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Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure. Methods: DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs). Results: One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426). Conclusion: Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (pNF) can be debilitating and until recently, surgery was the only potentially effective therapy for these tumors. Methods: We review critical steps in the path towards the FDA approval of the first medical therapy for NF1 pNF and the current status of MEK inhbitor therapy. Results: Sustained efforts by the NF community have resulted in a detailed understanding of the natural history and biology of NF1-related peripheral nerve sheath tumors. This work provided the basis for the development of meaningful clinical trials targeting pNF. Inhibition of the RAS/MAPK signaling pathway with MEK inhibitors identified the first medical therapy which resulted in shrinkage in the majority of children with NF1 and large inoperable pNF. Based on this finding and subsequent demonstration of clinical benefit, the MEK inhibitor selumetinib recently received approval by the United States Food and Drug Administration (FDA) for children with symptomatic pNF. Conclusions: Sustained efforts and collaborations have resulted in identification of MEK inhibitors as effective therapy for NF1 pNF. Future work work will be directed at prevention of pNF morbidity and deepening the reponse in symptomatic pNF. [ABSTRACT FROM AUTHOR]