bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPEN-07. PATTERNS OF EXTRANEURAL METASTASES IN PEDIATRIC SUPRATENTORIAL EPENDYMOMA: CASE SERIES AND REVIEW OF THE LITERATURE
Authors: Chan Priya P , Whipple Nicholas S , Perry Arie , Solomon David A , Zhou Holly , Linscott Luke L , Kestle John R W , Bruggers Carol 
Published: December 2020

Abstract

BACKGROUND
Ependymomas account for 10% of all malignant pediatric intracranial tumors. Standard therapy includes maximal safe surgical resection followed by involved-field radiation. Up to 50% of localized pediatric ependymomas recur. Extraneural metastases at time of recurrence are rarely reported.

OBJECTIVE
To describe extraneural metastases of pediatric ependymomas.

METHODS
Retrospective review of patients’ medical records and literature review.

RESULTS
Three patients with history of locally recurrent, supratentorial ependymoma developed extraneural metastases: one in a cervical lymph node, one with a scalp nodule, and one with a dural lesion. Each extraneural recurrence had similar histologic and molecular features as the initial diagnosis. The cervical lymph node recurrence was treated with multimodal therapy; she is without disease four years later. The isolated scalp nodule occurred at the exit site of a subgaleal drain placed during prior resection. Following nodule resection, he developed additional scalp and lymph node disease and is receiving palliative care. The isolated dural recurrence occurred at the exit site of a ventriculoperitoneal shunt placed following a previous resection. She died of progressive disease 18 months after dural lesion resection. Reports of lymph node, scalp, and dural metastases of ependymomas are exceedingly rare, and outcomes are poor.

CONCLUSIONS
Extraneural manifestations of ependymoma are rare. Regional seeding from prior surgical procedures may play a role in metastatic spread. Extraneural metastases should be considered in children previously treated for ependymoma who develop local findings even in the absence of CNS relapse. Salvage therapy with curative intent should be considered using a multimodal approach.
EPEN-11. ONGOING RESPONSE IN A MULTIPLY RELAPSED METASTATIC POSTERIOR FOSSA EPENDYMOMA A AFTER VORINOSTAT AND CONCOMITANT IRRADIATION
Authors: Gorsi Hamza S , Toll Stephanie , Yankelevich Maxim 
Published: December 2020

Abstract

BACKGROUND
Among the nine molecular subgroups of ependymoma identified, posterior fossa ependymoma A (PF-EPN-A) confers the worst prognosis. These tumors often relapse despite aggressive resection and irradiation, resulting in limited therapeutic options. Although the genomic profile of PF-EPN-A does not typically show any recurrent alterations; they demonstrate distinct epigenetic changes which can be targeted with modulators such as histone deacetylase (HDAC) inhibitors. These inhibitors have shown efficacy in pre-clinical studies in both their anticancer and radio-sensitizing properties. CASE: We describe a male diagnosed with a posterior fossa ependymoma at 3 years of age. After initial therapy with resection and focal irradiation, he went on to have a number of recurrences requiring multimodal therapy. Most recently, he developed diffuse intraventricular and leptomeningeal disease not amenable to surgical intervention. Genetic evaluation demonstrated a BCOR mutation and methylation profile was consistent with PF-EPN-A. He received 23.4 Gray craniospinal irradiation with a 30.6 Gray boost to the nodular lesions. Vorinostat was given concomitantly for radio-sensitization in 2 week intervals for a total of 6 weeks. Serial imaging after irradiation revealed decreased tumor burden with almost complete resolution of disease at 15 months. Unfortunately, MRI at 18 months exhibited mild interval growth of 2 lesions.

CONCLUSIONS
To our knowledge, this is the first report of a clinical response in a pediatric patient with PF-EPN-A following irradiation administered concomitantly with vorinostat therapy. This response highlights the importance of further studies evaluating this combination therapy and its potential use in this population.
EPEN-16. TRANSCRIPTIONAL REGULATORY CIRCUITRIES AS MOLECULAR TARGETS IN EPENDYMOMA
Authors: Bertrand Kelsey , Mack Stephen , Parsons Donald W 
Published: December 2020

Abstract
Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas resist chemotherapy and lack available targeted agents for clinical trial development. Based on our previous findings, we hypothesized that mapping chromatin landscapes and super enhancers (SE) could uncover transcriptional dependencies as targets for therapy (Mack, Pajtler, Chavez et al., Nature, 2018). To functionally test the requirement of these SE genes for ependymoma cellular growth, we designed a pooled RNA interference screen against 267 SE associated genes. Our screen was performed in one C11ORF95-RELA-fusion model and two PF-EPN-A models as controls in biological triplicates. As an indication that our screen was successful, positive controls scored among lead hits including KIF11, BUB1B, PHF5A and MYC. Importantly, we identified many subtype specific dependencies in both C11ORF95-RELA-fusion and PF-EPN-A models, thus revealing novel pathways that potentially govern subgroup-specific ependymoma cell growth. Further, several candidates detected across all ependymoma lines were also identified as pan-cancer dependencies or glioma/glioblastoma specific essential genes from the DepMap Cancer Dependency Gene Resource. Our findings reveal novel targets and pathways that are essential for ependymoma cell growth, which may provide new insight into therapeutic strategies against these aggressive brain tumors.
EPEN-26. NON-CANONICAL NF-κB SIGNALING DRIVES MESENCHYMAL EPENDYMAL CELL SUBPOPULATION IN PFA EPENDYMOMA
Authors: Griesinger Andrea , Harris Faith , Donson Andrew , Gillen Austin , Riemondy Kent , Venkataraman Sujatha , Amani Vladimir , Handler Michael , Hankinson Todd , Foreman Nicholas 
Published: December 2020

Abstract
NF-κB signaling is a hallmark of PFA1 ependymoma. Loss of LDOC1, through epigenetic silencing, leads to constitutively active NF-κB signaling and chronic IL-6 secretion. In this study, we investigate the loss of LDOC1 within the PFA tumor clusters. Using our PFA scRNAseq database, in which there are 5 clusters within the tumor cell compartment: mesenchymal (MEC), ciliated (CEC), transportive (TEC), and undifferentiated (UEC). LDOC1 expression was significantly reduced and had an inverse correlation with genes defining the unfavorable MEC subpopulation, predominate in PFA1. This is consistent with our findings that MEC was defined by an NF-κB2 signaling profile. In contrast, LDOC1 expression was higher and positively correlated with genes defining the favorable CEC subpopulation, mostly seen in PFA2. RELA expression, which we studied as a target of LDOC1, was not localized to MEC and was wide-spread throughout the PFA compartment. RELB, part of non-conical NF-κB signaling, was expressed only the MEC subpopulation correlating with IL-6 gene expression found only in this subpopulation. In MAF-811, a PFA cell line with more CEC-like gene phenotype, RELB co-immunoprecipates with the active form of NF-κB2 in both the nucleus and cytoplasm. IL-6 gene expression is almost completely lost when NF-κB2 is knock-down using shRNA. Additionally, loss of LDOC1 leads to over 3 fold increase in NF-κB2 expression. Combined with our previous work, this would suggest that NF-κB2 drives IL-6 expression by binding with RELB in MEC subpopulation and targeting loss of LDOC1 may shift the MEC subpopulation toward the more favorable CEC subpopulation.
EPEN-27. CDKN2A DELETION IN SUPRATENTORIAL EPENDYMOMA WITH RELA ALTERATION INDICATES A DISMAL PROGNOSIS – A RETROSPECTIVE ANALYSIS OF THE HIT EPENDYMOMA TRIAL COHORT
Authors: Jünger Stephanie T , Andreiuolo Felipe , Mynarek Martin , Dörner Evelyn , zur Mühlen Anja , Velez-Char Natalia , von Hoff Katja , Rutkowski Stefan , Warmuth-Metz Monika , Kortmann Rolf-Dieter , Timmermann Beate , von Bueren Andre O , Pietsch Torsten 
Published: December 2020

Abstract

INTRODUCTION
Since supratentorial RELA-fusion positive ependymomas are considered a biologically distinct disease, we aimed to identify histological and genetic predictors of outcome in a defined cohort of pediatric patients.

MATERIALS AND METHODS
We analyzed 54 RELA ependymomas in pediatric patients treated according to HIT2000-E protocols. All cases underwent central neuropathological review. Genome-wide copy number alterations were assessed by molecular inversion probe or SNP array. RELA alterations were detected by RT-PCR, sequencing and assessment of nuclear p65-RelA protein. Copy number alteration of the CDKN2A (cyclin dependent kinase inhibitor 2A) locus and concordant p16 protein expression were analyzed.

RESULTS
Fifty-two tumors were classified as WHO-grade III (96.3%) with high mitotic activity in 39 cases (72.2%), vascular proliferation in 47 (87.0%), necrosis in 43 (79.6%) and clear cell morphology in 19 (35.2%). All tumors harbored RELA alterations. Homo- or heterozygous CDKN2A deletions were detected in 9 (16.7%) and 14 (25.9%) cases, respectively. p16 protein expression was lost in all cases with homozygous deletion. Median follow-up was 5.4 years with 5-years EFS and OS of 74.1% and 92.6%. In Kaplan-Meier analysis high mitotic activity was related to shorter EFS (p=0.016) and clear cell morphology to longer OS (p=0.039); CDKN2A deletion was associated with shorter OS (homozygous deletion, p=0.009; homo-or heterozygous deletion, p=0.034). No correlation between CDKN2A deletion and high mitotic activity was found but with higher age at diagnosis (p=0.001).

CONCLUSION
Deletion of CDKN2A occurred in 42.6% of supratentorial ependymomas with RELA alteration and represented a genetic predictor of worse overall outcome in pediatric patients.
EPEN-34. THE CRISPR-Cas9 SYSTEM-MEDIATED ENDOGENOUS GENE REARRANGEMENT INDUCED C11orf95-RELA FUSION IN VITRO AND IN VIVO THAT LED TO THE DEVELOPMENT OF EPENDYMOMA-LIKE TUMOR
Authors: Takadera Mutsumi , Ozawa Tatsuya , Satomi Kaishi , Yamamoto Tetsuya , Ichimura Koichi 
Published: December 2020

Abstract
Recent large-scale genomic studies of ependymal tumors have identified recurrent RELA and YAP1 fusion genes in supratentorial ependymomas. The formation of the C11orf95-RELA fusion gene has been attributed to massive genomic rearrangement involving chromosome 11q termed Chromothripsis in many cases. However, the causal relationship has not been clarified experimentally. In this study, we developed a system to reproduce the oncogenic gene rearrangement using the CRISPR-Cas9 system and examined whether consequent endogenous ependymoma fusion genes are competent to form brain tumors in mice. Initially, to investigate whether C11orf95-RELA fusion can be formed by inducing the relevant gene rearrangement in vitro, we designed multiple guide RNAs on the human and mouse genomic loci and introduced them into cultured cells. RT-PCR and immunoblot analyses detected endogenous C11orf95-RELA fusion transcript and protein in both human and mouse cultured cells. Subsequently, we lentivirally introduced the gRNAs into a mouse brain. Brain tumor formation was observed from around 2 months after the lentivirus injection, thus indicating successful gene rearrangement followed by C11orf95-RELA fusion expression in vivo. Analysis of the tumor tissue confirmed the expression of the endogenous C11orf95-RELA fusion gene. These results suggested that a gene rearrangement is a primary mechanism to form the C11orf95-RELA fusion which is the direct driver of tumorigenesis. Our system to simulate a genomic event will provide significant insights into the understanding of the tumorigenic mechanism in ependymomas.
EPEN-39. CLINICAL STRATIFIED TREATMENT OF LOCALIZED PEDIATRIC INTRACRANIAL EPENDYMOMA WITH COMBINED LOCAL IRRADIATION AND CHEMOTHERAPY WITHIN THE PROSPECTIVE, MULTICENTER E-HIT TRIAL – THE MOLECULAR SUBGROUP MATTERS
Authors: von Hoff Katja , Obrecht Denise , Wening Janna , Mynarek Martin , Gerber Nicolas U , Benesch Martin , Juhnke B - Ole , Bison Brigitte , Warmuth-Metz Monika , Timmermann Beate , Faldum Andreas , Schüller Ulrich , Pfister Stefan M , Kool Marcel , Pietsch Torsten , Kortmann Rolf-D , Kwiecien Robert , Pajtler Kristian W , Witt Hendrik , Rutkowski Stefan 
Published: December 2020

Abstract

BACKGROUND
Pediatric ependymoma is a heterogenous disease. Subgroup-specific clinical information on prospectively treated patients will help to improve treatment stratification.

METHODS
Within the population based, prospective, multicenter E-HIT-trial (2001–2011) patients with localized ependymoma confirmed by neuropathological central-review, received hyperfractionated local radiotherapy (68Gy, 2x1Gy/day) followed by chemotherapy (stratum-A), or chemotherapy followed by local radiotherapy (54Gy, 1.8Gy/day) (children &lt; 4years, stratum-B), or age-adapted radiotherapy with pre-/post-irradiation chemotherapy (residual tumor, diagnosis after 2005, stratum-C). Retrospective classification of DNA-methylation was available for n=164 E-HIT-trial participants, and n=80 patients with comparable treatment and prospective registration in the subsequent HIT-interim-registry (2012–2014). FINDINGS: For 291 E-HIT-trial patients, 5-year progression-free (PFS) and overall survival (OS) were 61±3%, and 81±2%. Five-year PFS/OS after complete resection were 71±4% and 87±3% in stratum-A (n=127), and 64±5% and 86±4% in stratum-B (n=86). Outcome was poor after incomplete resection, irrespective of treatment-stratum (n=78, 5-year PFS/OS: 43±6%, 68±5%). In the pooled trial- and registry-cohort, there were 152 patients with PF-EPN-A (5-year PFS/OS: 44±4%, 77±4%), 40 of them with 1q-gain (5-year PFS/OS: 28±7%, 66±8%), 21 with PF-EPN-B (5-year PFS/OS: 90±7%, 100%), 59 with ST-EPN-RELA (5-year PFS/OS: 63±7%, 87±5%), and 4 with ST-EPN-YAP1 (2 progression/relapse, no death).

CONCLUSION
Outcome differed between molecular subgroups and insufficient survival rates were achieved for patients with PF-EPN-A with 1q-gain, despite combined radio- and chemotherapy treatment. Treatment reduction in the context of a clinical trial may be considered for PF-EPN-B.
EPEN-43. TARGETING INTRA-TUMOUR HETEROGENEITY IN PAEDIATRIC EPENDYMOMA: AN INTEGRATED OMICS STUDY TOWARDS PATIENT-TAILORED THERAPY
Authors: Pandele Alina , Woodward Alison , MacArthur Donald , Kamaly-Asl Ian , Barrett David A , Grundy Richard G , Kim Dong-Hyun , Rahman Ruman 
Published: December 2020

Abstract
Ependymoma (EPN) is the second most common malignant paediatric brain tumour, which despite extensive genomic sequencing, no novel therapeutic options have been discovered. Multi-omics are anticipated to reveal dysregulated pathways that may be predictive of patient-specific biomarkers. Given the close association between gene expression, active biochemical signaling and metabolism, there is an unmet scientific challenge to determine whether EPN gene expression correlates with aberrant metabolic pathways, thus presenting therapeutic vulnerabilities. We first compared two distinct subgroups of EPN, PF-A and ST-RELA, identifying 115 metabolites and 1580 upregulated genes between the two subgroups, therefore validating previously reported genetic clustering of these two subtypes. We next integrated transcriptomics and metabolomics, comparing 28 intra-tumour tissue regions from eight primary PF-A EPN patients. Polar metabolites and RNA were simultaneously extracted from the same population of cells. RNAseq identified dysregulated genes and liquid chromatography-mass spectrometry (LC-MS) detected 98 significantly altered metabolites between 18 multi-regions, the majority mapping onto the arginine and proline pathways. Integration of genes and metabolites using pathway-based network analysis revealed 124 aberrant gene-metabolite interactions between intra-tumour regions, with large numbers occurring in the glucogenesis and glycine metabolic pathways in 6/8 patients. These may represent ubiquitous and therapeutically relevant metabolic pathways critical for EPN survival. Additionally, patients presented at least one unique intra-tumour genomic-metabolomic interaction, applicable for patient-tailored therapy. This is the first exploration of EPN multi-omic integration and intra-tumour heterogeneity. Selected drug targets predicated on aberrant gene-metabolite networks will be validated in multi-region patient-derived cell lines and orthotopic models using repurposed therapeutics.
EPEN-51. CHILDHOOD INTRACRANIAL EPENDYMOMA: A MULTI-CENTER RETROSPECTIVE ANALYSIS
Authors: Pickle Emily Owens , Aguilar-Bonilla Ana , Khallouq Bertha Ben , Stapleton Stacie , Sandler Eric , Langevin Anne-Marie , Libes Jamie , Hanif Iftikhar , Smith Amy 
Published: December 2020

Abstract
Ependymoma is a heterogeneous disease which is resistant to improvement. Current challenges are the unreliability of histologic classification, the uncertain role of adjuvant chemotherapy, and a lack of clinical trials integrating molecular and clinical diagnostics into risk-guided therapy. Ependymoma can show surprising latency, reoccurring many years after the original diagnosis. In this study, we performed a retrospective analysis of ependymoma cases treated at six centers over a period of 12 years. A total of 73 cases were submitted from six sites; 68 cases were retained for review. Median age at diagnosis was 4.1 years and gender was reported as male (50%) and female (50%). Histologic grade was reported as Grade II (49%) and Grade III (50%)(not reported: 1). Anatomic location reported as supratentorial (27%) and infratentorial (73%). Metastatic disease was reported in 9% of patients. At diagnosis, gross total resection was achieved in 59% of cases. Twenty-eight percent of patients have died, 59% of patients are alive (with and without disease), and 13% of patients are lost to follow-up. Maximal safe surgical resection is currently the best predictor of long-term survival but was achieved in only 60% of cases. Biology-based therapy will be the next step towards improving the prognosis of pediatric ependymoma.
EPID-01. TRENDS OF INCIDENCE IN PEDIATRIC BRAIN TUMORS IN KUMAMOTO PREFECTURE, JAPAN
Authors: Itoyama Takashi , Shinojima Naoki , Yamamoto Takahiro , Fujimoto Kenji , Makino Keishi , Mukasa Akitake 
Published: December 2020

Abstract

BACKGROUND/PURPOSE
One of the most problematic issues Japan has is a declining birthrate resulting in an aging society. There are some reports on the trends of incidence in brain tumors in the elderly, whereas few reports on those in the children. The aim of this study is to investigate the trends of incidence in childhood primary brain tumors.

METHODS
The population of children aged &lt;15 years was available from Kumamoto Prefecture’s annual census between 1990 and 2017. During the period 301 childhood primary brain tumors (124 gliomas, including astrocytic tumors and ependymomas, 35 embryonal tumors, 34 germ cell tumors, 22 craniopharyngioma, and 86 others) were registered with the Kumamoto Brain Tumor Data Bank, and investigated.

RESULTS
The average of the annual incidence rate per 100,000 child populations was 3.90 for total brain tumors, 1.63 for gliomas, 0.44 for embryonal tumors, 0.42 for germ cell tumors, 0.26 for craniopharyngioma, and 1.15 for others. Divided into the first half from 1990 to 2003 and the second half from 2004 to 2017, there was no significant difference in the incidence of brain tumors aged &lt;15 years between the two periods. However, the average of the annual incidence rate/100,000 child populations was 3.02 in the first half, while significantly increased in the second half of 4.78 (p=0.00075, t-test). DISCUSSION &

CONCLUSIONS
The average number of children aged &lt;15 years in Kumamoto Prefecture was 31,2737.9 from 1990 to 2003, while decreased remarkably to 251460.2 from 2004 to 2017. A decrease in the number of children may affect increasing the incidence rate of pediatric brain tumors.
EPID-06. DIAGNOSTIC INTERVAL TIME OF PEDIATRIC CNS TUMORS: A REPORT OF THE CANCER IN YOUNG PEOPLE IN CANADA (CYP-C) DATABASE
Authors: AlNajjar Mohammad , Goel Divya , Larouche Valerie , Erker Craig , Cheng Sylvia , Barber Randy , Strother Douglas , Sung Lillian , Lafay-Cousin Lucie 
Published: December 2020

Abstract

INTRODUCTION
CNS tumors are the second most common neoplasm in children and have historically been associated with longer time to diagnosis. Data on the time-to-diagnosis for Canadian children with CNS tumors are limited and outdated. We aimed at evaluating the diagnostic interval time(DIT) for Canadian children, and identifying factors possibly associated with prolonged DIT.

METHODS
Using the CYP-C database, we analyzed data from children &lt;15 years, diagnosed with CNS tumors between 2001–2015. DIT was defined as time in weeks, elapsed from the first contact with a healthcare provider to confirming diagnosis. We described DIT according to patient’s demographics, socioeconomic, geographic factors as well as tumor-related criteria.

RESULTS
Patients from all Canadian provinces, except Ontario, had available timepoints to calculate DIT. The cohort included 842 patients. Mean DIT for all patients was 11.7 weeks(median 1.4). Gliomas had the longest mean DIT and embryonal tumors had the shortest(14.6 and 3.6 weeks p&lt;0.01). ATRT and medulloblastoma had a mean DIT of 1.3 and 4.3 weeks respectively. DIT for HGG was shorter than for LGG (6.4 versus 16.1 weeks, p&lt;0.01). Metastatic disease, infratentorial tumors, or age £36 months had significantly shorter DIT (5.6 vs 12.4 vs 18.4, 7.4 vs 13.1 and 8.6). Sex, annual income(QAIPPE), and distance from tertiary center did not influence DIT.

CONCLUSION
The current diagnostic interval time for pediatric CNS tumors in Canada is 11.7 weeks(median 1.4weeks). These results only reflect the healthcare system’s contribution toward diagnosis confirmation, but not the patient interval before seeking medical attention.