POEMS syndrome is a paraneoplastic syndrome whose acronym stands for less than half of the defining features of the disease, that is, polyradiculoneuropathy, organomegaly, potentially including coexisting Castleman disease, endocrinopathy, monoclonal plasma cell neoplasm, and skin changes. The other important features include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis, elevated VEGF, and abnormal pulmonary function. The diagnosis is based on having both the polyradiculoneuropathy and the monoclonal plasma cell disorder, and at least 1 of the other 3 major criteria (Castleman disease, sclerotic bone lesions, or elevated VEGF) and at least one minor criterion. The diagnosis is often delayed with intervening incorrect diagnoses of chronic inflammatory demyelinating polyradiculoneuropathy, myeloproliferative disorder, and monoclonal gammopathy of undetermined significance. Prompt treatment directed at the underlying plasma cell clone produces dramatic responses in the majority of patients. Although there are no randomized clinical trial data to direct best therapy, for patients with disseminated disease, high-dose chemotherapy with peripheral blood transplantation has yielded durable benefit, whereas radiation therapy is typically effective for patients with a more localized presentation. More universal recognition of and more scientific inquiry into the underpinnings of the disease will provide direction toward the best treatment strategies in the future.

During the past decade it was recognized that homeobox gene families such as the clustered Hox genes play pivotal roles both in normal and malignant hematopoiesis. More recently, similar roles have also become apparent for members of the ParaHox gene cluster, evolutionarily closely related to the Hox gene cluster. This is in particular found for the caudal-type homeobox genes (Cdx) genes, known to act as upstream regulators of Hox genes. The CDX gene family member CDX2 belongs to the most frequent aberrantly expressed proto-oncogenes in human acute leukemias and is highly leukemogenic in experimental models. Correlative studies indicate that CDX2 functions as master regulator of perturbed HOX gene expression in human acute myeloid leukemia, locating this ParaHox gene at a central position for initiating and maintaining HOX gene dysregulation as a driving leukemogenic force. There are still few data about potential upstream regulators initiating aberrant CDX2 expression in human leukemias or about critical downstream targets of CDX2 in leukemic cells. Characterizing this network will hopefully open the way to therapeutic approaches that target deregulated ParaHox genes in human leukemia.

Regulation of V(D)J recombination events at immunoglobulin (Ig) and T-cell receptor loci in lymphoid cells is complex and achieved via changes in substrate accessibility. Various studies over the last year have identified the DNA-binding zinc-finger protein CCCTC-binding factor (CTCF) as a crucial regulator of long-range chromatin interactions. CTCF often controls specific interactions by preventing inappropriate communication between neighboring regulatory elements or independent chromatin domains. Although recent gene targeting experiments demonstrated that the presence of the CTCF protein is not required for the process of V(D)J recombination per se, CTCF turned out to be essential to control order, lineage specificity and to balance the Ig V gene repertoire. Moreover, CTCF was shown to restrict activity of κ enhancer elements to the Ig κ locus. In this review, we discuss CTCF function in the regulation of V(D)J recombination on the basis of established knowledge on CTCF-mediated chromatin loop domains in various other loci, including the imprinted H19-Igf2 locus as well as the complex β-globin, MHC class II and IFN-γ loci. Moreover, we discuss that loss of CTCF-mediated restriction of enhancer activity may well contribute to oncogenic activation, when in chromosomal translocations Ig enhancer elements and oncogenes appear in a novel genomic context.

Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems. The in vivo roles of IgG receptors have been addressed using specific FcR knockout mice or in mice expressing a single FcR, and have demonstrated a predominant contribution of mouse activating IgG receptors FcγRIII and FcγRIV to models of autoimmunity (eg, arthritis) and allergy (eg, anaphylaxis). Novel blocking mAbs specific for these activating IgG receptors have enabled, for the first time, the investigation of their roles in vivo in wild-type mice. In parallel, the in vivo properties of human FcRs have been reported using transgenic mice and models of inflammatory and allergic reactions, in particular those of human activating IgG receptor FcγRIIA (CD32A). Importantly, these studies led to the identification of specific cell populations responsible for the induction of various inflammatory diseases and have revealed, in particular, the unexpected contribution of neutrophils and monocytes to the induction of anaphylactic shock.

Survival in severe aplastic anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive biologics and drugs, and supportive care. However, management of SAA patients remains challenging, both acutely in addressing the immediate consequences of pancytopenia and in the long term because of the disease's natural history and the consequences of therapy. Recent insights into pathophysiology have practical implications. We review key aspects of differential diagnosis, considerations in the choice of first- and second-line therapies, and the management of patients after immunosuppression, based on both a critical review of the recent literature and our large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute.

Inorganic polyphosphate is widespread in biology and exhibits striking prohemostatic, prothrombotic, and proinflammatory effects in vivo. Long-chain polyphosphate (of the size present in infectious microorganisms) is a potent, natural pathophysiologic activator of the contact pathway of blood clotting. Medium-chain polyphosphate (of the size secreted from activated human platelets) accelerates factor V activation, completely abrogates the anticoagulant function of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. Polyphosphate may have utility as a hemostatic agent, whereas antagonists of polyphosphate may function as novel antithrombotic/anti-inflammatory agents. The detailed molecular mechanisms by which polyphosphate modulates blood clotting reactions remain to be elucidated.

The treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been influenced by several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common definitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of definitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease. This paper summarizes the consensus of the panel on events and major end points of interest in CML. It also focuses on specific issues concerning the intention-to-treat principle and longitudinal data analyses in the context of long-term follow-up. The panel proposes that future clinical trials follow these recommendations.

Allogeneic hematopoietic stem cell transplantation (SCT) is well accepted as a curative treatment approach for younger patients with myelodysplastic syndrome (MDS) and has become one of the most frequent indications for allogeneic SCT as reported to the Center for International Blood and Marrow Transplant Research. However, MDS patients are usually elderly with a median age of approximately 75 years at diagnosis. Large register studies have confirmed the feasibility of the procedure in elderly MDS patients; and in the register of the European Group for Blood and Marrow Transplantation, one-third of the allogeneic transplant procedures for MDS were performed in 2010 in patients older than 60 years. Despite its curative potential, its role in the treatment of elderly MDS patients is less defined. Because of the inherent complications of the transplantation leading to treatment-related mortality and the risk of relapse, a careful calculation of the benefit for each patient is mandatory, taking into account comorbidities, disease status, donor selection, and effective nontransplant therapies. Prospective multicenter studies are needed to define optimal intensity of the conditioning regimen, timing of transplantation within a treatment algorithm, including drug-based therapies, and posttransplant strategies to reduce the risk of relapse.

Patients with essential thrombocythemia (ET) and polycythemia vera (PV) have an increased incidence of acute myeloid leukemia and new nonhematologic malignancies compared with the general population. However, information on the factors determining the risk for such complications is limited. In the present study, we investigated whether constitutional genetic variations in DNA repair predispose to leukemic transformation and new nonmyeloid neoplasias in patients with ET and PV. Case-control studies for predisposition to both types of malignancies were nested in a cohort of 422 subjects diagnosed with ET or PV during the period 1973-2010 in several institutions in Spain. A total of 64 incidence cases of leukemia and 50 cases of primary nonmyeloid cancers were accrued. At conditional regression analysis, the Gln/Gln genotype in the XPD codon 751 showed the strongest association with both leukemic transformation (odds ratio [OR] = 4.9; 95% confidence interval [95% CI], 2.0-12) and development of nonmyeloid malignancies (OR = 4.2; 95% CI, 1.5-12). Additional predictive factors were exposure to cytoreductive agents for leukemic transformation (OR = 3.5; 95% CI, 2.0-6.2) and age for nonmyeloid malignancies (OR = 2.0; 95% CI, 1.4-2.8). These findings provide further evidence about the contribution of inherited genetic variations to the pathogenesis and clinical course of myeloproliferative neoplasms.

Risk factors for deep-vein thrombosis have been shown not to be always the same as for pulmonary embolism. A well-known example is the factor V Leiden (FVL) paradox: the FVL mutation poses a clearly higher risk for deep-vein thrombosis (DVT) than for pulmonary embolism. We aimed to expand this paradox and therefore present risk estimates for several established risk factors for DVT and pulmonary embolism separately. When such separate risk estimates could not be retrieved from the literature, we calculated these risks in our own data, a large population-based case-control study on venous thrombosis (the MEGA study). Our results showed that the FVL paradox can be broadened (ie, the risk factors oral contraceptive use, pregnancy, puerperium, minor leg injuries, and obesity have an effect comparable with FVL). Furthermore, we found that pulmonary conditions, such as chronic obstructive pulmonary disease, pneumonia, and sickle cell disease, were risk factors with an opposite effect: a higher risk of pulmonary embolism, but little or no effect on DVT. These findings suggest that pulmonary embolism and DVT may not always have the same etiology, and encourage unraveling this phenomenon in further studies.

Hematologic malignancies are a heterogeneous group of conditions with an unclear etiology. We hypothesized that diabetes mellitus type 2 is associated with increased risk of developing lymphoma, leukemia, and myeloma. A literature search identified 26 studies (13 case-control and 13 cohort studies) evaluating such an association. Outcome was calculated as the odds ratio (OR) using a random effects model. Heterogeneity and publication bias were evaluated using the I(2) index and the trim-and-fill analysis, respectively. Quality was assessed using the Newcastle-Ottawa scale. The OR for non-Hodgkin lymphoma was increased at 1.22 (95% confidence interval [CI], 1.07-1.39; P < .01) but the OR for Hodgkin lymphoma was not. There was an increased OR for peripheral T-cell lymphoma (OR = 2.42, 95% CI, 1.24-4.72; P = .009) but not for other non-Hodgkin lymphoma subtypes. The OR for leukemia was 1.22 (95% CI, 1.03-1.44; P = .02) and the OR for myeloma was 1.22 (95% CI, 0.98-1.53; P = .08). Although diabetes mellitus type 2 seems to increase the risk of developing lymphoma, leukemia, and myeloma, future studies should focus on evaluating other potential confounders such as obesity, dietary habits, physical activity, and/or antidiabetic therapy.

Cancer is a leading cause of death and disability in sub-Saharan Africa and will eclipse infectious diseases within the next several decades if current trends continue. Hematologic malignancies, including non-Hodgkin lymphoma, leukemia, Hodgkin lymphoma, and multiple myeloma, account for nearly 10% of the overall cancer burden in the region, and the incidence of non-Hodgkin lymphoma and Hodgkin lymphoma is rapidly increasing as a result of HIV. Despite an increasing burden, mechanisms for diagnosing, treating, and palliating malignant hematologic disorders are inadequate. In this review, we describe the scope of the problem, including the impact of endemic infections, such as HIV, Epstein-Barr virus, malaria, and Kaposi sarcoma-associated herpesvirus. We additionally describe current limitations in hematopathology, chemotherapy, radiotherapy, hematopoietic stem cell transplantation, and supportive care and palliation. We review contemporary treatment and outcomes of hematologic malignancies in the region and outline a clinical service and research agenda, which builds on recent global health successes combating HIV and other infectious diseases. Achieving similar progress against hematologic cancers in sub-Saharan Africa will require the sustained collaboration and advocacy of the entire global cancer community.

Monoclonal B-cell lymphocytosis (MBL), a newly recognized entity found in approximately 3% of normal persons, precedes chronic lymphocytic leukemia. However, MBLs progress into overt malignancy only in a very minor portion of cases, thus raising the clinical concern of whether and how we can discriminate at diagnosis which rare cases will evolve into a fully fledged tumor. Understanding the molecular/biologic features underlying the risk of progression may significantly modify our strategies for correctly managing B-cell premalignant states. MBL cells bear the same chromosomal abnormalities of chronic lymphocytic leukemia. Genome-wide sequencing and animal models indicate that genetic abnormalities disrupting the control of cell growth and survival cooperate with microenvironment-triggered events, mainly represented by antigen-mediated B-cell receptor and coreceptor stimulation, to trigger and fuel clonal expansion. The initial functional activation of survival/proliferation pathways may later become subsidized by autonomous genetic abnormalities (eg, a single mutation) affecting the same or parallel critical signaling pathway(s).

During embryonic development, multilineage HSCs/progenitor cells are derived from specialized endothelial cells, termed hemogenic endothelium, within the yolk sac, placenta, and aorta. Whether hemogenic endothelial cells contribute to blood cell development at other sites of definitive hematopoiesis, such as in the fetal liver and fetal bone marrow, is not known. Also unknown is whether such cells exist within the vasculature of adult bone marrow and generate hematopoietic stem cells after birth. These issues and their clinical relevance are discussed herein.

In high-income countries, the large availability of coagulation factors for replacement therapy of patients with hemophilia A has raised the life expectancy of these lifelong bleeders to that of males from the general population. The practicing clinician is offered a multitude of choices among several commercial brands of factor VIII extracted from human plasma or engineered from mammalian cell cultures by means of recombinant DNA technology. This article has the goal to offer our opinions on how to choose among the different products, that we consider interchangeable relevant to their clinical efficacy in the control of bleeding and safety from pathogen transmission. Hence, the main determinants of our choices are price and the risk of occurrence of factor VIII inhibitory alloantibodies. With this as background, we present the rationale underlying the choices for different categories of patients with severe hemophilia A: previously untreated patients, multiply treated patients, and patients undergoing immune tolerance induction with large doses of factor VIII to eradicate inhibitors. Mention is also made to the possible strategies that should be implemented to make available coagulation factors for replacement therapy in developing countries.

For decades, hematopoietic stem cells (HSCs) were thought to be a homogeneous population of cells with flexible behavior. Now a new picture has emerged: The HSC compartment consists of several subpopulations of HSCs each with distinct, preprogrammed differentiation and proliferation behaviors. These programs are epigenetically fixed and are stably bequeathed to all daughter HSCs on self-renewal. HSCs within each subset are remarkably similar in their self- renewal and differentiation behaviors, to the point where their life span can be predicted with mathematical certainty. Three subsets can be distinguished when HSCs are classified by their differentiation capacity: myeloid-biased, balanced, and lymphoid-biased HSCs. The relative number of the HSC subsets is developmentally regulated. Lymphoid-biased HSCs are found predominantly early in the life of an organism, whereas myeloid-biased HSCs accumulate in aged mice and humans. Thus, the discovery of distinct subpopulations of HSCs has led to a new understanding of HCS aging. This finding has implications for other aspects of HSC biology and applications in re-generative medicine. The possibility that other adult tissue stem cells show similar heterogeneity and mechanisms of aging is discussed.

Hematopoietic stem cell transplantation is the only curative treatment for many malignant hematologic diseases, with an often critical graft-versus-leukemia effect. Despite peritransplant prophylaxis, GVHD remains a significant cause of posthematopoietic stem cell transplantation morbidity and mortality. Traditional therapies have targeted T cells, yet immunostimulatory dendritic cells (DCs) are critical in the pathogenesis of GVHD. Furthermore, DCs also have tolerogenic properties. Monitoring of DC characteristics may be predictive of outcome, and therapies that target DCs are innovative and promising. DCs may be targeted in vivo or tolerogenic (tol) DCs may be generated in vitro and given in the peritransplant period. Other cellular therapies, notably regulatory T cells (T(reg)) and mesenchymal stem cells, mediate important effects through DCs and show promise for the prevention and treatment of GVHD in early human studies. Therapies are likely to be more effective if they have synergistic effects or target both DCs and T cells in vivo, such as tolDCs or T(reg). Given the effectiveness of tolDCs in experimental models of GVHD and their safety in early human studies for type 1 diabetes, it is crucial that tolDCs be investigated in the prevention and treatment of human GVHD while ensuring conservation of graft-versus-leukemia effects.

Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research.

Silent cerebral infarct (SCI) is the most common form of neurologic disease in children with sickle cell anemia (SCA). SCI is defined as abnormal magnetic resonance imaging (MRI) of the brain in the setting of a normal neurologic examination without a history or physical findings associated with an overt stroke. SCI occurs in 27% of this population before their sixth, and 37% by their 14th birthdays. In adults with SCA, the clinical history of SCI is poorly defined, although recent evidence suggests that they too may have ongoing risk of progressive injury. Risk factors for SCI include male sex, lower baseline hemoglobin concentration, higher baseline systolic blood pressure, and previous seizures. Specific morbidity associated with SCI includes a decrement in general intellectual abilities, poor academic achievement, progression to overt stroke, and progressive SCI. In addition, children with previous stroke continue to have both overt strokes and new SCI despite receiving regular blood transfusion therapy for secondary stroke prevention. Studies that only include overt stroke as a measure of CNS injury significantly underestimate the total cerebral injury burden in this population. In this review, we describe the epidemiology, natural history, morbidity, medical management, and potential therapeutic options for SCI in SCA.