Histone deacetylase inhibitors (HDACi) are an emerging cancer therapy; however, their effect on natural killer (NK) cell-mediated anti-tumor responses remain unknown. Here, we evaluated the impact of a benzamide HDACi, entinostat, on human primary NK cells as well as tumor cell lines. Entinostat significantly upregulated the expression of NKG2D, an essential NK cell activating receptor. Independently, entinostat augmented the expression of ULBP1, HLA, and MICA/B on both rhabdomyosarcoma and Ewing sarcoma cell lines. Additionally, entinostat increased both cytotoxicity and IFN-γ production in human NK cells following coculture with these tumor cells. Mechanistically, entinostat treatment resulted in increased chromatin accessibility to the promoter region for interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) gene and thereby increasing the transcript and protein levels of IFIT1 that augmented the IFIT1-mediated IRF1, STAT4, and STING pathways. Corresponding transcriptome analysis revealed enrichment of IRF1 and STAT4 and gene sets responsible for NK cell-mediated IFN-γ production and cytotoxicity, respectively. Our results show a novel mechanism by which entinostat initiates an IFIT1-STINGmediated potentiation of STAT4 via IRF1 to augment NK cell-mediated anti-tumor responses.

Prophylactic administration of fluconazole to all ELBW infants was associated with significantly decreased rates of IFI without associated adverse effects.

Anthracycline induced cardiotoxicity remains a significant contributor to late morbidity/mortality in children and young adults with acute myeloid leukemia (AML). The cardioprotectant dexrazoxane can be used as prophylaxis to diminish risk for cardiomyopathy but whether it affects risk of relapse in pediatric AML is unclear. Our institution adopted the use of dexrazoxane prior to anthracyclines administration for all oncology patients in 2011. We compared patients with AML (ages 0 to 21 years) who received or did not receive dexrazoxane during the years 2008 to 2013. Forty-four patients with AML (ages 4.5 months to 21.7 years) were included. We identified no statistical difference in 2-year event rate (62% vs. 50%, p=0.41) or 2-year overall survival (OS) (69% vs. 69%, p=0.53) between patients receiving (n=28) or not receiving (n=16) dexrazoxane. Ejection fraction (p=0.0262) and shortening fraction (p=0.0381) trended significantly higher in patients that received dexrazoxane compared to those that did not receive dexrazoxane. Utilization of the cardioprotectant dexrazoxane prior to anthracycline chemotherapy in pediatric patients with AML demonstrated no significant difference in either event rate or OS relative to institutional controls and appears to improve cardiac function indices. Further studies in this patient population are needed to confirm these findings.

Enoxaparin can be used to reach recommended target range of anti-factor Xa concentrations in the PICU patient. However, younger patients and patients with higher illness severity are less likely to achieve target concentrations using currently recommended dosing and may require higher doses of enoxaparin to reach target anti-factor Xa concentrations. Starting enoxaparin dose at least 1.3 mg/kg dosed every 12 hours for treatment of thromboembolic disease in critically ill patients aged 61 days to 1 year or those requiring inotropic support should be confirmed in prospective study.