SummaryGivinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4Á5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients.
The pathophysiology and clinical severity of -thalassemia are related to the degree of ␣/non-␣-chain imbalance. A triplicated ␣-globin gene locus can exacerbate effects of excess ␣-chains caused by a defective -globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the ␣␣␣ anti-3.7 allele and a mutation in the -globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytosis and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases). Different phenotypes were also evident in the presence of the same -thalassemia mutation: in one family, two individuals had the same ␣-and -globin genotypes but presented with different hematologic phenotypes. In addition, the complex interaction involving a triplicated ␣-globin gene, 
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+27-thalassemia mutations is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A 2 and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical ␣-and -globin genotypes. Interaction with a triplicated ␣-gene can play a role in the clinical presentation of patients with defective -globin gene expression and should be considered in the diagnosis of atypical cases.
By guidelines, all laboratories are strongly advised to validate/verify the manufacturer's cutoff values. We recommend establishing low-positive, medium-/high-positive, and high-positive CliA IgG aCL and a-β2GpI ranges in order to help clinicians in the diagnosis and treatment of APS.
The management of major bleeding in patients treated with direct oral anticoagulants (DOACs) is still not well established. START-Events, a branch of the START registry (Survey on anTicoagulated pAtients RegisTer) (NCT02219984), aims to describe the actual management of bleeding or recurrent thrombotic events in routine clinical practice. We here present the results of the management of bleeding patients. The START-Event registry is a prospective, observational, multicenter, international study. Baseline characteristics (demographic, clinical, risk factors) of patients, laboratory data at admission and during follow-up, site of bleeding, therapeutic strategies, and outcomes at the time of hospital discharge and after 6 months were recorded on a web-based case report form. Between January 2015 and December 2016, 117 patients with major bleeding events were enrolled. Non-valvular atrial fibrillation (NVAF) was the indication for treatment in 84% (62% males); 53 patients had intracranial bleeding (13 fatal), 42 had gastrointestinal bleeding (1 fatal), and 22 had bleeding in other sites. Therapeutic interventions for the management of bleeding were performed in 71% of patients. Therapeutic strategies with/ without surgery or invasive procedures included: fluid replacement or red blood cells transfusion, prothrombin complex concentrates (3 or 4 factors), antifibrinolytic drugs, and the administration of idarucizumab. Creatinine, blood cell count, and PT/aPTT were the most frequent tests requested, while specific DOAC measurements were performed in 23% of patients. Mortality during hospitalization was 11.9%, at 6-month follow-up 15.5%. Our data confirm a high heterogeneity in the management of bleeding complications in patients treated with DOACs.
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