to profile 800 human miRNAs in each sample. Univariate (UVA) and multivariate (MVA) Cox regression analyses were performed using progression-free survival (PFS) and overall survival (OS) as clinical endpoints. Results: In our UVA, we identified 10 miRNAs that were significantly associated with PFS (P value < 0.05), however, no miRNAs had a false discover rate (FDR) P value < 0.2. Thirty-nine miRNAs were significantly predictive of OS (P value < 0.05) and 9 had a FDR P value < 0.2. Upon MVA, adjusting for age, grade, and IDH status, 8 miRNAs were found to be significant predictors of progression (P value < 0.05) and 25 miRNAs were significantly predictive of OS (P value < 0.05). FDR P values < 0.2 were not observed in the MVAs. Conclusion: These results provide valuable information that may aid in the development of new and improved classification systems for lower grade glioma, thus changing clinical practice. Additionally, the identification of novel prognostic molecular biomarkers may provide insight to potential therapeutic strategies combating disease progression. Future work will focus on validating these miRNAs in additional glioma cohorts and in preclinical models as well as identifying molecular biomarkers predictive of treatment response.

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Materials/Methods: Between 2008 and 2011, 53 patients with primary brain malignancies were treated with conventionally fractionated RT on a prospectively accrued clinical trial performed at our institution (WFU97100/91105). Tumor types included glioblastoma (13%), primitive neuroectodermal tumors (21%), and low grade/benign tumors (66%).Ten patients received whole brain RT with region boost, all other patients received partial brain RT. The median radiation dose was 54.0 Gy (range Z 40.0-60.6 Gy) delivered in 1.8 Gy/fraction (range Z 1.5-2.5 Gy/fraction). Dose-volume histogram analysis was performed for the hippocampus, parahippocampus, amygdala, and fusiform gyrus. Hopkins Verbal Learning Test-Revised (HVLT-R) scores were obtained at least 6 months after RT. Impairment was defined as a HVLT-R immediate recall score 15, based upon studies reporting optimal sensitivity and specificity for detecting impairment using HVLT-R cut-off scores of 14.5-15.5. For each anatomic region, serial regression was performed to correlate volume receiving a given dose (V D(Gy) ) with memory impairment. Results: Hippocampal V 53.4Gy -V 60.9Gy significantly predicted post-RT memory impairment (P < 0.05). Within this range, the hippocampal V 55Gy was the most significant predictor (P Z 0.004). Hippocampal V 55Gy of 0%, 25%, and 50% were associated with post-RT impairment rates of 14.9% (95% CI Z 7.2% -28.7%), 45.9% (95% CI Z 24.7% -68.6%), and 80.6% (95% CI Z 39.2% -96.4%), respectively. Dose received by the fusiform gyrus was a significant predictor of impairment, with the most significant relationship at V 46.5Gy (P Z 0.003). No statistically significant relationship was observed for the amygdala or parahippocampus. Conclusion: Injury to the hippocampus plays a fundamental role in CRCI. This analysis provides dosimetric guidelines to limit cognitive decline after cranial RT. The hippocampal V 55Gy is a significant predictor for impairment and limiting dose below 55 Gy may minimize treatment related neuro-cognitive toxicity.