Summary The eradication of Helicobacter pylori often leads to platelet recovery in patients with chronic idiopathic thrombocytopenic purpura (cITP). Although this clinical observation suggests the involvement of H. pylori, little is known about the pathogenesis of cITP. We initially examined the effect of H. pylori eradication on platelet counts in 20 adult Japanese cITP patients. Then, using platelet eluates as the probe in immunoblot analyses, we examined the role of molecular mimicry in the pathogenesis of cITP. Helicobacter pylori infection was detected in 75% (15 of 20) of cITP patients. Eradication was achieved in 13 (87%) of the H. pylori‐positive patients, seven (54%) of which showed increased platelet counts within the 4 months following treatment. Completely responsive patients also showed significant declines in platelet‐associated immunoglobulin G (PAIgG) levels. Platelet eluates from 12 (nine H. pylori‐positive and three H. pylori‐negative) patients recognized H. pylori cytotoxin‐associated gene A (CagA) protein, and in three completely responsive patients, levels of anti‐CagA antibody in platelet eluates declined after eradication therapy. Cross‐reactivity between PAIgG and H. pylori CagA protein suggests that molecular mimicry by CagA plays a key role in the pathogenesis of a subset of cITP patients.

Although voriconazole has been shown to interact with calcineurin inhibitors, this interaction has not been thoroughly examined. The purpose of this study was to evaluate the drug interaction between voriconazole and calcineurin inhibitors among recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-one recipients of allogeneic HSCT were evaluated. Those recipients had been on CsA (n ¼ 10) or tacrolimus (n ¼ 11) when voriconazole (400 mg per day orally, or 8 mg/kg per day, i.v.) was initiated. Trough concentrations of calcineurin inhibitors were measured before and periodically after initiating voriconazole to determine the concentration/dose (C/D) ratio of calcineurin inhibitors. Median C/D ratio significantly increased by initiating voriconazole: from 86.0 (range, 43.5-178.8) to 120.2 (range, 86.1-379.4) in CsA (Po0.05), and from 595.9 (range, 51.3-1643.3) to 890.7 (range, 94.1-4658.3) (ng/ml)/(mg/kg) in tacrolimus (Po0.01). Median increases in the C/D ratio did not differ significantly between CsA and tacrolimus (82.1%, ranging from À9.4 to 266.9% vs 115.6%, ranging from 25.4 to 307.6%). These results indicate that voriconazole alters the blood concentration of calcineurin inhibitors with a wide range of interindividual variability after allogeneic HSCT. Dose adjustment of calcineurin inhibitors on initiating voriconazole should not be decided uniformly, but determined on an individual basis by close monitoring of their blood concentrations.

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA; 15-39 years old, n = 193) and adults (40-64 years old, n = 161) with Philadelphia chromosome-negative B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with two novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified two novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.

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The clinical impact of KIT mutations in core binding factor acute myeloid leukemia (CBF-AML) is still unclear. In the present study, we analyzed the prognostic significance of each KIT mutation (D816, N822K, and other mutations) in Japanese patients with CBF-AML. We retrospectively analyzed 136 cases of CBF-AML that had gone into complete remission (CR). KIT mutations were found in 61 (45%) of the patients with CBF-AML. D816, N822K, D816 and N822K, and other mutations of the KIT gene were detected in 29 cases (21%), 20 cases (15%), 7 cases (5%), and 5 cases (4%), respectively. The rate of relapse-free survival (RFS) and overall survival (OS) in patients with D816 and with both D816 and N822K mutations was significantly lower than in patients with other or with no KIT mutations (RFS: p < 0.001, OS: p < 0.001). Moreover, stratified analysis of the chromosomal abnormalities t(8;21)(q22;q22) and inv(16)(p13.1q22), t(16;16)(p13.1;q22) showed that D816 mutation was associated with a significantly worse prognosis. In a further multivariate analysis of RFS and OS, D816 mutation was found to be an independent risk factor for significantly poorer prognosis. In the present study, we were able to establish that, of all KIT mutations, D816 mutation alone is an unfavorable prognostic factor.