A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups

BackgroundRelapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach.Methods and materialsWe analyzed 302 pediatric ependymoma cases. Tumor, demographic, and treatment variables were investigated for association with relapse risk, time to recurrence, and survival after relapse. DNA methylation profiling was performed for 135/302 cases, and predominant subgroups were EPN_PFA (n = 95) and EPN_RELA (n = 24). Chromosome 1q status was ascertained for 185/302 cases by fluorescent in‐situ hybridization (FISH), multiplex ligation‐dependent probe amplification (MLPA), and DNA methylation profiles. ResultsSixty‐two percent of cases relapsed, with a median of two recurrences with no difference between posterior fossa and supratentorial locations (66% vs 55% relapse rate). One hundred seventeen (38%) cases relapsed within two years and five (2%) beyond 10 years. The late relapses were clinically heterogeneous. Tumor grade and treatment affected risk and time to relapse variably across subgroups. After relapse, surgery and irradiation delayed disease progression with a minimal impact on survival across the entire cohort. In the EPN_PFA and EPN_RELA groups, 1q gain was independently associated with relapse risk (subhazard ratio [SHR] 4.307, P = 0.027 and SHR 1.982, P = 0.010, respectively) while EPN_PFA had increased relapse risk compared with EPN_RELA (SHR = 0.394, P = 0.018). ConclusionsRecurrent pediatric ependymoma is an aggressive disease with poor outcomes, for which current treatments are inadequate. We report that chromosome 1q gain increases relapse risk in common molecular subgroups in children but a deeper understanding of the underlying biology at relapse and novel therapeutic approaches are urgently needed

A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: safety, efficacy, visual morbidity, and outcomes

BACKGROUND: Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort "real life" safety and efficacy data including functional visual outcomes. METHODS: Children receiving bevacizumab-based treatments (BBT) for PLGG (2009-2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical-radiological correlation, survival outcomes and multivariate prognostic analysis. RESULTS: Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients' best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients' worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses. CONCLUSIONS: BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG

ICAR: endoscopic skull‐base surgery

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OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms.

The bHLH transcription factor, OLIG2, is universally expressed in adult human gliomas and, as a major factor in the development of oligodendrocytes, is expressed at the highest levels in low-grade oligodendroglial tumors. In addition, it is functionally required for the formation of high-grade astrocytomas in a genetically relevant murine model. The pediatric gliomas have genomic profiles that are different from the corresponding adult tumors and accordingly, the expression of OLIG2 in non-oligodendroglial pediatric gliomas is not well documented within specific tumor types. In the current study, the pattern of OLIG2 expression in a spectrum of 90 non-oligodendroglial pediatric gliomas varied from very low levels in the ependymomas (cellular and tanycytic) to high levels in pilocytic astrocytoma, and in the diffuse-type astrocytic tumors (WHO grades II-IV). With dual-labeling, glioblastoma had the highest percentage of OLIG2 expressing cells that were also Ki-67 positive (mean = 16.3%) whereas pilocytic astrocytoma WHO grade I and astrocytoma WHO grade II had the lowest (0.9 and 1%, respectively); most of the Ki-67 positive cells in the diffuse-type astrocytomas (WHO grade II-III) were also OLIG2 positive (92-94%). In contrast to the various types of pediatric astrocytic tumors, all ependymomas WHO grade II, regardless of site of origin, showed at most minimal OLIG2 expression, suggesting that OLIG2 function in pediatric gliomas is cell lineage dependent

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors

Histone Deacetylase Inhibition Attenuates Cell Growth with Associated Telomerase Inhibition in High-Grade Childhood Brain Tumor Cells

Aberrant epigenetic regulation of gene expression contributes to tumor initiation and progression. Studies from a plethora of hematologic and solid tumors support the use of histone deacetylase inhibitors (HDACi) as potent anticancer agents. However, the mechanism of HDACi action with respect to the temporal order of induced cellular events is unclear. The present study investigates the anticancer effects of the HDACi trichostatin A in high-grade childhood brain tumor cells. Acute exposure to trichostatin A resulted in marked inhibition of cell proliferation, an increase in the proportion of G(2)-M cells, activation of H2A.X, and subsequent induction of apoptosis in the majority of cell lines. These phenotypic effects were associated with abrogation of telomerase activity and human telomerase reverse transcriptase downregulation in the majority of cell lines. In contrast, no cytotoxicity was observed in primary ependymal cells with respect to cilia function. Thus, inhibition of histone deacetylases leads to antiproliferative and proapoptotic effects in childhood brain tumor cells, likely to involve altered chromatin regulation at the human telomerase reverse transcriptase promoter