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Acta Neuropathologica Aug 2018Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very...
Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.
Topics: Adolescent; Adult; Age Factors; Child; Cohort Studies; DNA Copy Number Variations; DNA Methylation; Ependymoma; Female; Gene Expression Profiling; Humans; Infratentorial Neoplasms; Kaplan-Meier Estimate; Male; Microarray Analysis; Middle Aged; Young Adult
PubMed: 30019219
DOI: 10.1007/s00401-018-1888-x -
Frontiers in Bioscience (Landmark... Apr 2023Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most... (Review)
Review
Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most malignant histologies, and intense preclinical and clinical research is needed to develop more effective therapeutic interventions against these tumors, most of which meet the FDA definition for orphan diseases. Increased attention is being paid to the repositioning of already-approved drugs for new anticancer indications as a fast-tracking strategy for identifying new and more effective therapies. Two pediatric CNS tumors, posterior fossa ependymoma (EPN-PF) type A and diffuse midline glioma (DMG) H3K27-altered, share loss of H3K27 trimethylation as a common epigenetic hallmark and display early onset and poor prognosis. These features suggest a potentially common druggable vulnerability. Successful treatment of these CNS tumors raises several challenges due to the location of tumors, chemoresistance, drug blood-brain barrier penetration, and the likelihood of adverse side effects. Recently, increasing evidence demonstrates intense interactions between tumor cell subpopulations and supportive tumor microenvironments (TMEs) including nerve, metabolic, and inflammatory TMEs. These findings suggest the use of drugs, and/or multi-drug combinations, that attack both tumor cells and the TME simultaneously. In this work, we present an overview of the existing evidence concerning the most preclinically validated noncancer drugs with antineoplastic activity. These drugs belong to four pharmacotherapeutic classes: antiparasitic, neuroactive, metabolic, and anti-inflammatory. Preclinical evidence and undergoing clinical trials in patients with brain tumors, with special emphasis on pediatric EPN-PF and DMG, are summarized and critically discussed.
Topics: Humans; Child; Drug Repositioning; Ependymoma; Brain Neoplasms; Central Nervous System Neoplasms; Blood-Brain Barrier; Tumor Microenvironment
PubMed: 37114548
DOI: 10.31083/j.fbl2804077 -
Brain Pathology (Zurich, Switzerland) Mar 2021Pediatric ependymomas frequently develop in the cerebellum and are currently treated using non-specific therapies, in part, because few somatically mutated driver genes...
Pediatric ependymomas frequently develop in the cerebellum and are currently treated using non-specific therapies, in part, because few somatically mutated driver genes are present, and the underlying pathobiology is poorly described. Circular RNAs (circRNAs) constitute as a large class of primarily non-coding RNAs with important roles in tumorigenesis, but they have not been described in pediatric ependymomas. To advance our molecular understanding of ependymomas, we performed Next Generation Sequencing of rRNA-depleted total RNA of 10 primary ependymoma and three control samples. CircRNA expression patterns were correlated to disease stage, outcome, age, and gender. We found a profound global downregulation of circRNAs in ependymoma relative to control samples. Many differentially expressed circRNAs were discovered and circSMARCA5 and circ-FBXW7, which are described as tumor suppressors in glioma and glioblastomas in adults, were among the most downregulated. Moreover, patients with a dismal outcome clustered separately from patients with a good prognosis in unsupervised hierarchical cluster analyses. Next, NanoString nCounter experiments were performed, using a custom-designed panel targeting 66 selected circRNAs, on a larger cohort that also included medulloblastomas and pilocytic astrocytomas. These experiments indicated that circRNA expression profiles are different among distinct pediatric brain tumor subtypes. In particular, circRNAs derived from RMST, LRBA, WDR78, DRC1 and BBS9 genes were specifically upregulated in ependymomas. In conclusion, circRNAs have different expression profiles in ependymomas relative to controls and between survivors and patients with a dismal outcome, suggesting that circRNAs could be exerted as diagnostic and prognostic biomarkers in the future if further validated in larger cohorts.
Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Ependymoma; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Male; RNA, Circular; Sequence Analysis, RNA
PubMed: 33247464
DOI: 10.1111/bpa.12922 -
Turkish Neurosurgery 2012Intramedullary tumors affecting the entire cord from the cervicomedullary junction to the conus are termed "holocord tumors". Ependymomas are the most frequent...
Intramedullary tumors affecting the entire cord from the cervicomedullary junction to the conus are termed "holocord tumors". Ependymomas are the most frequent intramedullary tumor in adults. Holocord ependymoma is an exceedingly rare condition. An extensive review of the literature revealed that only five other cases have been reported. We report the sixth case of holocord ependymoma. In this article, we present a case of holocord ependymoma in a 19-year-old girl which was totally resected in a two-stage approach. A two-staged operation is recommended for the aim of total resection for this disease. Besides, cysts are common feature of all spinal ependymomas. There was a solid mass not accompanied by a cyst a any level in our patient's tumor. To the authors' best knowledge, a pure solid mass not accompanied by a cyst has not been previously reported with holocord ependymoma cases.
Topics: Ependymoma; Female; Humans; Magnetic Resonance Imaging; Neurosurgical Procedures; Spinal Cord; Spinal Cord Neoplasms; Young Adult
PubMed: 22437304
DOI: 10.5137/1019-5149.JTN.3281-10.1 -
JPMA. the Journal of the Pakistan... Nov 2022To enumerate the burden of ependymoma in our region and identify the demographic, tumoural, surgical, clinical characteristics, and outcomes of patients diagnosed with...
OBJECTIVE
To enumerate the burden of ependymoma in our region and identify the demographic, tumoural, surgical, clinical characteristics, and outcomes of patients diagnosed with ependymoma.
METHODS
This retrospective cross-sectional study included patients admitted under neurosurgical service between January 1 and December 31, 2019. The inclusion criterion for the study was a histopathological diagnosis of the brain lesion. The experience of the ependymal brain tumours observed at the 32 participating sites in Pakistan is presented.
RESULTS
A total of 2750 patients with brain tumours were seen in 2019 at our centres of whom 58(2.1%) had a histopathological diagnosis of ependymoma. The median age at diagnosis was nine (IQR= 4.5-24.5) years. The median time to surgery from date of radiological diagnosis was 38.5 (IQR= 4-93.8) days. The median KPS score at presentation was 70 (IQR= 60-80), and post-surgery was 90 (IQR= 70-100), showing an average increase of 20. Our population's overall mortality rate for ependymoma was 31.1%, with the 30-day mortality rate being 2.2% (lower than the 4.5% on average for all brain tumours in our cohort).
CONCLUSIONS
Ependymomas were predominantly found in the paediatric population in the presented cohort. While gender distribution and histopathological grading seemed to follow international trends, this study had a much higher mortality rate and a much lower gross total resection rate than centres in high-income countries.
Topics: Child; Humans; Child, Preschool; Adolescent; Young Adult; Adult; Retrospective Studies; Cross-Sectional Studies; Brain Neoplasms; Ependymoma; Time
PubMed: 36591627
DOI: 10.47391/JPMA.11-S4-AKUB07 -
Folia Neuropathologica 2011Ependymal tumours are relatively uncommon primary neoplasms of the central nervous system. Histological criteria distinguishing ependymoma and anaplastic ependymoma are... (Review)
Review
AIM
Ependymal tumours are relatively uncommon primary neoplasms of the central nervous system. Histological criteria distinguishing ependymoma and anaplastic ependymoma are not clear-cut and other parameters are required to allow more precise prognostication in these tumours. We analysed the histological and immunohistochemical features of these tumours (Ki-67, cyclin D1, EGFR, hTERT, Olig2) and correlated them with the clinical outcome.
MATERIAL AND METHODS
We analysed 39 patients with grade II ependymoma (30) and anaplastic ependymoma (9). Twenty-eight tumours developed in children and the remaining 11 patients were adults with intracranial and intraspinal tumours. Eighteen patients died during the follow-up period.
RESULTS AND CONCLUSIONS
Overall survival was reduced significantly for paediatric patients and patients with intracranial tumour. High-grade tumours, increased mitotic index and increased cellularity had an unfavourable influence on survival. Other histological parameters such as nuclear atypia, necrosis and microvascular proliferation did not alter the survival rate. Increased Ki-67 and cyclin D1 indices correlated with worse prognosis. Furthermore, any level of cyclin D1 expression in WHO grade II ependymomas was strongly associated with higher risk of death. No correlation was identified between Olig2, EGFR and hTERT expression and the outcome of the patients.
Topics: Adolescent; Adult; Biomarkers, Tumor; Central Nervous System Neoplasms; Child; Child, Preschool; Ependymoma; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Young Adult
PubMed: 21845537
DOI: No ID Found -
Turk Patoloji Dergisi 2022Ependymomas are neuroepithelial tumors of the central nervous system with heterogeneous biology and clinical course. The aim of the present study is to investigate the...
OBJECTIVE
Ependymomas are neuroepithelial tumors of the central nervous system with heterogeneous biology and clinical course. The aim of the present study is to investigate the relationship between the methylation status and clinicopathological parameters in ependymomas.
MATERIAL AND METHOD
DNA methylation status of CDKN2A, RASSF1A, KLF4 and ZIC2 genes were quantitatively analyzed with pyrosequencing in 44 ependymoma tumor tissues. The relationship of methylation profiles with tumor subtype, histological grade and patient age was statistically analyzed.
RESULTS
DNA methylation analyses for CDKN2A revealed no difference in methylation levels. Of the 31 included samples for optimal ZIC2 methylation analysis, 10 were hypermethylated (32.3%) and this change was significantly found in the adult spinal ependymomas (p=0.01). KLF4 hypermethylation was observed in 6 of the overall included 35 samples (17.1%); however, there was no statistically significant relation of the methylation status with tumor subtype, histological grade or age group. RASSF1A hypermethylation was observed in overall 40 included samples with varying methylation levels. Higher levels of hypermethylation were significantly related to the grade 3 histology (p=0.01) and spinal ependymomas (p=0.006). The pediatric cases with grade 3 ependymomas and ependymomas of adulthood showed significantly increased RASSF1A hypermethylation levels (p < 0.001 and p=0.001, respectively).
CONCLUSION
DNA methylation changes are likely to have biological importance in ependymomas. Both ZIC2 and RASSF1A methylation status may be useful parameters in the subclassification of these tumors.
Topics: Adult; Child; DNA Methylation; Ependymoma; Humans
PubMed: 34854470
DOI: 10.5146/tjpath.2021.01565 -
Brain Pathology (Zurich, Switzerland) Jan 2019Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in...
Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved 14 anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: ≥5 mitoses per 10 high power fields, Ki-67 labeling index (LI) ≥10%, microvascular proliferation (MVP) and spontaneous necrosis. These features were typically encountered in the foci of hypercellularity and reduced mucin. There were eight male and six female patients (age range 6-57 years, median = 16.5). Ten tumors displayed anaplasia at initial resection, and 4 were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8% and 40% in the anaplastic foci and <3% in the foci of classic MPE. There was documented cerebrospinal fluid (CSF) dissemination in seven cases, recurrence following an anaplastic diagnosis in three cases and bone or soft tissue invasion in two cases. One patient suffered lung metastases. Two cases evaluated by targeted next-generation sequencing and one evaluated by fluorescence in situ hybridization (FISH) showed nonspecific chromosomal gains. We conclude that although rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, closer follow-up is recommended, given the concern for aggressive biologic potential. Further study is needed to determine WHO grading criteria and genetic indicators of tumor progression.
Topics: Adolescent; Adult; Antigens, Nuclear; Child; Ependymoma; Female; Humans; In Situ Hybridization, Fluorescence; Ki-67 Antigen; Male; Middle Aged; Neoplasm Recurrence, Local; Spinal Cord Neoplasms
PubMed: 30417460
DOI: 10.1111/bpa.12673 -
Cancer Medicine Sep 2021The prognostic factors for survival in patients with ependymoma (EPN) remain controversial. The aim of this study was to establish a prognostic model for 5- and 10-year...
BACKGROUND
The prognostic factors for survival in patients with ependymoma (EPN) remain controversial. The aim of this study was to establish a prognostic model for 5- and 10-year survival probability nomograms for patients with EPN.
METHODS
Clinical data from the Surveillance, Epidemiology, and End Results (SEER) database were used for patients diagnosed with ependymoma between 2000 and 2018 and were randomized 7:3 into a development set and a validation set. Factors significantly associated with prognosis were screened out using the least absolute shrinkage and selection operator (LASSO) regression. The calibration chart and consistency index (C-index) are used to evaluate the discrimination and consistency of the prediction model. Decision curve analysis (DCA) was used to further evaluate the established model. Finally, prognostic factors selected by LASSO regression were evaluated using Kaplan-Meier (KM) survival curves.
RESULTS
A total of 3820 patients were included in the prognostic model. Seven survival predictors were obtained by LASSO regression screening, including age, gender, morphology, location, size, laterality, and resection. The prognostic model of the nomogram showed moderate discriminative ability in the development group and the validation group, with a C-index of 0.642 and 0.615, respectively. In the development set and validation set survival curves, the prognosis index of high risk was less effective than low risk (p < 0.001).
CONCLUSIONS
Our nomograms may play an important role in predicting 5 and 10-year outcomes for patients with ependymoma. This will help assist clinicians in personalized medicine.
Topics: Adult; Ependymoma; Humans; Middle Aged; Nomograms; Prognosis; Retrospective Studies; Risk Factors; SEER Program; Survival Analysis; Young Adult
PubMed: 34342153
DOI: 10.1002/cam4.4151 -
Neuro-oncology Apr 2023The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use...
BACKGROUND
The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant.
METHODS
Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data.
RESULTS
PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA.
CONCLUSIONS
These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression.
Topics: Humans; Transcriptome; Infratentorial Neoplasms; Brain Neoplasms; Ependymoma; Epithelial-Mesenchymal Transition; Tumor Microenvironment
PubMed: 36215273
DOI: 10.1093/neuonc/noac219