bluuebunny/crossref_metadata_2025 huggingface dataset:
T Cell and NK Cell Lymphoproliferative Disorders
Authors: Greer John P. , Kinney Marsha C. , Loughran Thomas P.
Published: August 2003

This review covers the diagnosis and management of natural killer and peripheral T-cell lymphomas (PTCL). Problems with PTCL include their rarity, representing usually 10-15% of non-Hodgkin's lymphomas in the Western Hemisphere, morphologic heterogeneity, and lack of immunophenotypic markers for clonality. Additionally, their clinical behavior is variable and may not correlate with morphology.

Dr. Kinney gives a general overview of the diagnosis of PTCL and NK cell neoplasms. Emphasis will be placed on extranodal T cell and natural killer (NK) cell lymphomas such as hepatosplenic lymphoma, subcutaneous panniculitis-like lymphoma and nasal/nasal type T/NK-cell lymphoma. The use of ALK gene regulation in the classification of anaplastic large cell lymphoma is also reviewed.

Dr. Loughran describes current understanding of the pathogenesis of large granular lymphocyte (LGL) leukemia. The discussion focuses on LGL leukemia as an instructive model of dysregulated apoptosis causing both malignant and autoimmune disease. Current management options and mechanisms of therapeutic response are also described.

Dr. Greer addresses whether PTCL should be treated differently from the more common diffuse large B cell lymphomas. He discusses the therapeutic options for anaplastic large cell lymphoma (ALCL), from a conservative approach for primary cutaneous ALCL to combination chemotherapy for the highly chemosensitive ALCL expressing anaplastic lymphoma kinase. He reviews therapy options for the extranodal subtypes of PTCL by drawing from series in adults, pediatrics, dermatology, and the Far East.
Platelets: An Update on Diagnosis and Management of Thrombocytopenic Disorders
Authors: McCrae Keith R. , Bussel James B. , Mannucci Pier M. , Remuzzi G. , Cines Douglas B.
Published: August 2003

Thrombocytopenia in the pregnant patient may result from a number of causes, most of which involve either immune-mediated platelet destruction or platelet consumption. Many of these disorders share clinical and laboratory features, making accurate diagnosis difficult. Moreover, uterine evacuation is indicated in the therapy of some disorders, while in others alternative interventions may allow the pregnancy to be carried to term. These and other issues are discussed as part of a comprehensive review of the differential diagnosis and management of thrombocytopenia in pregnancy.

The term “refractory ITP” is used with reference to two distinct groups of patients: 1) patients in whom the platelet count cannot be easily increased, including those who are poorly responsive to initial single agent treatment, and 2) those with persistent thrombocytopenia despite the use of conventional therapies. An approach to management of the former group will be presented, followed by a discussion of patients with chronic refractory ITP. The latter will include presentation of new data on the role of Helicobacter pylori in ITP and whether its treatment ameliorates thrombocytopenia, as well as the use of rituximab and other modalities.

Thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) are rare, but life threatening causes of thrombocytopenia. Ultra-large multimers of von Willebrand factor (vWF) aggregate platelets intravascularly, and congenital or immune-mediated deficiencies of a metalloprotease that cleaves these ultra-large multimers may cause TTP. However, little information exists concerning the behavior of this protease in other physiological and pathological conditions. Levels of this protease have now been measured in healthy individuals of different ages, full-term newborns, pregnant women and a patients with variety of pathologic conditions, and these data will be reviewed herein.

Heparin-induced thrombocytopenia/thrombosis (HIT/T) remains the most common antibody-mediated, drug-induced thrombocytopenic disorder, and a leading cause of morbidity and mortality. Based on clinical correlations and murine models, there is increasing evidence that antibodies to complexes between platelet factor 4 (PF4) and heparin cause HIT/T, and the molecular composition of the relevant antigen has also become better defined. However, the introduction of sensitive ELISAs to measure anti-PF4/heparin antibodies has complicated diagnosis in some settings in which the incidence of such antibodies in unaffected patients exceeds the incidence of the disease. In addition, the FDA approval of Lepirudin and Argatroban has expanded the repertoire of agents available for therapy of HIT/T and may change the approach to management of asymptomatic patients with thrombocytopenia. However, the optimal use of these drugs in commonly encountered settings remains in evolution, and a need for alternative approaches to prevention and treatment is evident.
Unexpected Bleeding Disorders
Authors: Aledort Louis M. , Green David , Teitel Jerome M.
Published: August 2003

Patients with known coagulation deficiencies, either congenital or acquired, may bleed spontaneously with trauma or with surgical intervention. In contrast, however, are the unchallenged patients who bleed in a variety of clinical settings that demand rapid diagnosis so that appropriate therapy can be instituted.

In the first section Dr. Louis M. Aledort demonstrates a series of vignettes of actual cases who presented with unexpected bleeding or a screening laboratory abnormality prior to a needed surgical intervention. Settings include dental, oral surgical, obstetrical, surgical and gynecological. The differential diagnoses of these cases are discussed.

In the second section Dr. David Green also uses vignettes to demonstrate how the laboratory is used to differentiate the various clinical entities. The choice and priority of required tests indicated by the settings, history, site and type of bleeding, and the syllogisms used to define the abnormality are stressed.

In the third section, Dr. Jerome Teitel reviews in detail the therapeutic armamentarium available to the clinician and presents algorithms for the management of these bleeding disorders.
Sickle Cell and the Brain
Authors: Adams Robert J. , Ohene-Frempong Kwaku , Wang Winfred
Published: August 2003

Sickle cell disease affects many organ systems, but one of the major morbidities is brain disease, especially stroke. In this paper, the etiology, diagnosis, treatment, and prevention of clinical stroke, as well as so-called “silent stroke,” are examined. Risk factors, diagnostic tools, and data from prevention and treatment studies as well as issues pertaining to neuropsychological function, especially in younger patients, are discussed and current best options for treatment considered.
Thrombophilia: What's a Practitioner to Do?
Authors: Macik B. Gail , Rand Jacob H. , Konkle Barbara A.
Published: August 2003

Management of thrombophilia is an ever-changing field as new disorders are described and additional clinical experience accrues. This paper addresses three common management issues in the care of patients with thrombophilia. The first two topics are updates for common but perplexing hypercoagulable states and the last topic introduces a new option for optimal management of oral anticoagulant therapy. Dr. Jacob Rand updates and organizes the approach to patients with antiphospholipid syndrome. This syndrome is a common acquired thrombophilic state, but the diagnosis and treatment of patients remains a challenge. Dr. Rand outlines his diagnostic and treatment strategies based on the current understanding of this complicated syndrome. Dr. Barbara Konkle addresses the special concerns of managing women with thrombophilia. Hematologists are often asked to advise on the risks of hormonal therapy or pregnancy in a woman with a personal or family history of thrombosis or with an abnormal laboratory finding. Dr. Konkle reviews the available data on the risks of hormonal therapy and pregnancy in women with and without known underlying thrombophilic risk factors. In Section III, Dr. Gail Macik will discuss a new approach to warfarin management. Several instruments are now available for home prothrombin time (PT) monitoring. Self-testing and self management of warfarin are slowly emerging as reliable alternatives to traditional provider-based care and Dr. Macik reviews the instruments available and the results of studies that support this new management option.
Thromboembolic Disease and Antithrombotic Therapy in Newborns
Authors: Andrew Maureen E. , Monagle Paul , deVeber Gabrielle , Chan Anthony K.C.
Published: August 2003

This update uses an evidence based approach to analyze and present the epidemiology of neonatal thrombosis, etiologies, currently used techniques for diagnosis with their limitations, and current therapeutic approaches. In addition, the approaches to both prevention and optimal therapies are discussed.

In Section I Dr. Paul Monagle addresses the epidemiology of neonatal thrombosis outside of the central nervous system in both arterial and venous locations, and those that occur in utero. The specific contributions of catheters and congenital prothrombotic disorders are delineated. Dr. Monagle also describes currently used techniques for the diagnosis of thrombotic events as well as their limitations and the current therapeutic approaches.

In Section II, Dr. Gabrielle deVeber reviews the epidemiology of neonatal thrombosis within the central nervous system, in both arterial and venous locations and those that occur in utero. The neurological presentation, risk factors including congenital prothrombotic disorders, anatomical distribution, diagnostic tests, use of antithrombotic therapy and neurologic outcome of neonates with either sinovenous thrombosis or arterial ischemic stroke are discussed.

In Section III, Dr. Anthony Chan reviews the current approaches to the prevention and treatment of neonatal thrombosis. Information on the differences in the response of neonates compared to adults to antithrombotic therapy and new approaches to the prevention and treatment of thrombosis in neonates are emphasized.
Preventing Opportunistic Infections After Hematopoietic Stem Cell Transplantation: The Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and Beyond
Authors: Sullivan Keith M. , Dykewicz Clare A. , Longworth David L. , Boeckh Michael , Baden Lindsey R. , Rubin Robert H. , Sepkowitz Kent A.
Published: August 2003

This review presents evidence-based guidelines for the prevention of infection after blood and marrow transplantation. Recommendations apply to all myeloablative transplants regardless of recipient (adult or child), type (allogeneic or autologous) or source (peripheral blood, marrow or cord blood) of transplant.

In Section I, Dr. Dykewicz describes the methods used to rate the strength and quality of published evidence supporting these recommendations and details the two dozen scholarly societies and federal agencies involved in the genesis and review of the guidelines.

In Section II, Dr. Longworth presents recommendations for hospital infection control. Hand hygiene, room ventilation, health care worker and visitor policies are detailed along with guidelines for control of specific nosocomial and community-acquired pathogens.

In Section III, Dr. Boeckh details effective practices to prevent viral diseases. Leukocyte-depleted blood is recommended for cytomegalovirus (CMV) seronegative allografts, while ganciclovir given as prophylaxis or preemptive therapy based on pp65 antigenemia or DNA assays is advised for individuals at risk for CMV. Guidelines for preventing varicella-zoster virus (VZV), herpes simplex virus (HSV) and community respiratory virus infections are also presented.

In Section IV, Drs. Baden and Rubin review means to prevent invasive fungal infections. Hospital design and policy can reduce exposure to air contaminated with fungal spores and fluconazole prophylaxis at 400 mg/day reduces invasive yeast infection.

In Section V, Dr. Sepkowitz details effective clinical practices to reduce or prevent bacterial or protozoal disease after transplantation. In Section VI, Dr. Sullivan reviews vaccine-preventable infections and guidelines for active and passive immunizations for stem cell transplant recipients, family members and health care workers.
Preserving the National Blood Supply
Authors: Brittenham Gary M. , Klein Harvey G. , Kushner James P. , Ajioka Richard S.
Published: August 2003

This paper examines the current state of the blood supply in the US and focuses on the potential for augmenting blood availability by attention to the iron status of donors. Increasing demands are being made upon the national blood supply as rates of blood donation are declining, in part because of the loss of blood donors as a result of enhanced screening and testing procedures. Iron-related means of expanding the blood supply include the use of blood from individuals undergoing therapeutic phlebotomy for hereditary hemochromatosis and enhancing the retention and commitment of women of childbearing age as donors by using iron supplementation to prevent iron deficiency.

In Section I, Dr. Klein discuss the circumstances responsible for a decline in the population of eligible donors, including public attitudes toward donation, factors influencing the retention of donors by blood centers, and the effects of increased screening and testing to maintain the safety of the blood supply.

In Section II, Drs. Kushner and Ajioka focus on the consequences of the decision by the US Food and Drug Administration (FDA) to develop recommendations to permit blood centers to collect blood from patients with hereditary hemochromatosis and to distribute this blood obtained without disease labeling if all other screening and testing procedures are passed. After summarizing the pathophysiology of hereditary hemochromatosis, the use by blood centers of blood obtained from heterozygotes and homozygotes for hereditary hemochromatosis is considered.

In Section III, Dr. Brittenham reviews the use of low dose, short-term carbonyl iron supplementation for women donors of childbearing age. Replacing the iron lost at donation can help prevent iron deficiency in women of childbearing age and, by decreasing deferral, enhance the retention and commitment of women who give blood regularly. He emphasizes the use by blood centers of iron-related means to enhance recruitment and retention of blood donors.
Reducing the Risk of Blood Transfusion
Authors: Snyder Edward L. , Dodd Roger Y.
Published: August 2003

There are continuing concerns over the safety of the nation's and the world's blood supply. The allogeneic blood supply is tested for antibodies to HIV1/2, HTLVI/II, hepatitis B, hepatitis C (HCV) and syphilis. Testing is also performed for donor ALT (SGOT) levels, for the presence of hepatitis B surface antigen, human immunodeficiency virus (HIV) p24 antigen and, using nucleic acid amplification testing (NAT), for HIV and HCV nucleic acids. Still, there are concerns regarding other pathogenic agents.

Dr. Roger Dodd addresses a series of pathogens that are already known to be transmissible by transfusion. These include malaria, Chagas' disease, babesiosis, bacteria and some viral agents. The need for new donor screening assays to protect the integrity and purity of the blood supply must be balanced against the loss of potential donors and the cost of developing and implementing these new screening assays. This issue will be highlighted.

Dr. Edward Snyder reviews the status of research into development of systems for pathogen inactivation (PI) of blood and its components. A proactive technology wherein PI reagents such as psoralen, riboflavin, dimethylmethylene blue or inactine are added to blood collection bags could assure multiple log reduction of a variety of pathogens including viruses, bacteria, protozoa and fungi without the need to initially pre-screen the blood for a specific pathogen. Such a program could also cover new pathogens as they enter the blood supply. As a key issue relates to the toxicology of these agents, Dr. Snyder provides data on a novel carcinogenicity assay that uses a heterozygous p53 knock-out mouse model. The criteria likely to be needed for PI technology to be adopted by the transfusion community are summarized.
Rational Approaches to Design of Therapeutics Targeting Molecular Markers
Authors: Klasa Richard J. , List Alan F. , Cheson Bruce D.
Published: August 2003

This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology.

In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis.

In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.
Hematologic Aspects of HIV/AIDS
Authors: Levine Alexandra M. , Scadden David T. , Zaia John A. , Krishnan A.
Published: August 2003

This review addresses various aspects of HIV infection pertinent to hematology, including the consequences of HIV infection on specific aspects of hematopoiesis and an update on the current biologic, epidemiologic and therapeutic aspects of AIDS-related lymphoma and Hodgkin's disease. The results of the expanding use of progenitor cell transplantation in HIV infected patients are also reviewed.

In Section I, Dr. Scadden reviews the basis for HIV dysregulation of blood cell production, focusing on the role of the stem cell in HIV disease. T cell production and thymic function are discussed, with emphasis placed upon the mechanisms of immune restoration in HIV infected individuals. Results of clinical and correlative laboratory studies are presented.

In Section II, Dr. Levine reviews the recent epidemiologic trends in the incidence of lymphoma, since the widespread availability of highly active anti-retroviral therapy (HAART). The biologic aspects of AIDS-lymphoma and Hodgkin's disease are discussed in terms of pathogenesis of disease. Various treatment options for these disorders and the role of concomitant anti-retroviral and chemotherapeutic intervention are addressed.

Drs. Zaia and Krishnan will review the area of stem cell transplantation in patients with AIDS related lymphoma, presenting updated information on clinical results of this procedure. Additionally, they report on the use of gene therapy, with peripheral blood CD34+ cells genetically modified using a murine retrovirus, as a means to treat underlying HIV infection. Results of gene transfer experiments and subsequent gene marking in HIV infected patients are reviewed.
Secondary Iron Overload
Authors: Kushner James P. , Porter John P. , Olivieri Nancy F.
Published: August 2003

Transfusion therapy for inherited anemias and acquired refractory anemias both improves the quality of life and prolongs survival. A consequence of chronic transfusion therapy is secondary iron overload, which adversely affects the function of the heart, the liver and other organs. This session will review the use of iron chelating agents in the management of transfusion-induced secondary iron overload.

In Section I Dr. John Porter describes techniques for the administration of deferoxamine that exploit the pharmacokinetic properties of the drug and minimize potential toxic side effects. The experience with chelation therapy in patients with thalassemia and sickle cell disease will be reviewed and guidelines will be suggested for chelation therapy of chronically transfused adults with refractory anemias.

In Section II Dr. Nancy Olivieri examines the clinical consequences of transfusion-induced secondary iron overload and suggests criteria useful in determining the optimal timing of the initiation of chelation therapy. Finally, Dr. Olivieri discusses the clinical trials evaluating orally administered iron chelators.
Major Hematologic Diseases in the Developing World— New Aspects of Diagnosis and Management of Thalassemia, Malarial Anemia, and Acute Leukemia
Authors: Greenberg Peter L. , Gordeuk Victor , Issaragrisil Surapol , Siritanaratkul Noppadol , Fucharoen Suthat , Ribeiro Raul C.
Published: August 2003

The three presentations in this session encompass clinical, pathophysiological and therapeutic aspects of hematologic diseases which impact most heavily on developing world countries. Dr. Victor Gordeuk discusses new insights regarding the multi-faceted pathogenesis of anemia in the complicated malaria occurring in Africa. He describes recent investigations indicating the possible contribution of immune dysregulation to this serious complication and the implications of these findings for disease management.

Dr. Surapol Issaragrisil and colleagues describe epidemiologic and clinical characteristics of the thalassemic syndromes. In addition to being considered a major health problem in Southeast Asia, the migration throughout the world of people from this region has caused the disease to have global impact. A unique thalassemia variant, Hb Eβ-thalassemia, with distinctive clinical features, has particular relevance for this demographic issue. Special focus will be reported regarding recent prenatal molecular screening methods in Thailand which have proven useful for early disease detection and disease control strategies. Dr. Raul Ribeiro describes a clinical model for providing effective treatment for a complex malignancy (childhood acute lymphoblastic leukemia) in countries with limited resources. With the multidisciplinary approach in Central American of the joint venture between St. Jude Children's Research Hospital International Outreach Program and indigenous health care personnel, major therapeutic advances for this disease have been achieved.

Given the major demographic population shifts occurring worldwide, these illnesses also have important clinical implications globally. These contributions demonstrate that lessons learned within countries of disease prevalence aid our understanding and management of a number of disorders prominently seen in developed countries. They will show how effective partnerships between hematologists in more and less developed nations may work together to produce important advances for treating major hematologic diseases in less developed regions. A major focus relates to the socio-economic and medical burden of these diseases in developing countries with limited resources. As such, these problems provide a challenge and an opportunity for collaborative interaction between hematologists and policy makers worldwide.
Hematology Grants Workshop—2001
Authors: Todd Robert F. , Miller Donald M. , Silverstein Roy L.
Published: August 2003

This year the Hematology Grants Workshop, chaired by Dr. Todd, includes a comprehensive listing of available National Institutes of Health, Department of Veterans Affairs, and non-federal grants applicable to fellows and junior faculty as well as to established investigators.

In Section II, Dr. Miller discusses the essential principles of successful grant writing with a special emphasis on the young investigator. He highlights the best strategies to take and the common mistakes to avoid.

In Section III, Dr. Silverstein outlines the structure of the current NIH Integrated Review Group (IRG) system and the study sections of the most relevance to hematology. He traces the path that a grant takes from review to funding including the way in which grants are reviewed at NIH Study Section Meetings and provides advice in the preparation of revised applications.
Acute Myeloid Leukemia
Authors: Appelbaum Frederick R. , Rowe Jacob M. , Radich Jerald , Dick John E.
Published: August 2003

Through the hard work of a large number of investigators, the biology of acute myeloid leukemia (AML) is becoming increasingly well understood, and as a consequence, new therapeutic targets have been identified and new model systems have been developed for testing novel therapies. How these new therapies can be most effectively studied in the clinic and whether they will ultimately improve cure rates are questions of enormous importance. In this article, Dr. Jacob Rowe presents a summary of the current state-of-the-art therapy for adult AML. His contribution emphasizes the fact that AML is not a single disease, but a number of related diseases each distinguished by unique cytogenetic markers which in turn help determine the most appropriate treatment. Dr. Jerald Radich continues on this theme, emphasizing how these cytogenetic abnormalities, as well as other mutations, give rise to abnormal signal transduction and how these abnormal pathways may represent ideal targets for the development of new therapeutics. A third contribution by Dr. Frederick Appelbaum describes how AML might be made the target of immunologic attack. Specifically, strategies using antibody-based or cell-based immunotherapies are described including the use of unmodified antibodies, drug conjugates, radioimmunoconjugates, non-ablative allogeneic transplantation, T cell adoptive immunotherapy and AML vaccines. Finally, Dr. John Dick provides a review of the development of the NOD/SCID mouse model of human AML emphasizing both what it has taught us about the biology of the disease as well as how it can be used to test new therapies. Taken together, these reviews are meant to help us understand more about where we are in the treatment of AML, where we can go and how we might get there.
Chronic Myelogenous Leukemia
Authors: Druker Brian J. , Sawyers Charles L. , Capdeville Renaud , Ford John M. , Baccarani Michele , Goldman John M.
Published: August 2003

The treatment recommendations for chronic myelogenous leukemia (CML) are evolving rapidly. In the past year, pegylated interferon and STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, have become commercially available and non-myeloablative stem cell transplants continue to be refined. Clinicians and patients face a bewildering array of treatment options for CML. In this article Dr. Sawyer reviews the clinical results with STI571 and ongoing investigations into mechanisms of resistance to STI571. Given the newness of STI571, a practical overview on the administration of STI571 is presented by Drs. Druker and Ford, focusing on aspects such as optimal dose, management of common side effects, and potential drug interactions. The most recent data on interferon-based regimens are reviewed by Dr. Baccarani in the third section. In the last section Dr. Goldman presents recent results of allogeneic stem cell transplants, including the reduced intensity conditioning regimens. Lastly, the proposed place of each of these treatments in the management of CML patients is addressed to assist in deciding amongst treatment options for CML patients.
Ham-Wasserman Lecture
Authors: Mannucci Pier M.
Published: August 2003

Known since the beginning of the first millennium, the hemophilias are among the most frequent inherited disorders of blood coagulation and definitely the most severe. In the 1970s, with the availability of concentrated preparations of the deficient coagulation factors VIII and IX and with the large-scale adoption of home treatment, hemophilia care became one of the most gratifying examples of successful secondary prevention of a chronic disease. Unfortunately, in the early 1980s it was recognized that factor concentrates prepared from plasma pooled from thousands of donors transmitted the hepatitis and the human immunodeficiency viruses. The scientific community reacted promptly to the devastation brought about by hepatitis and AIDS. The last 15 years of the second millennium have witnessed the development of methods that, when applied during concentrate manufacturing, inactivate viruses escaping the screening procedures. The adoption of these measures has reduced dramatically the risk of transmission of bloodborne infections. The production of recombinant factors and their availability for patients’ treatment epitomize progress in hemophilia care through DNA technology. Methods based on the polymerase chain reaction (PCR) have unraveled an array of gene lesions associated with hemophilia, permitting improved secondary control of the disease through carrier detection in women from affected families and prenatal termination of their affected male infants. This article will review the aforementioned areas of progress and discuss unresolved problems (such as treatment of patients with antibodies, the risk of new infectious complications, and the issue of secondary tumors). Hopes and expectations for further improvement in the third millennium and particularly the prospects of hemophilia cure though gene replacement therapy will also be mentioned.
Novel Therapeutic Approaches in Sickle Cell Disease
Authors: Walters Mark C. , Nienhuis Arthur W. , Vichinsky Elliott
Published: August 2003

In this update, selected clinical features of sickle cell disease and their management are reviewed. In addition, the current status of interventions that have curative potential for sickle cell disease is discussed, with particular attention focused on indications, methodology, recent results, and challenges to wider clinical application.

In Section I, Dr. Nienhuis describes recent improvements in vector technology, safety, and replacement gene expression that are creating the potential for clinical application of this technology.

In Section II, Dr. Vichinsky reviews our current understanding of the pathophysiology and treatment of pulmonary injury in sickle cell disease. The acute and chronic pulmonary complications of sickle cell disease, modulators and predictors of severity, and conventional and novel treatment of these complications are discussed.

In Section III, Dr. Walters reviews the current status of hematopoietic cell transplantation for sickle cell disease. Newer efforts to expand its availability by identifying alternate sources of stem cells and by reducing the toxicity of transplantation are discussed.
Chronic Myelogenous Leukemia
Authors: Druker Brian J. , O’Brien Stephen G. , Cortes Jorge , Radich Jerald
Published: August 2003

The treatment options for chronic myelogenous leukemia (CML) continue to evolve rapidly. Imatinib mesylate (Gleevec, Glivec, formerly STI571) has continued to show remarkable clinical benefits and the updated results with this agent are reviewed. As relapses using single agent imatinib have occurred, particularly in advanced phase patients, the issue of whether combinations of other antileukemic agents with imatinib may yield improved results is addressed. In addition, data on new agents that have potential in the treatment of CML are reviewed. These agents are presented in the context of their molecular mechanism of action. The most recent data for stem cell transplantation, along with advances in nonmyeloablative transplants, are also reviewed.

In Section I, Drs. Stephen O’Brien and Brian Druker update the current status of clinical trials with imatinib and review ongoing investigations into mechanisms of resistance and combinations of imatinib with other agents. They also present their views on integration of imatinib with other therapies.

In Section II, Dr. Jorge Cortes describes the most recent data on novel therapies for CML, including farnesyl transferase inhibitors, arsenic trioxide, decitabine, and troxatyl, among others. These agents are discussed in the context of their molecular mechanism of action and rationale for use.

In Section III, Dr. Jerald Radich updates the results of stem cell transplants for CML, including emerging data on nonmyeloablative transplants. He also presents data on using microarrays to stratify patients into molecularly defined risk groups.
Myelodysplastic Syndromes
Authors: Greenberg Peter L. , Young Neal S. , Gattermann Norbert
Published: August 2003

The myelodysplastic syndromes (MDS) are characterized by hemopoietic insufficiency associated with cytopenias leading to serious morbidity plus the additional risk of leukemic transformation. Therapeutic dilemmas exist in MDS because of the disease’s multifactorial pathogenetic features, heterogeneous stages, and the patients’ generally elderly ages. Underlying the cytopenias and evolutionary potential in MDS are innate stem cell lesions, cellular/cytokine-mediated stromal defects, and immunologic derangements. This article reviews the developing understanding of biologic and molecular lesions in MDS and recently available biospecific drugs that are potentially capable of abrogating these abnormalities.

Dr. Peter Greenberg’s discussion centers on decision-making approaches for these therapeutic options, considering the patient’s clinical factors and risk-based prognostic category.

One mechanism underlying the marrow failure present in a portion of MDS patients is immunologic attack on the hemopoietic stem cells. Considerable overlap exists between aplastic anemia, paroxysmal nocturnal hemoglobinuria, and subsets of MDS. Common or intersecting pathophysiologic mechanisms appear to underlie hemopoietic cell destruction and genetic instability, which are characteristic of these diseases. Treatment results and new therapeutic strategies using immune modulation, as well as the role of the immune system in possible mechanisms responsible for genetic instability in MDS, will be the subject of discussion by Dr. Neal Young.

A common morphological change found within MDS marrow cells, most sensitively demonstrated by electron microscopy, is the presence of ringed sideroblasts. Such assessment shows that this abnormal mitochondrial iron accumulation is not confined to the refractory anemia with ring sideroblast (RARS) subtype of MDS and may also contribute to numerous underlying MDS pathophysiological processes. Generation of abnormal sideroblast formation appears to be due to malfunction of the mitochondrial respiratory chain, attributable to mutations of mitochondrial DNA, to which aged individuals are most vulnerable. Such dysfunction leads to accumulation of toxic ferric iron in the mitochondrial matrix. Understanding the broad biologic consequences of these derangements is the focus of the discussion by Dr. Norbert Gattermann.
Acute Lymphoblastic Leukemia
Authors: Hoelzer Dieter , Gökbuget Nicola , Ottmann Oliver , Pui Ching-Hon , Relling Mary V. , Appelbaum Frederick R. , van Dongen Jacques J.M. , Szczepański Tomasz
Published: August 2003

This is a comprehensive overview on the most recent developments in diagnosis and treatment of acute lymphoblastic leukemia (ALL).

Dr. Dieter Hoelzer and colleagues give an overview of current chemotherapy approaches, prognostic factors, risk stratification, and new treatment options such as tyrosine kinase inhibitors and monoclonal antibodies. Furthermore the role of minimal residual disease (MRD) for individual treatment decisions in prospective clinical studies in adult ALL is reviewed.

Drs. Ching-Hon Pui and Mary Relling discuss late treatment sequelae in childhood ALL. The relation between the risk of second cancer and treatment schedule, pharmacogenetics, and gene expression profile studies is described. Also pathogenesis, risk factors, and management of other complications such as endocrinopathy, bone demineralization, obesity, and avascular necrosis of bone is reviewed.

Dr. Fred Appelbaum addresses long-term results, late sequelae and quality of life in ALL patients after stem cell transplantation. New options for reduction of relapse risk, e.g., by intensified conditioning regimens or donor lymphocyte infusions, for reduction of mortality and new approaches such as nonmyeloablative transplantation in ALL are discussed.

Drs. Jacques van Dongen and Tomasz Szczepanski demonstrate the prognostic value of MRD detection via flow cytometry or PCR analysis in childhood ALL. They discuss the relation between MRD results and type of treatment protocol, timing of the follow-up samples, and the applied technique and underline the importance of standardization and quality control. They also review MRD-based risk group definition and clinical consequences.
Chronic Lymphocytic Leukemia
Authors: Kay Neil E. , Hamblin Terry J. , Jelinek Diane F. , Dewald Gordon W. , Byrd John C. , Farag Sherif , Lucas Margaret , Lin Thomas
Published: August 2003

This update of early stage B-cell chronic lymphocytic leukemia (B-CLL) embraces current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management.

In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic procedures, evidence for an early “preclinical” phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease.

In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered.

In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated progressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B-CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered.
Multiple Myeloma
Authors: Anderson Kenneth C. , Shaughnessy John D. , Barlogie Bart , Harousseau Jean-Luc , Roodman G. David
Published: August 2003

This update provides new insights into the biology, diagnosis, prognosis, and treatment of multiple myeloma (MM) and its complications.

In Section I, Drs. John Shaughnessy, Jr., and Bart Barlogie first correlate global gene microarray expression profiling of patient MM samples with normal plasma cells to provide the basis for a developmental stage-based classification of MM. The powerful clinical utility of these analyses is illustrated in delineating mechanism of drug action, identifying novel therapeutic targets, and providing a molecular analysis not only of the tumor cell, but also of the tumor microenvironment, in MM.

In Section II, Dr. Jean-Luc Harousseau reviews the rationale and current results of high dose therapy and autologous stem cell transplantation in MM, including optimal patient selection, prognostic factors, conditioning regimens, sources of stem cells, use of tandem transplantation, and maintenance therapy. He then provides an update on the results of allotransplantation approaches in MM, focusing on proposed methods to reduce toxicity and exploit the graft-versus-MM alloimmune effect by transplantation earlier in the disease course, T cell depletion, and nonmyeloablative transplantation.

In Section III, Dr. G. David Roodman provides recent insights into the mechanisms of osteoclast activation, interactions between bone and MM cells, adhesive interactions in MM bone disease, and osteoblast suppression. These recent advances not only provide insights into pathogenesis of MM bone disease, but also form the framework for novel therapeutics.

In Section IV, Dr. Kenneth Anderson provides an up-to-date discussion of the role of the bone marrow microenvironment in promoting growth, survival, drug resistance, and migration of MM cells and the signaling cascades mediating these sequelae. These studies provide the framework for evaluation of novel therapeutics targeting the MM cell-host interaction in vivo in animal models and in derived clinical trials.
Lymphoma of the Skin
Authors: Connors Joseph M. , Hsi Eric D. , Foss Francine M.
Published: August 2003

This chapter describes the various ways in which the non-Hodgkin’s lymphomas can involve the skin, how these diseases should be assessed, standard treatments available in 2002, and new directions in research. The goal of the session is to succinctly review recent developments in lymphoma classification and treatment as they apply to the unique aspects of lymphoma when manifest in the skin.

In Section I, Dr. Eric Hsi reviews the special characteristics of the lymphomas seen when they proliferate in the skin and the application of the new World Health Organization classification system to the cutaneous lymphomas, emphasizing the unique challenges of recognizing and correctly classifying these diseases. He summarizes the evidence in favor of including the skin lymphomas in the overall lymphoma classification scheme and concludes with a practical description of the specific skin lymphoma entities.

In Section II, Dr. Joseph Connors describes the current optimal treatment of the B-cell lymphomas when they present in or metastasize to the skin. Building on the classification scheme described by Dr. Hsi, Dr. Connors outlines a treatment approach based on current understanding of pathophysiology of these diseases and application of each of the effective modalities available for cutaneous lymphoma including radiation, chemotherapy, and immunotherapy.

In Section III, Dr. Francine Foss concludes the session with a discussion of the different T-cell lymphomas that start in or spread to the skin concentrating on mycosis fungoides, cutaneous anaplastic large cell lymphoma and peripheral T-cell lymphoma. She includes comments on the newer anti-T-cell chemo- and immuno-therapeutics focusing on agents and techniques specific for cutaneous T-cell lymphomas.
Central Nervous System Lymphoma
Authors: Lister Andrew , Abrey Lauren E. , Sandlund John T.
Published: August 2003

Central nervous system involvement with malignant lymphoma whether primary or secondary is an uncommon but not rare complication observed in the management of patients with hematological malignancy. Its importance lies in the considerable morbidity and mortality with which it is associated and the inadequacy of therapy.

In Section I, Dr. Lauren Abrey addresses the totality of the problem of primary central nervous system lymphoma, with emphasis on strategies increasingly dependent on systemic chemotherapy.

In Section II, Dr. John Sandlund reviews the success of sequential clinical trials of overall therapy for acute lymphoblastic leukemia in childhood, identifying those patients at high risk of central nervous system leukemia and the development of a rational therapeutic strategy for prevention.

In Section III, Dr. Andrew Lister discusses the issue of secondary central nervous system involvement with lymphoma and the indications for prophylaxis.
Atypical Cellular Disorders
Authors: Arceci Robert J. , Longley B. Jack , Emanuel Peter D.
Published: August 2003

Atypical cellular disorders are commonly considered part of the gray zone linking oncology to hematology and immunology. Although these disorders are relatively uncommon, they often represent significant clinical problems, provide an opportunity to understand basic disease mechanisms, and serve as model systems for the development of novel targeted therapies. This chapter focuses on such disorders.

In Section I, Dr. Arceci discusses the pathogenesis of Langerhans cell histiocytosis (LCH) in terms of the hypothesis that this disorder represents an atypical myeloproliferative syndrome. The clinical manifestations and treatment of LCH in children and adults is discussed along with possible future therapeutic approaches based upon biological considerations.

In Section II, Dr. Longley considers the molecular changes in the c-Kit receptor that form the basis of mastocytosis. Based on the location and function of c-Kit mutations, he develops a paradigm for the development of specific, targeted therapies.

In Section III, Dr. Emanuel provides a review of the “mixed myeloproliferative and myelodysplastic disorders,” including novel therapeutic approaches based on aberrant pathogenetic mechanisms. Taken together, these chapters should provide an overview of the biological basis for these disorders, their clinical manifestations, and new therapeutic approaches
Coagulation: Consultative Hemostasis
Authors: Hambleton Julie , Leung Lawrence L. , Levi Marcel
Published: August 2003

Clinical hematologists are frequently consulted for the care of hospitalized patients with complicated coagulopathies. This chapter provides an update on the scientific and clinical advances noted in disseminated intravascular coagulation (DIC) and discusses the challenges in hemostasis consultation.

In Section I, Dr. Marcel Levi reviews advances in our understanding of the pathogenic mechanisms of DIC. Novel therapeutic strategies that have been developed and evaluated in patients with DIC are discussed, as are the clinical trials performed in patients with sepsis.

In Section II, Dr. Lawrence Leung provides an overview of the challenging problems in thrombosis encountered in the inpatient setting. Patients with deep vein thrombosis that is refractory to conventional anticoagulation and those with extensive mesenteric thrombosis as well as the evaluation of a positive PF4/heparin ELISA in a post-operative setting are discussed. Novel treatments for recurrent catheter thrombosis in dialysis patients is addressed as well.

In Section III, Dr. Julie Hambleton reviews the hemostatic complications of solid organ transplantation. Coagulopathy associated with liver transplantation, contribution of underlying thrombophilia to graft thrombosis, drug-induced microangiopathy, and the indication for postoperative prophylaxis are emphasized. Dr. Hambleton reviews the clinical trials evaluating hemostatic agents in patients undergoing liver transplantation.