidity is the'sentinel node'technique. Surgical standards are lacking, however, and many fundamental questions pertaining to precise lymphatic mapping remain unanswered. Whether the sentinel node concept is of general relevance or whether it is applicable in only a few organs remains to be determined. This book offers intensive discussion of the concept from methodological and tu­ mor biological viewpoints. World-renowned experts with long­ term involvement in related basic and clinical research provide the reader with a broad survey of actual knowledge together with a critical appraisal of recent and future developments. We sincerely hope this book succeeds in providing an outlook as a reference for all clinicians on future prospects and serving and researchers in this extremely important field.

Apoptosis is a fascinating concept for the basic scientist. This is not only because of the multifaceted variety of proposed and discovered mechanisms, but because apoptosis represents a fundamental pathway for cell renewal. The study of apoptosis has resulted in an array of discoveries on signal transduc­ tion and downstream effects that have facilitated and advanced many fields in biology, including research on cancer and other diseases. Thus, the apoptotic process can be viewed as the largest effort of the scientific community to understand how cells work and tissues assemble or remodel. The most direct consequence of this accumulated knowledge is a greater understanding of disease and pathological mechanisms. The end result of these efforts will be significant contributions to health and the adoption of new, never anticipated, therapeutic approaches. This book represents the summation of considerable effort from a significant group of contributors from all over the world as well as from its editors. In this fashion, many viewpoints have been collected and SUbjected to thorough academic discussion. The concepts contained in this medically important volume will stimulate and renew the ideas of scientists and indeed, will generate additional work to advance biological knowledge even further. The emphasis of this volume cements what has been established, adds what has not been explored fully, and creates a fertile ground for further hypotheses that will lead to a more complete understanding of the apoptotic process.

Genetically-engineered mouse models for cancer research have become invaluable tools for studying cancer biology and evaluating novel therapeutic approaches. This volume focuses on state-of-the-art methods for generating, analyzing and validating such models for studying aspects of human cancer biology. Additionally, these models are emerging as important pre-clinical systems in which to test cancer prevention and therapeutic strategies in order to select compounds for testing in clinical trials.

In Gene Regulatory Sequences and Human Disease, the Editor will introduce the different technological advances that led to this breakthrough. In addition, several examples will be provided of nucleotide variants in noncoding sequences that have been shown to be associated with various human diseases.

It is particularly gratifying to prepare a second edition of a book, because there is the necessary impli­ cation that the first edition was well received. Moreover, now an opportunity is provided to correct the problems or limitations that existed in the first edition as well as to address recent developments in the field. Thus, we are grateful to our friends, colleagues, and students, as well as to the reviewers who have expressed their approval of the first edition and who have given us valuable input on how the revision could best be structured. Perhaps the first thing that the reader will notice about the second edition is that it is more extensive than the first. The volume currently has 41 chapters, in contrast to the 31 chapters that comprised the earlier version. Chapters 3, 9, 29, and 30 of the first edition either have been dropped or were combined, whereas 14 new chapters have been added. In effect, we are gratified in being able to reflect the continued growth of behavior therapy in the 1980s. Behavior therapists have addressed an ever-increasing number of disorders and behavioral dysfunctions in an increasing range of populations. The most notable advances are taking place in such areas as cognitive approaches, geriatrics, and behavioral medicine, and also in the treatment of childhood disorders.

The idea for this book arose during the 1985 Gordon Conference on'Mammary Gland Biology'. New developments in the methodology of cell biology and the explosive growth of molecular biology had begun to impact upon our understanding of mammary gland growth and function. It seemed a propitious time for summarizing the current status of knowledge of the cell and molecular biology of mammary cancer and for attempting to outline future areas of concern and interest. The reviews presented here were completed by the Fall of 1986. Although new insights will surely continue to emerge, it is hoped that the material in this volume will form not only a current update but a basic core of information for future experiments. We have not attempted to cover all areas of mammary gland transformation. Those areas where recent detailed reviews are already available have been omitted. Also, the areas of normal gland development, cell ultrastructure, hormone responsiveness, chemotherapy and clinical aspects of mammary cancer have not been included. Instead, we have selected those areas where the development of new methodology, reagents and results have led to new ideas about mammary gland function and development as they are related to neoplasia.

New developments in testosterone therapy are summarized here by internationally renowned experts. They review both basic and clinical knowledge in fourteen chapters. The book begins with the biochemistry of testosterone, its biosynthesis, metabolism and mechanisms of action in target organs. Three chapters deal with specific aspects of testosterone action, namely its role in spermatogenesis, its psychotropic effects and its effects on bones. Syndromes caused by androgen resistance are described in order to highlight the importance of properly functioning enzymes and receptors in the target organs. Causes and symptoms of male hypogonadism, the major indication for testosterone treatment, are described. Five chapters are devoted to the pharmacology, pharmacokinetics and clinical uses and abuses of testosterone preparations. The new transdermal testosterone application is described in detail. Side effects of testosterone treatment are reviewed. The possible role of androgens in the development of prostatic hypertrophy and carcinoma is discussed extensively since this question is of major concern to the clinician.

In oncology today the accent lies on a multi-disciplinary approach, and consequently this handbook aims to provide wide-ranging information regarding all aspects of the surgical treatment of cancer. It deals with the basic subjects: the biology of cancer, detection and diagnosis, and treatment concepts. From screening to the application of markers, from new transplantation techniques to psychological aspects, an overall picture is presented. The surgeon will find chapters to enhance his knowledge of those areas which may not have required his attention until now. This volume should serve as a valuable reference for many years to come.

Malignant disease of the genitourinary tract continues to provide a major health hazard. The study of these disease processes has been hampered at the clinical level as there has been a serious lack of reasonably controlled treatment trials, and at the basic science level as many of the animal model systems do not compare favorably with the human tumor situation. This volume defines current cancer treatment and research and its appli­ cation to the control of human genitourinary malignancy. The authors have developed their chapters in such a way as to provide an up-to-date resource for the clinician who is involved in day-to-day patient care problems, for the clinician-investigator who is attempting to construct programs designed to evaluate the impact of current treatments, and for the clinician-scientist who is seeking to apply basic research technology and skills to understand­ ing and control in this disease area. This book does not attempt to cover the entire breadth of urinary malig­ nant disease, but focuses in depth on specific problem areas. It provides the reader with sufficient background and understanding for him to be able to evaluate future studies in the areas addressed, or even to develop his own projects. A reasonable balance has been established between clinical and basic research problems, recognizing that the two disciplines truly are not separable. The book serves to define the state of the art and, as such, will of urologic oncology.

The methodology of drug development has been the subject of extensive dis­ cussion by a relatively small group of individuals in industry and government who have been intimately concerned with the identification and study of new anticancer drugs. The Chemotherapy Program of the National Cancer In­ stitute has represented the major focus of initial efforts in drug development, as summarized in the historical perspective presented in chapter 1 and its references. It is no coincidence that the Chemotherapy Program was the origin of the Division of Cancer Treatment, a government entity that has had a pivotal role in the growth of clinical oncology. In an analogous fashion this book presents the methodology employed in the clinical study of anticancer drugs within the broad context of cancer treatment. The research orientation promulgated in the study of new drugs is a central theme in most oncolo­ gists'approach to the clinical problem of cancer. Therefore, we hope that this book will introduce readers to treatment research in clinical oncology. For the oncologist, the clinical evaluation of antitumor therapy is both part of the day-to-day management of specific patients and the critical considera­ tion of developing therapeutic alternatives. For physicians in other fields of medicine it is important to acquaint themselves with the basic tools of the oncologist. For people without medical training, including patients who might be interested in treatment research, many of the chapters may be overly technical.

Metastasis to bone is a common event in cancer. However, due to the skeleton's unique structure, exploring how cancer cells target the skeleton and interact with the bone microenvironment is challenging. The Biology of Skeletal Metastases covers areas that are important to both clinicians and basic scientists seeking an enhanced understanding of mechanisms of skeletal metastasis, as well as descriptions of cutting edge therapies for skeletal metastases. Both increased efforts by many investigators and advances in research methodologies have provided a wealth of information in the area of skeletal metastases. The Biology of Skeletal Metastases brings together experts to describe these many advances. This book provides background in basic bone biology and biology of metastasis for novice investigators and highlights many advances in this challenging field for the experienced investigator.