The role of iron chelation therapy in myelodysplastic syndrome (MDS) remains controversial. Averting cardiac dysfunction in low-grade MDS patients who have sufficient longevity to experience deleterious cardiac effects of iron overload has been the major argument in favor of iron chelation. Although there is significant evidence showing the adverse impact of transfusion dependency on survival in MDS, direct evidence linking tissue iron overload to poor survival or in particular to cardiac dysfunction is lacking. Given the heterogeneity of MDS, it is likely that the pathophysiology of iron overload is equally heterogeneous and complex in these patients. In this article, I argue that prevention of cardiac dysfunction in patients with lower grades of MDS may not be the major benefit of iron chelation therapy, and present evidence suggesting a potential benefit of iron chelation on 3 other outcomes, namely (1) lowering infection risk, (2) improving the outcome of allogeneic hematopoietic stem cell transplantation, and (3) delaying leukemic transformation. These outcomes have particular relevance for patients with higher grades of MDS and should be evaluated in future prospective clinical trials that include patients with all grades of MDS to fully evaluate the benefit of iron chelation therapy.

Extravasation of polymorphonuclear leukocytes (PMNs) to the site of inflammation precedes a second wave of emigrating monocytes. That these events are causally connected has been established a long time ago. However, we are now just beginning to understand the molecular mechanisms underlying this cellular switch, which has become even more complex considering the emergence of monocyte subsets, which are affected differently by signals generated from PMNs. PMN granule proteins induce adhesion as well as emigration of inflammatory monocytes to the site of inflammation involving beta(2)-integrins and formyl-peptide receptors. Furthermore, modification of the chemokine network by PMNs and their granule proteins creates a milieu favoring extravasation of inflammatory monocytes. Finally, emigrated PMNs rapidly undergo apoptosis, leading to the discharge of lysophosphatidylcholine, which attracts monocytes via G2A receptors. The net effect of these mechanisms is the accumulation of inflammatory monocytes, thus promoting proinflammatory events, such as release of inflammation-sustaining cytokines and reactive oxygen species. As targeting PMNs without causing serious side effects seems futile, it may be more promising to aim at interfering with subsequent PMN-driven proinflammatory events.

The most common subtypes of primary cutaneous T-cell lymphomas are mycosis fungoides (MF) and Sézary syndrome (SS). The majority of patients have indolent disease; and given the incurable nature of MF/SS, management should focus on improving symptoms and cosmesis while limiting toxicity. Management of MF/SS should use a "stage-based" approach; treatment of early-stage disease (IA-IIA) typically involves skin directed therapies that include topical corticosteroids, phototherapy (psoralen plus ultraviolet A radiation or ultraviolet B radiation), topical chemotherapy, topical or systemic bexarotene, and radiotherapy. Systemic approaches are used for recalcitrant early-stage disease, advanced-stage disease (IIB-IV), and transformed disease and include retinoids, such as bexarotene, interferon-alpha, histone deacetylase inhibitors, the fusion toxin denileukin diftitox, systemic chemotherapy including transplantation, and extracorporeal photopheresis. Examples of drugs under active investigation include new histone deacetylase inhibitors, forodesine, monoclonal antibodies, proteasome inhibitors, and immunomodulatory agents, such as lenalidomide. It is appropriate to consider patients for novel agents within clinical trials if they have failed front-line therapy and before chemotherapy is used.

Hypereosinophilic syndromes (HESs) are a heterogeneous group of uncommon disorders characterized by marked peripheral eosinophilia and end organ manifestations attributable to the eosinophilia or unexplained in the clinical setting. Whereas corticosteroids remain the mainstay of treatment for most patients, recent diagnostic advances and the development of novel targeted therapies, including tyrosine kinase inhibitors and humanized monoclonal antibodies, have increased the complexity of therapeutic decisions in HESs. This review presents a treatment-based approach to the diagnosis and classification of patients with peripheral blood eosinophilia of 1.5 x 10(9)/L (1500/mm3) or higher and discusses the role of currently available therapeutic agents in the treatment of these patients.

A fraction of fibrinogen contains a differently spliced gamma chain called gamma', which presents itself mainly as heterodimer with the common gammaA chain as gammaA/gamma' fibrinogen. The gamma' chain differs from the gammaA chain in its C-terminus and has important functional implications for fibrinogen. The presence of the gamma' chain modulates thrombin and FXIII activity, influences clot architecture, and eliminates a platelet-binding site. Associations of gammaA/gamma' fibrinogen levels with arterial and venous thrombosis have been reported, indicating that the functional effects of gammaA/gamma' fibrinogen may contribute to the pathology of thrombosis. This review summarizes the key biologic aspects of this interesting variant of fibrinogen and discusses inconsistencies in current reports.

Molecular monitoring in chronic myeloid leukemia (CML) is a powerful tool to document treatment responses and predict relapse. Nonetheless, the proliferation of clinical trials and "guidelines" using the molecular endpoints of CML has outpaced practice norms, commercial laboratory application, and reimbursement practices, leaving some anxiety (if not confusion and despair) about molecular monitoring in the day-to-day treatment of CML. This article will try to address these issues by describing how I monitor CML, which, in summary, is with interest and without panic.

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide remarkable cellular platforms to better understand human hematopoiesis and to develop clinically applicable hematopoietic cell-based therapies. Over the past decade, hESCs have been used to characterize molecular and cellular mechanisms underpinning the differentiation of hematopoietic progenitors and mature, functional hematopoietic cells. These advances are now poised to lead to clinical translation of hESC- and iPSC-derived hematopoietic cells for novel therapies in the next few years. On the basis of areas of recent success, initial clinical use of hematopoietic cells derived from human pluripotent stem cells will probably be in the areas of transfusion therapies (erythrocytes and platelets) and immune therapies (natural killer cells). In contrast, efficient development and isolation of hematopoietic stem cells capable of long-term, multilineage engraftment still remains a significant challenge. Technical, safety, and regulatory concerns related to clinical applications of human PSCs must be appropriately addressed. However, proper consideration of these issues should facilitate and not inhibit clinical translation of new therapies. This review outlines the current status of hematopoietic cell development and what obstacles must be surmounted to bring hematopoietic cell therapies from human PSCs from "bench to bedside."

The development of reduced intensity conditioning regimens has increased the number of patients diagnosed with chronic lymphocytic leukemia that are referred for allogeneic hematopoietic cell transplantation (allo-HCT). However, given the toxicity of allo-HCT, it should only be offered to eligible patients whose life expectancy is significantly reduced by the disease. Accordingly, the European Group of Blood and Marrow Transplantation has recently identified those patients in whom allo-HCT could be a reasonable therapeutic approach. In this review, we have evaluated the outcome of chronic lymphocytic leukemia patients undergoing allo-HCT, either after conventional or reduced intensity conditioning regimens, in the context of current nontransplantation strategies. We have also analyzed the most important predisposing factors that might interfere with the procedure as well as posttransplantation complications that are particularly common in these patients. Finally, we have addressed the most relevant factors when deciding what patients should be considered for allo-HCT and the timing of the procedure.

Regulatory T cells play important roles in the control of autoimmunity and maintenance of transplantation tolerance. Foxp3, a member of the forkhead/winged-helix family of transcription factors, acts as the master regulator for regulatory T-cell (Treg) development and function. Mutation of the Foxp3 gene causes the scurfy phenotype in mouse and IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome) in humans. Epigenetics is defined by regulation of gene expression without altering nucleotide sequence in the genome. Several epigenetic markers, such as histone acetylation and methylation, and cytosine residue methylation in CpG dinucleotides, have been reported at the Foxp3 locus. In particular, CpG dinucleotides at the Foxp3 locus are methylated in naive CD4+CD25- T cells, activated CD4+ T cells, and TGF-beta-induced adaptive Tregs, whereas they are completely demethylated in natural Tregs. The DNA methyltransferases DNMT1 and DNMT3b are associated with the Foxp3 locus in CD4+ T cells. Methylation of CpG residues represses Foxp3 expression, whereas complete demethylation is required for stable Foxp3 expression. In this review, we discuss how different cis-regulatory elements at the Foxp3 locus are subjected to epigenetic modification in different subsets of CD4+ T cells and regulate Foxp3 expression, and how these mechanisms can be exploited to generate efficiently large numbers of suppressive Tregs for therapeutic purposes.

In multiple myeloma (MM), the impact of complete response (CR) could be shown only after introduction of high-dose therapy plus autologous stem cell transplantation (ASCT). In the context of ASCT, achieving CR (negative immunofixation and normal bone marrow) or at least very good partial response is associated with longer progression-free survival and in most studies longer survival. With novel agents, high CR rates are achieved and this prognostic impact of CR is being shown as well, both in relapsed and in newly diagnosed MM. However the benefit of CR achievement depends on the type of treatment and is not identical for all patients. In elderly patients, treatments inducing more CR may be more toxic. Although CR achievement is necessary in patients with poor-risk disease, it might not be as critical for long survival in more indolent MM. CR achievement is not the only objective of treatment because it is possible to further improve the depth of response and the outcome by continuing treatment after CR achievement. Finally, there are several levels of CR and in the future it will be necessary to confirm the prognostic impact of immunophenotypic or molecular CR or of CR defined by imaging procedures.

Adenosine deaminase deficiency is a disorder of purine metabolism leading to severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal and requires early intervention. Haematopoietic stem cell transplantation is the major treatment for ADA-SCID, although survival following different donor sources varies considerably. Unlike other SCID forms, 2 other options are available for ADA-SCID: enzyme replacement therapy (ERT) with pegylated bovine ADA, and autologous haematopoietic stem cell gene therapy (GT). Due to the rarity of the condition, the lack of large scale outcome studies, and availability of different treatments, guidance on treatment strategies is limited. We have reviewed the currently available evidence and together with our experience of managing this condition propose a consensus management strategy. Matched sibling donor transplants represent a successful treatment option with high survival rates and excellent immune recovery. Mismatched parental donor transplants have a poor survival outcome and should be avoided unless other treatments are unavailable. ERT and GT both show excellent survival, and therefore the choice between ERT, MUD transplant, or GT is difficult and dependent on several factors, including accessibility to the different modalities, response of patients to long-term ERT, and the attitudes of physicians and parents to the short- and potential long-term risks associated with different treatments.

The most widely recognized long-term risk of splenectomy is overwhelming bacterial infection. More recently, thrombosis has become appreciated as another potential complication of the procedure. Because of these long-term risks, the indications for and timing of splenectomy are debated in the medical community. Accordingly, the adverse effects and benefits of splenectomy for hematologic disorders and other conditions demand further study. This comprehensive review summarizes the existing literature pertaining to vascular complications after splenectomy for hematologic conditions and attempts to define the potential pathophysiologic mechanisms involved. This complex topic encompasses diverse underlying conditions for which splenectomy is performed, diverse thrombotic complications, and multiple pathophysiologic mechanisms.

Despite major therapeutic advances, most mature B-cell malignancies remain incurable. Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B-cell growth and drug resistance. Therefore, disrupting the crosstalk between malignant B cells and their milieu is an attractive novel strategy for treating selected mature B-cell malignancies. Here we summarize the current knowledge about the cellular and molecular interactions between neoplastic B lymphocytes and accessory cells that shape a supportive microenvironment, and the potential therapeutic targets that are emerging, together with the new problems they raise. We discuss clinically relevant aspects and provide an outlook into future biologically oriented therapeutic strategies. We anticipate a paradigm shift in the treatment of selected B-cell malignancies, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role. Such approaches hopefully will help eliminating residual disease, thereby improving our current therapeutic efforts.

Amyloidosis is an uncommon disorder in which proteins change conformation, aggregate, and form fibrils that infiltrate tissues, leading to organ failure and death. The most frequent types are light-chain (AL) derived from monoclonal B-cell disorders producing amyloidogenic immunoglobulin light chains, and the hereditary and "senile systemic" (ATTR) variants from mutant and wild-type transthyretin (TTR). Diagnosis requires tissue biopsy. AL is more frequent and causes more organ disease than ATTR. Although both can cause cardiomyopathy and heart failure, AL progresses more quickly, so survival depends on timely diagnosis. Typing is usually based on clinical and laboratory findings with monoclonal gammopathy evaluation and, if indicated, TTR gene testing. Direct tissue typing is required when one patient has 2 potential amyloid-forming proteins. In coming years, widespread use of definitive proteomics will improve typing. New therapies are in testing for ATTR, whereas those for AL have followed multiple myeloma, leading to improved survival. Challenges of diagnosing and caring for patients with amyloidosis include determination of type, counseling, and delivery of prompt therapy often while managing multisystem disease. Recent advances grew from clinical research and advocacy in many countries, and global husbandry of such efforts will reap future benefits for families and patients with amyloidosis.

Waldenström macroglobulinemia (WM) is a distinct B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related IgM-secreting lymphoplasmacytic cells. Genetic factors play an important role, with 20% of patients demonstrating a familial predisposition. Asymptomatic patients should be observed. Patients with a disease-related hemoglobin level less than 10 g/L, platelet count less than 100 x 10(9)/L, bulky adenopathy or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or evidence of disease transformation should be considered for therapy. Plasmapheresis should be considered for symptomatic hyperviscosity and for prophylaxis in patients in whom rituximab therapy is contemplated. The use of rituximab as monotherapy or in combination with cyclophosphamide, nucleoside analog, bortezomib, or thalidomide-based regimens can be considered for the first-line therapy of WM and should take into account specific treatment goals, future autologous stem cell transplantation eligibility, and long-term risks of secondary malignancies. In the salvage setting, the reuse or use of an alternative frontline regimen can be considered as well as bortezomib, alemtuzumab, and stem cell transplantation. Newer agents, such as bendamustine and everolimus, can also be considered in the treatment of WM.

The recent approval of 3 drugs for the treatment of myelodysplastic syndromes (MDSs) has resulted in a revolution in therapeutic options that was absent a decade ago. At the same time, the changing MDS environment is raising new challenges in clinical trial design and defining new indications for MDS drugs. Many current trials still rely on IPSS-based enrollment criteria, despite the well-recognized limitations of the IPSS. Clinical trialists designing studies struggle with several important trial design challenges, including which patients constitute the "previously treated" and "relapsed/refractory" MDS populations, and how specifically to define disease "progression." This article considers some of these issues as they relate to study design, including how to identify certain MDS populations and define disease progression.

This article discusses how we approach medical decision making in the treatment of the various facets of the antiphospholipid syndrome (APS), including secondary prophylaxis in the setting of venous and arterial thrombosis, as well as treatment for the prevention of recurrent miscarriages and fetal death. The role of primary thromboprophylaxis is also discussed in depth. Great emphasis is given to incorporating the most up-to-date and relevant evidence base both from the APS literature, and from large, recent, randomized controlled trials (RCTs) of primary and secondary thrombotic prophylaxis in the general population setting (ie, the population that has not been specifically investigated for APS).

The horseshoe crab is often referred to as a "living fossil," representative of the oldest classes of arthropods, almost identical to species in existence more than 500 million years ago. Comparative analyses of the defense mechanisms used by the horseshoe crab that allowed it to survive mostly unchanged throughout the millennia reveal a common ancestry of the coagulation and innate immune systems that are totally integrated-indeed, almost inseparable. In human biology, we traditionally view the hemostatic pathways and those regulating innate immune responses to infections and tissue damage as entirely separate entities. But are they? The last couple of decades have revealed a remarkable degree of interplay between these systems, and the linking cellular and molecular mechanisms are rapidly being delineated. In this review, we present some of the major points of intersection between coagulation and innate immunity. We attempt to highlight the potential impact of these findings by identifying recently established paradigms that will hopefully result in the emergence of new strategies to treat a range of inflammatory and hemostatic disorders.

Mantle cell lymphoma is included in the World Health Organization classification as distinct lymphoma subtype characterized by the t(11;14)(q13;q32) translocation, which results in overexpression of Cyclin D1. The clinical presentation often includes extranodal involvement, particularly of the bone marrow and gut. The prognosis of patients with mantle cell lymphoma (median overall survival, 3-5 years) is poorest among B-cell lymphoma patients, even though a prospectively difficult to identify subgroup can survive for years with little or no treatment. Conventional chemotherapy is not curative but obtains frequent remissions (60%-90%) which are usually shorter (1-2 years) compared with other lymphoma entities. Very intensive regimens, including autologous and allogeneic stem cell transplantation, seem required to improve the outcome, but with the median age of diagnosis being 60 years or more, such approaches are feasible only in a limited proportion of patients. The possibility of treating patients based on prognostic factors needs to be investigated prospectively.

Red blood cells deliver O(2) from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O(2)-regulated alpha subunit and a constitutively expressed beta subunit. Hydroxylation of HIF-1alpha or HIF-2alpha by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1alpha or HIF-2alpha by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2alpha have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.