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At the time of the first edition of Principles of Cancer Biotherapy in 1987, this book represented the first comprehensive textbook on biological therapy. In 1991, when the second edition was published, there was still some doubt on the part of many oncologists and cancer researchers as to the therapeutic value of these new approaches. By 2003 and the fourth edition, it was generally agreed that biopharmaceuticals were producing major opportunities for new cancer therapies. Cancer biotherapy has now truly matured into the fourth modality of cancer treatment. This fifth revised edition describes the tremendous progress that has been made in recent years using biologicals in cancer treatment. This book summarizes an evolving science and a rapidly changing medical practice in biotherapy. In this new millennium, it is now possible to envision a much more diversified system of cancer research and treatment that will afford greater opportunities for a patient's personalized cancer treatment. This was first envisioned in the 1987 initial edition of this textbook and is now a'new'and popular approach to cancer treatment. Some forms of cancer biotherapy use the strategy of tumor stabilization and control though continued biological therapy, akin to the use of insulin in the treatment of diabetes. This textbook illustrates new methods of thinking and new strategies for control of cancer. It is always difficult to move from past dogma to future opportunity, but this fifth edition of Principles of Cancer Biotherapy illustrates why it is so important to the patients for researchers and clinicians to explore and quickly apply these new opportunities in cancer biotherapy.

This book offers a state-of-the-art report on recent discoveries concerning viral, bacterial, and parasite infectious cancers. Cancer is one of the most common causes of death and diseases in human populations, and 15%-25% of human cancers in worldwide are considered to result from chronic infection by pathogens. Most oncology textbooks address genetic mutation, but not infectious agents such as viruses, bacteria and parasites. As such this book stimulates further research in the new area between cancers and chronic infection, and discusses the epidemiology and molecular biology of infectious causes of cancers. It also explores the prevention and treatment of infection-related cancers, and brings pathogenic research to the forefront in the never-ending endeavor to understand how pathogens maneuver and negotiate in a complex environment, including the micro/macro- environment of the human host. Further, it highlights the urgent need for a concerted program to develop vaccines and other diagnosis and interventions that will eventually help prevent and treat infectious cancers, and decrease their burden on human populations. It offers graduate students and researchers a comprehensive overview of the infectious causes of cancers.

Im ersten Teil des Buches werden Entwicklung, Aufbau und Systematik der Interferone sowie ihre Stellung innerhalb des Zytokin-Netzwerkes dargestellt. Weiterhin werden durch Interferone stimulierbare zytoplasmatische und nukleäre Veränderungen beschrieben. Der zweite Teil beschäftigt sich mit der klinischen Anwendung von Interferonen. Bei den wichtigsten malignen und benignen Krankheitsbildern werden die bisherigen Ergebnisse der Interferongabe dargestellt - auch in Kombination mit anderen systemischen und lokalen Behandlungsmaßnahmen - und mit herkömmlichen Behandlungsmethoden verglichen. Ziel des vorliegenden Buches ist es, möglichst umfassend und klar über Aufbau und Systematik des Interferonsystems sowie über seine bisherige klinische Bedeutung zu informieren.

'Where are all these kidney patients coming from? A few perfection the study of the urinary sediment, clinically years ago we had never heard of kidney disease and now practical kidney function tests, and the natural history of a number of kidney diseases including glomerulonephritis. you are speaking of patients in the hundreds of thousands and indeed potentially millions.'My reply, not meant to William Goldring, Herbert Chasis, Dana Atchley, and others studied the effects of hypertension, endocarditis, be grim, was'From the cemetery, Sir.'This is a summary and circulatory diseases on the kidney and spawned suc­ of some Congressional testimony lance gave on behalf of extending kidney disease under Medicare. Where indeed cessive generations of alert clinical investigators, who be­ gan to chronicle the natural histories of a wide variety of were all the patients with kidney disease in the United States before World War II? They were certainly not kidney diseases. Quantitative studies of renal function flourished under a school headed by Homer Smith, and under the care of nephrologists! Nephrology was not listed in the questionnaires for any state or the American Medi­ surprisingly precise techniques were developed for study­ ing a whole range of explicit nephron functions. Imagine cal Association as a subspecialty or even as a special the joy with the advent of vascular catheterization to be interest.

On March 27, 1990, the National Cancer Institute sponsored a workshop on the epidemiology of multiple myeloma, held at the National Institutes of Health. This book comprises articles prepared by participants in this work­ shop. Discussed in these papers are: the descriptive and analytic epidemi­ ology, differences in risk factors between blacks and whites, monoclonal gammopathies and their progression, and hypotheses regarding the etiology and pathogenesis of multiple myeloma. Several epidemiologic research areas received particular attention during this workshop, and are reviewed in detail in this volume. There have been striking increases in the incidence of multiple myeloma over the past thirty years, especially among older individuals and blacks, which may not be entirely explained by changes in diagnostic capabilities. Occupational and environmental exposures have been associated with an increased risk of multiple myeloma, including farming exposures, occupational exposure to petroleum and rubber processing, exposure to ionizing radiation, and asso­ ciations with persistent virus infections. The most striking epidemiological finding is reflected in the differences in incidence rates of multiple myeloma which are twice as high in blacks as compared with whites. Further, since 1950 the mortality rates for multiple myeloma have quadrupled in blacks while doubling for whites. Among hematopoietic malignancies, multiple myeloma is the only one with increased incidence and mortality rates among blacks. 1\vo major possibilities for explaining ethnic/racial differences in suscepti­ bility to multiple myeloma are genetic and environmental factors.

Previous volumes in this series have discussed the current progression have identified a variety of targets and strategies state of our knowledge concerning the pathophysiology of to allow these goals to be realized. This volume critically cancer growth and progression. The complexity of the in­ reviews approaches towards cancer management in man at teraction of malignant neoplasms and the host, the the levels of: detection, diagnosis, surgery, radiology, heterogeneity of malignant cell subpopulations, and the chronobiology and endocrine treatment. existence of metastatic tumor cells resistant to drug thera­ Several chapters review selected methods of cancer diag­ pies remain as significant clinical challenges to clinical on­ nosis. In addition, a variety of on-going and novel ap­ cologists. Indeed, conventional treatment regimens of che­ proaches for cancer treatment are also presented in this volume. Progress in the early detection of malignant neo­ motherapy, surgery and radiology are often ineffective for the therapy of a large variety of established metastatic can­ plasms, coupled with novel approaches for the therapy of cer in patients. When one considers the insidiousness of such neoplasms, may ultimately yield safe and well-tolerated agents for the selective therapy of solid malignancies. New progressive neoplastic growth and the emergence of con­ tinuously more aggressive and malignant cellular subpop­ therapeutic approaches, directed towards the biochemical ulations one is overwhelmed with the challenges inherent in and molecular targets identified in the earlier volumes of this series, may ultimately lead to the generation of new mo­ attempting to control malignant neoplasms.

Where do you begin to look for a recent, authoritative article on the diagnosis or management of a particular malignancy? The few general on­ cology 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. Un­ fortunately, these reviews and supplements appear sporadically, 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, genitourinary 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.

At the time of the first edition of Principles of Cancer Biotherapy, this book represented the first comprehensive textbook on biological therapy. Whereas in 1991, when the second edition was published, there was still some doubt on the part of many oncologists and cancer researchers as to the therapeutic value of these new approaches, it is now generally agreed that biopharmaceuticals are producing major opportunities for new cancer therapies. Cancer biotherapy has truly matured into the fourth modality of cancer treatment. The third edition is now needed as a result of the tremendous progress that has been made in recent years using biologicals in cancer treatment. The book summarizes an evolving science and a rapidly changing medical practice. As we near the millennium, it now becomes possible to envision a much more diversified system of cancer research and treatment that will afford greater opportunities for patients. Some forms of cancer biotherapy use the strategy of tumour stabilization and control through continued biological therapy, akin to the use of insulin in the treatment of diabetes. This textbook illustrates new methods of thinking and new strategies for control of cancer. It is always difficult to move from past dogma to future opportunity, but this third edition of Principles of Cancer Biotherapy illustrates why it is so important to the patients, for researchers and clinicians to explore and apply these new opportunities in cancer biotherapy.

Lung cancer is one of the biggest challenges in oncology today. The challenge is due to the recognition of the possibility of prevention in at least 70-80% of all the cases and the extreme difficulties encountered in the treatment of this neoplasm. Despite the knowledge of prevention measures such as cessation of cigarette smoking the incidence continues to increase in many countries. The increase is particularly notable in females in the west­ ernized countries where the death rate in females in certain regions sur­ passes that of breast cancer. Furthermore, in many developing countries lung cancer is now being diagnosed with increasing frequency in both sexes and it is expected to be a major cause of death in those countries later in this century or the beginning of next century if the tobacco consumption will continue its rapid rise. With respect to therapy the 1970'es brought considerable progress in understanding of the clinical behaviour of lung cancer thereby establishing the importance of distinguishing between the major histologic types. Thera­ peutic advancement was particularly experienced in small cell carcinoma with the introduction of combination chemotherapy after this special dis­ ease entity among lung cancers was recognized as being a disseminated dis­ ease in almost all cases at the time of diagnosis. It was expected that the improvement in therapy would have continued in the early 1980'es, not only for small cell lung cancer but also for the other cell types.

The assessment of tumour response after treatment is one of the most important challenges in Oncology and the picture is so often complicated by the effects of therapy itself. Clinical assessment is still by far the most important method of assessment at our disposal but there is increasing dependence on investigations of all types as indices of response. This depen­ dence may be misplaced if inappropriate investigations are pursued and we have tried to emphasise in this book the importance of selectivity. Some indices of assessment (e. g. tumour markers, organ imaging) have a vital role to play; others (e. g. histopathology, genetics) are assuming greater impor­ tance as tumour behaviour becomes better understood. One subject, Immu­ nology, is still in its infancy as regards tumour follow-up, but shows much promise so that a full account of tumour immunology and trends in immu­ notherapy has been included. I am grateful to Dr. Brian Ross for his help with the chapter on Organ Imaging, to the Department of Medical Illustration for their ever-ready co-operation with illustrations and photographs and to Miss Shirley Francis for doing much of the typing. B. W. HANCOCK List of Contributors HANCOCK, B. W., MD, DCH, MRCP, Senior Lecturer in Medicine, Hon­ orary Consultant Physician, Royal Hallamshire & Weston Park Hospitals, Sheffield, U. K. NEAL, F. E., KSG, MBChB, FRCR, DMRT, Consultant Radiotherapist & Oncologist, Weston Park Hospital, Sheffield, u. K. POTTER, AM.

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.

Biological response modifiers are increasingly used in viral and cancer therapy. Since alterations of the immune system are the primary symptoms of HIV infection, especially therapies directed towards the modulation of the immune response have been under intense evaluation. This volume summarizes current knowledge of the interferon-based natural antiviral protection system including 2',5'-oligoadenylate and double-stranded RNA. It will also help to develop further a solid scientific rationale for the practical use of heterologous immunomodulators in the clinics.

Primary malignant tumors of the gastrointestinal tract account for 23% of all invasive cancers and 24% of all the deaths in 1988. In the United States, the American Cancer Society estimates that there will be 227500 new cases of gastrointestinal malignancy di­ agnosed, with 122350 deaths. This includes 9800 new cases of carcinomas of the esopha­ gus, 24800 carcinomas of the stomach, 2500 new cases of malignant tumors of the small intestine, 105000 new cases of tumors of the large intestine, and 42000 new cases of car­ cinoma of the rectum, 14000 new cases involving the liver and biliary passages, 27000 new cases of carcinoma of the pancreas, and 2400 other unspecified digestive tract ma­ lignancies. This combined incidence is second only to the number of new cases of lung cancer. Bleeding from the gastrointestinal tract represents one of the earliest findings with re­ gard to malignancy of the gastrointestinal tract. In general, personal or family history of colon and rectal cancer, personal or family history of polyps in the colon or rectum, or inflammatory bowel disease are high risk factors with regard to tumors in these loca­ tions. Dietary behavior is also important in that a diet high in fat and/or low in fiber content may be a significant causative factor.

The acknowledgment that viruses are potent biological factors in driving many cancers have seen a dramatic upsurge in recent years in large part to the success of the human papilloma virus vaccine against invasive cervical carcinomas and followed by the awarding of the noble prize in medicine in 2008 to Dr. Harald zurHausen who identified the link between papilloma virus and cervical cancers. Over the last few years there have been some volumes addressing different aspects of viruses and cancers and to some extent focusing on the DNA viruses, more specifically the human DNA viruses. This proposed volume will attempt to review and address the major gaps in current knowledge in DNA viruses as well as RNA viruses bringing a historical perspective of where studies began to a more recent molecular approach and vaccine successes in tumor viruses. We will also cover other known oncogenic viruses associated cancers in other mammals in addition to humans.

New methods in immunocytochemistry and hybridization techniques enable the pathologist active in diagnosis to clarify more effectively problems in the classification and prognosis of tumors. By adopting these methods into his diagnostic repertoire it will be possible to create a closer, more productive connection between morphological diagnosis and clinical work. This volume gives the reader an up-to-date general survey from international experts of the method, technique and practical application of these new procedures.

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.

Over the last several decades, many biologists have been intrigued with the'immunological paradox'of pregnancy, where maternal and fetal tissues peaceably coexist despite their genetic differences. With the development of new insights on the interactive components of the immune system as well as the generation of powerful new molecular and cellular tools, singular progress has been made in understanding immunological events that culminate in successful pregnancy. This volume contains the proceedings for the first US symposium on the'Immunobiology of Reproduction'held August 26 - 29, 1993 in Boston, Massachusetts. Papers address hemotopoietic cells in reproductive tissues; growth factors/cytokines in the female reproductive tract and placenta; growth factor networks in pregnancy loss and cancer; placental expression of major histocompatibility complex and associated genes; experimental models of MHC gene expression; and immunological aspects of human infertility.

This volume, Biological and Hormonal Therapies of Cancer, which is part of the series Cancer Treatment and Research, presents selected new information concerning biologic and hormonal therapy of cancer. We have attempted to provide the reader with topics of major interest in a timely fashion. There is renewed interest in biologic therapy of cancer. Two chapters review the role of interferon in the hematologic malignancies and in solid tumors. Vaccine therapies have come to the forefront of cancer therapy re­ cently, and two chapters approach different strategies of vaccine therapies; one reviews the cellular vaccine therapies and another the anti-idiotype ap­ proach. The hormonal therapy chapters focus on current uses of endocrine therapy in endometrial, breast, and prostate cancer. In addition, hormonal strategies for the prevention of breast cancer and endometrial cancer, including excit­ ing information relating to phytochemicals, are presented. The effects of tamoxifen on endometrium is a topic of major interest and is discussed in detail. Finally, there is a chapter on estrogen receptor expression and regula­ tion in human breast cancer. These chapters are all written by experts in the field and contain timely and relevant information of interest to laboratory and clinical scientists and practitioners alike. Biologic and endocrine therapies represent major areas of cancer research interest. The advent of newer biologic therapies, including new antibody­ targeted treatments, and the use of biologics as tumor modulators to enhance the effects of other treatment regimens is an exploding avenue of research.

The 7th volume of the book series Acute Leukemias provides new updates on the biology of acute leukemias and especially the underlying genetic and molecular events. High quality contributions are provided by leading scientists and clinicians making the book an excellent overview over most recent achievements which translate into new treatment strategies and hence an improved outlook for patients suffering from acute leukemias.

From a logical point of view, cell division is regulated by the environment and by the ability of the cell to respond to the environmental signals. The terminology of the cell cycle, the elaborate mathematical models, and the kinetic analyses are all convenient notations and descriptions of the behavior of populations of cells. However, they tell us very little about the fundamental molecular mechanisms that control cell proliferation. Stated in other terms, what controls cell reproduction are growth factors in the environment and genes and gene products inside the cell or at its surface. This book examines the aforementioned growth factors, the study of which has made very rapid progress in the past few years. The selection of topics has been influenced by logistic considerations, but the book, as a whole, gives a broad survey of the state of the art of this exciting field. For this, thanks are due to the contributors, who have given much time to the preparation of the manuscripts and have met the deadline with a punctuality that is uncommon among biomedical scientists. I would also like to thank Ms. NORA PERRETT and the staff of Springer-Verlag for their help in editing the manuscripts and in preparing the production of the book.

This book provides the current state of knowledge of basic mechanisms of adverse drug reactions (ADRs). The main focus is on idiosyncratic drug reactions because they are the most difficult to deal with. It starts with a general description of the major targets for ADRs followed by a description of what are presently believed to be mediators and biochemical pathways involved in idiosyncratic drug reactions. There is also a description of several examples of ADRs that serve to illustrate specific aspects of ADR mechanisms. Eventually the book shows that ultimately better methods are needed to predict which drug candidates are likely to cause ADRs and which patients are at increased risk. But at present research seems to be far from this goal.

This book describes all human leukemia-lymphoma cell lines that have been established and that grow continuously under standardised in vitro conditions. These lines are derived from cells belonging to all the major hematopoietic cell lineages, i.e. B- and T-lymphocytes, natural killer cells, granulocytic cells and megakaryocytic cells. The clinical data, the culture conditions and the major phenotypic features of the cell lines are described with citations. This book is the first book describing human leukemia-lymphoma cell lines and will be of interest to scientists involved in the areas of hematology, oncology, immunology, molecular biology and cytogenetics. Cancer Cell Lines, Volumes 1-3: These 3 volumes provide a comprehensive text on the culture of established cell lines from every type of human cancer. The volumes provide a basic manual and reference resource for every cancer research scientist using human cancer cells.

Workshops on the mechanisms of B cell neoplasia have been organized alternatively in Bethesda and Basel since 1983. Prog­ ress in our understanding of the development and responses of B lymphocytes is presented and discussed with the aim and hope to understand what might go wrong when B lymphocytes are transformed into malignant cells. Such knowledge might lead to better diagnosis, prevention and even cure of these terri­ ble diseases. The presentations at the Bethesda workshops are published as papers in volumes of Current Topics in Microbiol­ ogy and Immunology, while the presentations and discussions in Basel were transcribed and published in Editions Roche. For the first time, a Basel workshop (held 4th-6th October 1998) that has been recorded and, in part, transcribed is being published as papers and discussions within Current Topics. This volume is the latest of a long series which documents the excitements of ground-breaking discoveries as well as the frustrations of our inability to fully understand the mechanisms leading to B cell neoplasia. The papers at the workshop are presented when possible in the sequence in which they were given. However, to facilitate the organization and reading of the book and to highlight gen­ eral topics and themes, the papers are organized into five sec­ tions: I B Cell and Plasma Cell Development II Chemokines and Chemokine Receptors III Chromosomal Translocations, DNA Rearrangements and Somatic Hypermutations IV Biology of Lymphomagenesis, B-CLL, Autoimmunity V Myeloma, Plasmacytomas and Related Subjects.