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Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort.

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

SUBMITTER: Junger ST

PROVIDER: S-EPMC6857225 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort.

Jünger Stephanie T ST Mynarek Martin M Wohlers Inken I Dörner Evelyn E Mühlen Anja Zur AZ Velez-Char Natalia N von Hoff Katja K Rutkowski Stefan S Warmuth-Metz Monika M Kortmann Rolf-Dieter RD Timmermann Beate B Rahmann Sven S Klein-Hitpass Ludger L von Bueren Andre O AO Pietsch Torsten T

Acta neuropathologica communications 20191114 1

<h4>Introduction</h4>Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols.<h4>Methods</h4>Tumor samples of 134 patients aged 0.2-15.9 years treated between 1999 and 2010 ...[more]

PMID: 31727173

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Project description:BackgroundPosterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long-term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years.MethodsDemographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome-wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3).ResultsA total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042).ConclusionsData from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.

Dataset Information

Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort.

Publications

Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features - a retrospective analysis of the HIT ependymoma trial cohort.

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