Introduction: Risk stratification of children with ependymomas of the posterior fossa in current therapeutic\nprotocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease\nentity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of\npatients treated according to the German HIT protocols.\nMethods: Tumor samples of 134 patients aged 0.2â??15.9 years treated between 1999 and 2010 according to HIT\nprotocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and\ngenomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier\nmethod with log rank test and multivariate Cox regression analysis.\nResults: Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as\npredictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features\nincluding vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox\nregression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS\nand OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that\nseparates patients with standard, intermediate and high risk, and which outperforms current stratification procedures.\nConclusion: The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification\nmodel for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide\nthe basis for risk-adapted treatment of children with ependymomas of the posterior fossa.
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