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Background Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. Objectives This study sought to develop a clinical and genetic 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 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m2), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell–derived cardiomyocytes, 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 case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10–15). 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-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. Conclusions Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778), Central Illustration

Wingless-activated (WNT) medulloblastoma have been identified over the past decade as being a candidate for therapy de-escalation based on their excellent survival, however a paucity of relapses in any single cohort have precluded any additional analysis of markers of relapse. To address this gap in knowledge, an international cohort of 91 WNT-MB was assembled where we identified 14 relapsed cases where five-year progression free survival was 0.84 (95% 0.763-0.925). Maintenance chemotherapy was identified as a strong predictor of relapse, where no relapses were observed in cases receiving high doses of cyclophosphamide or ifosphamide (p=0.0026). The location of relapse was metastatic in 10/14 of relapses, with 7/10 metastatic relapses presenting along the ependymal lining in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide dose is a significant predictor of relapse across WNT-MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen, and the propensity to metastatic relapses.

Background The objective was to compare 5-year overall survival (OS) between adolescent and young adult (AYA) patients (age 15–19) with acute lymphoblastic leukemia (ALL) treated at a pediatric versus an adult center. Patients and methods This was a population-based analysis using administrative data of Ontario ALL AYA patients diagnosed between 1986–2009. We calculated predicted survival proportions (PSPs) and 95% confidence intervals (CI). We also surveyed sites to determine whether pediatric or adult-based protocols were used in each period. Results Overall, 290 patients between 15–19 years of age were diagnosed with ALL during the study period; 144 patients (49.7%) were treated at an adult center. When adjusted for gender, age, income quintile and time period, AYA patients treated at a pediatric center did not have a significantly different PSP (0.65, 95% CI: 0.56–0.75) in comparison to those treated at an adult center (0.62, 95% CI 0.52–0.73; P = 0.87). Most AYA patients treated at adult centers received pediatric protocols in the recent periods. Conclusions Using population-based data, AYA ALL patients had similar outcomes whether treated at a pediatric or an adult center. Early introduction of aggressive treatment protocols in adult centers may have negated differences in outcomes among AYA patients by site of care.

Background Vocal cord dysfunction (VCD) can present with signs and symptoms that mimic asthma. This may lead to unnecessary pharmacologic treatment or more invasive measures including intubation. Presently, the diagnosis of VCD can only be confirmed when a patient is symptomatic, via pulmonary function testing (PFT) or visualization of adduction of the vocal cords during inspiration by direct laryngoscopy. Objective Multidimensional Voice Program (MDVP) analysis, a computer program which analyzes various aspects of voice, can detect abnormal voice patterns of patients with upper airway pathology. We determined whether MDVP analysis was useful in the diagnosis of VCD. Methods We conducted chart reviews of patients referred to our department from 1995 to 1998 with the presumed diagnosis of VCD who had undergone MDVP analysis. The diagnosis of VCD was based on the presenting history, PFT results, laryngoscopy results, as well as voice evaluation conducted by a speech-language pathologist. We analyzed six consecutive patients referred for this investigation. We delineated common trends in the variables measured on MDVP analysis in VCD patients, and compared these with controls and other vocal cord pathology. Results Five cases of possible VCD had abnormalities in the MDVP variable of soft phonation index (SPI). All five also had abnormalities in the variation in fundamental frequency (vFo). In one case, MDVP analysis was conducted pre- and posttreatment for VCD, and SPI and vFo both normalized. In a sixth case of possible VCD, the diagnosis was not confirmed as the patient had normal PFTs and laryngoscopy. MDVP analysis was normal in this individual. The pattern of abnormal SPI and vFo was not seen in a group of normal controls or in patients with vocal cord nodules. Conclusions MDVP analysis may be a useful tool when diagnosingVCD, as well as in evaluating response to treatment.

We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged ≤18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments.