bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPEN-23. A COMPUTATIONAL ANALYSIS OF THE TUMOUR IMMUNE MICROENVIRONMENT IN PAEDIATRIC EPENDYMOMA
Authors: Ritzmann Timothy , Lourdusamy Anbarasu , Jackson Andrew , Storer Lisa , Donson Andrew , Griesinger Andrea , Foreman Nicholas , Rogers Hazel , Grundy Richard 
Published: December 2020

Abstract
Ependymoma is the third commonest childhood brain tumour. Relapse is frequent, often fatal and current therapeutic strategies are inadequate. Previous ependymoma research describes an immunosuppressive environment with T-cell exhaustion, indicating a lack of response to T-cell directed immunotherapy. Understanding the immune microenvironment is therefore critical. We present a computational analysis of ependymoma, gene expression derived, immune profiles. Using 465 ependymoma samples from gene expression datasets (GSE64415, GSE50385, GSE100240) and two RNA-seq databases from UK ependymomas, we applied bulk tumour deconvolution methods (CIBERSORT and xCell) to infer immune cell populations. Additionally, we measured checkpoint blockade related mRNAs and used immunohistochemistry to investigate cell populations in ependymoma sections. CIBERSORT indicated high proportions of M2-like macrophages and smaller proportions of activated natural killer (NK) cells, T follicular helper cells, CD4+ memory T-cells and B-cells. xCell overlapped with the M2-like macrophage and CD4+ memory T-cell signatures seen in CIBERSORT. On immunohistochemistry, T and B cells were scarce, with small numbers of CD8+, CD4+ and CD20+ cells in the parenchyma but greater numbers in surrounding regions. CD68 was more highly expressed in the parenchyma. Analysis of nine checkpoint ligands and receptors demonstrated only the TIM3/GAL9 combination was reliably detectable. GAL9 is implicated in tumour interactions with T-cells and macrophages elsewhere, possibly contributing to poorer outcomes. Our study supports the presence of myeloid cells being leading contributors to the ependymoma immune microenvironment. Further work will delineate the extent of myeloid contribution to immunosuppression across molecular subtypes. Modulation of tumour immunity may contribute to better clinical outcomes.
EPEN-28. NOVEL ONCOGENE AMPLIFICATION IN SPINAL EPENDYMOMA INVOLVING THE MYC LOCUS (8q24)
Authors: Shatara Margaret , Boué Daniel R , Pierson Christopher R , Thomas Diana L , Sribnick Eric A , Jones Jeremy , Rodriguez Diana P , Schieffer Kathleen M , Deeg Carol , Hamelberg Elizabeth , LaHaye Stephanie , Magrini Vincent , Wilson Richard K , Mardis Elaine R , Cottrell Catherine E , Varga Elizabeth A , AbdelBaki Mohamed S , Finlay Jonathan L , Osorio Diana S 
Published: December 2020

Abstract

BACKGROUND
We report a unique case of spinal ependymoma with classic histology and aggressive clinical behavior which harbored a focal MYC (8q24) amplification. CASE REPORT: A-12-year old male presented with a three months history of back pain and acute onset weakness with ataxia. A spine MRI revealed an avidly enhancing intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. The tumor demonstrated mild diffusion restriction and was associated with severe cord compression and mild edema. He underwent gross total resection. Pathological diagnosis was classic grade II ependymoma. Eleven months later, he re-presented with acute onset lower extremity paresthesia and left-handed weakness. Spine MRI demonstrated tumor recurrence extending from C2 through T1-T2 with resultant severe cord compression, again demonstrating avid enhancement and restricted diffusion. He underwent subtotal resection of the mass and focal proton beam irradiation. MOLECULAR CHARACTERISTICS: The patient was enrolled on an institutional comprehensive genomic profiling protocol. The tumor’s copy number profile was complex, including homozygous loss of 17p and notably, amplification of the MYC oncogene. Using fluorescence in situ hybridization, we identified &gt;20 copies of MYC in interphase cells, confirming the gene amplification, while two copies of MYCN (2p24) were seen. DNA methylation further classified this tumor as clustering near posterior fossa group A (score=0.6073) tumors.

CONCLUSION
We report a unique case of an adolescent male with aggressive spinal ependymoma harboring focal MYC amplification. Testing for MYC amplification may be reasonable in newly-diagnosed spinal ependymomas to aid in characterization.
EPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVEL GENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH
Authors: Arabzade Amir , Zhao Yanhua , Varadharajan Srinidhi , Chen Hsiao-Chi , Stuckert Austin , Rivas Bryan , Agnihotri Sameer , Hodges Courtney , Parsons Donald , Blaney Susan , Westbrook Thomas , Lin Charles , Yi Joanna , Deneen Benjamin , Bertrand Kelsey , Mack Stephen 
Published: December 2020

Abstract

RATIONALE
Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95-RELA fusion is frequently the sole genetic driver detected in ST ependymoma, thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB pathway activation in processes such as inflammation, cellular metabolism, and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA during embryonic development. Our IUE approach allowed us to develop C11ORF95-RELA driven tumor models and cell lines. We comprehensively characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq.

RESULTS
This data revealed that: 1) C11ORF95-RELA directly engages ‘open’ chromatin and is enriched at regions with known RELA TF binding sites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentially binds to both H3K27ac (active) enhancers and promoters, and 3) Bound C11ORF95-RELA promoter loci are associated with increased transcription of genes shared with human ependymoma.

CONCLUSION
Our findings shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes and molecular targets.
EPEN-36. THE TREATMENT OUTCOME OF PAEDIATRIC SUPRATENTORIAL C11ORF95-RELA FUSED EPENDYMOMA: A COMBINED REPORT FROM E-HIT SERIES AND AUSTRALIAN NEW ZEALAND CHILDREN’S HAEMATOLOGY/ONCOLOGY GROUP
Authors: Ng Chia Huan , Obrecht Denise , Buntine Molly , Wells Olivia , Campbell Martin A , Bhatia Kanika , Sullivan Michael , Williams Molly , Quang Dong Anh Khuong , Kinross Kathryn , White Christine , Algar Elizabeth , Witt Hendrik , Schuller Ulrich , Mynarek Martin , Pietsch Torsten , Gerber Nicolas U , Benesch Martin , Warmuth-Metz Monika , Kortmann Rolf , Bison Brigitte , Taylor Michael D , Ramaswamy Vijay , Rutkowski Stefan , Pfister Stefan M , Jones David T W , Gottardo Nicholas G , Von Hoff Katja , Pajtler Kristian W , Hansford Jordan R 
Published: December 2020

Abstract

AIM
Advances in molecular classification of paediatric ependymoma have been pivotal in improving risk stratification and understanding of this disease. C11orf95-RELA fused supratentorial ependymoma (ST-EPN) have been reported to have a poor outcome, with 10-year overall survival (OS) of 49% and progression free survival (PFS) of 19%. A cohort of patients from multiple international institutions with molecularly confirmed C11orf95-RELA fused ST-EPN were reviewed to assess their disease behaviour. METHOD: We reviewed patients with molecularly determined C11orf95-RELA supratentorial ependymoma diagnosed between 1999 – 2019. Demographic information, extent of surgical resection, use of radiotherapy and/or chemotherapy, disease recurrence, treatment at recurrence and clinical outcome data was collected. PFS and OS of all patients were estimated using Kaplan-Meier method.

RESULTS
A total of 76 ST-EPN patients with C11orf95-RELA fusion were identified (median age: 7 years3 months, range: 5 months – 18 years7 months). 58 patients (76.3%) had complete surgical resection. 70 patients(92.1%) received radiotherapy. 55 patients(72.3%) received chemotherapy. The 10-year OS of C11orf95-RELA fused ST-EPN was 72.4% and PFS was 63.8%. In contrast, ST-EPN at a single institution with unconfirmed molecular status had an OS of 61.1% and PFS of 34.9%.

CONCLUSION
Detailed molecular analysis identified distinct subgroups of patients with ST-EPN. Patients from this cohort with C11orf95-RELA methylation profiles had a significantly higher OS compared to previous reports and those with unconfirmed fusion status, emphasising the critical importance of complete molecular profiling to assist in treatment decision making. Complete molecular analysis in future prospective cohorts is essential for accurate risk stratification and treatment selection.
EPEN-41. C11orf95-RELA FUSION REGULATES ABERRANT GENE EXPRESSION THROUGH THE UNIQUE GENOMIC BINDING SITES FOR EPENDYMOMA FORMATION
Authors: Ozawa Tatsuya , Kaneko Syuzo , Takadera Mutsumi , Holland Eric , Hamamoto Ryuji , Ichimura Koichi 
Published: December 2020

Abstract
A majority of supratentorial ependymoma is associated with recurrent C11orf95-RELA fusion (RELAFUS). The presence of RELA as one component of the RELAFUS leads to the suggestion that NF-kB activity is involved in the ependymoma formation, thus being a viable therapeutic target in these tumors. However, the oncogenic role of another C11orf95 component in the tumorigenesis is not still determined. In this study, to clarify the molecular mechanism underlying tumorigenesis of RELAFUS, we performed RELAFUS-ChIP-Seq analysis in cultured cells expressing the RELAFUS protein. Genomic profiling of RELAFUS binding sites pinpointed the transcriptional target genes directly regulated by RELAFUS. We then identified a unique DNA binding motif of the RELAFUS different from the canonical NF-kB motif in de novo motif discovery analysis. Significant responsiveness of RELAFUS but not RELA to the motif was confirmed in the reporter assay. An N-terminal portion of C11orf95 was sufficient to localize in the nucleus and recognizes the unique motif. Interestingly, the RELAFUS peaks concomitant with the unique motif were identified around the transcription start site in the RELAFUS target genes as previously reported. These observations suggested that C11orf95 might have served as a key determinant for the DNA binding sites of RELAFUS, thereby induced aberrant gene expression necessary for ependymoma formation. Our results will give insights into the development of new ependymoma therapy.
EPEN-42. MOLECULAR PROFILING REVEALS DISTINCT SUBGROUPS OF PEDIATRIC SPINAL EPENDYMOMA
Authors: Ahmad Omar , Chapman Rebecca , Storer Lisa , Luo Li , Resar Linda , Cohen Kenneth , Grundy Richard , Lourdusamy Anbarasu 
Published: December 2020

Abstract
Paediatric spinal ependymomas are important, albeit uncommon, malignant central nervous system tumours. Unlike adults, children with these tumours are likely to experience a more aggressive disease course, with a higher rate of local failure and a higher rate of metastases. The clinical and molecular factors underlying these differences remain poorly characterized. We analyzed spinal ependymoma (SEPN) tumour samples from 27 paediatric patients (female: 11, male: 15; age range: 4–18 years) using genome-wide DNA methylation profiling, copy-number analysis, as well as transcriptome profiling. Using DNA methylation profiles, two distinct unsupervised consensus-clustering approaches, hierarchical clustering and non-negative matrix factorization reliably identified two subgroups. These subgroups were designated as Myxopapillary ependymomas (SP-MPE) and spinal ependymomas (SP-EPN) based on the online Classifier tool (MNP2.0). The genome-wide copy-number analysis showed differences in numbers and pattern of copy-number alterations between these groups. The gain of chromosome 20 (39%) followed by loss of chromosomes 6 (28%), 10 (28%), and 13 (28%) were detected in the SP-MPE group, whereas loss of chromosome 22 was frequent (60%) in the SP-EPN group. Transcriptomics analysis showed that genes associated with oxidative phosphorylation, TCA cycle components, electron transport, and Interferon-gamma production characterize the SP-MPE group whereas potassium ion import and regulation of astrocyte differentiation characterize the SP-EPN group. Western blot analysis validated the increased protein expression of oxidative phosphorylation complexes in SP-MPE. With this study, we provide a foundation for further molecular characterization of pediatric SEPN subgroups. Our results suggest that mitochondrial oxidative phosphorylation may drive the regulation of energy metabolism of SP-MPE tumours.
EPEN-44. EXTRACELLULAR VESICLES OF SUPRATENTORIAL EPENDYMOMA RELA MEDIATE INTERACTIONS WITH CELLS OF THE TUMOR MICROENVIRONMENT
Authors: Maass Kendra K , Roosen Mieke , Benzel Julia , Wedig Tatjana , Statz Britta , Mueller Torsten , Kalxdorf Mathias , Krijgsveld Jeroen , Pfister Stefan M , Pajtler Kristian W 
Published: December 2020

Abstract
Ependymal tumors (EPNs) account for ~10% of all pediatric brain tumors. Supratentorial EPN characterized by RELA fusions (ST-EPN-RELA) and posterior fossa EPN group A (PF-EPN-A) form the two most frequent molecular groups, both of which are associated with poor prognosis and for which only limited therapeutic options are available. Since pediatric EPNs have a relatively low mutational burden, identification and characterization of tumor-associated pathways and molecular processes is of critical importance to inform potential therapeutic targets. Previous transcriptional studies implicated aberrant vesicular pathways in ST-EPN-RELA, prompting further investigation into their putative role in EPN pathogenesis. To this aim, we isolated extracellular vesicles (EVs) of ST-EPN-RELA patient derived cell lines and performed protein mass spectrometry. The specific ST-EPN-RELA EV protein content resembles the parental cells as well as primary tumors. Promising candidates to be transferred by ST-EPN-RELA EVs but not control EVs were associated with unfolded protein response and endoplasmic reticulum stress. When uptaken by recipient cells of the tumor microenvironment, brain endothelial cells or microglia, ST-EPN-RELA EVs induced proliferation and had a chemoattractant effect towards the tumor. ST-EPN-RELA EVs stimulated angiogenesis of brain endothelial cells potentially by the transfer of ER stress proteins. Uptake of ST-EPN-RELA EVs by microglia changed their activation status indicating a tumor promoting function through EV transfer. Therefore, we hypothesize that vesicular pathways play an important role in the pathogenesis of pediatric ST-EPN-RELAs and that an improved understanding may promote new therapeutic opportunities.
EPEN-45. NORMALIZING AND FACILITATING GENOMIC TESTING AT DIAGNOSIS IN PEDIATRIC EPENDYMOMA
Authors: Pickle Emily Owens , Aguilar-Bonilla Ana , Smith Amy 
Published: December 2020

Abstract
The current consensus is that diagnosis and treatment of ependymoma should be based upon clinical and molecular classification. As we move into this paradigm, it is important all ependymoma cases undergo tumor collection, preservation, and molecular profiling at diagnosis. Our group of 6 sites gathered data on a cohort of 72 ependymoma cases. Sites were asked to report known molecular findings; 60/68 eligible cases (88%) did not include genetic findings. The low number of cases with molecular findings was surprising and since cases were diagnosed from as early as 2004, we asked collaborators to share their current practice in profiling (e.g., how frequently; in what setting were ependymomas sent for testing) to try and better understand current practice at sites. Since the publication of ependymoma molecular data, sites with a neuro-oncology program report sending almost all newly diagnosed ependymomas for molecular testing, whereas current practices at sites without dedicated neuro-oncology were less consistent. Profiling in the setting of relapse was more frequently reported at all centers. The implementation of molecular testing at diagnosis may need support at sites without dedicated neuro-oncology. Lead investigators for upcoming ependymoma clinical trials will need to think carefully about the logistics of profiling at centers where this is not standard practice at diagnosis.
EPEN-46. DNA METHYLATION LANDSCAPE OF RECURRENT PEDIATRIC EPENDYMOMA IDENTIFIES KEY DRIVER EVENTS
Authors: Zhao Sibo , Li Jia , Zhang Huiyuan , Qi Lin , Du Yuchen , Kogiso Mari , Braun Frank , Lindsay Holly , Genevini Paola , Veillard Anne-Clemence , Schvartzman Sol , Laczik Miklos , Berguet Geoffrey , Adesina Adekunle , Stephan Clifford , Chintagumpala Murali , Parsons Williams , Perlaky Laszlo , Song Yongcheng , Sun Deqiang , Li Xiao-Nan 
Published: December 2020

Abstract
Pediatric ependymoma has a propensity of developing late and multiple relapses over many years. About 50% of patients will experience relapses and eventually succumb to their disease. Our study is aimed to understand the mechanism of resistance and drivers associated with pediatric ependymoma relapse. We developed 10 sets of patient-derived orthotopic xenograft (PDOX) models of recurrent pediatric ependymoma from both RELA and PFA tumors. Time from primary tumor to last recurrence ranges from 2.75 – 13 years. Number of recurrences per patient ranges from 1 – 7 times. We performed Reduced Representation Bisulfite Sequencing (RRBS) and Whole Genome Bisulfite Sequencing (WGBS) to map the DNA methylation landscape of total of 30 samples of matched primary and recurrent tumors. Molecular subtypes and DNA methylation profiles were maintained, and RELA/PFA signature genes showed similar expression pattern during serial relapses. RELA- and PFA-specific Differentially Methylated CpGs (DMCs) are identified from primary tumors. During the recurrent process, individual patients displayed consistent changes of DMCs and shared DMCs among patients became convergent. We then identified shared common specific DMCs in recurrent RELA and PFA tumors that emerged as the driver signatures. We found that these recurrent DNA methylation signatures could be identified from primary tumors. Our analysis of the PDOX models showed that they can mostly recapitulate humor tumors’ DNA methylation and we were able to identify shared recurrent specific DMCs associated genes in PDOX models. Our comprehensive data is the first of its kind aimed to investigate the epigenetic mechanisms during pediatric ependymoma recurrence.
EPEN-47. PEDS: PEDIATRIC EPENDYMOMA DISCOVERY STUDY
Authors: Smith Amy , Pajtler Kristian , Ichimura Koichi , Pickle Emily Owens , Fleischhack Gudrun , Tippelt Stephan , Aguilar-Bonilla Ana 
Published: December 2020

Abstract
The prognosis for pediatric ependymoma remains unaffected by recent discovery. Upfront therapy is maximal surgical resection followed by radiation and the utility of histologic diagnosis remains unreliable. Nine molecular subgroups and possible genetic drivers of ependymoma have been identified, but the implementation of these findings into targeted therapy and stratified clinical trials has not occurred. It is imperative that researchers work collaboratively to move discovery towards clinical testing. Heterogeneity of ependymoma requires that we collect a large amount of data; progress in the field is dependent on deep analysis of this information. As we further subclassify ependymoma, it will be important to have a large patient population for enrollment onto clinical trials, which will maximize data collection and the amount of materials available for experimentation and analysis. Researchers in the United States, Europe, and Japan propose an international ependymoma research collaborative which aims to synthesize research across sites, foster drug discovery, and prove strategies to integrate clinical and molecular diagnostics into biology-based therapy. Our goal is to maximize information and materials from existing bio and data repositories and not to ‘re-create the wheel’. We envision PEDS as an open science platform and present this concept at ISPNO to invite our colleagues to harmonize efforts towards pediatric ependymoma discovery.
EPID-08. FINDING THE NEEDLE IN THE HAY STACK – POPULATION-BASED STUDY OF PREDIAGNOSTIC SYMPTOMATIC INTERVAL IN CHILDREN WITH CNS TUMORS
Authors: Lambert Clare , Goldman Ran , Cochrane Douglas , Dahiya Anita , Mah Heidi , Buttar Arsh , Cheng Sylvia 
Published: December 2020

Abstract

PURPOSE
Delay in diagnosis of central nervous system (CNS) tumors in children is well documented. The aims of this study were to characterize the symptomatology of CNS tumors and the time to diagnosis in a large pediatric hospital in Canada.

METHODS
Retrospective chart review of children diagnosed with a CNS tumor between 2000 and 2016 in Vancouver, British Columbia, Canada was performed. Data collected included demographics, symptomatology, tumor type, age at diagnosis, known visits to healthcare professionals, neuroimaging, therapy and post treatment relapse or progression.

RESULTS
148 children with complete medical records were reviewed. The average age at diagnosis was 87.8 months (standard deviation (SD) = 59.7; median = 72). 50.7% of patients had posterior fossa tumors and 49.3% had supratentorial tumors. 30% of patients were diagnosed after a single visit to a health care provider. 7.7% of children needed more than 4 visits. Median total time to diagnosis (PSI) was 62 days (range = 0-2047 days). The longest prediagnostic interval was first symptom onset to first healthcare provider visit (PSI1, median 37 days). Patients with posterior fossa tumors, presence of metastases, and symptoms of ataxia and paresis were associated with shorter PSI.

CONCLUSIONS
CNS tumors in children continue to pose a diagnostic challenge with significant variability in time to diagnosis. Our population-based study found that median time from symptoms to seeking medical advice by parents was over a month. It is essential to uncover the reasons for delay and address them where possible.
EPID-12. TEMPORAL AND GLOBAL GEOGRAPHIC VARIATION IN THE INCIDENCE OF PEDIATRIC CNS TUMORS, 1998–2012
Authors: Ribeiro Karina , Epelman Sidnei 
Published: December 2020

Abstract

AIMS
To describe the temporal and geographic variation in the incidence of pediatric CNS malignancies worldwide, presenting analyses by sex, period, region, and histological subtype between 1998 and 2012.

METHODS
Data were extracted from volumes IX to XI of the Cancer Incidence in 5 Continents, covering the periods 1998–2002 (1), 2003–2007 (2), and 2008–2012 (3). We pooled data from 44 countries, classifying them into 6 regions (Africa (AF), Asia (AS), Oceania (O), Europe (E), Central/South America (CSA), North America (NA)). Age-standardized incidence rates (ASIR per million, 0–19 years) were calculated and temporal variation was evaluated using incidence rate ratios (IRR) (95% CI).

RESULTS
The highest incidence (Period 3) was observed in NA (34.0 and 30.2 for males and females, respectively). Astrocytic tumors were predominant in all regions, with percentages ranging between 24.5% (E, females) and 45.6% (NA, females). Increasing trends (Period 3 x 1) were observed in AS (IRR=1.15, 95% CI 1.06–1.25), CSA (IRR=1.25, 95% CI 1.01–1.55), and NA (IRR=1.05, 95% CI 1.03–1.07), for males and in AS (IRR=1.15, 95% CI 1.05–1.26) and NA (IRR=1.08, 95% CI 1.06–1.11) for females. Geographic discrepancies in time-trends were observed for astrocytomas, ependymomas, medulloblastomas, other embryonal tumors, and other specified tumors. Reductions in the incidence of unspecified tumors from period 1 to 3 were noted in E, AS, and NA, ranging from -20% (E, females) to -66% (AS, females).

CONCLUSIONS
Heterogeneous trends and improvement in the registration of histological types were noted. Geographic variation can help to raise hypotheses to investigate etiologic factors.