PURPOSE: This retrospective study aims to show a real-life single-center experience with clinical management of relapsed pediatric ependymomas using results from comprehensive molecular profiling. METHODS: Eight relapsed ependymomas were tested by whole exome sequencing, RNA sequencing, phosphoproteomic arrays, array comparative genome hybridization, and immunohistochemistry staining for PD-L1 expression and treated with an individualized approach implementing targeted inhibitors, immunotherapy, antiangiogenic metronomic treatment, or other agents. Treatment efficacy was evaluated using progression-free survival (PFS), overall survival (OS), survival after relapse (SAR), and PFS ratios. RESULTS: Genomic analyses did not reveal any therapeutically actionable alterations. Surgery remained the cornerstone of patient treatment, supplemented by adjuvant radiotherapy. Empiric agents were chosen quite frequently, often involving drug repurposing. In six patients, prolonged PFS after relapse was seen because of immunotherapy, MEMMAT, or empiric agents and is reflected in the PFS ratio ≥ 1. The 5-year OS was 88%, the 10-year OS was 73%, the 2-year SAR was 88%, and the 5-year SAR was 66%. CONCLUSION: We demonstrated the feasibility and good safety profile. Promising was the effect of immunotherapy on ZFTA-positive ependymomas. However, further research is required to establish the most effective approach for achieving sustained remission in these patients.

• Keywords
• Individualized treatment, Molecular profiling, Pediatric ependymoma, Refractory, Relapsed, Targeted therapy,
• MeSH
• Child MeSH
• Ependymoma * therapy   genetics   pathology   MeSH
• Immunotherapy MeSH
• Precision Medicine * methods   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * therapy   pathology   genetics   MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Brain Neoplasms * therapy   genetics   pathology   MeSH
• Follow-Up Studies MeSH
• Child, Preschool MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

PURPOSE: Current management of pediatric intramedullary ependymoma is extrapolated from adult series since large studies in children are unavailable. This has led us to share our experience with this rare tumor and compare it to the literature and to review and highlight important aspects of current management and point out inconsistencies. METHODS: This is a retrospective analysis of patients with intramedullary ependymoma managed at our institution between 2004 and 2021. RESULTS: During the study period, 5 patients were treated for intramedullary ependymoma. Cases of myxopapillary ependymoma were excluded. The mean age of our cohort was 11.2 years. We identified 4 cases of grade II ependymoma and 1 case of grade III ependymoma. Gross tumor removal (GTR) was achieved in two patients (40%) of patients. One patient was treated with radiotherapy for recurrence and two patients received chemotherapy. There were no cases of recurrence among patients treated with GTR, but in all patients treated with STR. Eighty percent of patients either improved or stayed stable neurologically. During follow-up (mean 73 months), 2 patients died of disease. CONCLUSION: GTR and tumor grade remain the key prognostic factor of long-term tumor-free survival. Many questions prevail regarding outcomes, correct use of adjuvant therapy, and prognostic factors.

• Keywords
• Ependymoma, Intramedullary tumor, Pediatric series, Prognostic factors, Review,
• MeSH
• Child MeSH
• Adult MeSH
• Ependymoma * surgery   pathology   MeSH
• Combined Modality Therapy MeSH
• Humans MeSH
• Spinal Cord Neoplasms * surgery   pathology   MeSH
• Neurosurgical Procedures MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.

• Keywords
• ASCL1, Atypical teratoid/rhabdoid tumor, DNA methylation profiling, GFAP, Gene expression, Neuroradiology, OLIG2, Overall survival, Prognosis, Sonic hedgehog,
• MeSH
• SMARCB1 Protein genetics   metabolism   MeSH
• Humans MeSH
• DNA Methylation MeSH
• Central Nervous System Neoplasms * genetics   MeSH
• Neoplasms, Neuroepithelial * genetics   MeSH
• Prognosis MeSH
• Hedgehog Proteins genetics   metabolism   MeSH
• Rhabdoid Tumor * genetics   MeSH
• Teratoma * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• SMARCB1 Protein MeSH
• Hedgehog Proteins MeSH
• SHH protein, human MeSH Browser

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

• Keywords
• Brain tumor, EWSR1, Gene fusion, MN1, Neuroepithelial, Neurooncology, PATZ1, Pediatric,
• MeSH
• Child MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Brain Neoplasms genetics   pathology   MeSH
• Neoplasms, Neuroepithelial genetics   pathology   MeSH
• Oncogene Fusion MeSH
• Child, Preschool MeSH
• Repressor Proteins genetics   MeSH
• Kruppel-Like Transcription Factors genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Oncogene Proteins, Fusion MeSH
• Biomarkers, Tumor MeSH
• PATZ1 protein, human MeSH Browser
• Repressor Proteins MeSH
• Kruppel-Like Transcription Factors MeSH

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

• Keywords
• EP300, EWSR1, FOXO1, Gene fusion, Neuroepithelial tumor, PLAGL1, Supratentorial,
• MeSH
• Child MeSH
• Ependymoma genetics   MeSH
• Humans MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Oncogene Fusion MeSH
• Cell Cycle Proteins genetics   MeSH
• Supratentorial Neoplasms genetics   MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Tumor Suppressor Proteins MeSH
• PLAGL1 protein, human MeSH Browser
• Cell Cycle Proteins MeSH
• Transcription Factors MeSH

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.

• MeSH
• Gene Amplification * MeSH
• Chromosome Deletion MeSH
• Child MeSH
• Adult MeSH
• Transcription, Genetic MeSH
• Genome, Human MeSH
• Gene Rearrangement genetics   MeSH
• Glioma genetics   pathology   MeSH
• Cyclin-Dependent Kinase Inhibitor p15 metabolism   MeSH
• Cyclin-Dependent Kinase Inhibitor p16 metabolism   MeSH
• Kaplan-Meier Estimate MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local pathology   MeSH
• DNA Methylation genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Receptor, Platelet-Derived Growth Factor alpha genetics   metabolism   MeSH
• Cluster Analysis MeSH
• Radiation MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CDKN2A protein, human MeSH Browser
• CDKN2B protein, human MeSH Browser
• Cyclin-Dependent Kinase Inhibitor p15 MeSH
• Cyclin-Dependent Kinase Inhibitor p16 MeSH
• Receptor, Platelet-Derived Growth Factor alpha MeSH

BACKGROUND: Posterior 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. METHODS: Demographic, 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). RESULTS: A 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). CONCLUSIONS: Data 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.

• Keywords
• ependymoma, molecular subgroup, neurocognitive outcome, survival,
• MeSH
• Survival Analysis MeSH
• Child MeSH
• Ependymoma mortality   psychology   therapy   MeSH
• Infratentorial Neoplasms mortality   psychology   therapy   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Neoadjuvant Therapy adverse effects   MeSH
• Neurosurgical Procedures adverse effects   MeSH
• Neurocognitive Disorders etiology   MeSH
• Child, Preschool MeSH
• Radiotherapy adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Geographicals
• Ontario MeSH

BACKGROUND: The goal of this study was to evaluate outcomes in children with relapsed, molecularly characterized intracranial ependymoma treated with or without craniospinal irradiation (CSI) as part of a course of repeat radiation therapy (re-RT). METHODS: This was a retrospective cohort study of 31 children. Patients with distant relapse received CSI as part of re-RT. For patients with locally recurrent ependymoma, those treated before 2012 were re-irradiated with focal re-RT. In 2012, institutional practice changed to offer CSI, followed by boost re-RT to the site of resected or gross disease. RESULTS: Median follow-up was 5.5 years. Of 9 patients with distant relapse after initial RT, 2-year freedom from progression (FFP) and overall survival (OS) were 12.5% and 62.5%, respectively. There were 22 patients with local failure after initial RT. In these patients, use of CSI during re-RT was associated with improvement in 5-year FFP (83.3% with CSI vs 15.2% with focal re-RT only, P = 0.030). In the subgroup of patients with infratentorial primary disease, CSI during re-RT also improved 5-year FFP (100% with CSI, 10.0% with focal re-RT only, P = 0.036). Twenty-three patients had known molecular status; all had posterior fossa group A tumors (n = 17) or tumors with a RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) fusion (n = 6). No patient developed radiation necrosis after fractionated re-RT, though almost all survivors required assistance throughout formal schooling. Five out of 10 long-term survivors have not developed neuroendocrine deficits. CONCLUSIONS: Re-irradiation with CSI is a safe and effective treatment for children with locally recurrent ependymoma and improves disease control compared with focal re-irradiation, with the benefit most apparent for those with infratentorial primary tumors.

• Keywords
• ependymoma, pediatrics, re-irradiation, recurrence,
• MeSH
• Child MeSH
• Ependymoma radiotherapy   MeSH
• Infant MeSH
• Craniospinal Irradiation methods   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local radiotherapy   MeSH
• Child, Preschool MeSH
• Re-Irradiation methods   MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Intracranial ependymoma represents one of the most common pediatric central nervous system malignancies, and exhibits a wide range of clinical behavior from relatively indolent lesions to highly malignant anaplastic ependymomas. Due to the heterogeneous nature of this disease there is lack of prognostic markers, which would reliably predict the outcome of patients. MicroRNAs (miRNAs) have emerged as important molecules in cancer biology during past decade; however, very little is known about their role in ependymomas. The aim of the present study was to evaluate expression of miRNAs in archived formalin-fixed paraffin-embedded (FFPE) samples of pediatric intracranial ependymomas. The expression of miRNAs were examined in 29 samples of ependymoma and we observed that miR-135a-3p, miR-137, miR-17-5p, miR-181d and let-7d-5p were upregulated. In addition, a significantly higher expression of miR-203a was detected in Grade III tumors suggesting its possible use as a prognostic or diagnostic marker. The present study also demonstrated that storage of (FFPE) ependymoma samples for >20 years did not result in a deterioration of miRNAs. The present findings broaden the presently available knowledge regarding miRNA expression in ependymomas and provide further evidence for the employment of miRNA analysis as a supplementary method for the morphological assessment of ependymoma samples.

• Keywords
• ependymoma, let-7d, miR-137, miR-203, microRNA,
• Publication type
• Journal Article MeSH

• MeSH
• Ependymoma * MeSH
• Humans MeSH
• Prognosis MeSH
• Telomerase * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Comment MeSH
• Editorial MeSH
• Names of Substances
• Telomerase * MeSH