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Objective To 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. Design Prospective, randomised, multicentre, non-inferiority trial. Setting Patients with STEMI treated with primary percutaneous coronary intervention (PCI) and second generation zotarolimus-eluting stent. Participants Patients 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. Interventions Patients 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 measures The 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. Results A 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. Conclusions DAPT 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 registration Clinicaltrials.gov NCT01459627.

Zusammenfassung: Stent-Thrombosen (ST) stellen eine schwerwiegende Komplikation der perkutanen Behandlung der koronaren Herzkrankheit dar und sind mit einer hohen Sterblichkeitsrate von bis zu 45% verbunden. Bare-Metal-Stents (BMS) und Drug-Eluting-Stents (DES) haben eine ähnliche Inzidenz für frühe (0,6-1,2%) und späte (0,3-0,4%) ST. Sehr späte ST (über 1Jahr nach Stent-Implantation) weisen einen unabhängigen pathogenetischen Mechanismus auf und werden fast ausschließlich nach der Implantation von DES der 1. Generation mit einer Rate von 0,6% Ereignissen/Jahr beobachtet. Starke Determinanten für das Auftreten früher und später ST sind eine unzureichende Thrombozytenaggregationshemmertherapie, ein akutes Koronarsyndrom, Auftreten von Komplikationen während des Eingriffs, das unmittelbare postprozedurale Resultat sowie Begleiterkrankungen des Patienten. Sehr späte ST haben eine eigenständige Pathogenese - eine direkt medikamentös bedingte Hemmung der Reendothelialisierung und eine durch das Medikament oder das Polymer des Stent verursachte chronische Entzündung der Gefäßwand mit in der Folge gestörter Reendothelialisierung, welche zu einem positivem Remodelling der Arterienwand mit sekundärer Malapposition des Stent führt. In der Prävention der ST spielt die duale Thrombozytenaggregationshemmertherapie eine zentrale Rolle. Das vorzeitige Absetzen dieser Therapie in den ersten 6Monaten nach Stent-Implantation führt zu einer erhöhten Inzidenz von ST. Zur Prävention gehört auch der Fortschritt. Erfreulicherweise haben die Verwendung von DES der 2. Generation und neue Thrombozytenaggregationshemmertherapien die Inzidenz der ST signifikant verringert

The genomic landscape of children with acute myeloid leukemia (AML) who do not carry any cytogenetic abnormality (CN-AML) is particularly heterogeneous and challenging, being characterized by different clinical outcomes. To provide new genetic insights into this AML subset, we analyzed through RNA-seq 13 pediatric CN-AML cases, corroborating our findings in an independent cohort of 168 AML patients enrolled in the AIEOP AML 2002/01 study. We identified a chimeric transcript involving NUP98 and PHF23, resulting from a cryptic t(11;17)(p15;p13) translocation, demonstrating, for the first time, that NUP98-PHF23 is a novel recurrent (2.6 %) abnormality in pediatric CN-AML.

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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%). BiCEBPa 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.

The genomic landscape of children with acute myeloid leukemia (AML) who do not carry any cytogenetic abnormality (CN-AML) is particularly heterogeneous and challenging, being characterized by different clinical outcomes. To provide new genetic insights into this AML subset, we analyzed through RNA-seq 13 pediatric CN-AML cases, corroborating our findings in an independent cohort of 168 AML patients enrolled in the AIEOP AML 2002/01 study. We identified a chimeric transcript involving NUP98 and PHF23, resulting from a cryptic t(11;17)(p15;p13) translocation, demonstrating, for the first time, that NUP98-PHF23 is a novel recurrent (2.6 %) abnormality in pediatric CN-AML.