Current Opinion in Hematology最新文献

Purpose of review: The purpose of this review is to outline current graft versus host disease (GvHD) prophylaxis, in the era of posttransplant cyclophosphamide (PTCY), in patients with malignant and nonmalignant hematologic disorders. The original combination of PTCY with a calcineurin inhibitor (CNI) and mycophenolate (MMF), reported from the Johns Hopkins University in Baltimore, was designed for patients receiving a graft from a donor mismatched at one haplotype, so called haploidentical donor (HAPLO). In the past decade, PTCY has been widely used in HAPLO transplants worldwide, confirming the amazing efficacy of PTCY in preventing GvHD in mismatched grafts.

Recent findings: More recently, PTCY is being tested also in grafts from human leukocyte antigen (HLA) identical related or unrelated donors. In the present review we will also answer several open questions, such as: PTCY and cardiac toxicity; PTCY dose; PTCY timing; PTCY and antithymocyte globulin (ATG); engraftment kinetics; infections; PTCY and leukemia relapse; PTCY and HLA identical grafts.

Summary: PTCY is currently one of the most effective measures to prevent GvHD, and can be customized in different transplant platforms, together with other immunosuppressive agents. There is place for improvement, and several possible modifications of PTCY dose and schedule can be tested in prospective trials.

Purpose of review: DDX41 mutations are the most common cause of germline predisposition to adult-onset myeloid neoplasms. The unique mutational landscape and clinical features indicate a distinct molecular pathogenesis, but the precise mechanism by which DDX41 mutations cause disease is poorly understood, owing to the multitude of DDX41 functions. In this review, we will update DDX41's known functions, present unique clinical features and treatment considerations, and summarize the current understanding of the molecular pathogenesis of the disease.

Recent findings: Large cohort studies have revealed that germline DDX41 variants are heterozygous and predominantly loss-of-function. Acquired mutation of the contralateral DDX41 allele, typically R525H, is present in more than half of patients at disease onset, which occurs after age 50. DDX41 is essential for hematopoiesis and has versatile functions in RNA metabolism and innate immune sensing. Experimental models have suggested that innate immune activation downstream of defects in R-loop resolution and ribosome biogenesis plays a key role in the pathogenesis.

Summary: While intensive investigations unveiled a strong genotype-phenotype relationship, the optimal therapeutic approach and long-term outcome are undefined. There is an urgent need to scrutinize the patients at single cell and multiomics level and to advance experimental animal and human models to fully elucidate the molecular pathogenesis.

Purpose of review: Despite being discovered decades ago, metastasis remains a formidable challenge in cancer treatment. During the intermediate phase of metastasis, tumor cells detach from primary tumor or metastatic sites and travel through the bloodstream and lymphatic system to distant tissues. These tumor cells in the circulation are known as circulating tumor cells (CTCs), and a higher number of CTCs has been linked to poor prognoses in various cancers. The blood is an inhospitable environment for any foreign cells, including CTCs, as they face numerous challenges, such as the shear stress within blood vessels and their interactions with blood and immune cells. However, the exact mechanisms by which CTCs survive the hostile conditions of the bloodstream remain enigmatic. Platelets have been studied for their interactions with tumor cells, promoting their survival, growth, and metastasis. This review explores the latest clinical methods for enumerating CTCs, recent findings on platelet-CTC crosstalk, and current research on antiplatelet therapy as a potential strategy to inhibit metastasis, offering new therapeutic insights.

Recent findings: Laboratory and clinical data have provided insights into the role of platelets in promoting CTC survival, while clinical advancements in CTC enumeration offer improved prognostic tools.

Summary: CTCs play a critical role in metastasis, and their interactions with platelets aid their survival in the hostile environment of the bloodstream. Understanding this crosstalk offers insights into potential therapeutic strategies, including antiplatelet therapy, to inhibit metastasis and improve cancer treatment outcomes.

Purpose of review: Many epidemiological studies have evidenced an increased bleeding risk associated with selective serotonin reuptake inhibitors (SSRIs), yet the underlying mechanisms remain unclear. This review summarizes data on SSRIs' effects on platelet functions assessed with assays used in clinical practice and highlights the areas that deserve further investigation.

Recent findings: Conflicting results of SSRI effects on platelet aggregation were observed irrespectively of the agonist used, the antidepressant drug or the study type. Alike, discrepant results were reported with flow-cytometry-based assays assessing either platelet surface glycoprotein levels, integrin activation, agonist-induced secretion of intraplatelet granule content or membrane anionic phospholipid exposure. Other tests may have detected a platelet function defect in SSRIs samples, however, results were largely inconsistent.

Summary: Critical literature examination unveils very low certainty of evidence on potential SSRI effect on platelet functions. Findings are often inconsistent even when similar methods are used, most likely because of differences in study design, included patients (age, comorbid conditions), SSRIs' type and dose, uncontrolled confounding factors, and statistical analysis power. Further studies are needed to disentangle any intrinsic antiplatelet effect of SSRIs and the multiple confounding factors, mainly the depression control itself and the degree of platelet SERT inhibition.

Purpose of review: Hematopoietic stem cell transplantation (HSCT) and inborn errors of immunity (IEI) have been closely linked since transplantation was first used to cure severe combined immunodeficiency (SCID) in 1968. Since then, novel genes and diseases have been continually added to the ongoing list of IEI, and new data on indications and outcomes have emerged. We review recent data and progress in the field of hematopoietic cell transplantation (HCT) for IEI including new diseases and complications.

Recent findings: Emerging data from haploidentical transplants, newborn screening results, and multicentric studies reveals promising outcomes for IEI. Immune dysregulation diseases deserve special attention regarding disease control and may require additional drugs pretransplant. Female carriers of X-linked Chronic granulomatous may present with a severe phenotype warranting the need for HCT. Insights from infectious complications and long-term comorbidities should help guide decisions to treat IEI patients.

Summary: From classical indications to recently described diseases, HCT for immunodeficiencies is a rapidly growing field. Novel data regarding alternative donor transplants, results from large cohorts, and long-term complications provide valuable knowledge for clinical practice.

Purpose of review: Platelet transfusions, used as prophylaxis or treatment for bleeding, are potentially life-saving. In many countries, demand for platelet transfusion is rising. Platelets are a limited and costly resource, and it is vital that they are used appropriately. This study will explore the evidence behind platelet transfusions in different contexts, in particular recent and important research in this area.

Recent findings: Recent randomized clinical trials demonstrate the efficacy of platelet transfusions in some contexts but potential detrimental effects in others. Platelet transfusions also carry risk of transfusion reactions, bacterial contamination and platelet transfusion refractoriness. Observational and clinical studies, which highlight approaches to mitigate these risks, will be discussed. There is growing interest in cold-stored or cryopreserved platelet units, which may improve platelet function and availability. Clinical trials also highlight the efficacy of other supportive measures such as tranexamic acid or thrombopoietin receptor agonists in patients with bleeding.

Summary: Although platelet transfusions are beneficial in many patients, there remain many settings in which the optimal use of platelet transfusions is unclear, and some situations in which they may have detrimental effects. Future clinical trials are needed to determine optimal use of platelet transfusions in different patient populations.

Purpose of review: Cardiovascular disease (CVD) remains a major global health burden. Rising incidences necessitate improved understanding of the pathophysiological processes underlying disease progression to foster the development of novel therapeutic strategies. Besides their well recognized role in CVD, platelet-derived extracellular vesicles (PEVs) mediate inter-organ cross talk and contribute to various inflammatory diseases.

Recent findings: PEVs are readily accessible diagnostic biomarkers that mirror pathophysiological disease progression but also may confer cardioprotective properties. Monitoring the effects of modulation of PEV signatures through pharmacotherapies has also provided novel insights into treatment efficacy. Furthermore, exploiting their inherent ability to infiltrate thrombi, atherosclerotic plaques and solid tumours, PEVs as well as platelet-membrane coated nanoparticles are emerging as novel effective and targeted treatment options for CVD and cancer.

Summary: Collectively, in-depth characterization of PEVs in various diseases ultimately enhances their use as diagnostic or prognostic biomarkers and potential therapeutic targets, making them clinically relevant candidates to positively impact patient outcomes.

Purpose of review: Loss of surface sialic acid by neuraminidases is known as 'desialylation'. Platelets are desialylated in bacterial or viral infections, during storage, senescence, various mutations, platelet auto antibodies, hemostasis and shear stress. In this review the recent literature on the different sialic acid capped glycan structures will be covered as well as platelet desialylation in inherited glycan disorders and induced by external neuraminidases.

Recent findings: Neuraminidases are released from platelet intracellular stores and translocated to the platelet surface. Apart from clearance, loss of surface sialic acid by neuraminidases ('desialylation') affects platelet signaling including ligand binding and their procoagulant function. Platelets are also desialylated in infections, various mutations, presence of platelet auto antibodies.

Summary: Since platelet desialylation occurs in various healthy and pathological conditions, measuring desialylation might be a new diagnostic tool.