This concise, clinically focused pocket handbook assembles and synthesizes the latest developments and trends in the diagnosis and treatment of CML and provides an authoritative and convenient summary of the latest progress in TKI trials, the molecular monitoring of CML responses, and the development of new therapies to overcome resistance and improve patient care. Chronic myeloid leukemia (CML) is a rare type of leukemia (1-2 per 100,000 people) but is the most common chronic myeloproliferative neoplasm. CML remains a key model for the improved understanding of the pathophysiology of a malignancy at a molecular level; CML was the first cancer to be associated with a recurring chromosome abnormality, which generates the Philadelphia (Ph) chromosome and its associated fusion gene BCR-ABL1. The clinical outcome for patients with CML has changed dramatically in the past 15 years and this has been due to the development of tyrosine kinase inhibitors (TKIs), compounds that inhibit the activity of the oncogenic BCR-ABL1 protein. A number of first-, second- and third-generation TKIs are now available for the treatment of CML, although a number of treatment challenges remain, not least the development of treatment-resistant CML. Parallel to the development of specific drugs for treating CML, major advances have been made in the field of disease monitoring and standardization of response criteria.

The extravasation of cytotoxic agents can result in severe local tissue damage and medical emergencies during tumour therapy. This revised compendium is intended to help clinicians assess any situation speedily and with certainty. The general section of the book includes topics such as predisposition, prevention, type of harm, general measures in handling extravasated drugs, specific antidotes, and documentation. In the 2nd edition, the scientific information contained in the general section and relating to the actual substances has been updated. The substance specific part of the book includes detailed instructions on handling more than 50 cytotoxic drugs, to initiate targeted measures. Templates for an extravasation set, overview tables, documentation sheets, and patient information, as we as a CD-ROM are included to support clinical practice. The book is the outcome of a consensus of an interdisciplinary working group that has collected and systematically reviewed all published literature on the topic.

Granulocyte colony-stimulating factor (G-CSF or GCSF) is a secreted glycoprotein that stimulates the proliferation and differentiation of granulocyte precursor cells, and induces mobilization of peripheral blood progenitor cells from the bone marrow. Development of recombinant human G-CSF has had a profound impact on the treatment of many diseases, including severe chronic neutropenia and cancer, and has enabled peripheral stem cell transplantation to supplant bone marrow transplantation in the autologous setting. This Milestones in Drug Therapy volume describes the experience of the last 20 years of treatment with recombinant human G-CSF, including the basic science, the use of recombinant human G-CSF in both the oncology and nononcology settings, and the safety and economics of its use. Many of the authors were the original investigators of recombinant human G-CSF and other authors are key researchers who provide their outlook for the next 20 years for use of and research with recombinant human G-CSF.

Myelodysplastic syndromes (MDS) are the most common hematological malignancies involving mostly the elderly population. The major morbidity relates to patients' symptomatic cytopenias.MDS was previously named as "preleukemia " or " smoldering leukemia" as the lack of terminal cells in MDS and because about 25% of all cases progresses into acute myeloid leukemia. According to various reports the annual incidence of MDS ranges widely from 2-12 per 100.000, increasing to 30-50 cases per 100.000 among persons aged 70 or older. It is believed that the true incidence of MDS have been underestimated however it seems to be comparable to that for multiple myeloma and chronic lymphocytic leukemia. In the past decade much progress had been made; we know more on the disease pathology, there is more emphasis on the care and more targeted therapy had been invested. Athors provide updated knowledge in this book on all clinically important aspects of the disease. Hot topics of our days are discussed in chapters by outstanding and well known scientists from all over the world. We would offer this product both for medical students and postgraduates as well as for all who are interested in this very exciting and fast progressing field of hematology. With this work authors should call attention on the disease for decision makers in healt care systems as well.

WEGENER'S GRANULOMATOSIS & ANCA-ASSOCIATED DISEASES: THE STORY CONTINUES The disease now designated as Wegener's granulomatosis (WG) was first described in 1931 by Heinz Klinger, who considered it to be a special form of polyarteritis nodosa. Klinger's friend, Friedrich Wegener, expanded on the first observations and interpreted the pathological and clinical fmdings to represent a distinct disease entity (Wegener, 1939). He described this entity as a "peculiar rhinogenous granulomatosis with a unique participation of the arterial system and the kidneys". Later, Godman and Churg (1954) established the classical diagnostic criteria (the "WG triad"): granuloma, vasculitis, and glomerulonephritis. In 1958 Walton pointed out the poor prognosis of WG based on a small number of published cases (mean survival time: 5 months). In 1966 Carrington and Liebow reported "limited forms" of WG with a defmitely more favorable prognosis. Since then positive results have been reported with cyclophosphamide therapy. In addition, a retrospective study of combined low-dose cyclophosphamide and prednisolone in 85 WG patients over a period of 21 years found a similarly encouraging outcome. The*latter experience led to the current "standard" treatment protocol (FAUCI et al. , 1973 and 1983). More recently, strong evidence has emerged that some of the morbidity and mortality ofWG - and other types of systemic vasculitis - may be a consequence of this treatment (Hoffman et al. , 1992).

The term "lymphoma" was originally used by Billroth in 1871 [55], and by Virehow [763] some years before that, for the designation of swelling of lymph nodes that was not due to "eareinoma, sareoma, ehondroma, myxoma, ete. " In his paper, Billroth reeounted sueeessful treatment with arsenie (" Fowler's solution") of multiple "lymphomas" that had developed in a 40-year-old woman during a 10-month period. From this report it is not entirely clear if the multiple" lymphomas" deseribed were infeetious or if they were eonsis- te nt with what we now mean by "malignant lymphoma. " Today, the term "malignant lymphoma" is generally used eolleetively for malignant lymphoproliferative neoplasms that tend to arise in lymph nodes and also eneompasses Hodgkin's disease and non-Hodgkin's lymphomas. The adjeetive "malignant" seems somewhat superfluous sinee, in addition to Bill- roth's original eonnotation, the sense of malignaney is nowadays read into the word "lymphoma. " To be sure, true, i. e. , malignant, lymphomas have to be differentiated from "pseudolymphomas," or to put it more exaetly, "pseudomalignant lymphomas. " In this book, "lymphoma" and "malignant lymphoma" are used interehan- geably for malignant neoplastie lymphoproliferative disorders, and "pseudo- lymphoma" is used for benign lymphomatous proeesses. Our editorial eonsultant, Dr. M. Leider, disagrees with all of this. In his Dictionary of Dermatological Words, Terms, and Phrases [421] and other works, he maintains that there is no etymologieal basis for words bearing the eontrived suffix" -oma" or the true Greek suffix" -ma" to denote malignaney.

Principles and Practice of Cancer Infectious Diseases is a comprehensive and insightful work dedicated to elucidating the problem of infections in cancer patients. This essential volume reviews common and less often encountered infections, while establishing the difficulties behind preventing, diagnosing, and treating infectious diseases in cancer patients. Key sections are devoted to the presentation of clinical symptoms and the identification of major etiologic agents. A cadre of leading clinicians provide a detailed assessment of the risk factors for various infections, critical strategies in preventing and managing infections, and study of the interactions between the pathogen and host's immune function and inflammatory response. With its in-depth knowledge and concise treatment of the distinct facets of infections in cancer patients, this volume is an indispensible tool for all infectious disease specialists and clinical oncologists.

This series of books, devoted to aspects of blood cell biochemistry, development, immu nology, and ultrastructure, has evolved and separated from the long-established Plenum series Subcellular Biochemistry. It is the intention of these volumes to draw together related areas of investigation and to provide, in the fullness of time, complete coverage of this rapidly advancing important biomedical discipline. Both fundamental and medically applied topics, dealing with normal and pathological cells, will be included. This, the first volume of the series, contains a diverse collection of chapters, all of which relate to erythroid cells. The range of material included is extremely broad and the authors have used contrasting technical approaches, both within their personal experimen tal studies and within their manuscripts. This has led to the production of a very interest ing compilation, which does, nevertheless, possess a strong overall thematic unity. As with all edited volumes, some topics of importance and interest are not included. This may be because of oversight on my part, as editor, or because the authors originally selected failed to submit their manuscript by the agreed-upon submission date. For these omissions I take full responsibility and trust that at least some of the topics omitted, for instance membrane cation transport systems, will be covered within a future volume of the series. This book commences with two chapters of a developmental nature."

In recent years a dramatic increase in knowledge of the biology of the lymphomas has been accompanied by the emergence of new treatments offering improvements in efficacy and reduction in toxicity. In this volume an internationally recognized group of experts review relevant aspects of the biology, diagnosis and management, with particular emphasis on the emerging data available for this disease.

Proceedings, with Commentary, of the Symposium held at London, England October 3-4, 1981

Historically, the field of hematopoietic growth factor research began with the work of Carnot and Deflandre-in 1906 they suggested that the rate of erythropoiesis is regulated by a humoral factor found in the blood, namely, erythropoietin. From this comparatively early start, accelerating progress has been made in erythropoietin research, which demon strates the general trends in this field of study. Erythropoietin was purified to homogeneity by 1977 (from enormous quantities of urine from aplastic anemia patients). Subsequently, the gene for erythropoietin has been cloned (1985), and massive quantities of this growth factor have been produced for clinical trials (late 1980s onward). Erythropoietin has become established as a pharmaceutical product of great value in the treatment of a number of diseases, most notably chronic renal failure. Once the ligand had been cloned, interest turned to the erythropoietin receptor, which was cloned in 1989. Since then, structure/ function studies have been performed on receptor mutants, cellular signaling events down stream from the occupied receptor have been identified, and the specific producer cell types and molecular stimuli for erythropoietin production have been thoroughly investigated, as has the regulation of erythropoietin gene transcription. This schedule of events since the 1970s typifies that seen for a number of hematopoietic growth factors. Along the way, the hematopoietic growth factors have been recognized as members of the cytokine family of signaling molecules that are important in a number of different physiological and patholog ical situations (see below).

Blood Cell Biochemistry was initially conceived as part of the Plenum series Subcellular Biochemistry, from which it has developed into a separate series. The present volume is devoted primarily to contributions on megakaryocytes and platelets and, to a lesser extent, to macrophages and eosinophils. The book does not attempt a rigorous or total coverage of the particular topics; it represents the areas of current scientific activity and interest that were selected by the editor at the commencement of this project. In general, the approach has been similar to that adopted for Volume 1 of the series (Erythroid Cells); the same approach will be followed subsequently in Volume 3 (Lymphocytes and Granulocytes). This book opens with a developmentally oriented chapter by Janine Breton-Gorius on megakaryocyte maturation and platelet release in normal conditions, which serves to set the scene ultrastructurally for much of the data that follow. The biosynthesis and process ing of platelet glycoproteins in megakaryocytes is dealt with by Alain Duperray and his colleagues, and thereby provides an in-depth biochemical survey of the megakaryocyte. The applications and strengths of crossed immunoelectrophoresis for the study of platelet membrane proteins is then covered by Simon Karpatkin, and a detailed account of the heredity disorders of platelet function is provided by Francine Rendu and Evelyne Dupuy."

Experimental Hematology Today - 1988 presents the latest results of research reflecting the diverse interests of basic and clinical hematologists. The major areas explored are hematopoietic regulation by cytokines; hematopoietic cellular growth regulation, with emphasis on the interaction of stromal with hematopoietic stem and progenitor cells; granulopoietic regulators; gene transfers into hematopoietic progenitor cells; leukemogenesis; and bone marrow transplantation. All chapters report on research or clinical findings of the past year.

To produce a comprehensive overview of macrophages and related cell types in a short review volume is an impossible task. When I selected the topics to be included, some equally important areas were omitted by necessity, and for this I apologize. My choices have been somewhat eclectic, touching subjects of personal interest (such as osteoclast biology and macrophage electrophysiology) or of current fashion (apopto sis, antigen processing, cell adhesion molecules). The book has also had to encompass areas of a more general flavor to provide balance for the general reader (such as reviews of macrophage development, heterogeneity, and function, and of the surface molecules expressed by macrophages). I thank all the authors for their prompt sub missions; all have been of high quality, and my editorial tasks, thankfully, have been minimal. Michael A. Horton London, United Kingdom ix Contents Chapter J An Overview of Receptors of MPS Cells lain Fraser and Siam on Gordon 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. The Mononuclear Phagocyte System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3. Diversity of Macrophage Plasma Membrane Receptors. . . . . . . . . . . . . . . . 6 3. 1 A Structural Approach to Classification . . . . . . . . . . . . . . . . . . . . . . . . . . 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3. 2 Multisubunit Receptors 3. 3 Soluble Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3. 4 Lectins and Lectin-Like Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4. Functions and Selected Examples. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4. 1 Growth, Differentiation, and Modulation . . . . . . . . . . . . . . . . . . . . . . . . 14 4. 2 Cell-Cell and Cell-Matrix Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4. 3 Endocytosis and Scavenger Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4. 4 Secretory Responses and Biosynthesis of Effector Molecules . . . . . . 17 5. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 . . . . . . . . . . . . . . . . . . . .

There is no field of medicine in which advances in therapy have been so closely linked to a better understanding of molecular medicine than in the area of hematologic malignancies. For example, recent insights into the understanding of Epstein-Barr virus have led to new treatment options for patients with posttransplant lymphoproliferative disorders, as discussed in the chapter by Dr. Richard Ambinder et al. Similarly, Drs. Slack and Gallagher discuss the explosion of recent information regarding the molecular pathogenesis of acute promyelocytic leukemia. This particular morphologic subtype of acute my- eloid leukemia warrants separate discussion because of our increased under- standing of the pathogenesis of leukemia, as well as the dramatic advances in outcome that have occurred with differentiation therapy provided by the vitamin A derivative aW-trans retinoic acid, as discussed in the chapter by Drs. Frankel and Powell. New approaches in the therapy of diffuse aggressive lymphomas in relationship to prognostic factors are discussed by Drs. Koc and Schenkein. Novel approaches to cutaneous T-cell lymphomas are discussed by Drs. Foss and Kuzel. Drs. Fonseca and Greipp discuss prognostic factors in myeloma, which are potentially important since they may serve to identify patients who may benefit from aggressive therapy such as bone marrow trans- plantation, which is discussed in the chapter by Dr. David Vesole. State-of-the-art reviews are provided in the chapters on AIDS-related non- Hodgkin's lymphoma by Drs. Volm and Von Roenn, adult acute lympho- blastic leukemia by Drs.

Proceedings of a NATO ARW held in Cargese, France, October 9-13, 1989

This comprehensive treatise on the reticuloendothelial system is a project jointly shared by individual members of the Reticuloendothelial (RE) Society and bio- medical scientists in general who are interested in the intricate system of cells and molecular moieties derived from those cells that constitute the RES. It may now be more fashionable in some quarters to consider these cells as part of what is called the mononuc1ear phagocytic system or the lymphoreticular system. Nevertheless, because of historical developments and current interest in the subject by investigators from many diverse areas, it seems advantageous to present in one comprehensive treatise current information and knowledge con- cerning basic aspects of the RES, such as morphology, biochemistry, phylogeny and ontogeny, physiology, and pharmacology, as well as c1inical areas inc1uding immunopathology, cancer, infectious diseases, allergy, and hypersensitivity. It is anticipated that, by presenting information concerning these apparently het- erogeneous topics under the unifying umbrella of the RES, attention will be focused on the similarities as well as interactions among the cell types constitut- ing the RES from the viewpoint of various disciplines. The treatise editors and their editorial board, consisting predominantly of the editors of individual vol- umes, are extremely grateful for the enthusiastic cooperation and enormous task undertaken by members of the biomedical community in general and especially by members of the American as well as European and Japanese Reticuloen- dothelial Societies.

It can honestly be said that the scope and magnitude of this meeting surpassed initial expectations with respect to the number and quality of the papers presented. Our group has grown since we last met in Dortmund in 1971. This is a good indication that a spiraling of our interests has taken place with the effects of the initial good work felt, not just in one corner of the globe, but in all four. With such a start, it was only appropriate that an international society was formed at the meeting to further coordinate our mutual undertaking. Henceforth it shall be known as the International Society of Oxygen Transport to Tissue. A final note of acknowledgement should be made to those who were in the supporting cast, not only in making the meeting in Charleston and Clemson a success, but also in the compiling of this book. Gratitude is due to Dr. Daniel H. Hunt for his efforts, the end product of which you have in your hands. Considerable service was rendered by Mr. Robert J. Adams, Mr. Buddy Bell and Mr. Nathan Kaufman during the symposium itself. Much typing, organizing and record keeping was done by our lovely secretaries, Laura B. Grove, Muff Graham and Kaye Y. Zook.

This book covers a wide range of disorders such as atrial fibrillation, artificial heart valves, deep vein thrombosis, pulmonary embolism and stroke. Handbook of Oral Anticoagulation aims to provide an accessible overview of the exciting new developments in this field. Incorporating numerous quick-reference tables and figures and fully referenced throughout to key papers and the latest reviews, it will be a useful resource for all healthcare professionals involved in thromboprophylaxis.

It was the year of 1969 when this monograph was originally published in Japanese by Professor TADASHI KAWAI, titled as "The Plasma Proteins, Their Fundamental and Clinical Aspects." After I read through the Japanese edition, I was impressed by its rather complete coverage of the subjects and their detailed descriptions. I have felt that this excellent monograph should be distributed not only among our Japanese scien tists but also among many other colleagues throughout the world. I am happy, the refore, to know that the English edition of his monograph, partly revised, is ready to be published at this time. Professor KAWAI received his postgraduate medical training in U.S.A. for seven years, and was certified by the American Board of Pathology in both Anatomical and Clinical Pathology in Fall, 1962. Thus, I believe, he is the most suitable fellow for publishing the English edition of this kind.

This volume contains those papers which were presented at the Second International Symposium on Oxygen Transport to Tissue, to- gether with the discussions which followed. These discussions were generously summarized by the chairmen of the various sessions. This symposium in Mainz was the third international meeting, after those held in Dortmund in 1971 and Charleston-Clemson in 1973, which dealt primarily with problems relating to oxygen transport to tissue under physiological and pathophysiological conditions. It was the second symposium conducted by the International Society on Oxygen Transport to Tissue which was founded in 1973. We dedicate this volume to the memory of the first president of the International Society on Oxygen Transport to Tissue, Dr. Mel- vin H. Knisely. July, 1975 JUrgen Grote Daniel D. Reneau Gerhard Thews Contents Welcome xxi G. Thews Session I - OXYGEN MEASUREMENTS IN BLOOD AND TISSUE A Method for Simultaneous Measurements of Bioelectric Activity and Local Tissue P02 in the CNS * * . * ...* * . * 3 A. Lehmenkuhler, H. Caspers, and E. -J. Speckmann Oxygen Fields Induced by Recessed and Needle Oxygen Microelectrodes in Ho- geneous Media * . * . * 9 G. Schneiderman and T. K. Goldstick The Application of Histological Analysis for the Localization of Tissue P02 and Local Blood Flow with the Example of the Glomus Caroticum of the Rabbit (Oryctolagus cuniculus) . . * * ...* * * . . * . * . . * . 17 H. Weigelt, E. Seidl, H. Acker, and D. W.

Since there are many different tissues and organs in the body, a study of oxygen transport to tissue necessarily involves a great diversity of bodily functions. Furthermore, these tissue functions can be approached from the viewpoint of several disciplines. Even tually, however, all of these approaches must be combined to arrive at a comprehensive picture. This multidisciplinary effort, though imperative, has been implemented slowly because traditional biologi cal science has been largely organ- or discipline oriented. Initia tives to realize an effective international multidisciplinary collab oration have assumed increasing momentum for the past 20 years. These include meetings held in Bad Oeynhausen in 1965 (book in 1968, edited by D. W. Lubbers, U. C. Luft, G. Thews and E. Witzleb), in Nijmegen in 1968 (book in 1969, edited by F. Kreuzer), in Vancouver in 1970 (J. Strauss), and in Dortmund in 1971; this last was in connection with the 25th International Physiological Congress in Munich (book in 1973, edited by M. Kessler, D. F. Bruley, L. C. Clark, Jr., D. W. Lubbers, I. A. Silver and J. Strauss). This increasing international cooperation called for a more formal organization of these individual initiatives. The credit for taking this decisive step goes to H. I. Bicher and D. F. Bruley from the U. S. A. and D. W. Lubbers and M. Kessler from Germany, who got together in 1972 to plan a large-scale inter national meeting and to organize an international society."

The International Workshop - Conference on Atherosclerosis was held at the University of Western Ontario, London, Ontario, Canada, September 1 - 3, 1975. This book does not represent in a strict sense the entire proceedings of the above Workshop - Conference, but does reflect largely the format and the essential content of the scientific sessions. Thus, each of the three Sections of the book is comprised of the summarized presentations either at the Plenary Sessions (Section I), Proffered Papers (Section II) or Workshops (Section III). Section I comprises all the presentations of the Plenary Session on September 1 and the first three presentations at the Plenary Session on the last day of the Conference (September 3). The remaining two addresses of the latter Session (Resume of Workshop - Conference and Closing Remarks) follow the Section III at the end of the book. Sections II and III are subdivided into Chapters which correspond to the individual Sessions of Proffered Papers and Workshops, respectively. To facilitate the orientation, particularly for those who attended the Workshop - Conference, a Summary Table of all Sessions of Proffered Papers designated as Chapters in this book, precedes Section II, and a similar Summary Table of Workshops, also designated as Chapters, precedes Section III. The Tables include, in addition, the names of both Chairmen of each Session. The Chairmen whose names do not appear on either Summary Table are those who chaired the two Plenary Sessions, i. e.

Before the introduction of DDA VP, centrnl diabetes insipidus was treated by the administration of a more or less purified extract from bovine or porcine posterior pituitaries, and the prepamtions were mostly given in the form of nasal snuff. In 1956, the structure of vasopressin became known and two forms were found, namely arginine vasopressin (A VP) in humans and most other species, and lysine vasopressin (L VP) which was found in the pig. In 1967, Zaornl et al. were the frrst to synthesize l-desamino-8-D-arginine vasopressin, DDA VP. In comparison with the compounds which were previously available, DDA VP offered increased antidiuretic potency and an equally distinct shift of the antidiuretic to pressor potency rntio. As a result of the pioneering studies of Cash and Mannucci, numerous publications appeared in the medical literature of the 80's, widening the fields of clinical application of the drug. A very important aspect of this drug is that it can be used as an alternative treatment for mild factor VllI deficiencies, mild hemophilia A and von Willebrnnd's disease. These congenital deficiencies are far from mre and have, up to now, been treated with plasma-derived factor VIII concentrates; in the countries in which desmopressin has not been used a consistent proportion of these patients have seroconverted for HIV 1 and hepatitis.

The book combines general concepts and methods to investigate calcium signalling in cells ranging from molecular biology approaches to manipulation of calcium in living cells. The focus within these methods in on the broad range of fluorescence imaging technology, in particular on optical sectioning techniques and fast image acquisition. In addition to these general guidelines there are application examples in a context beyond calcium signalling in two major fields: investigations of isolated cardiac myocytes and red blood cell related research. While the cellular cardiology section provides snapshots of certain calcium signalling aspects, the red blood cell part presents an overview from the functional identification of calcium-channels to a concept of physiological and pathophysiological relevance.