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Background: Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is currently based on only few previous molecular studies, which mainly focused on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics., Methods: Using mass spectrometry, proteome data were acquired from 16 ETMR and the ETMR cell line BT183. Proteome data were integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further embryonal and pediatric brain tumors., Results: Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Integrated proteomics showcased that ETMR and BT183 cells harbor proteasome regulatory proteins in abundance, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Indeed, in vitro assays using BT183 highlighted that ETMR tumor cells are highly vulnerable toward treatment with the CNS penetrant proteasome inhibitor Marizomib., Conclusions: In summary, histomorphology stipulates the proteome signatures of ETMR, and proteasome regulatory proteins are pervasively abundant in these tumors. As validated in vitro, proteasome inhibition poses a promising therapeutic option in ETMR., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Biological subtypes of ependymoma (EPN) have been introduced by the recent WHO classification and appear to have great impact on the clinical course, but have not yet found their way into clinical risk stratification. Further, the overall unfavorable prognosis underlines the fact that current therapeutic strategies need further evaluation for improvement. To date, there is no international consensus regarding first-line treatment for children with intracranial EPN. Extent of resection is known to be the most important clinical risk factor, leading to the consensus that consequent evaluation for re-surgery of postoperative residual tumor needs to have highest priority. Furthermore, efficacy of local irradiation is unquestioned and recommended for patients aged>1 year. In contrast, efficacy of chemotherapy is still under discussion. The European trial SIOP Ependymoma II aims at evaluating efficacy of different chemotherapy elements, leading to the recommendation to include German patients. The BIOMECA study, as biological accompanying study, aims at identifying new prognostic parameters. These results might help to develop targeted therapies for unfavorable biological subtypes. For patient who are not qualified for inclusion into the interventional strata, the HIT-MED Guidance 5.2 provides specific recommendations. This article is meant as an overview of national guidelines regarding diagnostics and treatment as well as of treatment according to the SIOP Ependymoma II trial protocol., Competing Interests: Die HIT-MED Studiengruppe (Leitung Prof. S. Rutkowski) wird durch die Deutsche Kinderkrebsstiftung gefördert.S. Rutkowski: Advisory board Fa. Roche Pharma AG, Fa. Bayer Vital GmbH; DMSC Celgene International II, B. Bison: Vortragshonorar von der Firma Merck Medical Healthcare erhalten; G. Fleischhack: Advisory Board Fa. Novartis, Fa. Bayer Vital GmbH, Vortragstätigkeit FomF GmbH (Forum für medizinische Fortbildung), Forschungsförderung durch Deutsche Kinderkrebsstiftung HIT-REZ-Studie/-Register seit 2005., (Thieme. All rights reserved.)

Purpose: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy., Methods: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors., Results: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% ( P = .0187), respectively. In multivariable analysis, localized relapse ( P = .0073), SHH molecular subgroup ( P = .0103), CSI use after relapse ( P = .0161), and age ≥ 36 months at initial diagnosis ( P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy ( P = .007)., Conclusion: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population., Competing Interests: Craig ErkerConsulting or Advisory Role: Novartis Canada Pharmaceuticals Inc Martin MynarekEmployment: Novartis, BioNTech SE Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Juliette HukinStock and Other Ownership Interests: AbbVieConsulting or Advisory Role: AstraZeneca, Novartis Vijay RamaswamyHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca Canada Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Jazz Pharmaceuticals, Servier, Alexion Pharmaceuticals Sébastien PerreaultLeadership: BayerStock and Other Ownership Interests: NovocureHonoraria: BayerConsulting or Advisory Role: BayerSpeakers' Bureau: BayerExpert Testimony: Bayer Cassie N. KlineResearch Funding: Regeneron (Inst), Curis (Inst), Midatech Pharma (Inst), Ipsen (Inst), Day One Therapeutics (Inst), Bristol Myers Squibb (Inst), Kazia Therapeutics (Inst), Chimerix (Inst) Eric S. SandlerConsulting or Advisory Role: Protara Therapeutics Lindsey M. HoffmanHonoraria: AstraZeneca Kathleen DorrisStock and Other Ownership Interests: Amgen, Gilead SciencesConsulting or Advisory Role: Day One Biopharmaceuticals Helen ToledanoConsulting or Advisory Role: AstraZeneca, Novartis Derek S. TsangTravel, Accommodations, Expenses: Mevion Medical Systems Jeffrey KnipsteinEmployment: PRA Health Sciences, ServierConsulting or Advisory Role: Atheneum Zhihong J. WangHonoraria: AstraZenecaConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: AstraZeneca Kenneth J. CohenConsulting or Advisory Role: Novartis, Bristol Myers Squibb, DNAtrixResearch Funding: Novartis, Bristol Myers Squibb Jordan R. HansfordStock and Other Ownership Interests: AnteotechConsulting or Advisory Role: Bayer Sabine MuellerResearch Funding: Regeneron (Inst), DayOne Pharmaceuticals (Inst), Curis Pharamceuticals (Inst), Curis Pharamceuticals (Inst), Bristol Myers Squibb (Inst) Amar GajjarConsulting or Advisory Role: Roche/Genentech, QED Therapeutics, Day One Therapeutics, Geanno BioResearch Funding: Genentech (Inst), Kazia Therapeutics (Inst) Stefan RutkowskiConsulting or Advisory Role: Bristol Myers Squibb GmbH & Co. KGaA, Germany, Celgene, Roche Pharma AG, Grenzach-Wyhlen, Bayer Germany Giles RobinsonResearch Funding: Novartis (Inst), Genentech/Roche (Inst), Novartis (Inst), SpringWorks Therapeutics (Inst) Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche (Inst) Lucie Lafay-CousinHonoraria: Servier, Innomar StrategiesNo other potential conflicts of interest were reported.

Background: Medulloblastoma is the most common malignant paediatric brain tumour, and cerebrospinal fluid (CSF) dissemination (M1 stage) is a high-risk prognostic factor. Criteria for CSF evaluation and for differentiating M0 from M1 stage are not clearly defined, and the prognostic significance of M1 stage in this context is unknown., Patients and Methods: CSF investigations from 405 patients with medulloblastoma of the prospective multicenter trial HIT-2000 (HIirnTumor-2000) were reviewed. Data from 213 patients aged ≥4 years were related to 5-year progression-free (5y-PFS) and overall survival., Results: Patients with cytological tumour dissemination only (M1 stage only) aged ≥4 years (n = 18) and patients with radiologically detected metastases (M2/3, n = 85) showed a worse 5y-PFS than M0 patients (n = 110) without signs of metastatic disease (5y-PFS 61.1% and 59.6% vs 80.7%; p < 0.02 and p < 0.01, log rank). Patients with positive samples drawn early after surgery who turned negative within 14 days postoperatively (n = 9) and patients with atypical cells (n = 6) showed a 5y-PFS similar to M0 patients. No tumour cells were detected in samples containing <10 nucleated cells. Analysis of cytological criteria showed a better predictive value for tumour cell clusters than ≥2 individual tumour cells., Conclusion: Based on our results, we suggest that CSF medulloblastoma staging should be performed 14 days postoperatively by lumbar puncture, and specimens should contain at least 10 nucleated cells. Cytological tumour dissemination alone (M1 stage only) appears a high-risk prognostic factor associated with an outcome comparable to M2/M3 stage. Tumour cell clusters seem to have a greater impact on prognosis than single tumour cells. This should be validated further., Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results., Methods: Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas., Results: Fifty-three patients with a median age of 6.9 years (1.25-25.4) at first recurrence and a median follow-up time of 36 months (2-115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9-120.1) vs. 95 (CI: 20.7-169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7-31.3) vs. 7 (CI: 0-15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%., Conclusion: The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%)., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

According to the WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas, and RELA-fusion-positive ependymomas (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e., the clear cell, papillary, and tanycytic ependymoma. In parallel, global DNA methylation patterns distinguish nine molecular groups, some of which tightly overlap with histopathological subgroups. However, the match of the aforementioned histological variants to DNA methylation classes remains unclear. We analyzed histomorphology, clinical parameters, and global DNA methylation of tumors with the initial histological diagnoses of tanycytic (n = 12), clear cell (n = 14), or papillary ependymoma (n = 19). Forty percent of these tumors did not match to the epigenetic profile of ependymomas, using a previously published DNA methylation-based classifier for brain tumors. Instead, they were classified as low-grade glioma (n = 3), plexus tumor (n = 2), CNS high-grade neuroepithelial tumor with MN1 alteration (n = 2), papillary tumor of the pineal region (n = 2), neurocytoma (n = 1), or did not match to any known brain tumor methylation class (n = 8). Overall, integrated diagnosis had to be changed in 35.6% of cases as compared to the initial diagnosis. Among the tumors molecularly classified as ependymoma (27/45 cases), tanycytic ependymomas were mostly located in the spine (5/7 cases) and matched to spinal or myxopapillary ependymoma. 6/8 clear cell ependymomas were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas with a positive ependymoma match (12/19 cases) showed either a "papillary" (n = 5), a "trabecular" (n = 1), or a "pseudo-papillary" (n = 6) growth pattern. The papillary growth pattern was strongly associated with the methylation class B of posterior fossa ependymoma (PFB, 5/5 cases) and tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Tumors with pseudo-papillary histology matched to the methylation class of myxopapillary ependymoma (4/6 cases), whereas the trabecular case was anatomically and molecularly a spinal ependymoma. Our results show that the diagnosis of histological ependymoma variants is challenging and epigenetic profiles may improve diagnostic accuracy of these cases. Whereas clear cell and papillary ependymomas display correlations between localization, histology, and methylation, tanycytic ependymoma does not represent a molecularly distinct subgroup.