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Background: Despite known clinical and genetic risk factors, predicting anthracycline cardiotoxicity remains challenging. Objective: To develop a risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. Methods: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 cases with LV ejection fraction (LVEF) ≤55% despite low-dose doxorubicin (DOX) (≤250 mg/m2), and 106 controls with LVEF >55% despite DOX >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between cases and controls. The top-ranked genes were functionally evaluated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. Results: Thirty-one genes were differentially enriched for variants between cases and controls (p-15 ] suggesting that absence of these variants may predispose to cardiotoxicity. A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical model. In vitro inhibition of gene-associated pathways ( PI3KR2, ZNF827 ) provided protection from cardiotoxicity in CMs. Conclusions: Our study identified variants that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and also provided new targets in autophagy genes for development of cardio-protective drugs.

BACKGROUND The prevalence and severity of Clostridium difficile infection (CDI) has increased over time in adult patients, but little is known about CDI in pediatric cancer. The primary objectives were to describe the incidence and characteristics of CDI in children with de novo acute myeloid leukemia (AML). The secondary objective was to describe factors associated with CDI. METHOD We performed a multicenter, retrospective cohort study of children with de novo AML and evaluated CDI. Recurrence, sepsis and infection-related death were examined. Factors associated with CDI were also evaluated. RESULTS Forty-three CDI occurred in 37 of 341 (10.9%) patients during 42 of 1277 (3.3%) courses of chemotherapy. There were 6 children with multiple episodes of CDI. Three infections were associated with sepsis, and no children died of CDI. Only 2 children had an associated enterocolitis. Both days of broad-spectrum antibiotics (odds ratio 1.03, 95% confidence interval: 1.01 to 1.06; P = 0.003) and at least 1 microbiologically documented sterile site infection (odds ratio 10.81, 95% confidence interval: 5.88 to 19.89; P < 0.0001) were independently associated with CDI. CONCLUSIONS CDI occurred in 11% of children receiving intensive chemotherapy for AML, and outcomes were not severe. CDI is not a prominent issue in pediatric AML in terms of prevalence, incidence or associated outcomes.

Methadone is effective in the treatment of cancer-related pain in adults. Pediatric oncologists may be reluctant to use methadone, given the paucity of existing research and a lack of familiarity with its use. This study's purpose was to assess pediatric oncologists' experience, comfort and practice of methadone prescription, and determine interest in and appropriate venues for education on methadone. A 22-item survey was sent by electronic mail to 1912 practicing pediatric oncologists. Six hundred thirty-one pediatric oncologists (33%) responded to the survey. Seventy-two percent of respondents reported they prescribe methadone to10% of their patients receiving opioids. Physicians practicing ≥10 years (84% vs. 76%, P=0.01), at centers that see ≥100 new patients per year (86% vs. 76%, P=0.003), or who have received prior education on methadone (89% vs. 54%, P0.001) were more likely to have prescribed methadone. The primary reasons respondents did not utilize methadone included a lack of knowledge of methadone's pharmacodynamics (39%), effectiveness (39%), and/or dosing equivalence (34%). Perceived competence with dose equivalence, belief that methadone is effective, and working in a division where20 patients per year died were all independently associated with having prescribed methadone to10% of patients on opioids. Eighty-five percent of respondents would like additional education on methadone. Many pediatric oncologists lack experience and education in the use of methadone. Formal education initiatives should be implemented to enhance pediatric oncologists' comfort and expertise in methadone use.