bluuebunny/crossref_metadata_2025 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

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

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 >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

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

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

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

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

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

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

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

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

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

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.
EPID-13. A POPULATION-BASED ANALYSIS OF CNS TUMOR DIAGNOSES, TREATMENT, AND SURVIVAL IN CONGENITAL AND INFANT AGE GROUPS
Authors: Hart Muriel , Mellies Amy , Beltrami Alina , Gilani Ahmed , Green Adam
Published: December 2020

BACKGROUND

Congenital (<3 months) and infant (3 to 11 months) brain tumors are biologically different from tumors in older children, but epidemiology of these tumors has not been studied comprehensively. Insight into epidemiological differences could help tailor treatment recommendations by age and increase overall survival (OS).

METHODS

Population-based data from the SEER 18 registries was obtained for 14,493 0-19-year-olds diagnosed with CNS tumors between 1990 and 2015. Incidence, treatment, and survival were analyzed using Chi-square and Kaplan-Meier analyses.

RESULTS

Between the <3 month, 3–5 month, 6–11 month, and 1–19 year age groups, tumor type distribution differed significantly (p<0.001); high-grade glioma (HGG) was most common in the <3-month-olds, while low-grade glioma (LGG) was most common in the other groups. 5-year OS for all tumors was 36.7% (<3 months), 56.0% (<3–5 months), 63.8% (6–11 months), and 74.7% (1–19 years) (log rank p<0.001). OS by tumor type was worst for <3-month-olds with LGG, medulloblastoma, and other embryonal tumors; OS was worst for 3-5-month-olds with ependymoma, <1-year-olds collectively with atypical teratoid-rhabdoid tumor, and 1-19-year-olds with HGG (log rank p<0.02 for all tumor types). <3-month-olds were least likely to receive any treatment for each tumor type and least likely to undergo surgery for all except HGG. <1-year-olds were far less likely than 1-19-year-olds to undergo radiation for embryonal tumors, as expected, but were also less likely to undergo chemotherapy.

CONCLUSIONS

Congenital/infant CNS tumors differ pathologically, therapeutically, and prognostically from those in older children. Treatment changes could help address poorer outcomes for these young patients.
EPID-14. GABRIELLA MILLER KIDS FIRST DATA RESOURCE CENTER: COLLABORATIVE PLATFORMS FOR ACCELERATING RESEARCH IN PEDIATRIC CANCERS & STRUCTURAL BIRTH DEFECTS
Authors: Heath Allison P , Zhu Yuankun , Mattioni Michele , Farrow Bailey , Lilly Jena , Guo Yiran , Rokita Jo Lynne , Storm Phillip B , Volchenboum Samuel L , Nazarian Javad , Vasilevsky Nicole , DiGiovanna Jack , Haendel Melissa , Grossman Robert L , Davis-Dusenbery Brandi , Taylor Deanne M , Ferretti Vincent , Resnick Adam
Published: December 2020

Since launching to the public in September 2018, the Gabriella Miller Kids First Data Resource Center (DRC) has made an increasing number of pediatric genomic studies available to the research community. Currently, 1.3 PBs of genomic and clinical data drawn from 12,000 participants are available across a variety of pediatric cancer and structural birth defect studies. The DRC has architected a secure, cloud-based platform with over 1,300 users that supports the ability of researchers to not only find, access, and reuse data, but also integrate, collaborate, and analyze data quickly at scale. Users can use integrations with platforms such as Cavatica for bioinformatics workflows and PedcBioPortal for cancer genomic visualizations. Additionally, a set of framework services, powered by Gen3, provide a foundation for interoperability with other large-scale data sources, platforms, and a growing ecosystem of analysis and visualization applications. These integrations allow users to search across both TARGET and Kids First clinical data in one location while allowing data governance to be maintained by the original approvers. The new “explore data” feature allows users to search across all studies in order to identify virtual cohorts. Within the portal, these cohorts can be saved and shared with collaborators for iterative refinement and analysis. With appropriate approvals, the associated genomic data can be accessed and analyzed seamlessly in Cavatica or other platforms with interoperable framework services. Additionally, gene searching capabilities will be available in 2020. Data is free to download and cloud credits are available for analysis support.
EPID-15. THE INTERNATIONAL DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)/DIFFUSE MIDLINE GLIOMA (DMG) REGISTRY AND REPOSITORY (IDIPGR) EXPANSION
Authors: Torontali Marianne , Doughman Renee , Chaney Brooklyn , Black Katie , Asher Anthony , Rupert Andrew , Fuller Christine , Leach James , Jones Blaise , Fouladi Maryam , DeWire Mariko
Published: December 2020

Established in April 2012, the mission of the IDIPGR is to provide secure integrated data sets including clinical, pathologic, radiologic and molecular genomics to the research community to promote hypothesis driven research. Over 600 data points per patient are securely stored on a CCHMC constructed web resource and domain using the open-source data mart development framework Harvest (PMID:24303304) (‘Links’). Genomic data is stored in the cloud-enabled VIVA platform and accessed through cross-platform integration and standardization algorithms for comparison across datasets. Features include source identification, data wrangling, and standardization of molecular and phenotypic data (2017), a web-enabled data mart that provides phenotype-genotype query/exploration, along with raw and processed data file downloads to authorized investigators (Harvest, 2017), additional tools for filtering and analysis of genomic datasets at the level of a phenotype, sample, gene, and variant (VIVA, 2017–2018), and uploaded digitized slides (Aperio, 2019). The IDIPGR Repository stores abstracted datasets for >1020 patients with DIPG/DMG, of whom 366 have tumor tissue available through biopsy and/or autopsy, and centrally reviewed and digitized specimens from 124 patients. The Repository contains >5000 radiology studies from >700 patients, with >550 patients centrally reviewed, and genomics data from 80 patients. Currently 27 IDIPGR approved projects utilize these datasets. The DIPG/DMG Registry constructed a robust database platform and integration system that provides the infrastructure to promote highly collaborative, international, hypothesis-driven research. Broadening collaboration among investigators for hypothesis-driven research studies will lead to better classification and more effective treatment of patients with DIPG and DMG.
ETMR-11. A CASE OF PRIMARY DIFFUSE LEPTOMENINGEAL PRIMITIVE NEUROECTODERMAL TUMOR
Authors: Sugawa Masahiro , Terashima Keita , Matsukawa Yukihiro , Mizuno Takanori , Isshiki Kyohei , Tsujimoto Shinichi , Uchiyama Meri , Sakamoto Kenichi , Gocho Yoshihiro , Osumi Tomoo , Shioda Yoko , Kiyotani Chikako , Kato Motohiro , Tomizawa Daisuke , Usami Kenichi , Ogiwara Hideki , Tsutsumi Yoshiaki , Nakano Masayuki , Yoshioka Takako , Matsumoto Kimikazu
Published: December 2020

BACKGROUND

Primary diffuse leptomeningeal primitive neuroectodermal tumor (PDL PNET) is a rare embryonal brain tumor which arises primarily in the meninges without an intraparenchymal mass. Few previous reports of this condition exist, and the clinical outcomes are poor. We herein report a case of a child with PDL PNET and present a cursory review of the literature. CASE: A 3-year-old female patient was seen at a local clinic due to vomiting, headaches, and seizures. As a head MRI revealed hydrocephalus but no mass, acute encephalopathy was initially diagnosed. She received steroid pulse therapy, but the symptoms progressed to hallucination and lethargy. Another MRI at the 1-month follow-up revealed diffuse leptomeningeal enhancement. Thereafter she was transferred to our hospital. A spine MRI revealed spinal dissemination. She underwent a dura mater biopsy, and the pathological analysis led to the diagnosis of PDL PNET. She received chemotherapy consisting of vincristine, cyclophosphamide, etoposide, cisplatin, and intrathecal methotrexate injections two months after the initial presentation. The progressive hydrocephalus was managed with external ventricular drainage. Two weeks after the first cycle of chemotherapy the hydrocephalus resolved, and the external ventricular drainage was removed. A follow-up MRI showed that the leptomeningeal enhancement decreased during the four cycles of chemotherapy without radiotherapy. The patient is scheduled to receive high-dose chemotherapy as consolidation therapy.

CONCLUSION

PDL PNET is extremely rare, and its diagnosis is often delayed. Treatment of PDL PNET is very difficult due to its aggressive course, and surgical resection is impossible. Early diagnosis may help improve outcomes.
ETMR-20. IMPACT OF HIGH DOSE CHEMOTHERAPY WITH AND WITHOUT METHOTREXATE (MTX) ON OUTCOME OF PATIENTS WITH EMBRYONAL TUMORS WITH MULTI-LAYERED ROSETTES (ETMRs): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334
Authors: Mazewski Claire , Kang Guolian , Kellie Stewart , Gossett Jeffrey , Leary Sarah , Li Bryan , Aridgides Paul , Hayes Laura , Reddy Alyssa , Shaw Dennis , Burger Peter , Judkins Alexander , Geyer Jeffrey Russell , Fouladi Maryam , Huang Annie
Published: December 2020

Infant embryonal brain tumors comprise a spectrum of histologic and molecular entities including medulloblastoma (MB) and tumors collectively called CNS PNET’s, including supratentorial PNET (sPNET), pineoblastoma and other less common histologic entities. Non-MB embryonal tumors, historically considered high risk disease, were included in ACNS0334, A Children’s Oncology Group prospective phase III trial which compared efficacy of an induction regimen with and without methotrexate combined with high dose chemotherapy and stem cell rescue; no radiation was mandated. Molecular testing performed after ACNS0334 closure identified 14 patients with embryonal tumors with multi-layered rosettes (ETMRs), a new molecular entity previously classified under various diagnostic categories. ETMR patients made up 20% of the molecularly analyzed ACNS0334 cohort and were predominantly females. Tumors were largely non-metastatic (10/14 M0, 1 M1, 3 M2/M3) and originated in the cerebrum (8), cerebellum (3) and pineal gland (3). Gross total tumor resection was achieved in 5/11 patients with M0/M1 disease; 9/14 patients completed full treatment with 5 randomized to MTX induction and 9 to no-MTX. Five of 14 patients progressed on treatment, one had a toxic death. Disease progression was primarily local (88 %). No difference by methotrexate randomization was observed. Four patients are alive without progression 5–10+ years off therapy, none received radiation. No patients received radiation prior to progression. Four were irradiated after progression and died from disease within 3 to 13 months. Our study, a first report on ETMRs prospectively treated on a clinical trial, suggests high dose chemotherapy benefits a portion of ETMR patients.
GCT-08. PROTON BEAM RADIOTHERAPY FOR PEDIATRIC AND YOUNG-ADULT PATIENTS WITH INTRACRANIAL GERM CELL TUMOR
Authors: Sugiyama Minako , Hashimoto Takayuki , Mori Takashi , Hara Kazuya , Terashita Yukayo , Hirabayashi Shinsuke , Cho Yuko , Iguchi Akihiro , Okamoto Michinari , Ishi Yukitomo , Motegi Hiroaki , Yamaguchi Shigeru , Manabe Atsushi
Published: December 2020

BACKGROUND

To reduce treatment-related adverse events in pediatric and young-adult patients with brain tumors, proton beam radiotherapy (PBT) has recently been performed instead of conventional X-ray radiotherapy. However, whether PBT is as effective as X-ray radiotherapy has not been sufficiently investigated, especially in patients receiving whole-ventricular irradiation.

METHODS

We report a retrospective observation of 15 patients with intracranial germ cell tumors (GCT), who received PBT at our institution from April 2014 to September 2019. We evaluated their clinical course, short-term adverse events, and prognosis. RESULTS/

CONCLUSION

Fifteen patients (9 males and 6 females; median age 13 years) who received PBT following induction chemotherapy were analyzed. Nine patients received 23.4–27.0 GyE of whole-ventricular irradiation due to GCT in the pituitary gland, pineal body, or hypothalamic area. Three patients received 23.4 GyE of whole-brain irradiation: one of them had boost irradiation for basal ganglia. Three patients received 30.6 GyE of craniospinal irradiation (CSI). Six of the 15 patients experienced nausea (grade 2, according to the CTCAE version 4.0). Four patients, including two who received CSI, showed myelosuppression: decrease in white blood cell count, lymphocyte cell count, and neutrophil count (grade 3). No other severe short-term adverse events of >grade 2 was observed in any of the patients. At a median follow-up of 21 months (2-62 months) after irradiation. all patients are alive without recurrence. Our results may be encouraging and further investigations with a larger scale is warranted.
GCT-10. CAN HIGH LEVEL SERUM hCG-β BE CONSIDERED EQUIVALENT TO A DIAGNOSIS OF CHORIOCARCINOMA IN PRIMARY CENTRAL NERVOUS SYSTEM GERM-CELL TUMOR?
Authors: Motegi Hiroaki , Yamaguchi Shigeru , Ishi Yukitomo , Okamoto Michinari , Iguchi Akihiro , Cho Yuko , Sugiyama Minako , Manabe Atsushi , Houkin Kiyohiro
Published: December 2020

BACKGROUND

Primary central nervous system(CNS) choriocarcinoma(CC) is very rare and has the poorest prognosis among germ cell tumor (GCT). CC usually has extremely high level (HL) of serum beta-human chorionic gonadotropin (bhCG) over than 1,000 mIU/ml. Some studies assign HL bhCG cases to poor prognosis group even without biopsy. The purpose of this study was to find out if there was a good prognosis subset in the HL bh group.

MATERIALS AND METHODS

We analyzed 103 cases diagnosed with GCT from 1998 to 2019 in Hokkaido University Hospital and reviewed the literature of CNS CC and bhCG. Survival was assessed using Kaplan-Meier method and log-rank statistics between the group with CC component and that with no CC component but HL bhCG.

RESULTS

One out of 103 our cases was diagnosed as a mixed GCT with CC component and did not respond to treatment and died 9 months later. Two cases were treated as CC because of HL bhCG (1,226 and 2,739 mIU/ml) despite that the biopsy showed only germinomas and survived(105 and 37 months), that is, no CC component. Combining our cases with 69 cases in the literature, all 7 cases with no CC component but HL bhCG survived but the median survival of the other 65 cases with CC component was 38.2 months (P=0.02).

CONCLUSION

This study has a limitation of selection bias, however, it suggests that patients with no CC component but HL bhCG may have a better prognosis.
GCT-13. THE TREATMENT OUTCOMES OF INTRACRANIAL GERM CELL TUMORS WITH KSPNO PROTOCOL: SINGLE CENTER RETROSPECTIVE ANALYSIS
Authors: Go Kyeong-O , Ji Soyoung , Hwang Kihwan , Han Jung Ho , Choi Hyoung Soo , Kim You Jung , Choi Byung Se , Kim In Ah , Choe Gheeyoung , Jung Jin-Myung , Hong Yong-Kil , Kim Chae-Yong
Published: December 2020

Dho et al. (BTRT, 2017) reported that 1.1% (127/11,827) of primary brain tumors are intracranial germ cell tumors (iGCT) in Korea. We analyzed the epidemiology and treatment results of germ cell tumors in our institution. From 2004 to 2019, among 6494 patients with intracranial neoplasms the 61 (0.9%) patients with iGCTs were enrolled: histologically diagnosed in 50 patients and clinically in 11 respectively. Pediatric patients underwent treatment according to the KSPNO protocol, and adult patients were treated with bleomycin, etoposide, and cisplatin regimens. The median age was 20 years (range: 1–42) and the follow-up period was 7.7 months (range: 10.0–203.4 months), respectively. The tumors arise most frequently in the pineal area (n=30, 49.2%). There were no significant differences in outcomes between protocols, but in KSPNO protocol group showed lower tumor recurrence rate (11.5% vs. 20%, p=0.494) and mortality (0% vs. 5.2%, p=0.503). According to the pathological subtype, the outcomes showed statistically significant differences between germinoma and non-germinomatous germ cell tumor (NGGCT) groups. The 10-year progression-free survival was 93.2% and 67.1% in the germinoma and the NGGCT group, respectively (p=0.009). The NGGCT pathological type (p=0.021) was a significant recurrence associated factor in multivariate analysis. Significant adverse events (CTCAE version 5.0 grade≥3) were showed in 14 patients (7 patients in both KSPNO and other treatment protocol groups). Pure germinoma has a higher survival rate and a lower recurrence rate than NGGCT. And KSPNO protocol might be safe and effective. For appropriate treatment for iGTCs, a multidisciplinary approach might be needed.
GCT-14. SECOND-LOOK SURGERY FOR INTRACRANIAL GERM CELL TUMORS
Authors: Ogiwara Hideki
Published: December 2020

OBJECTIVE

The authors present their experiences of second-look surgery in patients with intracranial GCTs who showed less than complete response despite normalizing or decreasing tumor markers after chemotherapy.

METHODS

Retrospective review of 14 patients who underwent second-look surgery for an intracranial GCT was performed.

RESULTS

Of 40 consecutive patients with newly diagnosed intracranial GCTs treated between August 2003 and 2019, 14 patients (35%) underwent second-look surgery. The mean age was 9.2 years. The initial diagnoses were mixed germ cell tumor in 6, immature teratoma in 4, yolk sac tumor in 2, and germinoma 2. Second-look surgery was performed after 1–3 courses of chemotherapy. Magnetic resonance imaging (MRI) at the surgery demonstrated increasing residual tumor in 8 and stable residual tumor in 6. Tumor markers were normalized in 10 and nearly-normalized in 4. Gross total resection was achieved in 12 patients and near-total resection in 2. Histopatholgy at second-look surgery revealed mature teratoma in 6, immature teratoma in 3, fibrosis with atypical cells in 2, and fibrosis in 3. Eleven patients subsequently underwent additional chemo-radiation therapy according to the initial diagnosis. All patients are alive with no evidence of recurrence with a mean follow-up of 69 months.

CONCLUSIONS

Second-look surgery plays an important role in the treatment of intracranial GCTs. Surgery may be encouraged at a relatively early phase after chemotherapy when the residual tumor increases or does not change the size despite normalized or nearly-normalized tumor markers in order to achieve complete resection and improve the outcome.
GCT-16. LONG-TERM CLINICAL OUTCOMES OF GERM CELL TUMORS
Authors: Matsuda Kenichiro , Sakurada Kaori , Kayama Takamasa , Sonoda Yukihiko
Published: December 2020

BACKGROUND

Intracranial germ cell tumors (GCT) are mainly arising in adolescent term and treated with chemotherapy concomitant with radiation therapy. There is accumulating evidence that the progress of treatment. Besides, long-term outcome and adverse effects are major problem in treatment. So, we must grasp the influence of these outcomes on daily and social life. Then we investigated in clinical outcome in cases of GCT treated in our institution. METHOD: We reviewed the clinical features and outcomes of 52 cases of intracranial GCT in 1975 to 2019. Ages on diagnosis are 5–35 years old (median 14 years old), consisted with 44 male cases. The pathological distributions are these: pure germinoma: 40 cases, non-germinomatous germ cell tumor (NGGCT): 10 cases (mature teratoma: 4, mixed germ cell tumors: 3, and one cases of choriocarcinoma, embryonal carcinoma, yolk sac tumor), unidentified pathology: 2 cases. Almost all cases have biopsied and treated by chemotherapy and radiation therapy.

RESULTS

Chemotherapy with ICE regimen (ifosphamide, cisplatin, etoposide) or CARE regimen (carboplatin, etoposide) concomitant with radiation therapy (mainly, extended local irradiation) have done in almost cases by the era. Clinical outcomes are relatively well in our cases, but 10 cases experienced recurrence. 3 cases have dead. Some cases with suprasellar involvement have need hormone replacement in long term. There are 10 cases at work.

CONCLUSION

Almost cases have gained better outcome and ADL. But there is slightly lower rate in work or marriage. Serial evaluation in outcome, and higher brain functions should be performed in follow up.
GCT-17. WHAT IS THE CLINICAL OUTCOME OF PROTON BEAM THERAPY FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMOR IN KOREA?
Authors: Youn Sang Hee , Kim Joo-Young
Published: December 2020

PURPOSE

To evaluate the clinical outcome of patients with intracranial germ cell tumor treated with proton beam therapy (PBT).

MATERIALS AND METHODS

Fifty-seven patients with intracranial germ cell tumor treated with PBT between 2009 and 2016 were retrospectively analyzed.

RESULTS

Median follow-up duration was 63.7 months (range, 5.6–204.5). Thirty-seven patients (64.9%) were pure germinoma and 20 patients (35.1%) were non-germinomatous germ cell tumor (NGGCT). All patients except 2 patients received chemotherapy before PBT. Twenty-one patients (36.8%) of localized germinoma were treated with whole ventricle irradiation (WVI), while 36 (63.2%) patients who were diagnosed as disseminated germinoma or NGGCT received cranio-spinal irradiation (CSI). Two patients with pure germinoma in basal ganglia showed disease relapse at 3.0 and 6.9 years after PBT at the primary site and pituitary gland, respectively. There was one patient with NGGCT who died of chemotherapy-related mortality at 4.7 years after PBT while her disease was complete remission. The 7-year progression-free survival and overall survival were 70.8% and 100% for focal germinoma, 100% and 100% for disseminated germinoma, 100% and 100% for focal NGGCTs, and 100% and 80.0% for disseminated NGGCTs, respectively.

CONCLUSIONS

PBT of pure germinoma resulted in comparable clinical outcomes to that with photon radiotherapy. Our result for NGGCT is also excellent compared to other reports. Failure patterns of germ cell tumors originating in basal ganglia needs to be assessed in large pooled data.
GCT-20. EVALUATION OF NEURORADIOLOGICAL RESPONSE TO INDUCTION CHEMOTHERAPY FOR PATIENTS WITH LOCALISED GERMINOMA IN THE SIOP CNS GCT II TRIAL
Authors: Bison Brigitte , Morana Giovanni , Mitra Dipayan , Brisse Herve , Faure-Conter Cecile , Ajithkumar Thankamma , Alapetite Claire , Timmermann Beate , Nicholson James , Calaminus Gabriele , Murray Matthew
Published: December 2020

INTRODUCTION

The SIOP-CNS-GCT-96 trial demonstrated excellent survival for patients with germinoma. Localised patients received either craniospinal irradiation (CSI) 24Gy plus tumour-bed-boost 16 Gy or 2xcarboPEI chemotherapy (carboplatin/etoposide alternating with etoposide/ifosfamide) and focal-radiotherapy 40 Gy. Following trial closure, whole-ventricular-irradiation (WVI) was delivered with focal-radiotherapy to avoid ventricular relapse. Accordingly, current research priorities focus on reducing treatment burden and long-term neurocognitive sequelae.

METHODS

SIOP-CNS-GCT-II employed national central radiological review to assess whether dropping the 16Gy boost was safe for localized germinoma in complete-remission (CR) following 2xcarboPEI: i.e. no disease on clinical/marker/radiological assessment. Any abnormal thickening/enhancement after chemotherapy was to be classified as partial-remission (PR). Patients with less than CR after chemotherapy received a boost.

RESULTS

Shortly before trial closure (2018), it was noted that national CR rates were discrepant across the largest recruiting countries. For German patients, CR rates were ~80%, compared with ~30–40% for UK and France. A formal neuroradiology review was therefore convened. A total of 59 cases were randomly selected (UK, n=32; France, n=14 and Germany, n=13), including those deemed to be in CR and PR. Cases included those with disease at pituitary, pineal and bifocal sites. Both diagnostic scan and scan after induction chemotherapy were used for assessment. Detailed analysis is ongoing and will be presented.

CONCLUSION

Residual changes at both pituitary and pineal sites of uncertain significance may remain after chemotherapy. This process should facilitate consensus to define the best response criteria allowing treatment reduction for CNS germinoma for future clinical trials.