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Current Oncology Reports Aug 2022To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults. (Review)
Review
PURPOSE OF REVIEW
To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults.
RECENT FINDINGS
Ependymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy. Standard treatments are still the mainstay of treatment: the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.
Topics: Adult; Brain Neoplasms; Child; Ependymoma; Humans; Prognosis; Salvage Therapy
PubMed: 35384591
DOI: 10.1007/s11912-022-01260-w -
Neuro-oncology Mar 2018Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level... (Review)
Review
Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level of evidence of diagnostic and therapeutic interventions is higher in the pediatric compared with the adult patient population.The diagnosis and disease staging is performed by craniospinal MRI. Tumor classification is achieved by histological and molecular diagnostic assessment of tissue specimens according to the World Health Organization (WHO) classification 2016. Surgery is the crucial initial treatment in both children and adults. In pediatric patients with intracranial ependymomas of WHO grades II or III, surgery is followed by local radiotherapy regardless of residual tumor volume. In adults, radiotherapy is employed in patients with anaplastic ependymoma WHO grade III, and in case of incomplete resection of WHO grade II ependymoma. Chemotherapy alone is reserved for young children <12 months and for adults with recurrent disease when further surgery and irradiation are no longer feasible. A gross total resection is the mainstay of treatment in spinal ependymomas, and radiotherapy is reserved for incompletely resected tumors. Nine subgroups of ependymal tumors across different anatomical compartments (supratentorial, posterior fossa, spinal) and patient ages have been identified with distinct genetic and epigenetic alterations, and with distinct outcomes. These findings may lead to more precise diagnostic and prognostic assessments, molecular subgroup-adapted therapies, and eventually new recommendations pending validation in prospective studies.
Topics: Ependymoma; Humans; Practice Guidelines as Topic; Prognosis
PubMed: 29194500
DOI: 10.1093/neuonc/nox166 -
Brain Pathology (Zurich, Switzerland) Jul 2022Ependymal neoplasms occur at all ages and encompass multiple tumor types and subtypes that develop in the supratentorial compartment, the posterior fossa, or the spinal... (Review)
Review
Ependymal neoplasms occur at all ages and encompass multiple tumor types and subtypes that develop in the supratentorial compartment, the posterior fossa, or the spinal cord. Clinically, ependymomas represent a very heterogeneous group of tumors from rather benign subependymomas to very aggressive and often deadly childhood ependymomas of the posterior fossa. Newly identified biological markers and classification schemes, e. g. based on global DNA methylation profiling, have led to the definition of 10 types of ependymal tumors and an improved prediction of patients' outcome by applying the new classification system. While the exact genetic basis for several ependymoma types still remains unclear, the knowledge about ependymoma driving events has significantly increased within the last decade and contributed to a classification based on molecular characteristics and localization rather than histological features alone. Convincing evidence is now pointing towards gene fusions involving ZFTA or YAP1 causing the development of supratentorial ependymomas. Also, H3, EZHIP, or TERT mutations have been detected in a fraction of infratentorial ependymal tumors. Finally, MYCN amplifications have recently been identified in spinal ependymomas, in addition to the previously known mutations in NF2. This review summarizes how recent findings regarding biology, molecular tumor typing, and clinical outcome have impacted the classification of ependymomas as suggested by the updated 2021 WHO CNS tumor classification system. We focus on changes compared to the previous classification of 2016 and discuss how a formal grading could evolve in the future and guide clinicians to treat ependymoma patients.
Topics: Brain Neoplasms; Child; Ependymoma; Humans; Infratentorial Neoplasms; Supratentorial Neoplasms; World Health Organization
PubMed: 35307892
DOI: 10.1111/bpa.13068 -
Neuro-oncology Mar 2021No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its...
BACKGROUND
No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas.
METHODS
Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected.
RESULTS
The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients.
CONCLUSIONS
This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.
Topics: Adolescent; Adult; Brain Neoplasms; Dacarbazine; Disease-Free Survival; Ependymoma; Humans; Lapatinib; Prospective Studies; Spinal Cord Neoplasms; Temozolomide
PubMed: 33085768
DOI: 10.1093/neuonc/noaa240 -
Journal of Clinical Oncology : Official... Apr 2019The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery,... (Clinical Trial)
Clinical Trial
Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma.
PURPOSE
The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and-selectively-with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT).
METHODS
ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles.
RESULTS
The 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade ( = .0044) but not by age, location, fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% [95% CI, 74.4% to 91.2%] 47.4% [95% CI, 26.0% to 68.8%]; = .0013).
CONCLUSION
The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Child; Child, Preschool; Cytoreduction Surgical Procedures; Ependymoma; Female; Humans; Infant; Male; Progression-Free Survival; Radiotherapy, Conformal; Supratentorial Neoplasms; Transcription Factor RelA; Treatment Outcome; Young Adult
PubMed: 30811284
DOI: 10.1200/JCO.18.01765 -
Nature Communications Apr 2023Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and...
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.
Topics: Child; Humans; Child, Preschool; Neoplasm Recurrence, Local; Chromosomes; Chromosome Mapping; Ependymoma; Genome; Chromatin
PubMed: 37085539
DOI: 10.1038/s41467-023-38044-0 -
Cell Jun 2020Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are...
Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
Topics: Animals; Brain Neoplasms; Cell Line; Cell Proliferation; DNA Methylation; Ependymoma; Epigenome; Epigenomics; Histones; Humans; Infant; Infratentorial Neoplasms; Lysine; Male; Mice, Inbred C57BL; Mutation
PubMed: 32445698
DOI: 10.1016/j.cell.2020.04.047 -
Pathologica Dec 2022Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During... (Review)
Review
Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During the last few years, significant novel data concerning oncogenesis, molecular characteristics and clinical correlations of these tumours have been collected, with a strong relevance for their pathological classification. The recently published 5th edition of WHO Classification of Central Nervous System Tumours integrates this novel knowledge and represents a substantial update compared to the previous edition. Concerning supratentorial ependymomas, the previous fusion-positive ependymoma has been renamed into fusion-positive and the novel fusion-positive ependymoma subtype has been added. Posterior fossa ependymomas should now be allocated either to the Type A or Type B subtypes based on molecular profiling or using the H3 K27me3 immunohistochemical surrogate. Regarding spinal ependymomas, a novel subtype has been added based on a distinctive molecular trait, presence of amplification, and on the unfavourable outcome. Finally, myxopapillary ependymoma is now classified as a grade 2 tumour in accordance with its overall prognosis which mirrors that of conventional spinal ependymomas. The aim of this review is to present these changes and summarize the current diagnostic framework of ependymal tumours, according to the most recent updates.
Topics: Humans; Ependymoma; Prognosis
PubMed: 36534422
DOI: 10.32074/1591-951X-817 -
Cancer Cell Jul 2020Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze...
Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze ependymomas across molecular groups and anatomic locations to investigate their intratumoral heterogeneity and developmental origins. Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification. While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations. The delineated transcriptomic signatures correlate with patient survival and define molecular dependencies for targeted treatment approaches. Taken together, our analyses reveal a developmental hierarchy underlying ependymomas relevant to biological and clinical behavior.
Topics: Cell Differentiation; Cell Proliferation; Central Nervous System Neoplasms; Child; Ependymoma; Genomics; Humans; Neurons; Prognosis; Sequence Analysis, RNA; Single-Cell Analysis; Survival Analysis
PubMed: 32663469
DOI: 10.1016/j.ccell.2020.06.004 -
Nature Medicine May 2020Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all...
Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
Topics: Animals; Brain Neoplasms; Cancer Vaccines; Cerebellar Neoplasms; Cerebrospinal Fluid; Child; Child, Preschool; Drug Delivery Systems; Ependymoma; Female; HEK293 Cells; Humans; Immunotherapy, Adoptive; Infant; Injections, Intraventricular; Male; Medulloblastoma; Mice; Neoplasm Metastasis; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 32341580
DOI: 10.1038/s41591-020-0827-2