ETV6::RUNX1 positive pediatric acute lymphoblastic leukemia frequently has a prenatal origin and follows a two-hit model: a first somatic alteration leads to the formation of the oncogenic fusion gene ETV6::RUNX1 and the generation of a preleukemic clone in utero. Secondary hits after birth are necessary to convert the preleukemic clone into clinically overt leukemia. However, prenatal factors triggering the first hit are still not determined. Here, we explore the influence of maternal factors during pregnancy on the prevalence of the ETV6::RUNX1 fusion. To this end, we employed a nested interventional cohort study ( IMPACT-BCN trial), including 1221 pregnancies (randomized into usual care, Mediterranean diet, or mindfulness-based stress reduction) and determined the prevalence of the fusion gene in DNA of cord blood samples at delivery (n=741) using the state-of-the-art GIPFEL ( genomic inverse PCR for exploration of ligated breakpoints) technique. 6.5% (n=48 of 741) of healthy newborns tested positive for ETV6::RUNX1. Our multiple regression analyses showed a trend towards lower ETV6::RUNX1 prevalence in offspring of the high-adherence intervention groups. Strikingly, corticosteroid use for lung maturation during pregnancy was significantly associated with ETV6::RUNX1 (adjusted OR 3.9, 95%CI 1.6-9.8) in 39 neonates, in particular if applied before 26 weeks of gestation (OR 7.7, 95%CI 1.08-50) or if betamethasone (OR 4.0, 95%CI 1.4-11.3) was used. Prenatal exposure to corticosteroids within a critical time window may therefore increase the risk to develop ETV6::RUNX1+ preleukemic clones and potentially leukemia after birth. Taken together, this study indicates that ETV6::RUNX1 preleukemia prevalence may be modulated and potentially prevented.

Background: Radiofrequency(RF) ablation of premature ventricular complexes(PVCs) is a well-established treatment for patients high PVCs burden, even when arising from epicardial/intramural localization. Consistent data about safety of using high power RF is lacking in literature in these regions. Aim: The aim of this study is to investigate safety of different RF power settings, efficacy and outcome of non-endocardial PVCs ablation. Methods: Consecutive patients who underwent PVC ablation were included (2017-2023). We defined “Non-Endocardial Radiofrequency Ablation”(NERA) a procedure in which at least one ablation site has been identified into the cardiac venous system, aortic cusps, inter-leaflet region or pulmonary cusps. Results: Total number of NERA sites was 64 in 53 procedures. In 63% of the procedures, high power (≥40W) and in 60% long duration (≥60 seconds) RF was delivered in at least one site (mean power:37±9W(15-50), mean duration of single RF 88±65 seconds (30-304)). In 21% of the procedures, a combination of both high power and long duration RF applications was performed. Procedural success was achieved in 47 procedures(84%). Only one severe complication (pericardial bleeding) was observed. In 22(39%) procedures, multisite ablation was performed which was associated with procedural failure (OR 7,47;p=0,01). During follow-up, mean and median PVC burden reduction were 69±41% and 96% respectively. Multisite ablation and coronary venous system RF were predictors of recurrence (HR 3.6;p=0.026 and HR 3.85;p=0.014). Conclusion: Ablation from non-endocardial sites is a safe and effective procedure, even using high power and/or long duration RF with clear benefit in terms of PVC burden reduction.