Rare Central Nervous System Tumors Research Articles

Rare central nervous system tumors in adults: a population-based study of ependymomas, pilocytic astrocytomas, medulloblastomas, and intracranial germ cell tumors.

BackgroundEpendymomas, pilocytic astrocytomas, medulloblastomas, and intracranial germ cell tumors occur relative frequently in children, but are rare central nervous system (CNS) tumors in adults. In this population-based survey, we established incidence, treatment, and survival patterns for these tumors diagnosed in adult patients (≥18 years) over a 30-year period (1989–2018).MethodsData on 1384 ependymomas, 454 pilocytic astrocytomas, 205 medulloblastomas, and 112 intracranial germ cell tumors were obtained from the Netherlands Cancer Registry (NCR) on the basis of a histopathological diagnosis. For each tumor type, age-standardized incidence rates and estimated annual percentage change were calculated. Trends in incidence and main treatment modalities were reported per 5-year periods. Overall survival was calculated using the Kaplan–Meier method, and relative survival rates were estimated using the Pohar-Perme estimator.ResultsIncidence and survival rates remained generally stable for pilocytic astrocytomas, medulloblastomas, and germ cell tumors. Increasing incidence was observed for spinal ependymomas, mostly for myxopapillary ependymomas, and survival improved over time for grade II ependymomas (P < .01). Treatment patterns varied over time with shifting roles for surgery in ependymomas and for chemotherapy and radiation in medulloblastomas and germinomas.ConclusionsThe study provides baseline information for highly needed national and international standard treatment protocols, and thus for further improving patient outcomes in these rare CNS tumors.

Extraventricular neurocytoma.

Neurocytoma is a rare central nervous system neoplasm that usually arises in an intraventricular location (so-called Central Neurocytoma), but also exists in an extraventricular location (defined as Extraventricular Neurocytoma: EVN). Clinically EVN manifests as headache, nausea, vomiting, complex partial seizures or focal neurological deficits. In some cases, atypical signs characterizing an aggressive clinical behavior may be present. Topographically, EVN most frequently occurs as intrahemispheric (particularly in the frontal lobes), followed by the spinal cord. However, rarer sites have been described.1 Radiologically, EVN is a well-circumscribed, slow-growing neoplasm, usually hyperintense on T2-weighted MRI and isointense/hypointense with no contrast enhancement on T1-weighted MRI.2 Microscopically, EVN consists of small, round cells that show neuronal differentiation, without marked atypia and/or pleomorphism, without vascular endothelial proliferation and/or necrosis and with low mitotic and proliferation indexes. The 2016 World Health Organization classification of tumors of the central nervous system (WHO2016) assigns to EVN histological grade II.3 Immunohistochemically, the main marker to identify the neuronal nature of the neoplasm is Synaptophysin, but immunohistochemical positivity for Synaptophysin alone is not sufficient to conclude a diagnosis of EVN. In fact, there are other central nervous system tumors that may express it, including mainly: pilocytic astrocytoma, disembryoplastic neuroepithelial tumor, ganglioglioma, glioneuronal papillary tumor, some oligodendrogliomas and diffuse leptomeningeal glioneuronal tumor. For this reason, the immunohistochemistry of Synaptophysin should be supplemented with immunohistochemistry for OLIG2 (expression of this marker is usually incompatible with EVN) and molecular investigations to look for IDH mutations (in EVN, IDH must be non-mutated) and/or to look for co-deletion of chromosomes 1p and 19q (AVN must be 1p/19q non-codeleted).3 The pictures above refer to the case of an 86-year-old woman who was found unconscious on the ground at her home for no apparent reason. When she was taken to hospital, a febrile state set in but, before further investigation, she died. An autopsy was therefore carried out, which revealed acute pneumonia as the main cause of death. However, careful macroscopic examination of the formalin-fixed brain, after isolating the vessels of the polygon of Willis, revealed the presence of a 1.2 cm roundish mass at the bifurcation of the two anterior cerebral arteries (Figure1A). Figure 1 A – Macroscopic view of the Willis polygon with a mass at the emergence of the anterior cerebral arteries (arrow); B – Photomicrograph of the well- circumscribed nodular lesion with some micro calcifications (arrows) (H&E, 4x); C – High power field of the nodular lesion showing round cells, sometimes with evident nucleoli, without significant atypia and without mitosis (H&E; 60x); D – Immunohistochemistry, showing positivity for Synaptophysin.: Histological examination of this lesion showed a nodular proliferation of small, uniform round cells, sometimes with cleared cytoplasm (oligodendroglioma-like appearance), in the absence of mitosis, endothelial proliferation and/or necrosis (Figures 1B, 1C), expressing a neuronal-like immunohistochemical profile: widespread immunohistochemical positivity for S100, Synaptophysin (Figure 1D) and Neuron-specific Enolase (NSE) were detected; the proliferation index, assessed by Ki67, was less than 1%. Immunohistochemical staining was negative for: cytokeratins AE1/AE3; EMA; GFAP; OLIG2; Chromogranin; GH; Prolactin; ACTH; TSH; LH; FSH; TTF1; CD31 and CD34. Finally, also the immunohistochemical staining for R132-mutant IDH1 protein was negative. The molecular testing (FISH) for 1p/19q deletion status was not performed. The results were overall consistent with a low-grade neuronal neoplasm of the central nervous system and in particular - although the exceptional site - with an extraventricular neurocytoma.

Molecular Biology in Treatment Decision Processes-Neuro-Oncology Edition.

Computational approaches including machine learning, deep learning, and artificial intelligence are growing in importance in all medical specialties as large data repositories are increasingly being optimised. Radiation oncology as a discipline is at the forefront of large-scale data acquisition and well positioned towards both the production and analysis of large-scale oncologic data with the potential for clinically driven endpoints and advancement of patient outcomes. Neuro-oncology is comprised of malignancies that often carry poor prognosis and significant neurological sequelae. The analysis of radiation therapy mediated treatment and the potential for computationally mediated analyses may lead to more precise therapy by employing large scale data. We analysed the state of the literature pertaining to large scale data, computational analysis, and the advancement of molecular biomarkers in neuro-oncology with emphasis on radiation oncology. We aimed to connect existing and evolving approaches to realistic avenues for clinical implementation focusing on low grade gliomas (LGG), high grade gliomas (HGG), management of the elderly patient with HGG, rare central nervous system tumors, craniospinal irradiation, and re-irradiation to examine how computational analysis and molecular science may synergistically drive advances in personalised radiation therapy (RT) and optimise patient outcomes.

An Overview of Intracranial Ependymomas in Adults

Simple SummaryEpendymomas are neuroepithelial tumors arising from the central nervous system. They can form anywhere along the neuraxis. In adults, these tumors predominantly occur in the spine. Local therapy with surgery and radiotherapy represents the most effective treatment while systemic chemotherapy should be used in recurrent cases. However, in recent years, a deeper knowledge of molecular mechanisms of these tumors has been made, allowing for new potential systemic treatments. Here, we review these treatment approaches and provide an overview on the molecular characteristics of ependymomas.Ependymomas are rare primary central nervous system tumors. They can form anywhere along the neuraxis, but in adults, these tumors predominantly occur in the spine and less frequently intracranially. Ependymal tumors represent a heterogenous group of gliomas, and the WHO 2016 classification is based essentially on a grading system, with ependymomas classified as grade I, II (classic), or III (anaplastic). In adults, surgery is the primary initial treatment, while radiotherapy is employed as an adjuvant treatment in some cases of grade II and in all cases of anaplastic ependymoma; chemotherapy is reserved for recurrent cases. In recent years, important and interesting advances in the molecular characterization of ependymomas have been made, allowing for the identification of nine molecular subgroups of ependymal tumors and moving toward subgroup-specific patients with improved risk stratification for treatment-decisions and future prospective trials. New targeted agents or immunotherapies for ependymoma patients are being explored for recurrent disease. This review summarizes recent molecular advances in the diagnosis and treatment of intracranial ependymomas including surgery, radiation therapy and systemic therapies.

Embryonal tumor with multilayered rosettes; rare pediatric CNS tumor. A case report and review of literature

Embryonal tumor with multilayered rosettes (ETMR), C19MC-altered is a newly designated entity of the embryonal tumors of the central nervous system (CNS) according to the 2016 WHO classification system of CNS. Characteristically, these tumors are newly defined based on their specific molecular genetic amplification in chromosome 19q13.42 found at locus C19MC. To the best of our knowledge, we present the first reported case of ETMR in Saudi Arabian pediatric population. A 2-year-old boy presented to the hospital with generalized tonic-colonic seizure, vomiting, irritability, and inability to walk. Computed tomography (CT) scan showed a large left thalamic supratentorial brain tumor. The tumor measured 6.1 × 5.6 × 5.6 cm and was characterized by cystic changes, prominent vasculature, and calcifications. Histopathology, immunohistochemistry examination, and fluorescence in situ hybridization (FISH) analysis confirmed the diagnosis of ETMR. In addition to reporting this rare case, we provide a brief literature review, treatment options, patient outcome, and disease prognosis.

An unexpected sudden death due to a choroid plexus papilloma: an autopsy case report

BackgroundChoroid plexus papillomas (CPPs) are histopathologically benign and rare central nervous system tumors. These tumors remain more frequent in children than adults. It is infrequent for these tumors to cause a sudden unexpected death. We aim in this case to discuss the unusual and fatal presentation of choroid plexus papilloma and the mechanism of death.Case presentationwe report the case of a 61-year-old man with no medical history, diagnosed at autopsy with a previously unknown CPP. Initial complaints were chronic headache occurring in the last month and acute chest pain for two days. The forensic autopsy including the histopathologic examination showed a tumoral mass of the choroid plexus in the fourth ventricle diagnosed as a psammomatous CPP. The cause of death in this case was attributed to a massive cerebral edema caused by the tumoral mass.ConclusionsThrough this case report, we stress the importance of an early and a vigorous investigation of every headache and an early detection of this tumor and we highlight as well the role of the post mortem examination to detect such a fatal complication.

EPID-15. AGE AND DOSIMETRIC IMPACTS ON RADIOTHERAPY ASSOCIATED GROWTH IMPAIRMENT FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMORS (GCTs)

Abstract PURPOSE Intracranial germ cell tumors (GCTs) are rare pediatric central nervous system (CNS) tumors. Growth impairment induced by radiation treatments was rarely evaluated. We aimed to study the impacts of radiotherapy on height development and identify the dosimetric constraints. MATERIALS AND METHODS A total of 148 pediatric patients diagnosed with GCTs were retrospectively analyzed. Sex, age at irradiation, physical doses and biologically effective dose (BED), height, and endocrine status were obtained from patient records. The cumulative change in height was assessed using age-matched normalized height (ANH). Variables were assessed for correlations and statistical significance. RESULTS Cumulative physical doses and BEDs for the whole brain and pituitary were derived via DVHs and BEDVHs. In contrast to patients &amp;gt;11.5 yr, linear correlations between ANH and cumulative physical doses as well as BEDs to the whole brain and pituitary were identified in patients≤11.5 yr. Dosimetric constrains to the pituitary was 36 Gy for physical dose (AUC=0.70 [95% CI, 0.54-0.86], P&amp;lt; 0.05) and 63 Gy2 BED (AUC=0.69 [95% CI, 0.53-0.86], P&amp;lt; 0.05). Intriguingly, no significant differences in ANH were found among different CSI dose groups in patients ≤11.5 yr. (all P&amp;gt;0.05). Impaired hormone secretions in terms of GH and TSH were identified following cranial irradiation (both P&amp;lt; 0.001), particularly for those with tumors at the suprasellar region (GH: P&amp;lt; 0.01, TSH: P&amp;lt; 0.001). CONCLUSION Our study revealed the impacts of age, dosimetrics and tumor locations for growth impairment. This study will contribute to the optimization of radiation treatment planning and facilitate more individualized therapeutic strategies in pediatric patient with GCTs.

Rare central nervous system tumors: the path to progress.

Rare central nervous system tumors: the path to progress.

Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers.

Patients with rare central nervous system (CNS) tumors typically have a poor prognosis and limited therapeutic options. Historically, these cancers have been difficult to study due to small number of patients. Recent technological advances have identified molecular drivers of some of these rare cancers which we can now use to generate representative preclinical models of these diseases. In this review, we outline the advantages and disadvantages of different models, emphasizing the utility of various in vitro and ex vivo models for target discovery and mechanistic inquiry and multiple in vivo models for therapeutic validation. We also highlight recent literature on preclinical model generation and screening approaches for ependymomas, histone mutated high-grade gliomas, and atypical teratoid rhabdoid tumors, all of which are rare CNS cancers that have recently established genetic or epigenetic drivers. These preclinical models are critical to advancing targeted therapeutics for these rare CNS cancers that currently rely on conventional treatments.

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma.

Simple SummaryH3K27M-mutant diffuse midline glioma is a rare childhood cancer originating in midline brain structures. The H3K27M mutation substitutes an amino acid on histone H3 that promotes gene expression and tumor growth. This cancer has a dismal prognosis and requires new and better treatment approaches. This review discusses controversies regarding tumor biopsy and summarizes molecular tumor characteristics that are therapeutic targets. We describe preclinical studies and clinical trials utilizing immunotherapy, radiation, and chemotherapy against this cancer. H3K27M-mutant diffuse midline gliomas (DMGs) are rare childhood central nervous system tumors that carry a dismal prognosis. Thus, innovative treatment approaches are greatly needed to improve clinical outcomes for these patients. Here, we discuss current trends in research of H3K27M-mutant diffuse midline glioma. This review highlights new developments of molecular pathophysiology for these tumors, as they relate to epigenetics and therapeutic targeting. We focus our discussion on combinatorial therapies addressing the inherent complexity of treating H3K27M-mutant diffuse midline gliomas and incorporating recent advances in immunotherapy, molecular biology, genetics, radiation, and stereotaxic surgical diagnostics.

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

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.

Analyses of DNA Methylation Profiling in the Diagnosis of Intramedullary Astrocytomas

Intramedullary astrocytomas (IMAs) consist of a heterogeneous group of rare central nervous system (CNS) tumors associated with variable outcomes. A DNA methylation-based classification approach has recently emerged as a powerful tool to further classify CNS tumors. However, no DNA methylation-related studies specifically addressing to IMAs have been performed yet. In the present study, we analyzed 16 IMA samples subjected to morphological and molecular analyses, including DNA methylation profiling. Among the 16 samples, only 3 cases were classified in a reference methylation class (MC) with the recommended calibrated score (≥0.9). The remaining cases were either considered “no-match” cases (calibrated score <0.3, n = 7) or were classified with low calibrated scores (ranging from 0.32 to 0.53, n = 6), including inconsistent classification. To obtain a more comprehensive tool for pathologists, we used different unsupervised analyses of DNA methylation profiles, including our data and those from the Heidelberg reference cohort. Even though our cohort included only 16 cases, hypotheses regarding IMA-specific classification were underlined; a potential specific MC of PA_SPINE was identified and high-grade IMAs, probably consisting of H3K27M wild-type IMAs, were mainly associated with ANA_PA MC. These hypotheses strongly suggest that a specific classification for IMAs has to be investigated.

Prognostic factors in adult brainstem glioma: a tertiary care center analysis and review of the literature

IntroductionAdult brainstem gliomas (BSGs) are rare central nervous system tumours characterized by a highly heterogeneous clinical course. Median survival times range from 11 to 84 months. Beyond surgery, no treatment standard has been established. We investigated clinical and radiological data to assess prognostic features providing support for treatment decisions.Methods34 BSG patients treated between 2000 and 2019 and aged ≥ 18 years at the time of diagnosis were retrospectively identified from the databases of the two largest Austrian Neuro-Oncology centres. Clinical data including baseline characteristics, clinical disease course, applied therapies, the outcome as well as neuroradiological and neuropathological findings were gathered and analysed. The tumour apparent diffusion coefficient (ADC), volumetry of contrast-enhancing and non-contrast-enhancing lesions were determined on magnetic resonance imaging scans performed at diagnosis.ResultsThe median age at diagnosis was 38.5 years (range 18–71 years). Tumour progression occurred in 26/34 (76.5%) patients after a median follow up time of 19 months (range 0.9–236.2). Median overall survival (OS) and progression-free survival (PFS) was 24.1 months (range 0.9–236.2; 95% CI 18.1–30.1) and 14.5 months (range 0.7–178.5; 95% CI 5.1–23.9), respectively. Low-performance status, high body mass index (BMI) at diagnosis and WHO grading were associated with shorter PFS and OS at univariate analysis (p < 0.05, log rank test, respectively). ADC values below the median were significantly associated with shorter OS (14.9 vs 44.2 months, p = 0.018).ConclusionECOG, BMI, WHO grade and ADC values were associated with the survival prognosis of BSG patients and should be included in the prognostic assessment.

Targeted Therapies in Rare Brain Tumours.

Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for these tumours supported by high quality evidence, and knowledge regarding the impact of standard treatments (i.e., surgery, radiotherapy or chemotherapy) is commonly based on retrospective studies. Recently, new molecular techniques have led to the discovery of actionable molecular alterations. The aim of this article is to review recent progress in the molecular understanding of and therapeutic options for rare brain tumours, both in children and adults. We will discuss options such as targeting the mechanistic target of rapamycin (mTOR) pathway in subependymal giant cells astrocytomas (SEGAs) of tuberous sclerosis and BRAF V600E mutation in rare glial (pleomorphic xanthoastrocytomas) or glioneuronal (gangliogliomas) tumours, which are a model of how specific molecular treatments can also favourably impact neurological symptoms (such as seizures) and quality of life. Moreover, we will discuss initial experiences in targeting new molecular alterations in gliomas, such as isocitrate dehydrogenase (IDH) mutations and neurotrophic tyrosine receptor kinase (NTRK) fusions, and in medulloblastomas such as the sonic hedgehog (SHH) pathway.

IMMU-07. “STROKE MIMICS” ARE NOT BENIGN IN IMMUNOCOMPROMISED CHILDREN

ObjectiveTo determine the clinical variances between strokes and stroke mimics in a pediatric immunocompromised population that consists of children with central nervous system (CNS) and non-CNS malignancies and a history of solid organ transplantation. MethodsWe performed a retrospective cohort analysis of stroke alert activations in patients with high-grade gliomas, low-grade gliomas, atypical teratoid rhabdoid tumors, rare CNS tumors, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, osteosarcoma, and solid organ transplants at St. Louis Children’s Hospital between February 2013 and September 2019. We categorized final diagnoses as strokes or stroke mimics. We classified diagnoses as a neurologic emergency if the diagnosis necessitated changes in management. ResultsOut of 217 stroke alerts, 31 alerts occurred for 28 patients meeting inclusion criteria. All final diagnoses constituted neurologic emergencies, including: stroke (39%), chemotherapy-related neurotoxicity (29%), tumor progression (19%), and seizures/posterior reversible encephalopathy syndrome (13%). Patients meeting inclusion criteria with strokes and stroke mimics presented similarly, with the exception of altered mental status, which was more prevalent in patients with strokes than stroke mimics (p = 0.03). One child received hyperacute thrombectomy for stroke. Only 58% of children with stroke mimics had complete resolution of their presenting neurologic symptoms. Children with strokes and stroke mimics had similar mortality incidences of 33% and 37%, respectively. ConclusionsAlthough all acute neurologic changes in immunocompromised children are not strokes, stroke mimics in this population are neither benign nor self-limited and carry long-term neurologic morbidity and mortality. This study highlights the utility of an acute stroke evaluation infrastructure and the need for acute and long-term neurology involvement in the care of these patients.

Papillary glioneuronal tumors: Distinctive cytological characteristics and cyto-histologic correlation

Intraoperative cytological examination and cyto-histologic correlation of papillary glioneuronal tumors have rarely been described in detail in the literature. A 23-year-old female presented at our institution with seizure-like activity, and a 3.0 cm left temporal lobe hypoattenuating lesion. She was accurately diagnosed with papillary glioneuronal tumor on Intraoperative cytology. The patient subsequently proceeded to stealth-guided awake left temporal craniotomy, confirming the diagnosis. In this article, we present a detailed report of papillary glioneuronal tumor (extremely rare central nervous system neoplasm) describing the cytologic and histologic morphologic features, its differential diagnosis with review of the literature.

Papillary meningioma of the central nervous system: a SEER database analysis.

Papillary meningioma (PM) is a rare central nervous system tumor. We aimed to analyze the characteristics and outcomes of patients with PM (WHO grade III) and identify risk factors that influence survival using the Surveillance, Epidemiology, and End Results (SEER) database. Clinical characteristics, tumor features, and outcomes of 108 PM patients included in the SEER database between 1990 and 2016 were retrieved. Risk factors related to prognosis of PM were assessed by Kaplan-Meier curves and the Cox proportional hazards model. All 108 patients, including 65 males and 43 females (1.5:1), with a median age of 52years (range, 9 to > 85years) had undergone surgical resection. Gross total resection (GTR) was achieved in 50%, and 50% underwent subtotal resection (STR). While 55.6% underwent postoperative radiation therapy, 48% did not. The median disease-specific survival (DSS) was 128months, and the 5-year DSS rate was 77%. In multivariate analysis, age ≤ 52years and GTR were both independently associated with higher probability of DSS (p = 0.033 and p = 0.029, respectively). Stratification analysis showed that postoperative radiotherapy had no significant impact on the DSS, irrespective of resection extent (p = 0.172). Our SEER analysis showed that age and extent of resection were prognostic factors for PM, but race, tumor size, gender, chemotherapy, and postoperative radiotherapy did not significantly impact DSS of PM patients. There was no significant improvement in survival of patients who underwent radiotherapy and GTR, or radiotherapy and STR, compared with GTR or STR alone.

Integrative molecular characterization of pediatric spinal ependymoma: the UK Children’s Cancer and Leukaemia Group study

BackgroundPediatric spinal ependymomas (SP-EPNs) are rare primary central nervous system tumors with heterogeneous clinical course. Considering that ependymomas in children are biologically distinct from their adult counterparts, this study aimed to define the molecular landscape of SP-EPNs in children.MethodsIn this retrospective study, we have collected tumor samples from 27 SP-EPN patients younger than 18 years and carried out the histological review, DNA methylation, and gene expression profiling.ResultsUnsupervised analyses with methylation profiles revealed 2 subgroups where all grade I tumors (n = 11) were in Group 1, but the grade II/III tumors split into 2 groups (n = 7 in Group 1 and n = 9 in Group 2). The Heidelberg classifier assigned Group 1 tumors as spinal myxopapillary ependymomas (SP-MPEs), 5 Group 2 tumors as SP-EPNs, and failed to classify 4 Group 2 tumors. Copy numbers derived from DNA methylation arrays revealed subgroup-specific genetic alterations and showed that SP-EPN tumors lack MYCN amplification. Gene expression profiling revealed distinct transcriptomic signatures, including overexpression of genes involved in oxidative phosphorylation in SP-MPEs that were validated by Western blot analysis. We discovered widespread decreases in DNA methylation at enhancer regions that are associated with the expression of oncogenic signaling pathways in SP-MPEs. Furthermore, transcription factor motifs for master regulators, including HNF1B, PAX3, and ZIC3, were significantly overrepresented in probes specific to distal regulatory regions in SP-MPEs.ConclusionOur findings show substantial heterogeneity in pediatric SP-EPN and uncover novel enhancers and transcriptional pathways specific to the SP-MPE subgroup, providing a foundation for future therapeutic strategies.

ETMR-08. INTERNATIONAL CONSENSUS PROTOCOL FOR EMBRYONAL TUMOR WITH MULTILAYER ROSETTES

Embryonal tumors with multilayer rosettes (ETMR) are rare and highly-aggressive central nervous system (CNS) neoplasms which occur primarily in young children and carry a dismal prognosis. To date, no large clinical investigations have been conducted to determine the optimal therapy for ETMR. Data from retrospective case series suggest that our most aggressive standard therapies are not sufficient for cure in the majority of cases. New treatment approaches incorporating pre-clinical data and the known biology of ETMR are therefore urgently needed. A German drug screen using the patient-derived ETMR BT183 cell line and its xenograft revealed anti-tumor activity of topotecan, doxorubicin, and actinomycin D; three agents used infrequently for treating infant CNS tumors. Additional results from a small series of ETMR patients suggest that optimization of induction chemotherapy using these active agents may improve response and survival outcomes. In 2019, an international panel of pediatric neuro-oncology experts convened to advance therapy for ETMR. A consensus protocol was developed incorporating maximal safe surgical resection, induction chemotherapy with active pre-clinical agents, intrathecal chemotherapy, radiotherapy, and high-dose chemotherapy. This international consensus protocol represents the first prospective clinical investigation specific to ETMR and will be available through a treatment registry globally and as a clinical trial at select centers. The study aims to improve survival by providing aggressive, optimized therapy for ETMR and will serve as a platform to explore new biologically-promising agents. The investigation will also provide valuable prospective outcome data and correlative biological studies to serve as baseline comparators for future clinical trials.

Treatments of gliosarcoma of the brain: a systematic review and meta-analysis.

Gliosarcoma (GSM) is a rare central nervous system tumor. Clinical management of it is similar to glioblastoma (GBM). However, due to a few comparative studies exist, uncertainty and disagreements remain in the literatures. To assess the available evidence on the value of different treatments and to carry out an up-to-date evaluation to summarize the evidence for the optimal treatment in GSM patients. Free words were used to search for the relevant studies without language limitations in electronic databases including PubMed, Ovid EMBASE, Cochrane Central Register of Controlled Trials from inception to September 15, 2019. Pooled hazard ratio (HR) with 95% confidence interval (CI) were calculated using a random-effects model. The main endpoint was all-cause mortality. Overall, 10 studies published between 2008 and 2018 including 803 patients were selected for the meta-analysis. Temozolomide (TMZ)-dominated chemotherapy was associated with a reduced risk of overall survival (OS), with HR 0.49 (95% CI 0.37-0.66). The pooled HR of OS was 0.40 (95% CI 0.29-0.56) between radiotherapy and without radiotherapy. The pooled HR (0.52, 95% CI 0.32-0.85) indicated gross total resection (GTR) had a positive impact on OS in GSM. In patients with GSM, survival benefits as currently performed are associated with TMZ-dominated chemotherapy and high-dose radiotherapy. Our systematic review and meta-analysis also demonstrate GTR is associated with a reduction in all-cause mortality in patients with primary GSM.