Proceedings of the Eighth Annual Symposium on Blood Transfusion, Groningen 1983, organized by the Red Cross Blood Bank Groningen-Drenthe

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.

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.

Through numerous discussions with colleagues it became apparent that the time was right to begin a series of workshop-like meetings on myeloid tumorigenesis. Myeloid tumors are the nonlymphocytic tumors of the hematopoietic system which include tumors of the neutrophilic, monocytic, erythrocytic, basophilic (mast cell) and megakaryocytic lineages. Pioneering studies in myeloid tumorigenesis were initially made in chickens with the discovery of retroviruses that induce various kinds of myeloid tumors acutely (myelocytomatosis, myeloblastosis, and erythroblastosis). These avian retroviruses were subsequently shown to contain the oncogenes v-myb, v-~, v-~, v-erbA, or v-erbB. There have been dramatic advances in studying the pathogenesis of hematopoietic tumors in genetically defined mammalian systems. Many of the well developed model systems in inbred mice, have focused on T- and B-1ymphoma development. Although myeloid tumors have been found in mice, they have not been studied as intensively as lymphoid tumors. Possibly this is because myeloid tumors are less common than lymphoid tumors. Recently, there has been renewed interest in murine myeloid tumor systems. This focus has resulted from 1) the discovery of inbred strains of mice (e. g. BXH-2, AKXD- 23, SJL/J) that are highly susceptible to spontaneous or induced myeloid tumorigenesis; 2) establishment of transplantable murine myeloid tumors (e.

Battle is a practical and sometimes lasting way of solving man's problems. It relies on the strength of the combatants and ignores the truth of the dispute. Discussion face to face can dissolve attitudes which have incorrectly determined judgements. The most striking example of this that I know is a Battle in Ireland in the eleventh century, where the king of Leinster fought a Viking prince. The Icelanders had raided Ireland for several generations in search of women, which they lacked since most of the population of Iceland were men who had arrived there by rowing long-boats from Norway. The prince was leading such a raid for the first time. Standing in the prow of the leading boat he saw Irish cavalry galloping along the beach to meet them. As they approached the shore the Irish king rode out of the band to challenge single combat. The Icelander jumped into the surf to meet him. As they raised their swords each realized that the other's face was like his own. When the Irish king spoke the other recognized the language. It had been spoken in Iceland by his grandmother who had been captured and taken there from Ireland. Swords were dropped and replaced by drinking horns. It was soon established that they were cousins. The battle gave way to a life-time of close co-operation.

J.J. Van Loghem Previously to this symposium, five others have taken place in Groningen. The first one in 1976. This yearly scientific happening has continued. It has greatly stimulated the in terest in blood transfusion and all allied disciplines in our country. It is clear that these meetings are organized not only by a good scientist, but at the same time by a gifted or ganizer who, as director of the Red Cross Blood Bank Gro ningen-Drenthe, has shown that the heavy load of daily routine work can very well be combined with a large amount of experimental and clinical research in blood component therapy, coagulation disorders, blood group genetics and serology, the latter in cooperation with the Blood Group laboratory of the University Hospital Groningen under the directorship of Dr. Van Dijk. All these activities show how much a well-organized blood bank can contribute to a national blood transfusion orga nization."

The theme of this 14th International Symposium on Blood Transfusion is closely related to the work and scientific contributions of the Dutch cryobiology pioneer Dr. Herman W. Krijnen of the Dutch Red Cross Central Laboratory. Dr. Krijnen was known and respected in the national and interna tional blood transfusion community as an extremely competent scientist and a beloved and admired colleague. Dr. Krijnen was intentionally honoured with the invitation to open this symposium on cryopreservation and low temperature biology in blood transfusion and be the guest of honour at this event. Unfortunately, Dr. Krijnen suddenly died on the first of June 1989. In honour and mem ory of Dr. Krijnen this symposium will therefore be dedicated to him. Since the lOth International Symposium on Blood Transfusion in 1985 highlighted the theme of "Future developments in blood banking", major changes have occurred in the blood banking world. Most of these changes were forced upon the Blood Banks by the fear of spreading AIDS through contaminated donations. This not only led to the wide spread testing of blood, but also to a more appropriate counselling of the community and the blood donors in specific. Additionally, virus inacti vation techniques were introduced for those components derived from multiple donations and intended for a regular transfusion in haemophi lia patients and others.

Much of the attention presently paid to leukemia is the result of recent progress in understanding and treatment. Chemotherapy of leukemia started in the late 1940s, and combination therapy evolved in the late 1950s. It was at that time that the clonality of leukemia was realized, after the discovery of chromosomal and then biochemical and immunological markers. And now we have the new data on retroviral and cellular oncogenes and the reports on human T -cell lymphoma/ leukemia viruses. Many more steps forward could be enumerated in a field which is so rapidly making the hematological textbooks outdated. In this volume, thirteen in-depth reviews from large multicenter trials in the Federal Republic of Germany summarize the current state of diagnosis and management of leukemias. Childhood ALL and AML adult ALL and AUL were investigated. While cure appears to be achievable for more and more patients with acute leukemia, we still pursue the aim of optimal palliation in chronic leukemias. The management of patients with leukemia therefore varies to a large extent in aggressiveness of therapy. In some situations, rescue from an otherwise lethal disease is provided by bone marrow transplanta tion, which is discussed in two chapters."

Current problems in research and treatment of leukemias as discussed at the symposium of the International Society of Haematology on leukemias in Dresden (Germany) are dealt with in detail in this volume. The characterization of leukemic cells and the evaluation of their function are themes, with the first hints emerging of the possibility of relating them to the intensity of treatment required. The cytokines, responsible for cooperation between cells, are also of great importance, and the beginnings of therapeutic applications can be discerned here. Not only are the cytokines themselves very interesting, but also the application of cells producing cytokines according to the range of macrophages found. The emphasis on cell-to-cell relationship is thus a main topic of the book. Of course, other treatment such as bone marrow transplantation and interferon therapy play an important part, too, and the latest results of chemotherapy are reported. A further essential area covered is the diagnosis and therapy of chronic leukemic diseases, the inclusion of which suitably rounds off the book. I am very grateful to the out standing specialists from both the West and the East who contributed to the symposium and this book: an important sign of collaboration and integration for the future."

th This book contains most of the papers presented at the Iy Inter- national Symposium on Bone Circulation which was held in Tou- louse, France, in September of1987. The symposium was attended by over 200 specialists from 17 different countries. Some of them were in Toulouse for the fourth time to discuss their favourite topic of study and research: bone circulation, its exploration, its pathol- ogy. Many, including a group of Japanese orthopaedic surgeons, were present for the first time, delighted to meet the authors of papers they had read. There were more than 100 oral presentations and posters, but many meaningful informal discussions took place both in and outside of the auditorium, in the hall and during meals. The organizers wished to maintain a balance between funda- mental themes and subjects of clinical and practical interest. This balance was accomplished: recent developments including scintig- raphy, magnetic resonance imaging and bone grafts played just as important a part as more sophisticated topics such as the evalua- tion of the blood flow rate in animal bone tissue. Thus, as did the previous symposia, this book aims to present a progress report on developments during the last 5 years in the study of bone circulation. We wish to thank all those who helped and encouraged us throughout the organization of the congress, especially C. Ar- noldi, M. Brookes, R. Burkhardt, L. Coutelier, S.P.F. Hughes, P. Kehr, J.P. Jones, A. Trias, K.Ono, T. Yizkelety and G.J.

Leading international experts contribute to this selection of reviews covering the merging fields of growth factors, differentiation factors, and cytokines. These appear to play fundamental roles in a wide variety of physiological and pathophysiological processes that include the regulation of growth in normal and malignant cells, embryogenesis, the immune response, wound healing, inflammation, and atherogenesis. The major aspects of recent research and development are discussed, providing an important update in this pioneering field.

This volume contains all relevant information discussed in a Workshop on thromboplastin calibration held in Leiden, The Netherlands on July 1, 1983. The Workshop was an initiative of the Dutch foundation for a Reference Laboratory for Anticoagulant Control (RELAC) and it was organized by the Boerhaave Committee for postgraduate teaching of the Faculty of Medicine of the University of Leiden. The Workshop was held under the auspices of five organizations i. e. the European Community Bureau of Refer ence (BCR), the European Committee for Clinical Laboratory Standards (ECCLS), the International Association of Biological Standardization (lABS), the International Committee for Standar dization in Haematology (ICSH), .and the International Committee on Thrombosis and Haemostasis (ICTH). The aim of the Workshop was to discuss and develop a method for calibration of reagents, i. e. thromboplastins and/or plasmas used for the prothrombin time. During the Workshop three recent thromboplastin calibration studies were discussed, the results of which are presented in chapters 4, 7 and 9. These studies were carried out on the basis of a new calibration model developed by experts working with BCR and WHO. The usefulness of this model and the standardization system based on it is the leading thread running through this volume. Statisticians and clinicians discuss the results from a scientific point of view. Thromboplastin manufacturers, for whom especially the use of the model and the system is intended, discuss the matter also from an economic and legal point of view."

From the world renowned Fred Hutchinson Cancer Research Center, this book is written for all physicians who treat patients with acute or chronic leukemias or myelodysplasia. It is designed to answer questions about treatment approaches that commonly arise in day-to-day practice. In keeping with the Center's groundbreaking research in bone marrow transplantation, the book provides exceptional coverage of the role of allogeneic transplant in treatment. It also addresses the important issues of supportive care and long-term complications of successful treatment. *Edited and written by experts at the Fred Hutchinson Cancer Research Center *Clinically focused and comprehensive coverage of treatment approaches *Allogeneic transplant addressed in detail *Separate chapters on supportive care and long-term complications

Contents: Introduction and Overview Lymphopoietic Growth Factors: Pathophysiology of T-Cell Mediated Shock Induced by Bacterial Superantigens - Natural Killer Cells and Interleukin-2-Activated Killer Cells - TumourImmunogenicity Induced by Exogenous Interleukins - Cytokine Gene Therapy of Cancer - Analysis of T-Cell Receptor Variability in Tumour Infiltrating Lymphocytes - Clinical Studies with Interleukin-2: An Overview - Clinical Trials with Local Administration of Lymphopoietic Growth Factors - Clinical Trials with Interlaukin-2. The Rome Experience. Haematopoietic Growth Factors: Lymphohaematopoietic Growth Factor Use in Lung Cancer Patients - Clinical Trials with Haematopoietic Growth Factors and Peripheral Blood Stem Cells

The monograph edited by Drs. Wunder and Henon on "Peripheral Blood Stem Cell Autogtafts" is extremely useful as well as timely. It covers the "state of the arts" with respect to the use of hemopoietic stem cells collected from the peripheral blood for the reconstitution of hematopoiesis after myeloablative therapy. If is is accepted that hematopoietic function in the mammalian organism is the result of stem cell seeding of an appropriate stromal matrix, then the use of blood derived stem cells for hematopoietic reconstitution represents the "physiological form" of the (re) establishment of a hematopoietic bone marrow. All observations to date are compatible with the assumption that stem cells migrate via the blood stream from extraembryonic hematopoietic tissue to the fetal liver to establish there a first intraembryonic site of blood cell formation and especially of stem cell replication and proliferation. This fetal liver tissue appears then to be the major source for the seeding offetal bone marrow stroma as it develops sequentially in all the bones of the skeleton - in other words during most of the entire embryonic development. There is a very high concentration of stem cells in the blood of the embryo (more than 20000 CFU-GM per ml in the 22nd week) and the stem cells in cord blood seem to be the "tail end" of a dramatic "stem cell traffic" in the embryo to establish the hemopoietic as well as lymphopoietic tissue."

This second volume reports on the reaction patterns of lymph nodes in neoplastic and immunodeficient diseases. Based on the contents of volume 1, it presents a detailed survey of lymph node structures and their cellular components under these conditions. The patterns of nodal reactions to the development and spread of cancer have recently been investigated and discussed by several authors. Here, the immediate interactions between tumor tissue and the regional nodes have been assessed in experimental models and in human material. Using modern morphological methods such as im munohistochemistry on the light and electron microscopic level, new insights have been gained into the stepwise process of lymphogenous metastasis. Macrophages/reticulum cells were found to playa signifi cant role in this process, which is duly emphasized. Based on appro priate animal models, one chapter focuses on various subtypes of these cellular elements and their role in the two separate phases of tumor spread and the development of true metastases. The induction of fibronectin in lymph nodes is effected by tumor cells forming a special part of the extracellular matrix. The multifunctional fibronec tin molecule serves as a mediator between tumor cells and fibroblasts, furthering the formation of tumor stroma. This volume also contains a comprehensive survey of primary im munodeficiency syndromes and their nodal manifestations, reference being made to the most recent immunological knowledge."

Due to the topology and structure of the lymph nodes, their role in the pathogenesis and development of diseases is a very special one. Each organ and even each organ-related region of the body has its own group of lymph nodes, specific topological reactions, such as in circumscribed inflammation or in the metastatic spread of malignant tumors. On the other hand, all the lymph nodes of an organism join in a uniform function effected by highly differentiated structures. Volume 84 of Current Topics in Pathology presents our current knowledge about the structure and reaction patterns of this "sec ondary" lymphoid organ. Despite our original intention to publish all the contributions in one book, it became necessary to divide them: Part 1 focuses on the involved nodal compartments, cell types, and functions, while Part 2 describes their reactions in inflammatory, neo plastic, and immune-deficient diseases. Even with the cooperation of more than 30 authors, the coverage cannot be exhaustive. The scope of both parts is limited to those reactions that can be described by direct and indirect morphological methods, including modern tech niques such as immune electron microscopy."

The European School of Oncology came into existence to respond to a need for informa tion, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidisciplinary approach which is difficult for the Universi ties to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice.

Sixty years ago, G. Fanconi published a paper entitled: "Familiiire infantile pemiziosaartige Aniimie (pemizioses Blutbild und Konstitu- tion)", in which he reported that this type of severe aplastic anemia represents a hereditary disease distinct from other pancytopenias of childhood (Fanconi 1927). Later this syndrome was named Fan- coni anemia (FA; van Leeuwen 1933). A more recent study of the genetics of FA confirmed that the syndrome is inherited in an au- tosomal recessive manner (Schroeder et al. 1976). Prenatal diagno- sis in FA families showed that about 25% of fetuses are affected (Auerbach et al. 1985, 1986). In 1964, Schroeder et al. discovered high frequencies of chro- mosomal aberrations in cultured peripheral blood lymphocytes from patients with FA. Schuler et al. (1969) reported that cells from FA patients are particularly sensitive to the chromosome-breaking activity or clastogenic effect of a polyfunctional alkylating agent. Since that time, studies of baseline and induced frequencies of chromosomal aberrations have been used for the identification of patients with FA. There is now a large body of data concerning the possible mechanism(s) underlying the hypersensitivity of FA cells to DNA cross-linking agents, the biochemical basis for which is still unknown. Complementation analysis, using cells from different FA pa- tients, has demonstrated genetic heterogeneity in the syndrome.

Estimates reveal that there are some 200 million heterozygous carriers of abnormal hemoglobins genes worldwide, and tens of thousands of severely affected patients. Effective application of imaging techniques is essential to combat the continuing development of the disease and to ensure risk-free follow-up of the chronically ill. This is the first book to offer complete coverage of such radiologic applications with both conventional and the most modern imaging modalities. Interventional radiology, marrow transplantation, prenatal diagnosis by ultrasonography, and radiotherapy for bone marrow heterotopia are also featured.

1 2 D. FITZGERALDI, I. PASTAN , and J. ROBERTUS Introduction . . . . . . . . . . . . . I 2 Toxin Structure-Function Properties 2 2. 1 Functions. . . . . . . . . . . . . . . . . . . . . . . . 2 2. 2 Binding. . . . . . . . . . . . . . . . . . . . . . . . . 3 3 Intracellular Processing - Cleavage and Reduction . . . . . . 4 3. 1 Cytosolic Activity . . . . . . . . . . . . . . . . 5 4 Immunotoxin Design and Testing. 6 5 Conclusion. . 8 References. . . . . 8 1 Introduction While various treatment approaches for cancer include reversal of the transformed phenotype, stimulation of immune responses, inhibition of metastatic spread and deprivation of key nutrients, the goal of immunotoxin treatment is the direct killing of malignant cells. Because they are enzymatic proteins that act catalytically to kill cells, bacterial and plant toxins are often employed as the cell-killing component of immunotoxins. Here we provide background information into the structure-func tion relationships of toxins and discuss how they can be combined with cell-binding antibodies or other ligands to generate immunotoxins. Bacterial and plant toxins (e. g. , diphtheria toxin, Pseudomonas exotoxin and ricin) are among the most toxic substances known. However, because they bind to cell surface receptors that are present on most normal cells, unmodified toxins are generally useless as anti-cancer agents. To convert toxins into more selective agents, their binding domains are either eliminated or disabled and replaceq with cell binding antibodies that are tumor-selective.

THE PHILOSOPHY OF QUALITY ASSURANCE IN THE BLOOD BANK H. F. Taswell One year before this symposium, Cees Smit Sibinga and I began to discuss an approach to quality assurance in the blood bank which we felt would be both important and practical and could serve as the basis for the choice of subjects to be presented in the symposium. As an introduction to this book, I would like to outline our approach, the subjects chosen and the rationale behind our choice. What is the fundamental purpose of a blood bank and trans fusion service? Simply stated, the purpose of a blood bank and transfusion service and of a quality assurance program in blood banking is, for the one to provide and, the other to assure safe and effective transfusion therapy. This objective is in contrast to that of other clinical laboratories. The objective in a clinical chemistry laboratory is to produce accurate test results which will be meaningful to the clinician taking care of his patient. In most clinical laboratories, therefore, the goals of a quality assurance program are largely quantitative, that is, to assure accurate numerical test results. In contrast, in the blood bank, the goals of quality assurance are primarily qualitative, that is, to assure safe and effective transfusion. As a result, two somewhat different approaches to quality assurance are necessary.

This book reviews the respiratory function of vertebrate red cells. I have defined the phrase "respiratory function" broadly to include, in addition to the actual oxygen and carbon dioxide transport, erythropoiesis, haemoglobin synthesis, red cell structure, the deformability of red cells in circulation, ion and substrate transport across the cell membrane, cellular metabolism, and control of cellular volume and pH. All of these aspects of the red cell function may affect gas transport between the respiratory epithelia and the tissues. Throughout the book, I have tried to relate our current knowledge about the nucleated red cell function to the wealth of information about the function of mammalian red cells. However, whenever possible, I have placed the emphasis on the nucleated red cell function for two reasons. First, the erythro cytes of 90% of vertebrate species are nucleated, and, second, nucleated red cell function has not been reviewed earlier in a single volume. This being the case, I have tried to make the reference list as complete as I could with regard to nucleated red cells. I hope that the approach adopted is useful for both com parative and human physiologists. Many people have contributed to the making of this book directly or in directly. Antti Soivio started me in this field. Prof. Henrik Wallgren has always encouraged fresh scientific ideas in his department. My present ideas of red cell function have been influenced by work carried out with Prof. Roy E."

Das ist das Schwerste von aHem, was Dir das Leichteste diinket: mit den Augen zu sehen, was vor den Augen Dir liegt. Goethe, Xenien, 1797 That is the most difficult which seems the easiest: to see with your eyes what lies there to be seen. All the diseases in question here are rare. The most common, mucopolysacchari- . dosis (MPSosis III), occurs at a rate of 1 in 160000. Consequently, anyone doctor will only encounter a few cases as a rule, and the literature offers mainly casuistic descriptions. Up till now, there has been no systematic and comprehen- sive review. We thus felt that it would be of interest and benefit to prepare a collective report on a large body of material gathered over a period of many years, the material being extensive enough to provide adequate possibilities for making comparisons. In so doing, we were also able to describe for the first time the specific, and, in some cases, the pathognomonic symptoms for each disease.

The translation of Blood Smears Reinterpreted was begun when the French original was still undergoing revisions. I was accorded the oppor tunity to question any statement or turn of phrase that was unclear to me or appeared liable to misinterpretation. It is my hope that as a result, ambiguities-particularly those inherent in differences between American and Eu ropean usage-have been removed and that I have at least ap proached the ultimate goal of any translation: to reflect the author's intention accurately while remaining as readable as the original. Beyond the role of translator, I was encouraged to assume the role of critic. As a result, some pages or even single sentences were hotly debated, sometimes for hours, as Marcel Bessis insisted that any inter pretations on which we could not agree should be so indicated. In fact our discussion invariably ended in agreement, though they led to changes of a sentence here or a word there and, on occasion, to the addition of a footnote or a brief paragraph.