Leading oncologists, hematologists, and nephrologists comprehensively review the role of HGFs in clinical practice, explain the molecular basis of their effects, and consider potential future developments. The authors focus on the use of HGFs in oncology, describing their cutting-edge application to patients with lung cancer, Hodgkin's and nonhodgkin's lymphoma, breast cancer, chronic lymphocytic leukemia, AIDS-related malignancies, myelodysplastic syndromes, and aplastic anemias. Among the HGFs described are granulocyte colony-stimulating factor, erythropoietc factors, thrombopoietic factors, and stem cell factor and its receptor, C-kit. To complete their survey, the contributors also consider the safety and economic implications of HGFs and the future potential for HGF antagonists in oncology.

The Fondazione Lorenzini has been sponsoring Postgraduate Courses for physicians and specialists, in Italy, since 1970. Its aim, as an institution, has been that of promoting post graduate medical education. In these years, recent advances in a wide range of medical fields have been discussed by distinguished experts from many countries throughout the world. Courses dealing with methodo logies and technical problems have been designed to include practical demonstrations of the various methods and techniques in the relevant fields. The Postgraduate Course on "Platelets and Thrombosis: Methods of Study" was held in Milan, at the Fondazione Lorenzini, from February 24th to 26th, 1972. This volume contains the edited and somewhat extended papers presented at the Course, which was sponsored and organized by the Italian Society for the Study of Atherosclerosis. The special contribution of the present volume is that of gathering a large amount of up-to-date information on the formidable problem of the methods used for testing platelet function in thrombosis.

In the summer of 1988, my developmental biology professor announced to the class that hematopoietic stem cells (HSCs) had finally been purified. Somehow, I never forgot the professor's words. When I started working in Dr. Irv Weissman's labo- tory at Stanford as a postdoctoral fellow, I realized that the findings mentioned by the professor were from Weissman's laboratory and had been published in a 1988 edition of the journal Science. It has been over 20 years since the publication of that seminal paper, and since then tremendous advances in understanding the biology and maturation of HSCs, namely the process of hematopoiesis, which includes lymphocyte development, have been made. These discoveries were made possible in part by advancements in technology. For example, recent availability of user friendly fluorescence activated cell sorting (FACS) machines and monoclonal an- bodies with a variety of fluorescent labels has allowed more scientists to sort and analyze rare populations in the bone marrow, such as HSCs. All classes of hematopoietic cells are derived from HSCs. Stem cell biology draws enormous attention not only from scientists, but also from ordinary people because of the tremendous potential for development of new therapeutic application to diseases that currently lack any type of effective therapy. Thus, this type of "regenerative medicine" is a relatively new and attractive field in both basic science and clinical medicine.

This monograph is a collection of invited contributions from a group of investiga tors who share a common interest in the interrelationships between the shape, struc ture, and functional characteristics of normal and pathologic erythrocytes. Most of the authors participated in a workshop on red cell shape held in June, 1972 at the Institute of Cell Pathology, Hopital de Bicetre, Paris. We hope that these various contributions on the physiology, pathology, and ultrastructure of red cell shape will be useful and stimulating for other investigators interested in the correlation of shape and structure with the biochemistry and biophysics of the red cell. The text is divided into four sections. Section I deals with red cell shape, including the presentation of a rational descriptive nomenclature and a discussion of post splenectomy changes. Section II deals with biochemical factors that underlie the disco cyte-echinocyte (crenated) and discocyte-stomatocyte (cup-shaped) transformation. This section includes discussions of plasma factors, and of the biochemical dynamics of erythrocyte lipids and consideration of the effects of such factors as cellular ATP, calcium, aging, and various chemical agents as determinants of shape. Section III, which deals with biophysical measurements, includes studies of the deformability of cells of different shapes, descriptions of ways to define precisely the geometric dimensions of the red cell under various circumstances, and a model of membrane structure, which is proposed to account for the dimensions of red cells that undergo shape change."

In the last decade, remarkable advances have been made in bone marrow transplantation (BMT), which is now becoming a powerful tool in the treatment of diseases such as leukemia, aplastic anemia, and congenital immunodeficiency. In animal experiments, it has been found that BMT can be used to treat not only systemic autoimmune diseases but also organ-specific autoimmune diseases. In humans, it has recently been shown that rheumatoid arthritis, ulcerative colitis, and Crohn's disease can be successfully treated after BMT. This volume contains new information on how to prevent graft rejection, how T cell functions can be completely restored, and how concomitant BMT can prevent the rejection of organ allografts without the use of immunosuppressive agents. BMT will become an increasingly useful and powerful treatment for various currently intractable diseases, and this book will contribute by providing details of the latest research in the field.

This, the third volume of the Blood Cell Biochemistry series, follows the pattern estab- lished in the two previous volumes by containing up-to-date specialist reviews of topics of current interest within the field of study defined by the subtitle. Thus, the topics included can be loosely classified under the broad subtitle "Lymphocytes and Granulocytes," but this does not indicate the full scope of content, scientific interest, and emphasis of the present volume. The opening chapter, by Antonio Bonati, surveys the currently available bio- chemical, immunological, and molecular markers of hemopoietic precursor cells. This is followed, appropriately, by a contribution from Arnold S. Freedman on the cell surface markers in leukemia and lymphoma. In a detailed chapter, Annette Schmitt-Graff and Giulio Gabbiani discuss the cytoskeletal organization of normal and leukemic lympho- cytes and lymphoblasts. John C. Cambier and his colleagues then present a discussion of the signaling events in T-Iymphocyte-dependent B-Iymphocyte activation. Lymphocyte IgE receptors and IgE-binding factors are dealt with by Kwang-Myong Kim and his colleagues, and the role ofgranule mediators in lymphocyte-mediated cytolysis is covered by John Ding-E Young and his associates. A short contribution from James D. Katz deals with the intricacies and difficulties of studies on the complement C3b (CRl) receptor and its cytoskeletal interactions in neutrophils. Arthur K. Sullivan then presents an in-depth survey of the membrane biochemistry surrounding the flow of granule organelles in leukocyte differentiation.

The discussion of some diseases is only occasionally enlivened by the emergence of new worthwhile facts. In the case of others, it would seem that, even if only a few years have passed, each new discussion wears the air of a revolution. Hodgkin's disease, at least from the pathological standpoint, is not so extraordinarily fickle and certainly does not touch either of these two extremes of variability. But it is still a fertile field of study and presents its full share of innovations and practical results. This is perhaps due to the special position it occupies between tumours and inflammatory diseases, or possibly to a lucky series of coincidences; the truth is that events have been on the move for some years now in the case of this disease. There can be no doubt that surprising progress has been made in connec tion with Hodgkin's disease, due, one feels, to close cooperation between several branches of medical science, each of which has had occasion to make new and useful contributions. This does not, however, hide the fact that certain important matters are still not clear, in particular the cause of the disease, its essential nature and, indeed, the best method for its treatment.

Managing infections that complicate care of neutropenic patients with leukemia and hematopoietic stem cell recipients has become a distinct specialty. In Managing Infections in Patients with Hematological Malignancies, the authors and editor draw on their extensive expertise while providing a roadmap for hematologists to efficiently manage the complex infections within their patients. The first section of the text reviews viral, bacterial, and fungal pathogens, and provides brief descriptions of the microbes and diseases they cause in patients with hematological malignancies. The second section is devoted to management of infections in patients with the different underlying hematological malignancies, while the third addresses several important topics that are often ignored in most books about infections and hematological malignancies. Managing Infections in Hematological Malignancies is a useful tool for all clinicians and practicing hematologists who treat individual patients and aspire to build stronger infectious diseases programs within their respective cancer centers.

Recent years have seen great strides in research on the pathogenesis of thromboses, unmatched by progress in other branches of hemostasiology. The orthodox concepts of the mechanisms of thrombus formation described by Virchow have come down to us as a "classical triad" of factors. Now, due to developments in molecular biology, pharmacology, and patho- physiology, they appear in a basically new light. The fruits of modern research, currently being tested or already imple- mented in clinical practice, have opened up the possibility of controlling the hemostatic process and developing effec- tive antithrombotic drugs. Much progress has been achieved in the past years, but much more remains to be achieved in such areas as the patho- genesis of venous and arterial thromboses, early diagnosis, therapy, and control of disorders. Many scientists in the U.S.S.R. are involved in studying these problems. Their data, from years of research carried out in leading laboratories and clinics in the U.S.S.R., are summarized in this monograph. This work is written by experts in various fields of biology and medicine. It deals with new and original con- cepts on the structure and function of the fibrinolytic sys- tem, the role of nonenzymatic fibrinolysis in regulating physiological hemostasis, the heterogeneous and discrete pat- terns of the system regulating blood coagulation, the molecu- lar mechanisms of fibrin polymerization, and the anticoagu- lating effects of fibrinogen/fibrin degradation products.

I am prepared to predict that this monograph by Dr. Ernest Beutler will long serve as a model for monographs dealing with topics in medical science. I make this bold statement because we encounter in this work a degree of accuracy and authoritativeness well beyond that found in much of the medical literature. Too often, a monograph is simply a review of past reviews. The preparation of an exhaustive and completely accurate study such as the present one is a very laborious task; consequently, many authors make extensive use of the reviews of earlier writers assum ing that the latter have checked and evaluated each previously published report. Unfortunately, however, this assumption of validity has not al ways been correct. Dr. Beutler, who is a world authority on the subject about which he writes, was determined to make this book as correct and complete as possible, and, to this end, has checked all the original sources. Nowhere else will such an exhaustive bibliography be found. Moreover, he has also undertaken to reevaluate in the light of current knowledge material pub lished in earlier days. This he is eminently able to do, and in some in stances his investigations have resulted in new interpretations. The result is a volume that will be recognized as truly the last word on this important subject.

Kurz nach Erscheinen unseres Handbuchs iiber die Non-Hodgkin-Lymphome wurden Stimmen laut, die nach einem klein en handlichen AbriB der Lymphom- diagnostik riefen. Auch die Mitglieder des Europiiischen Lymphom-Clubs (1. DIEBOLD, Paris, R. GERARD-MARCHANT, Villejuif, Y. KAPANCI, Genf, G. KE- LENYI, Pecs, H. NOEL, Briissel, F. RILKE, Mailand, A.G. STANSFELD, London, und J.A.M. VAN UNNIK, Utrecht) bestiirkten mich darin, einen solchen Ratgeber fUr den diagnostischen Alltag zu schreiben. Ja sie identifizierten sich mit diesem Plan und stell ten sich fUr die Obersetzung in mehrere Sprachen zur VerfUgung. So habe ich J. DIEBOLD, R. GERARD-MARCHANT, F. RILKE und A.G. STANSFELD fUr die prompte Obertragung ins Franzosische, Italienische und Englische zu danken. F. RILKE iibernahm die Initiative, einen Beitrag zur "Working Formula- tion for Clinical Usage" zu verfassen. Obersetzungen in weitere Fremdsprachen wurden von ehemaligen Mitarbeitern und befreundeten Kollegen bereitwillig durchgefUhrt, so von A. LLOMBART BOSCH ins Spanische, von IRENE LORAND und J.M. MACHADO ins Portugiesische und von N. MOHRI ins Japanische. Das Erscheinen in verschiedenen Sprachen einschlief3lich meiner Muttersprache sollte den Gebrauch des Abrisses im Alltag we iter erleichtern.

The development of new techniques such as immuno phenotyping, cytogenetic investigations and, more recently, molecular studies has considerably increased our diagnostic repertoire and broadened our ideas about the biology of acute leukemias. While immunophenotyping with mono clonal antibodies has yielded increased diagnostic precision and made it possible to develop a highly reproducible classification of acute leukemias based on cell-biological features, further insights have been gained into the patho genetic mechanisms involved in leukemogenesis by means of cytogenetic detection of acquired structural chromosomal abnormalities. Analysis of the leukemia-associated chromo somal breakpoints using molecular techniques can now pinpoint many genomic sites essential for normal develop ment and maturation of hematopoietic cells but functionally disrupted in leukemic cells. The main goal of the international workshop that we held in Berlin with a select group of scientists and clinicians involved in leukemia research was to describe the state of the art and new developments in the immunologic, cytogenetic, and molecular characterization of acute leukemias and to discuss the clinical importance of cell biological features. After introductory survey lectures dealing with the immunological and molecular-biological characteristics of normal vs. malignant lymphatic and myeloid progenitor cells, the workshop centered on con tributions characterizing the immunophenotype and both numerical and structural chromosomal abnormalities in acute leukemias."

Each of the four authors of this book has a particular interest in disorders of porphyrin metabolism and special experience in their management. Their individual involvement in the field varies from 12 to 52 years and, combined, represents more than a century of personal experience. Since it has been written by both basic scientists and practicing physicians, the book is intended to be of value to all those involved in porphyrin metab olism and the porphyrias. It is hoped that the fascination of porphyrin metabolism and the clinical challenge of the porphyrias experienced by each of the authors will be conveyed to the readers. Michael R. Moore Kenneth E. L. McColl Claude Rimington Abraham Goldberg vii CONTENTS Color Plates ............................................ xvii 1. The History, Classification, and Incidence of the Porphyrias 1 1.1. History ........................................ 1 1.1.1. Early Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.1.2. Early Descriptions of Porphyria .............. 4 1.1.3. Biochemical Developments .................. 4 1.1.4. Acute Porphyria . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.1.5. A Complete Pathway ...................... 8 1.2. Classification of the Porphyrias . . . . . . . . . . . . . . . . . . . . . 9 1.2.1. The Current Classification. . . . . . . . . . . . . . . 12 . . . .

The Second Conference of the International Society of Hemorheology took place under the auspices of the University of Heidelberg from July 27 - August 1,1969 in Heidel berg. At this conference the name of the Society was changed to THE INTERNA TIONAL SOCIETY OF BIORHEOLOGY, since the members decided to enlarge the scope of the Society to include all fields of biorheology. Meanwhile the Society has become an Affiliated Commission of the International Union of Pure and Applied Biophysics. The abstracts of the scientific papers, as they appeared in the program of the Confe rence, have been reprinted in BIORHEOLOGY (volume 6, No.4, April 1970). This international journal has become the official organ of our Society. We are greatly indebted to the Honorary Chairman, Professor G. QUADBECK, Dean of the University of Heidelberg Medical School, who gave substantial aid to one of us (H. H. H.), the Conference Chairman, in organizing this international meeting. We are grateful to the Mayor of the City of Heidelberg who welcomed the participants and their families in the Cellar of the Great Barrel of the Heidelberger SchloB. We thank the members of the Ladies' Committee, Mrs. IRMGARD QUADBECK, Mrs. ELISABETH HARTERT and Mrs. KARIN KREITER, who arranged a most successful social program in Heidelberg and the romantic Neckar valley."

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.

A great deal of new information has been obtained during the past four years, and this monograph provides a clear and well reviewed update on biochemical mechanisms and the results of important new clinical studies using the interferons. Reviews include what is presently known about the biosynthesis, physiological role and mechanisms of action of the interferons (alpha, beta, gamma). New biochemical information on interferon-receptor interactions and signalling pathways is provided. The pharmacokinetic considerations in treating leukemia, lymphoma, myeloma, neuroendocrine tumors and other solid tumors are reviewed with special emphasis on studies of adjuvant chemotherapy in malignancies of the immune system.

As the demographics of the population shift toward an increasingly aged society, the number of individuals with cancer increases and with it the need to give the most comprehensive possible health care delivery. Although much has been written about the specific therapy best suited for the various types of cancer and about the basic and clinical research which has dramatically improved treat ment, overall patient care requires attention to supportive care, which includes such items as pain management, the use of blood products, nutrition, and psychosocial needs. Yet infection remains the leading cause of death in cancer patients and is a major cause of morbidity and hospitaliza tion, making it a major aspect of the supportive care of cancer patients. It therefore deserves a full exposition. Bone marrow transplantation is increasingly being utilized as part of a therapeutic modality in the treatment of cancer patients. Transplantation patients are at such a particularly high risk of developing a wide variety of different types of infection, that they inevitably can serve as an excellent framework for discussion of all the types of infections that occur during the treatment of cancer. The patient undergoing allogeneic bone marrow transplantation is at particularly high risk of infection due to the major perturbations of host defenses, which include granulo cytopenia, cellular immune dysfunction, humoral immune dysfunction, blood product transfusions, and vascular access devices. Each of these perturbations results in a different set of infectious disease problems."

Endocrine glands may be involved in patients with thalassemia major. In the last 20 years, new therapies have significantly improved life expectancy, while several endocrine abnormalities have been described in children, adolescents, and young adults suffering from thalassemia major.
The practical objective of this book is to establish guidelines for the management of endocrine disorders underlying the various phases of thalassemic life. Internationally acknowledged experts give a state-of-the-art account of physiopathological and therapeutical approaches to endocrine disorders in thalassemia and focus on such topics as growth hormones, thyroid diseases, puberty, hypogonadism, diabetes, and bone metabolism.

Scientists and engineers have been involved in medical radiology from the very beginning. At times advances in this field occur at a tremen dously fast pace. Developments in radiological diagnostics have - technologically and medically speaking - focused on morphology. At present, computer-aided tomography (CAT) is at a high point in deve1opment, medical application, and validation. The preconditions for this success were rapid advances in electronics and computer technology - in hardware and in software - and an unexpected cost reduction in these fields; the co operation of various scientific disci plines was also essential. Functional radiological diagnosis has been neglected in part, owing to the emphasis on morphology, but alone the synthesis of morphology and function prornises further advances. Apart from the limited capabilities ofuItrasonic techniques there is no way other than using X-rays to carry out functional studies of organs and their systems through an intact body surface. It is frequently necessary to do further processing and evaluation of image series which have been recorded from the morphological viewpoint. This further picture processing may be of selected points (pixels) in the image, of certain regions of interest (ROI), or of the overall picture. For the measure ment of rapid phenomena, such as the blood flow in the main arteries, high image-frame rates are required, and at the moment these can only be achieved with cinemascopic techniques. For slower processes, other techniques such as videography have some advan tages.

Jaundice ofnewbom infants was described by several authors in the 17th century. The condition, however, was usually thought of as being similar to adult jaundice and due ro occlusion of the bile ducts by 'glutinous humours'. On the other hand, some writers reported on the fact that more than one consecutive baby was often affected, and there is a classic example of the disease in twins written by Louyse Bourgeois, the midwife of Marie de Medici, in 1609. It was not until early in the 20th century that it was realised that the common link between these familial cases was anaemia, and later still that this was of the haemolytic type. The breakthrough, in terms of an idea, came in 1938, when Darrow postulated that the baby's red cells were destroyed by an immune reaction on the part of the mother, the result of immunisation by paternal factors in the fetus. Shortly afterwards Wiener discovered an entirely new blood group system, 'Rh', and it was found that it was in compatibility within this system that was responsible for the vast majority of cases of haemolytic disease of the newborn."

Stress, high blood pressure, smoking, pollution, fast foods, overweight, excessive travelling, surgery, less movement are common features in our modern life. These features are risky for blood clotting disorders. According to WHO, over 29% of the total mortalities worldwide are due to thrombosis. By the year, 2020 cardiovascular diseases (CVDs) may cause an estimated 25 million deaths per year, thus antithrombotic therapy is of great interest.

The available thrombolytic agents such as urokinase are highly expensive, antigenic, quite unspecific, pyretogenic and hemorrhagenic. Therefore, the production of fibrinolysing enzymes, which rapidly dissolute thrombi within the vascular tree, without the detriments by microorganisms, as described in this book, is the desirable aim of today s research. "

Scientific and Ethical Discipline in Clinical Trials on Acute Leukemia G. MATHE Institut de Cancerologie ct d'Immunogenetique "', Hi'ipital Paul-Brousse "."", Villejuif/France Clinical research is still in an evolutionary stage. Although scientific technology was readily accepted and applied, scientific methodology has been accepted much more slowly and is very rarely properly applied. There are three reasons why this is so. First, medical ethics frequently limits the applicability of clinical research, for doctors have to be more than scientists. They must also remain moral philosophers, as they were before medicine became a science. Second, the heterogeneity of the material on which clinical researchers work in studying human diseases makes the application of scientific methodology difficult. Third, researchers must publish. This means that they must obtain publishable results, and too often this means results in accordance with established concepts, easily accepted by the editors of established journals, which are read by the establishment. It is the privilege of too many people to be able to accept "truth" and recipes from other people and confirm their truth and results. It is the mission of a very few others to accept nothing as "truth" and to consider no recipe ideal, either in concept or detail.

After many years of relative neglect, the importance of study of factors governing blood flow has at last achieved recognition; in this volume are documented many of the techniques, and the basic scientific and clinical observations, which have helped to open up understanding of this highly important aspect of human physiology and pathology in recent years. The text is logically divided into five sections beginning with blood cell deformability, then moving on to theoretical consideration of blood rheology, followed by accounts of the interrelationships between rheology, blood flow and vascular occlusion. The final two sections deal with blood rheology in clinical practice and therapeutic aspects of the study of blood flow. As regards blood cell deformability (Section A), the basic problem is set out by Kiesewetter and colleagues in the first paragraph of chapter 1 (p. 3), in which they point out that whereas human erythrocytes at rest have a diameter of approxi mately 7. 5 /-tm, nutritive capillaries have diameters ranging from 3-5 /-tm, and chapters in section A give an account of the ways in which the red cell can undergo deformation to permit capillary perfusion and the maintenance of the microcirculation."

The first International Meeting on Apheresis was held in Dyon in 1984. At the congress it became clear that both the technical and therapeutic sides developed very rapidly and it appeared fruitful to bring together the investigators of the different countries working in the areas. At that time immunology had come to pervade many clinical specialities, and hemapheresis, especially plasmapheresis was considered a therapeutic tool in many immunological diseases which hitherto had proved to be fatal. New methods to identify certain antibodies and circulating immune complexes in the serum and the possibilities to remove them from the blood by several techniques (filtration, centrifugation, immunoabsorp tion) led to an almost uncontrolled use of plasma exchange in a variety of diseases. Since then the technical possibilities of this technique were further recognized, as was the impact of immunology on many diseases, and the possibilities to collect specific components for therapeutic pur poses. But also we became aware of the limited contributions of anec dotal data on successes or failures of apheresis as adjuvant treatment. Therefore international prospective studies were initiated to make critical assessment possible of apheresis in various diseases.