SUMMARY Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated based on anatomical location – supratentorial region (ST) or posterior fossa (PF) – and further divided into distinct molecular subgroups that reflect differences in age of onset, gender predominance, and response to therapy1–3. The most common and aggressive subgroup, Posterior Fossa Ependymoma Group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, Posterior Fossa Ependymoma Group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses yet favourable clinical outcomes1,3. Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1).1,3,4 Subependymomas, a distinct histologic variant, can also be found within the ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively1. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts with the goal of identifying essential super enhancer associated genes on which tumour cells were dependent. Enhancer regions revealed putative oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, diminished proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.
Background: Earlier diagnosis of chylothorax following pediatric cardiac surgery is associated with decreased duration of chylothorax. Pleural uid testing is used to diagnosis chylothorax which may delay detection in patients who are not enterally fed at time of chylothorax onset. Our aim was to develop and externally validate a prediction model to detect chylothorax earlier than pleural uid testing in pediatric patients following cardiac surgery.Methods: A Multivariable logistic regression model was developed to detect chylothorax using a stepwise approach. The model was developed using data from patients <18 years following cardiac surgery from Primary Children's Hospital, a tertiary-care academic center, between 2017 and 2020. External validation used a contemporary cohort (n=171) from Lucille Packard Children's Hospital.Results: A total of 763 encounters (735 patients) were analyzed, of which 72 had chylothorax. The nal variables selected were chest tube output (CTO) the day after sternal closure (dichotomized at 15.6 mL/kg/day, and as a continuous variable) and delayed sternal closure. The highest odds of chylothorax was associated with CTO on post sternal closure day 1 >15.6mL/kg/day (odds ratio 11.3, 95% CI 6,3, 21.3). The c-statistic for the internal and external validation datasets using the dichotomized CTO variable were 0.78 (95% CI:0.73, 0.82) and 0.84 (95% CI, 0.78, 0.9) and performance improved when using CTO as a continuous variable (OR 0.84, CI: 95% CI 0.80, 0.87) Conclusions: Using the models described, chylothorax after pediatric cardiac surgery may be detected earlier and without reliance on enteral feeds.
Introduction: The success of quality improvement (QI) projects depends on many factors, with communication and knowledge of project-specific practice change being fundamental. This project aimed to improve the knowledge of active safety and QI projects. Methods: Two interventions were trialed to improve knowledge: paired email and meeting announcements followed by a daily huddle to review ongoing projects. Knowledge, measured as the ability to recall a project and its practice change, was the primary outcome. The frequency and duration of the Huddle were process and balancing measures, respectively. Results: Seven days after a meeting/email announcement, 3 of 13 (23%) faculty and fellows recalled the announced practice change. Investigators then tested the effects of the Huddle by assessing practitioners’ knowledge of safety and QI project-related practice changes on the first and last day of a service week. The average percentage of items recalled increased from the beginning to end of a service week by 33% [46% to 79%, 95% confidence interval (CI) 12–53] for faculty and 27% (51% to 77%, 95% CI 13–40) for fellows. The Huddle occurred in four of seven (interquartile range 2–5) days/wk with a mean duration of 4.5 (SD 2) minutes. Follow-up assessment 2 years after Huddle implementation demonstrate sustained increase in item recall [faculty +36% (95% CI +13% to 40%); fellows +35% (95% CI +23% to 47%)]. Conclusions: A daily huddle to discuss safety and QI project-related practice change is an effective and time-efficient communication method to increase knowledge of active projects.
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