• The CBFA2T3-GLIS2 fusion transcript is common in pediatric cytogenetically normal AML and not restricted to FAB M7 subtype.• The CBFA2T3-GLIS2 fusion transcript is associated with poor prognosis in pediatric patients with AML.Pediatric cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous subgroup of myeloid clonal disorders that do not harbor known mutations. To investigate the mutation spectrum of pediatric CN-AML, we performed whole-transcriptome massively parallel sequencing on blasts from 7 CN-AML pediatric patients. In 3 patients we identified a recurrent cryptic inversion of chromosome 16, encoding a CBFA2T3-GLIS2 fusion transcript. In a validation cohort of 230 pediatric CN-AML samples we identified 17 new cases. Among a total of 20 patients with CBFA2T3-GLIS2 fusion transcript out of 237 investigated (8.4%), 10 patients (50%) did not belong to the French-American-British (FAB) M7 subgroup. The 5-year event-free survival for these 20 children was worse than that for the other CN-AML patients (27.4% vs 59.6%; P 5 .01). These data suggest that the presence of CBFA2T3-GLIS2 fusion transcript is a novel common feature of pediatric CN-AML, not restricted to the FAB M7 subtype, predicting poorer outcome. (Blood. 2013;121(17):3469-3472) IntroductionPediatric acute myeloid leukemia (AML) is a molecularly heterogeneous disease that arises from genetic alterations of pathways that regulate self-renewal and myeloid differentiation. While the majority of patients carry recurrent chromosomal translocations, almost 20% of childhood AMLs do not show any recognizable cytogenetic alteration and are defined as cytogenetically normal AML (CN-AML). 1Many genetic abnormalities have been identified in AML with normal karyotype, with the most frequent affecting genes such as NPM1, FLT3, CEBPA, and WT1. 1-5Genome-wide analyses have been used with the aim of determining the full array of genetic lesions of CN-AML. Recent studies have provided new insight into the molecular genetics and biology of AML, confirming both the complexity and the heterogeneity of this disease.6 Novel lesions such as mutations in IDH1 and DNMT3A have been identified. 7,8 However, these alterations are rare in pediatric AML, with IDH1/IDH2 accounting for 2% to 4% of cases 9,10 and DNMT3A not even being found mutated in childhood AML.11 Recently, 2 studies identified a novel recurrent translocation involving CBFA2T3 and GLIS2 in about 30% of children with non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, AML French-American-British [FAB] M7).12,13 Nevertheless, there are many children with CN-AML in whom no genetic abnormality has been detected. The identification of the different genetic profiles characterizing this subgroup is a primary objective to be pursued. To this end, we performed whole-transcriptome massively parallel sequencing of 7 cases of pediatric CN-AML with the aim of identifying recurrent somatic mutations or genomic rearrangements. Subsequently, we validated our findings in a larger cohort of 230 pedi...

ObjectiveTo show that limiting dual antiplatelet therapy (DAPT) to six months in patients with event-free ST-elevation myocardial infarction (STEMI) results in a non-inferior clinical outcome versus DAPT for 12 months.DesignProspective, randomised, multicentre, non-inferiority trial.SettingPatients with STEMI treated with primary percutaneous coronary intervention (PCI) and second generation zotarolimus-eluting stent.ParticipantsPatients with STEMI aged 18 to 85 that underwent a primary PCI with the implantation of second generation drug-eluting stents were enrolled in the trial. Patients that were event-free at six months after primary PCI were randomised at this time point.InterventionsPatients that were taking DAPT and were event-free at six months were randomised 1:1 to single antiplatelet therapy (SAPT) (ie, aspirin only) or to DAPT for an additional six months. All patients that were randomised were then followed for another 18 months (ie, 24 months after the primary PCI).Main outcome measuresThe primary endpoint was a composite of all cause mortality, any myocardial infarction, any revascularisation, stroke, and thrombolysis in myocardial infarction major bleeding at 18 months after randomisation.ResultsA total of 1100 patients were enrolled in the trial between 19 December 2011 and 30 June 2015. 870 were randomised: 432 to SAPT versus 438 to DAPT. The primary endpoint occurred in 4.8% of patients receiving SAPT versus 6.6% of patients receiving DAPT (hazard ratio 0.73, 95% confidence interval 0.41 to 1.27, P=0.26). Non-inferiority was met (P=0.004 for non-inferiority), as the upper 95% confidence interval of 1.27 was smaller than the prespecified non-inferiority margin of 1.66.ConclusionsDAPT to six months was non-inferior to DAPT for 12 months in patients with event-free STEMI at six months after primary PCI with second generation drug-eluting stents.Trial registrationClinicaltrials.gov NCT01459627.

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Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (<1%) present at diagnosis and undergoing expansion (60%) at relapse. Taken together, these findings provide molecular clues for designing optimal therapeutic strategies, in terms of target selection, adequate schedule design and reliable response-monitoring techniques.