bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPEN-24. Biological markers of ependymoma in children and adolescents (BIOMECA): Systematic comparison of methods for the precise evaluation of biomarkers for ependymoma diagnosis and prognostication
Authors: Chapman Rebecca , Ghasemi David R , LeBlond Pierre , Witt Hendrik , Grill Jacques , Kilday John-Paul , Modena Piergiorgio , Varlet Pascale , Tauziede-Espariat Arnault , Haberler Christine , Buttarelli Francesca , Giangaspero Felice , Paine Simon M L , Jacques Thomas S , Scott Ian , Andreiuolo Felipe , Pietsch Torsten , Massimino Maura , Grundy Richard , Pajtler Kristian W , Ritzmann Timothy A 
Published: June 2022

Abstract
The identification and validation of prognostic and diagnostic biomarkers is a key element of The SIOP Ependymoma II trial, realised through the Biomarkers of Ependymoma in Children and Adolescents study (BIOMECA). BIOMECA aims to identify and validate biomarkers for prediction of outcome whilst enhancing stratification for the next generation of ependymoma trials. We outline our findings from the first 147 consecutive BIOMECA cases (posterior fossa, PF=111; supratentorial, ST=32; spinal, SP=4). We compared various methods for biomarker assessment, across six European laboratories to determine key analysis methods. Methods included: methylation-based classification (EPIC 850K DNA methylation array) (n=141); immunohistochemistry (IHC) for nuclear p65-RELA (n=32), H3K27me3 (n=115), and Tenascin-C (TNC) (n=147); copy number (CN) analysis by FISH, MLPA (1q, CDKN2A) (n=147), and MIP (molecular inversion probe) and DNA methylation array (1q, CDKN2A, 6q, 11q, 13q, 22q) (n=141); analysis of ZFTA- and YAP1-fusions by RT-PCR, sequencing, Nanostring assays and break-apart FISH (n=32). Using DNA methylation-based classification, 91% (n=101/111) of PF cases classified as PF ependymoma group A (PFA) and 69% (n=22/32) of ST cases as ST ependymoma, ZFTA fusion-positive (ZFTA). Most PFAs demonstrated inter-centre agreement for loss of H3K27me3, and were TNC positive, representing surrogate markers for PFA identification. Combinations of p65-RELA IHC, FISH analysis, and RNA-based methods were suitable to identify ZFTA- and YAP1- fused ST ependymomas. Predictive CN alterations were identified by high-resolution, quantitative MIP technology.The integration of histopathology assessment and molecular typing is now critical as the updated 2021 WHO CNS5 classification of ependymomas lists seven molecularly distinct entities. This study highlights the importance of evaluating different methods in a prospective trial cohort. Here, advanced molecular techniques represent powerful tools for the classification of ependymoma entities (DNA methylation array) and for the detection of CN alterations (MIP) and specific fusions, enabling the correct classification and identification of prognostic markers.
EPEN-25. A novel spontaneous model of ZFTA-RELA fusion ependymoma
Authors: Bell Sigourney , King Claire , Rahrmann Katherine Wickham , Jassim Amir , Taylor Jessica , Gilbertson Richard 
Published: June 2022

Abstract
Ependymomas driven by the ZFTA-RELA fusion account for &gt;70% of all supratentorial ependymomas. These tumours are now recognised in the WHO classification of CNS tumours and have been associated with a poor prognosis. Seven ZFTA-RELA fusion variants have been described: around two thirds of cases are fusion 1. No spontaneous genetically modified mouse models (GEMMS) have been described and current models require invasive intracranial injection (of transduced cells or RCAS-TVA system). Here we describe the first spontaneous GEMM of ZFTA-RELA fusion-driven ependymoma. Nestin-Flx-STOP-Flx-ZFTA-RELA (Fusion 1) or E1alpha-Flx-STOP-Flx-ZFTA-RELA open reading frames were targeted together with luciferase to the Rosa-26 locus. Breeding these mice with Nestin-CreERT2 or Blbp-Cre lines that drive recombination in neural progenitor cells resulted in forebrain tumours that could be tracked with bioluminescence imaging from P20. Tumours displayed NF-kB and L1CAM expression and ZFTA-RELA protein was detected using a novel in-house antibody. Tumours display expression of a known ZFTA-RELA fusion ependymoma transcriptomic signature. ZFTA-RELA tumours can be grown as neurospheres and passaged as allografts in nude mice. We provide the first spontaneous GEMM of this important group of ependymomas. We are now characterising these tumours histologically and transcriptomically relative to the human disease and using these to understand the lineage origins of ependymoma and plan use of conventional and novel treatments.
EPEN-28. Oncogenic dependency of pediatric ependymomas on extracellular vesicle pathways
Authors: Maass Kendra K , Roosen Mieke M , Mueller Torsten , Senfter Daniel , Benzel Julia , Wedig Tatjana , Kalxsdorf Mathias , Krijgsveld Jeroen , Pfister Stefan M , Pajtler Kristian W 
Published: June 2022

Abstract
INTRODUCTION: The majority of pediatric ependymoma (EPN) comprise either supratentorial EPN characterized by ZFTA-fusions (ST-EPN-ZFTA) or posterior fossa group A EPN (PF-EPN-A), for both of which only limited therapeutic options are available. Because pediatric EPNs have a relatively low mutational burden, identification and characterization of tumor-associated pathways and molecular processes are of critical importance to reveal potential therapeutic targets. Data from previous transcriptional studies and a cross-species in vivo screen implied aberrant vesicular pathways in ST-EPN-ZFTA, prompting further investigation of their putative role in EPN pathogenesis. METHODS: We investigated EPN group-specific differences in extracellular vesicle (EV) biogenesis pathways in human EPN transcriptome and proteome datasets. In addition, we characterized isolated EPN EVs by mass spectrometry. EPN-specific EV cargo was further investigated by immunofluorescence staining and western blotting. This enhanced understanding of EPN vesicular signaling allowed for a pre-selection of inhibitors targeting specific EV biogenesis pathways. In vitro proliferation and invasion assays as well as in vivo treatment studies were performed on EPN model systems. RESULTS: Integration of multi-omic data from both EPN tissues and EPN-EV-associated proteome led to the identification of ST-EPN-ZFTA-specific EV populations. We could spatially map specific EV markers to the perivascular niche that primarily harbors undifferentiated ST-EPN-ZFTA cell populations. Targeting EV biogenesis pathways by inhibiting factors of the lipid metabolism reduced the abundance of released EVs resulting in altered growth behavior and decreased invasion of tumor cells in vitro. In vivo validation of EV release inhibitors in an orthotopic ST-EPN-ZFTA PDX model significantly reduced tumor growth and increased survival. OUTLOOK: In summary, we have leveraged ST-EPN-ZFTA-specific EV pathways as a potential therapeutic vulnerability. Further mechanistic investigations on EPN EV biogenesis, release, or uptake are expected to improve our understanding of the cross-talk between tumor cells and cells of the microenvironment and may lead to potential new therapeutic avenues.
EPEN-30. 5FU with Radiation Followed by Maintenance of 5FU and ATRA Significantly Improves Survival of 1q+/6q- PFA Ependymoma Xenograft Models
Authors: Grimaldo Enrique , Donson Andrew , Harris Faith , Amani Vladimir , Norris Gregory , Steiner Jenna , Serkova Natalie , Dorris Kathleen , Foreman Nicholas , Griesinger Andrea 
Published: June 2022

Abstract
In a screen of over 100 FDA approved drugs on PFA 1q+ EPN cells, 5-fluorouracil (5FU) and All-Trans-Retinoic Acid (ATRA) were identified as inhibitors of EPN cell line growth. We performed in-vitro cell growth assays combining increasing doses of radiation and 5FU and found a significant synergistic effect on cell growth and apoptosis in 1q+ PFA EPN cell lines. Further growth attenuation was seen when ATRA was added 48 hours following radiation and 5FU treatment. This led us to development of preclinical studies in the 1q+ PFA orthotopic xenograft models MAF-811_XF and MAF-928_XF. In the initial cohort, tumors were allowed to establish prior to treatment start confirmed by MRI. In both MAF-811 and MAF-928, chemotherapy improved survival compared to no treatment. As consistent with standard of care, radiation significantly improved survival (p=0.0016) but there was no added benefit to combining 5FU or 5FU+ATRA with radiation. A second cohort was treated using the same treatment approach, however radiation and 5FU were started with minimal to no visible tumors by MRI. Interestingly, we found a significant increase in survival between vehicle control and combination 5FU+ATRA (HR 5.121, 95% CI: 0.2506, 2.409, p=0.048) in MAF-811 mice. However, again with radiation, there was no significant change in survival with only a single cycle of 5FU+ATRA. This led to continued maintenance of 5FU+ATRA cycles of 6 weeks with 2 weeks off for 4 cycles post radiation in mice with minimal tumor. When 5FU with radiation is followed by 5FU+ATRA and is continued in mice with minimal disease, survival significantly improved when compared to radiation alone (HR 9.020, 95% CI: 1.933 to 42.09, p=0.007). These studies highlight the importance of chemotherapy in minimal disease and is the rationale for a Phase I/II study in relapsed PFA EPN and in upfront 1q+ PFA EPN.
EPEN-32. Leveraging cell surface targets as therapeutic vulnerabilities for pediatric ependymoma
Authors: Bertrand Kelsey 
Published: June 2022

Abstract
Brain tumors are the leading cause of cancer-associated death in children. Ependymoma, an aggressive type of childhood brain tumor, is currently treated with surgery and radiotherapy. Ependymomas are a molecularly heterogeneous group of tumors driven by distinct genetic and epigenetic alterations. In children, 90% of ependymomas arise intracranially, with two thirds occurring in the posterior fossa (PF) and one third in the supratentorial brain (ST). PF ependymomas are divided into at least two groups termed, PFA and PFB, with PFA tumors associated with poor clinical outcomes. Over 70% of ST ependymoma are characterized by an oncogenic fusion between ZFTA and RELA and shown in some cohorts to have poor clinical outcome, particularly in the context of CDKN2A tumor suppressor gene loss. A major challenge in identifying therapies against ependymoma, has been the paucity of genetic abnormalities available for targeting. PFA ependymomas harbor largely balanced genomes with no recurrent CNVs, fusions, or somatic mutations that are amenable to pharmacologic inhibition. ZFTA-RELA ependymoma while representing a clear disease driver, functions as a transcription factor and lacks clear binding surfaces available for direct inhibition using small molecules. Therefore, alternative approaches are needed to identify new targets and effective therapies in ependymoma to be evaluated in pre-clinical models. In both human ependymoma cell culture lines and PDX models, we demonstrate that a multi-omic approach is promising for cell surface target discovery, and further, focused cell surface profiling can identify lead targets that can be rapidly translated for CAR T-cell therapy.
EPID-01. Differences in first-line treatment but comparable survival outcomes for pediatric brainstem and non-brainstem high-grade gliomas in the Netherlands – a population-based study
Authors: Hoogendijk Raoull , van der Lugt Jasper , Baugh Josh , Kremer Leontien , Hoving Eelco , van Vuurden Dannis , Karim-Kos Henrike 
Published: June 2022

Abstract
INTRODUCTION: Pediatric high-grade gliomas (pHGG) are among the most devastating childhood cancers. Due to their limited treatment options and tumor biology, brainstem (BS) pHGG are considered to have worse survival outcomes compared to non-brainstem (NBS) pHGG. METHODS: Detailed clinical data were gathered by trained registrars for all children diagnosed with a pHGG (including radiologically diagnosed brainstem tumors) in the Netherlands for the period 2003-2017. Tumors were grouped into BS and NBS tumors according to the ICD-O-3 topography codes. Differences in treatment characteristics were tested with the Chi-squared, Fisher exact or Mann-Whitney-Wilcoxon test. Median survival time was determined by Kaplan-Meier method. Trends and survival differences were tested with Cox Proportional-Hazards Models. RESULTS: In total, 276 pHGG patients (BS n=166, NBS n=110) were diagnosed during 2003-2017. Differences in first line treatment were found for neurosurgery (25% of BS versus 95% of NBS patients, p&lt;0.001) and systemic therapy (20% of BS versus 70% of NBS, p&lt;0.001). Notable, 10% of BS patients received temozolomide compared to 55% of NBS patients (p&lt;0.001). No significant difference was found for first-line radiotherapy. However, total cumulative dose and number of fractions differed significantly (BS: median 44.8 Gy and 16 fractions; NBS: median 57.4 Gy and 30 fractions, both p&lt;0.001), reflecting hypofractionation regimens in BS pHGG. Survival remained stable over time for both BS (p=0.9) and NBS (p=0.3). Median survival time was comparable between BS (9.7 months) and NBS patients (9.8 months, p=0.6).CONCLUSION: Despite differences in treatment characteristics we found comparable survival outcomes for BS and NBS pHGG. It remains unclear why survival for both BS and NBS pHGG in this retrospective population-based study is substantially inferior to published data. If the underlying reasons can be found in differences in treatment characteristics, data type (hospital-based versus population-based) or incompleteness of non-microscopically verified cases, is subject to further research.
EPID-02. Survival Experience in Pediatric Patients of Central Nervous System (CNS) Tumour in Canada
Authors: Yuan Yan , Liu JiaQi , Walker Emily , Davis Faith 
Published: June 2022

Abstract
Established in 2016, the Brain Tumour Registry of Canada Surveillance Research Collaboration aims to address the lack of detailed information on CNS tumours in Canada. Using Canadian Cancer Registry (CCR) data with linked vital status, we present survival estimates for all primary CNS tumours (excluding Quebec) among pediatric patients (age 0-14). Pediatric patients diagnosed with primary CNS tumours during 2010-2017 were included. Vital status was obtained by Statistics Canada through linkage to the Canadian Vital Statistics Database and the income tax returns file, with a cut-off date of December 31, 2017. We used the Pohar-Perme method to estimate the net survival rate (NSR) through the period approach. International Classification of Diseases for Oncology (3rd edition) site/histology codes were grouped into 25 histological categories, irrespective of tumour behaviour, according to the schema developed by the Central Brain Tumor Registry of the United States. Of 1725 pediatric CNS tumours, the 1-, 2- and 5-year NSR are 0.89 (95%CI 0.87-0.90), 0.84 (95%CI 0.81-0.86) and 0.80 (95%CI 0.78-0.82), respectively. All non-malignant CNS tumours have a median survival over 8 years. The 5-year NSR range from 0.90 (95%CI 0.47-0.99) for unique astrocytoma variants, 0.95 for tumour of sellar region (95%CI 0.85-0.98) and germ cell tumours, cysts and heterotopias (95%CI 0.67-0.99), to 1.0 for choroid plexus tumours, tumours of cranial and spinal nerves, and meningioma. For malignant CNS tumours, NSR vary greatly depending on histology grouping. 5-year NSR from lowest to highest are glioblastoma (0.10, 95%CI 0.03-0.23), anaplastic astrocytoma (0.19, 95%CI 0.05-0.40), glioma not otherwise specified (0.54, 95%CI 0.46-0.62), embryonal tumours (0.72, 95%CI 0.65-0.79), diffuse astrocytoma (0.74, 95%CI 0.59-0.85), ependymal tumours (0.78, 95%CI 0.67-0.87), germ cell tumours, cysts and heterotopias (0.85, 95%CI 0.70-0.93) and pilocytic astrocytoma (1.0). We report the most comprehensive and up-to-date data on the pediatric primary CNS tumour survival experience in Canada.
EPID-06. Transfusion related iron overload in pediatric patients with CNS tumors
Authors: Winzent-Oonk Shelby , Winters Amanda , Pounds Aneisia , Pacenta Holly , Levy Jean Mulcahy , McKinney Christopher 
Published: June 2022

Abstract
BACKGROUND: Patients receiving chemotherapy or autologous hematopoietic stem cell transplant (autoHSCT) routinely receive red cell transfusions as supportive care. Each unit of transfused red cells contains approximately 150mg of iron which the body has no natural mechanism for excreting. Transfusion-related iron overload (TRIO) is an under-recognized complication of therapy which left untreated may result in long-term damage to the liver, heart, or endocrine organs. We sought to identify the prevalence of TRIO in patients with pediatric CNS tumors and evaluate specific risk factors. METHODS: A retrospective record review of pediatric CNS tumor patients treated at Children’s Hospital Colorado was conducted including patients who completing therapy between 1/1/2014 – 12/1/2021. Patients at high risk for TRIO were defined as having a cumulative transfused blood volume of more than 150mL/kg or 4000mL total. The diagnosis of TRIO was confirmed if patients had a serum ferritin greater than 1000ng/mL or elevated liver iron content of 7mg/g dry weight or greater by MRI. RESULTS: There were 173 evaluable patients (40% embryonal tumors, 15% germ cell tumors, 10% ependymomas, 26% low grade gliomas, 5% high grade gliomas, and 3% other tumors). The mean age at completion of therapy was 8 years (range: 0.67 – 25 years). Patients receiving autoHSCT (24% of cohort) were at higher risk for TRIO based on transfused volumes (p&lt;0.0001) than patients not treated with autoHSCT (72% vs 6%, RR 12.0) The prevalence of TRIO in autoHSCT patients was 7.5% (3/40) vs 0.8% (1/121) in patients not undergoing autoHSCT (RR 9.37). For autoHSCT patients at high risk by transfused volume the prevalence of TRIO was 10.3% (3/29). CONCLUSIONS: Pediatric CNS tumor patients who have received an autoHSCT are at higher risk for TRIO than those who have not. Routine screening for TRIO should be offered to patients receiving autoHSCT.
EPID-07. Outcome disparities in children, adolescents and young adults with medulloblastoma: A population-based analysis
Authors: Genecin Isabel , Fullwood Dottington , Moisander-Joyce Hanna , Padilla Oscar , Minns Hanna , Garvin James , Szalontay Luca , Wu Cheng-Chia , Kahn Justine , Gartrell Robyn D 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common high-grade primary pediatric brain tumor. Recent registry-based studies in children with central nervous system (CNS) tumors have demonstrated that survival outcomes differ by race/ethnicity in multivariable analyses, with Hispanic patients having highest hazard of death overall. To investigate this finding in MB patients, we examined survival in children (0-14 years) and adolescent/young adults (15-39 years) with MB from 2007-2016 in the 2018 Surveillance Epidemiology and End Results Program database, using Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI). Race and ethnicity were categorized according to the U.S. Census, with Hispanic ethnicity (yes/no) analyzed separately from race (Black, White, Asian, Other). Among 1612 patients, 81% were White, 9% were Black, 8% were Asian or Pacific Islander, and 2% were from “other” or unknown racial groups. 28% of the cohort was of Hispanic ethnicity. Univariate analysis found that Black patients had a significantly higher hazard of death than White patients (HR=1.55, CI: 1.16 – 2.08, p=0.003). In contrast, Hispanic ethnicity was not significantly associated with outcome (HR=0.98, CI: 0.79-1.21, p=0.8). Medicaid or no insurance (vs. private) were each significantly associated with higher risk of death; Medicaid (HR =1.23, CI = 1.01 - 1.51, p=0.041); Uninsured (HR=2.07, CI=1.41-3.02, p=&lt;0.001). Of the treatment modalities analyzed, patients who received neither chemotherapy nor radiation experienced higher hazard of death than patients who received both treatments (HR=3.63, CI 2.78-4.76, p=&lt;0.001). Consistent with observations in other cancers, racial disparities are observed in patients with MB, with Black race conferring increased risk of death. Public insurance was also significantly associated with death, as was not receiving combined-modality therapy. Further work is needed to understand the multilevel factors impacting diagnosis, treatment and outcome among children and AYAs with MB and prospective studies are warranted.
ETMR-08. Treatment strategy for pineoblastoma in infant
Authors: Suzuki Mario , Shimizu Yuzaburo , Akiyama Osamu , Fujimura Junya , Kondo Akihide 
Published: June 2022

Abstract
Pineoblastoma is a rare malignant brain tumor that occurs in infancy and young adulthood. Although its prognosis has improved in recent years, it remains one of the difficult tumor types to treat. We will retrospectively review the treatment of pineoblastoma at our hospital and propose the possibility of a new treatment for this tumor type. Three cases were studied. All of them presented at less than three years of age and were treated for hydrocephalus simultaneously as the biopsy. Chemotherapy was administered after a possible resection, and local radiotherapy was administered at the age of 3 years. Overall survival ranged from 7 to 91 months, with one case of long-term survival. To date, the prognostic factors for pineoblastoma are the age of onset and the presence of radiation therapy. This is interpreted to mean that the prognosis is worse in infants and young children who cannot be immediately treated with radiation therapy, indicating that radiation therapy is essential for treating this tumor type. On the other hand, radiation therapy for infants can significantly interfere with the development of the central nervous system, and there is much controversy about its potential compatibility with tumor control. We have identified a favorable prognosis group based on the molecular biological background of this tumor type. We propose that early radiotherapy may improve the prognosis.