Obesity in children with acute promyelocytic leukemia: What is its prevalence and prognostic significance?

OBJECTIVE: To compare outcomes of obese and nonobese pediatric patients with acute promyelocytic leukemia (APL) from the Cancer and Leukemia Group B trial (CALGB) 9710 and the Children's Oncology Group trial AAML0631. METHODS: Data including demographics, adverse events, overall and event-free survival (EFS) were analyzed. RESULTS: The prevalence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall and EFS in the obese population on multivariable analysis on AAML0631 but not on CALGB 9710. Eleven patients died during therapy or in follow-up. CONCLUSION: The prevalence of obesity is higher in pediatric patients with APL compared to the general population. The decreased EFS and OS in obese patients on AAML0631 suggest that the presence of obesity can influence outcomes using the most current treatment. These findings support the need for further research on the potential role of obesity in pediatric APL leukemogenesis.

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma.

PURPOSE: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.Experimental Design: We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts. RESULTS: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy. CONCLUSIONS: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.