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Journal of Veterinary Diagnostic... Sep 2022Ependymoma, one of the most common gliomas in cats, occurs most often in the lateral and third ventricles and has variable histologic patterns that often form rosettes...
Ependymoma, one of the most common gliomas in cats, occurs most often in the lateral and third ventricles and has variable histologic patterns that often form rosettes and pseudorosettes. Oligodendrocyte transcription factor (OLIG2) is expressed in oligodendrocyte precursor cells and mature oligodendrocytes. Although widely used as a diagnostic marker for most gliomas, OLIG2 is reported to have minimal immunolabeling in ependymomas. Here we characterize the OLIG2 immunolabeling pattern in 19 cases of feline ependymoma, which occurred predominantly in the lateral and third ventricles. Immunohistochemistry for GFAP was variable in 14 cases and was typically localized in the cytoplasmic processes of the neoplastic ependymal cells, especially in the rosettes and pseudorosettes. Nuclear OLIG2 immunolabeling was present in 17 cases and varied in intensity from weak (4 cases) to strong (13 cases). The distribution of OLIG2 immunolabeling within the neoplasms included none (2 cases), <25% (7 cases), 25-50% (6 cases), 51-75% (2 cases), and >75% (3 cases). OLIG2 immunolabeling intensity and distribution is widespread in feline ependymoma, in contrast to ependymomas in other species, and should not be relied upon as a specific marker for feline oligodendroglioma.
Topics: Animals; Brain Neoplasms; Cat Diseases; Cats; Ependymoma; Glioma; Immunohistochemistry; Oligodendroglioma
PubMed: 35762120
DOI: 10.1177/10406387221107898 -
Primary spinal anaplastic ependymoma: A single-institute retrospective cohort and systematic review.Frontiers in Oncology 2023Primary spinal anaplastic ependymoma (PSAE) is an extremely rare disease. We aim to report the largest PSAE cohort, evaluate the treatments, and investigate the...
OBJECTIVE
Primary spinal anaplastic ependymoma (PSAE) is an extremely rare disease. We aim to report the largest PSAE cohort, evaluate the treatments, and investigate the prognostic factors for progression-free survival (PFS).
METHODS
Clinical data collected from the authors' institute and literature articles were pooled and described. Survival analysis and multivariable Cox regression analysis were performed to evaluate therapies and investigate prognostic factors for PFS.
RESULTS
Our cohort included 22 females and 16 males, with a median age of 33 years. PSAE developed mostly on cervical and cervicothoracic levels. The median length measured 3 segments. Half of PSAE were intramedullary. Pain was the most common symptom. The median duration of symptoms was 6 months. Neurological statuses were improved in 76% following treatments, whereas clinical tumor progression occurred in 41.7%. The estimated median progression-free survival was 132 months, and the estimated median survival was 192 months. The median Ki-67 index was 15%. Patients aged less than or equal to 25 experienced worse neurological statuses and more repeated progression. Age less than or equal to 25 (HR 10.312, 95%CI 1.535-69.260, p=0.016), gross total resection (HR 0.116, 95%CI 0.020-0.688, p=0.018), and radiotherapy (HR 0.084, 95%CI 0.009-0.804, p=0.032) are three prognostic factors for tumor progression.
CONCLUSION
Tumor progression remains a big concern in the clinical course of PSAE. Being aged above 25, undergoing GTR, and accepting adjuvant radiotherapy put patients at lower risk for tumor progression. Younger patients might have worse neurological statuses compared with those aged over 25.
PubMed: 36824145
DOI: 10.3389/fonc.2023.1083085 -
Pediatric Neurosurgery 2023Ependymoma is one of the most common malignant pediatric brain tumors and can be difficult to treat. Over the last decade, much progress has been made in the... (Review)
Review
BACKGROUND
Ependymoma is one of the most common malignant pediatric brain tumors and can be difficult to treat. Over the last decade, much progress has been made in the understanding of the underlying molecular drivers within this group of tumors, but clinical outcomes remain unchanged.
SUMMARY
Here, we review the most recent molecular advances in pediatric ependymoma, evaluate results of recent clinical trials and discuss the ongoing challenges in the field and questions that remain.
KEY MESSAGES
The field of ependymoma has vastly changed over the last several decades with ten distinct molecular subgroups now described, but much progress needs to be made in developing new therapeutic strategies and targets.
Topics: Child; Humans; Ependymoma; Brain Neoplasms
PubMed: 37231859
DOI: 10.1159/000530868 -
Cancers Dec 2021Ependymoma is a biologically diverse tumor wherein molecular classification has superseded traditional histological grading based on its superior ability to characterize... (Review)
Review
Ependymoma is a biologically diverse tumor wherein molecular classification has superseded traditional histological grading based on its superior ability to characterize behavior, prognosis, and possible targeted therapies. The current, updated molecular classification of ependymoma consists of ten distinct subgroups spread evenly among the spinal, infratentorial, and supratentorial compartments, each with its own distinct clinical and molecular characteristics. In this review, the history, histopathology, standard of care, prognosis, oncogenic drivers, and hypothesized molecular targets for all subgroups of ependymoma are explored. This review emphasizes that despite the varied behavior of the ependymoma subgroups, it remains clear that research must be performed to further elucidate molecular targets for these tumors. Although not all ependymoma subgroups are oncologically aggressive, development of targeted therapies is essential, particularly for cases where surgical resection is not an option without causing significant morbidity. The development of molecular therapies must rely on building upon our current understanding of ependymoma oncogenesis, as well as cultivating transfer of knowledge based on malignancies with similar genomic alterations.
PubMed: 34944845
DOI: 10.3390/cancers13246218 -
Neuro-oncology May 2018Intradural spinal tumors are rare tumors of the central nervous system. Due to the eloquence of the spinal cord and its tracts, the compact architecture of the cord and... (Review)
Review
Intradural spinal tumors are rare tumors of the central nervous system. Due to the eloquence of the spinal cord and its tracts, the compact architecture of the cord and nerves, and the infiltrative nature of some of these tumors, surgical resection is difficult to achieve without causing neurological deficits. Likewise, chemotherapy and radiotherapy are utilized more cautiously in the treatment of intradural spinal tumors than their cranial counterparts. Targeted therapies aimed at the genetic alterations and molecular biology tailored to these tumors would be helpful but are lacking.Here, we review the major types of intradural spinal tumors, with an emphasis on genetic alterations, molecular biology, and experimental therapies for these difficult to treat neoplasms.
Topics: Astrocytoma; Ependymoma; Humans; Prognosis; Spinal Neoplasms
PubMed: 29216380
DOI: 10.1093/neuonc/nox230 -
Neuro-oncology Jul 2016Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The... (Review)
Review
Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being age-specific. Genetically distinct subgroups have been identified by genomic studies based on locations in classic grade II and III ependymomas. They are supratentorial ependymomas with C11orf95-RELA fusion or YAP1 fusion, infratentorial ependymomas with or without a hypermethylated phenotype (CIMP), and spinal cord ependymomas. Myxopapillary ependymomas and subependymomas have different biology than ependymomas with typical WHO grade II or III histology. Surgery and radiotherapy are the mainstays of treatment, while the role of chemotherapy has not yet been established. An in-depth understanding of tumor biology, developing reliable animal models that accurately reflect tumor molecule features, and high throughput drug screening are essential for developing new therapies. Collaborative efforts between scientists, physicians, and advocacy groups will enhance the translation of laboratory findings into clinical trials. Improvements in disease control underscore the need to incorporate assessment and management of patients' symptoms to ensure that treatment advances translate into improvement in quality of life.
Topics: Animals; Brain Neoplasms; Disease Models, Animal; Ependymoma; Glioma, Subependymal; Humans; Quality of Life; Spinal Cord Neoplasms
PubMed: 27022130
DOI: 10.1093/neuonc/now016 -
Neuro-oncology Jul 2023A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain...
BACKGROUND
A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas.
METHODS
Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS).
RESULTS
The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes.
CONCLUSIONS
DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.
Topics: Adult; Humans; Retrospective Studies; DNA Methylation; Prognosis; Brain Neoplasms; Ependymoma
PubMed: 36734226
DOI: 10.1093/neuonc/noad030 -
Neuro-oncology Jun 2022SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3-21 years... (Clinical Trial)
Clinical Trial
BACKGROUND
SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3-21 years treated with a staged management strategy. A further aim was to assess the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide, and cyclophosphamide (VEC). We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers.
METHODS
Seventy-four participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation, 1q, hTERT, ReLA, Tenascin-C, H3K27me3, and pAKT status were evaluated.
RESULTS
Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (P = .003, HR = 2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (P = .005, HR = 2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (P = .003, HR = 2.70, 95%CI 1.49-6.10 and P = .014, HR = 5.8, 95%CI 1.2-28) and H3K27me3 loss with worse OS (P = .003, HR = 4.6, 95%CI 1.5-13.2). Methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, best chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding the prespecified 45%.
CONCLUSIONS
Participants with totally resected ependymoma had the best outcomes. RR of STR to VEC exceeded the pre-specified efficacy criterion. However, cases of inaccurate stratification highlighted the need for rapid central review. 1q gain, H3K27me3 loss, and hTERT expression were all associated with poorer survival outcomes.
Topics: Child; Chromosome Aberrations; Cyclophosphamide; Ependymoma; Etoposide; Follow-Up Studies; Histones; Humans; Treatment Outcome; Vincristine
PubMed: 35018471
DOI: 10.1093/neuonc/noac012 -
Journal of Neurosurgical Sciences Feb 2018Ependymoma can arise throughout all compartments of the central nervous system with prevalence for intracranial and spinal location in children and adults, respectively.... (Review)
Review
Ependymoma can arise throughout all compartments of the central nervous system with prevalence for intracranial and spinal location in children and adults, respectively. The current histopathology based WHO grading system distinguishes grade I, II 'classic', and III 'anaplastic' ependymoma. However, analysis of multiple cohorts of intracranial ependymoma demonstrate a wide variance in the utility of the grade II versus grade III distinction as a prognostic marker that may additionally be confounded by the anatomic compartment. Recent (epi)genomic profiling efforts have identified molecularly distinct groups of ependymoma arising from all three anatomic compartments of the central nervous system that outperform the current histopathological classification regarding clinical associations. These advances have led to the cognition that molecular classification should be part of all future clinical trials in ependymoma patients. Clinical management of intracranial ependymomas (WHO Grade II/III) is challenging and molecular classification based risk stratification may help to intensify treatment and surveillance in high-risk patients but to de-escalate therapy in certain patient groups at low risk for recurrence. Finally, experience of neurosurgeons, and other disciplines, as well as intensified co-operation between all stakeholders involved hold promise to finally improve outcome of patients affected with ependymoma.
Topics: Adolescent; Adult; Central Nervous System Neoplasms; Child; Ependymoma; Female; Humans; Incidence; Male; Molecular Epidemiology; Neoplasm Grading; World Health Organization; Young Adult
PubMed: 28895660
DOI: 10.23736/S0390-5616.17.04152-2 -
Science Translational Medicine Oct 2021Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress...
Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including and . Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at and , accompanied by enhanced glycolysis and TCA cycle metabolism. α, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.
Topics: Animals; Child; Ependymoma; Epigenesis, Genetic; Epigenomics; Histones; Humans; Metabolic Networks and Pathways; Mice
PubMed: 34613815
DOI: 10.1126/scitranslmed.abc0497