This monograph is the first of a series which is designed to present in depth timely reviews of subjects related to the blood. Insofar as each subject lends itself, the clinical aspects of each topic will be presented as fully as is appropriate, in addition to the basic features. As a consequence, the various monographs should be found useful not solely by hematologists. Depending on the nature of each topic, it is expected that these monographs will be found important by physiologists and specialists in fields other than hematology, as well as by scientists of very diverse interests. The present treatise illus trates this point. Doctors Garby and Meldon have brought together in a most useful way the spectacular advances which have been made in the last decade or two in a field of fundamental biologic impor tance. They have also brought to the discussion of this subject their own observations and interpretations as well as their profound understanding of the respiratory functions of the blood. Maxwell M. Wintrobe Salt Lake City, Utah v Preface This volume is an attempt to summarize the present state of know ledge of the respiratory functions of blood in health and disease. Though it deals fairly thoroughly with physicochemical aspects of the blood's gas transport properties and with the molecular chemis try of hemoglobin, its main emphasis is the gas transport function of the blood in vivo and modes of its disturbance in disease."

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.

Due to major advances in understanding the biology and pathogenesis of the disease, the management of multiple myeloma is changing rapidly. New diagnostic and prognostic criteria have been introduced, and treatment options are multiplying with high-dose chemotherapy regimens, stem cell transplants, and the development of novel agents and immune-based strategies that target tumor cells directly. This book is aimed at the practitioner who is looking to put these advances into clinical context. It will serve as an up-to-date resource for treatment of myeloma and related disorders. Chapters are written by international authorities and contain color photos, diagrams, and algorithms outlining preferred treatment strategies. Relevant scientific information is integrated throughout, but the focus here is on providing practical therapeutic guidance for oncologists and hematologists caring for myeloma patients. The book covers all myeloma subtypes and related disorders, including amyloidosis, Waldenstrom macroglobulinemia, plasmacytoma, MGUS, and POEMS syndrome.

The continuous advances in our understanding of hematology and neo plastic disorders have made possible this third volume of reviews. Their purpose is to summarize investigations which have defined new concepts, and, it is hoped, stimulate new ideas. In the choice of subjects, we have attempted to retain the balance between academic and clinical interests. We are grateful to the contributors, who have maintained the high stan dards set in the earlier volumes, and for feedback from readers. Both have helped to orient the direction of this series. It was a reader who pointed out that the title of the two earlier volumes, The Year in Hematol ogy, was misleading since it suggested a detailed review of trends and findings limited to the last year. In response to this valid comment, The Year . . . has been changed to Contemporary . . . and the scope has been expanded to encompass the kindred disciplines of hematology and oncol ogy. Another editor, Franco M. Muggia, has been added to provide addi tional expertise for the latter field. The title of the present and future volumes has been changed to Contemporary Hematology/Oncology. It has been pointed out to us that considerable ingenuity will be needed to find topics not already covered. We believe that the papers in the present volume have met this challenge. As before, the readers' comments con cerning Contemporary Hematology/Oncology will be appreciated. Joseph LoBue Albert S. Gordon Robert Silber Franco M."

In the last six years, a remarkable series of stUdies have demonstrated an intimate relationship between red cell metabolism and the function of the cell as an organ of gas transport. First came the demonstration of binding of organic phosphocompounds of the red cell to hemoglobin; this was followed by studies that demonstrated modification of hemoglobin oxygen affinity by such binding. At present we are in an exhilirating phase of accrual of data showing that the levels of these phosphorylated inter mediates can be rapidly altered in the red cell to modulate hemo globin function. At one time it was said that the red cell was an inert bag full of hemoglobin. Now we know not only that the cell has an active metabolism crucial to its viability, but that this metabolism is just as crucial to the whole organism in the proper adjustment of oxygen transport. On October first, second and third, 1969, red cell biochemists, general biochemists, geneticists, cardio-pulmonary physiologists, exercise physiologists, experts in blood storage, and represen tatives from many other disciplines met in the Towsley Center for Continuing Medical Education at the University of Michigan, Ann Arbor, to present recent findings and discuss developments in this new interdisciplinary field. The meeting was dedicated to Dr. Alfred Chanutin, Professor Emeritus of the University of Virginia, to honor his retirement in 1967 and in recognition of his great contributions to the studies outlined in the first paragraph of this preface."

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."

Hemoglobin and the red cell have continued to set a dizzying pace as the objects of research in the two and one-half year interval since the First International Conference on Red Cell Metabolism and Function. Most exciting perhaps, is a beginning molecular attack on sickle cell disease. The story of the inter action of red cell metabolism and oxygen transport has continued to unfold, and we can now infer that patients with hypoxia usually utilize red cell metabolic adjustments to improve oxygenation. This puts the red cell squarely in the center of medical practice, since much of medicine-heart, pulmonary, and blood disease- deals with inadequate oxygenation. On April 27th through the 29th, 1972, crystallographers, chemists, biochemists, physiologists, geneticists, and physi cians from many medical disciplines met in the Towsley Center for Continuing Medical Education at the University of Michigan, Ann Arbor to present new data, to review recent developments, and to try to piece together additional features of the red cell puzzle. The meeting was dedicated to Dr. Francis John Worsley Roughton, Professor Emeritus of Colloid Science, University of Cambridge, England, in recognition of his numerous excellent contributions to the understanding of hemoglobin and red cell function. The program got off to a good start with a paper from M. F. Perutz, Nobel Laureate, on the structure of hemoglobin. Dr."

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.

Extensive research into the molecular mechanisms of cancer disease has heralded a new age of targeted therapy. In malignant cells, key proteins that are crucial to tumor growth and survival are now being targeted directly with rationally designed inhibitors. Apart from monoclonal antibodies, small molecule therapeutics such as oncogenic protein kinase inhibitors are attracting a vast amount of investigational attention. This textbook, written by acknowledged experts, provides a broad overview of the small molecules currently used for the treatment of malignant diseases and discusses interesting novel compounds that are in the process of clinical development to combat cancer.

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.

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.

The mammalian erythrocyte is a very suitable model for the study of aging at the cellular and molecular level. It is not only a matter of apparent simplicity in terms of biochemistry, biophysics and physiology but more likely this cell offers a great possibility for elucidating some basic problems in the process of aging. In fact, nowadays, it is possible to follow individual cells all along their life span in circulation, it is possible to obtain these cells when young, middle aged or old and it is possible to obtain cells from individuals of defined ages and transfuse them into compatible recipients to investigate the role of the environment where the cell lives, and finally it is possible to easily manipulate the red cell content in terms of enzymatic activities and/or metabolic properties to investigate the possible effect of these manipulations on cell survival. This book, Red Blood Cell Aging, is based on a symposium held in Urbino, Italy, at the end of 1990 and examines the impact of age on the membrane, metabolism, structural and enzymatic proteins of mammalian erythrocytes. The various contributions to this symposium not only described those processes of aging which affect the cell but also provided a nearly complete picture of the event{s} and mechanism{s} that every day permits to recognize among 25 trillion circulating red cells {in an average adult} that 1 percent that have reached the end of their 120 day life span in circulation.

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.

Our understanding of the function of natural killer (NK) cells has dramatically changed in recent years. The discovery of NK receptors specific for MHC class I molecules, and the study of the role of co-stimulatory and adhesion molecules have led to an understanding of how NK cells recognize tumor and virally infected cells that have lost expression of MHC class I molecules or have altered distribution of normal cell surface molecules. Such recognition events lead to intracellular signals which can be either stimulatory or inhibitory. This book provides an insight into how NK cells develop, how they learn to distinguish altered cells from normal cells, and into their biological role in controlling infections and tumors.

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.

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."

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.

The European Study Group for Cell Proliferation held its XVth Meet ing at Sundvolden, Norway, in September 1987. The program included a symposium on the cell kinetics of the in flammatory reaction, with invited speakers. This volume of Current Topics in Pathology contains the manuscripts submitted by the speak ers. Inflammation is a very broad area, and the cell kinetics of the inflammatory reaction comprises a large number of topics. A full cover age would fill more than one book. This volume therefore contains only a few of the important aspects of the cell kinetics of the inflammatory reaction. It is hoped that it will serve as inspiration for further research in this important area. Inflammatory diseases are even more important than cancer, and there is a great need for a more detailed information about inflammation. OLAV HILMAR IVERSEN Contents Chapter I The Cell Kinetics of the Inflammatory Reaction. Introduction and Overview."

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."

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."

In the late 1940s investigators observed that mice given supralethai doses of total body irradiation were protected by infusion of viable spleen or marrow cells following irradiation, and that this was accomplished by hemopoietic reconsti tution with donor cells as proven using genetic markers. If a similar approach could be applied to humans, it should be possible to treat leukemia patients with any dose of chemoradiotherapy as far as nonmarrow toxicity permitted, and then rescue them by marrow transplantation. Early clinical attempts were gen erally unsuccessful, mostly due to a lack of knowledge of histocompatibility antigens and appropriate supportive care. These areas developed rather quickly during the 1960s, and for almost two decades now clinical marrow transplan tation has been carried out with increasing success. After initially using only bone marrow from HLA indentical siblings, the field has expanded rapidly to incorporate HLA nonidentical related donors, and recently even marrow from unrelated volunteer donors. Furthermore, since for numerous patients who oth erwise could benefit from transplantation a donor cannot be identified, there has been a growing interest in using the patient's own (autologous) bone marrow. Our understanding of the principles of transplantation and our knowledge of the potential risks and benefits have quickly grown. At times it is difficult, however, to decide what is the best option for a given patient."

In 1988 we presented our Guide to Bone Marrow Transplan tation. The reception has been enthusiastic and we have re ceived a flood of critical comments, suggestions and requests to provide an update in due time. Although several books on marrow transplantation have recently been published, their scope and goal have generally been different. Hence, we have decided to prepare a second edition of the Guide. Our aim was to maintain a short, concise text which never theless would incorporate changes that have occurred over the past four or five years. We have streamlined the description of pretransplant considerations, by condensing two sections into one (Treatment Planning and Timing of Transplantation). This also facilitated the review of controversial indications for marrow transplantation, for example in patients with acute myelogenous leukemia in first chemotherapy-induced remission. We have updated the chapter dealing with conditioning regimens and have expanded the section on donor selection, in particular in regard to the current level of tissue typing and the identification of unrelated volunteer donors. In the chapter on collection, processing, and infusion of marrow, we have incorporated recent developments, for example, the use of closed systems for marrow harvesting and processing and the use of solid phase separation of stem cells."

Recent developments in recombinant DNA technology have led to the large-scale production of human erythropoietin and to the demonstration that it is effective in the treatment of renal and possibly some other anaemias. This has lent a new impetus to studies of the pathophysiology and pharmacology of the hormone which is reflected in this report of the proceedings of a meeting held in Liibeck in June 1988. In 15 papers, all from European centres, the broad topics covered are erythropoietin's physiology and chemistry, the patho- physiology of erythropoiesis and the use of erythropoietin in the treatment of anaemia. Several of the papers include up-to-date reviews of the literature. The field is now expanding rapidly, and this volume, though not comprehensive, usefully points up many areas of recent understanding as well as others of continuing un- certainty. Overall, it contains material likely to be of interest to biochemists and experimental haematologists as well as to phar- macologists, clinical haematologists and nephrologists.

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."