bluuebunny/crossref_metadata_2025_split huggingface dataset:
ETMR-15. RECLASSIFICATION OF CHILDHOOD CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMOR: CLINICAL FEATURES AND OUTCOME
Authors: Simbozel Marie , Tauziède-Espariat Arnault , Saffroy Raphaël , Guillemot Delphine , Pierron Gaëlle , Hasty Lauren , le Lechapt Emmanuè , Chrétien Fabrice , Grill Jacques , Guerrini-Rousseau Léa , Abbou Samuel , Bolle Stéphanie , Bourdeaut Franck , Raimbault Sandra , Gourmel Antoine , Réguerre Yves , Pluchart Claire , Serre Jill , Faure-Conter Cécile , Blauwblomme Thomas , Beccaria Kevin , Puget Stéphanie , Varlet Pascale , Dufour Christelle 
Published: June 2024

Abstract

BACKGROUND
The “central nervous system primitive neuroectodermal tumor” (CNS-PNET) nosology was removed from the World Health Organization (WHO) classification after DNA methylation profiling and new tumor entities characterized by specific recurrent genetic alterations were described. The aim of this study was to re-evaluate the diagnosis of CNS-PNET and to describe their clinical characteristics.

METHODS
Patients aged &lt; 18 years with CNS-PNET or unclassified tumor, who were treated at Gustave Roussy between 1999 and 2019 or enrolled in the PNET HR trial were retrospectively identified. The study included all patients with sufficient archival material for diagnosis re-evaluation.

RESULTS
Sixty-two patients were eligible for the current analysis. The central histopathological review proposed a diagnosis according to the WHO classification in 58 cases. Out of these cases, 34 embryonal tumors were identified: 22 Embryonal Tumors with Multilayered Rosettes (ETMR), 4 CNS neuroblastomas with FOXR2 activation (CNS NB-FOXR2), 4 CNS high-grade neuroepithelial tumors with BCOR alteration (CNS HGNET-BCOR), 4 medulloblastomas. Another 24 tumors were classified as non embryonal tumors: 11 high-grade gliomas, 5 ependymomas, 4 pineoblastomas, 2 teratomas, one desmoplastic small round cell tumor, and one pilocytic astrocytoma. Four tumors without suspected diagnosis after first analysis remain unclassified after DNA methylation profiling. The 5-year event-free survival and overall survival for patients with ETMR were 14% (95% CI, 4.7-39%) and 27% (95% CI, 14-54%) respectively. For patients with CNS HGNET-BCOR and CNS NB-FOXR2 the median time to relapse was respectively 11 months (range, 0.5 to 1.3 year) and 3.1 years (range 1.7 to 4.4 years).

CONCLUSIONS
This study confirmed that the former nosology of CNS PNET does not correspond to a homogenous class but encompasses a diversity of rare histomolecular entities with specific clinical characteristics and outcomes.
ETMR-16. PEDIATRIC SPINAL EMBRYONAL TUMORS; PATHOLOGICAL INSIGHTS INTO THIS RARE ENTITY
Authors: Juneja Archita , Ranade Manali , Shetty Omshree , Sahay Ayushi , Shah Aekta , Prasad Maya , Chinnaswamy Girish , Sahu Arpita , Singh Vikas , Shetty Prakash , Moiyadi Aliasgar , Dasgupta Arychya , Chatterjee Abhishek , Gupta Tejpal , Epari Sridhar 
Published: June 2024

Abstract

BACKGROUND
Spinal cord is an extremely uncommon primary location for the CNS embryonal group of tumours. This study aims to collate the immunohistological spectrum of these rare spinal CNS embryonal tumours, diagnosed in the institute during the last 20 years.

METHODS
Of the total 446 spinal tumours, 15 were embryonal tumours. Of these, 5 were metastases, four from medulloblastoma and one from AT/RT (diagnosed subsequently) which were excluded and thus the study cohort comprised 10 cases. Eight were atypical teratoid/rhabdoid tumour (AT/RT; 80%), and 2 were embryonal tumour with multilayered rosettes (ETMR; 20%).

RESULTS
Six AT/RT cases were of ≤2 years age; while other two were 6 and 11 years of age with a M:F ratio of 1.3:1 (thoracic: 4; cervical: 2; lumbar: 2). Histologically, rhabdoid-like morphology (87.5%), necrosis (100%), and calcification (25%) were noted. All of them were of INI1 protein (SMARCB1)-deficient., all of them were negative for brachyury and all were variably positive for AE1/AE3. Two ETMR cases were of &lt;2 years of age, females and at lumbar and cervical levels respectively. C19MC amplification by FISH was done for one case which was not amplified. Histologically, one of them showed a medulloepithelioma-like pattern; while the other showed multilayered rosettes and neuropil-like matrix. LIN28A strong positivity, retained nuclear staining for INI1 protein and negativity for AE1/AE3 was noted in both. Significant BCOR positivity was seen in one but was negative for SATB2.

CONCLUSIONS
Spinal embryonal tumours are extremely rare and metastases needs to be ruled out before considering as primary. AT/RT is the most common embryonal tumour in the spine, commonly SMARCB1(INI1)-deficient. ETMR can also encountered in the spinal location.
ETMR-20. CARDIOLIPIN ACYL CHAIN MODULATION AS A NOVEL MITOCHONDRIAL-FOCUSED THERAPEUTIC TARGET IN ETMR
Authors: Liapis Evangelos , O’Neill Kelly C , Pamreddy Annapurna , Maas Allison , Hanson Derek R , Carter Claire L 
Published: June 2024

Abstract
Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm that occurs almost exclusively in infants and is associated with an extremely poor prognosis. Dysregulated mitochondrial bioenergetics and dynamics have been associated with the initiation and progression of diverse cancers and studies have linked metabolic rewiring to chemotherapy resistance. Cardiolipins are mitochondrial-specific lipids that reside in the mitochondrial membrane and their fatty acid composition has been extensively shown to regulate mitochondrial function and dynamics. Despite the known functional significance of cardiolipin structure, their role in mitochondrial regulation of brain tumors remains ill-defined. Using mass spectrometry imaging, we identified a shift to shorter acyl chain cardiolipins within the rapidly proliferating embryonal tumor cells in patient samples and patient-derived cell lines grown as 3D tumorspheres. Western blot analysis of the enzymes involved in cardiolipin synthesis and remodeling identified a significant increase in the expression of the cardiolipin remodeling enzyme, LCLAT1/ALCAT1. Orthogonal imaging techniques including immunohistochemistry, transmission electron microscopy and super-resolution microscopy correlated shorter acyl chain remodeling of cardiolipin with fragmented mitochondria (increased fission) and aberrant cristae structure. Further studies identified increased expression of the fission protein Drp1, decreased expression of respiratory chain enzymes and altered respiration in the embryonal tumor cells. Ongoing studies will utilize multiple methods to modulate cardiolipin acyl chain structure and use MS and MSI to correlate cardiolipin fatty acid structure to mitochondrial function and growth inhibition in the embryonal tumor cells.
ETMR-24. SOX2 INFLUENCES IDENTITY OF GLIA-LIKE PROGENITORS AND TUMORIGENESIS IN CHOROID PLEXUS THROUGH LIM HOMEODOMAIN TRANSCRIPTION FACTORS
Authors: Faltings Lukas , Zahran Mariam , Jalili Heena , Green Kristen , Virga James , Modi Siddhi , Guru Navjot , Cao Ping , Zhao Haotian 
Published: June 2024

Abstract
Choroid plexus (CP) tumors encompass a spectrum of rare brain neoplasms ranging from benign papilloma (CPP) to aggressive carcinoma (CPC) that collectively affect the pediatric population. Poor outcomes for high-grade lesions and side effects of current treatment paradigms underscore a critical need to develop safer and more efficacious therapies guided by biological understanding of these tumors. We developed mouse models from common molecular defects found in human disease. These models exploit sustained NOTCH signaling activation in the hindbrain upper rhombic lip to generate CPP and CPC. To delineate cellular composition of CP tumors, we conducted snRNA-seq in murine CP tumors. Similar to adult CP, cells in NOTCH-driven CPP partitioned into clusters identified as epithelial, mesenchymal, endothelial, immune, neuronal, and glial cells. Though tumor cells are confined to epithelial compartment based on inferCNV analysis of snRNA-seq data, they are derived from glia-like progenitors. Tumor cells are in a distinct differentiation state characterized by a lack of epithelial maturation, and aberrant expression of markers of neural progenitor/stem-like cells including SRY-Box Transcription Factor 2 (SOX2). Consistently, SOX2 inactivation decreased tumor cell proliferation and blocked NOTCH-driven CP tumor formation. ChIP-seq studies revealed SOX2 binding to promoters of LIM homeodomain transcription factors Lmx1a and Lmx1b. Enforced SOX2 expression activated the expression Lmx1a and Lmx1b, whereas Sox2 loss reduced their expressions in tumor cells. Importantly, knockdown of Lmx1a or Lmx1b decreased tumor cell proliferation, whereas overexpression of Lmx1a/b rescued proliferation of tumor cells subjected to SOX2 suppression. Contextualizing these results in CP development, SOX2 critically maintains progenitor cell identity through regulating Lmx1a/b expression in the rhombic lip. Finally, analysis of human CP tumor samples revealed abnormal expressions of SOX2 and LMX1A. Together, these results indicate that oncogenic signaling subverts SOX2 transcriptional programs that specify normal progenitor identity and lock tumor cells in unique differentiation state to facilitate CP tumor growth.
EPEN-05. SURGERY FOR CHILDHOOD EPENDYMOMA: THE EPENDYMOMA MULTIDISCIPLINARY ADVISORY GROUP (EMAG) CLINICAL TRIAL EXPERIENCE
Authors: Ritzmann Timothy A , Chapman Rebecca J , Leatherland Rheanne , Goodden John , Macarthur Donald , Mallucci Conor , Kamaly Ian , Pizer Barry , Grundy Richard G 
Published: June 2024

Abstract

INTRODUCTION
The National Ependymoma Multidisciplinary Advisory Group (EMAG) is the central review mechanism for the SIOP Ependymoma II clinical trial in the UK. EMAG is a multiprofessional group which meets weekly to support decision making. We report detailed surgical outcomes for children with confirmed intracranial ependymoma, discussed through EMAG between January 2020 and November 2022.

METHODS
Data was collected on resection status, surgical outcomes, reasons for not achieving Gross Total Resection (GTR), number of surgeries and adjuvant therapies. Data was analysed descriptively.

RESULTS
After first surgery, GTR or near total resection (NTR) rate was 69/105 (66%) rising to 83/105 (79%) following repeated surgeries. 17 patients underwent second-look surgery prior to further therapy, whilst 9 underwent second-look surgery after chemotherapy but before radiotherapy. Eight (17%) posterior fossa (PF) surgeries were not completed due to factors including patient instability and tumour attachments. Most post-operative problems were seen in PF tumours with 26/60 (43%) bulbar palsy, 13/60 (22%) focal weakness and 12/60 (20%) cerebellar mutism. Incomplete PF resections were associated with increased bulbar palsy risk (p=0.02, Chi-Square test). 73% of PF patients required hydrocephalus management with external ventricular drainage, endoscopic third ventriculostomy (ETV) or shunt. Longer term hydrocephalus management with ETV or shunt was required in 29% and was more common in those with subtotal resection (R3-RX, 8/16, 50%) compared to GTR or NTR (R0-R2, 9/43, 21%, p=0.03). 27/60 (45%) received post-op NG feeding and 2/60 (3%) needed tracheostomies. Second surgery was associated with lower complication rates.

DISCUSSION
Our National MDT approach supports collaborative surgical decision making without a need for centralisation of the surgery itself. There was no evidence of increased complication rates compared to historical trials despite a more aggressive surgical approach. We argue for continued centralisation of EPN evaluation to support optimal care for children with this devastating disease.
EPEN-08. MULTI-OMICS PROFILES REVEAL UNIQUE DEFINING MOLECULAR FEATURES OF POSTERIOR FOSSA EPENDYMOMA SUBTYPE A FROM INFANTS
Authors: Lourdusamy Anbarasu , Chapman Rebecca J , Ritzmann Timothy A , Grundy Richard G , Dineen Robert A 
Published: June 2024

Abstract

BACKGROUND
Ependymoma is a heterogeneous brain cancer with multiple subgroups based on locations and molecular profiles. Tumours of the methylation class, posterior fossa group A (PF-EPN-A) represent the most common and aggressive neoplasms and have a poor outcome. PF-EPN-A tumours in infants (under three years of age) are understudied; this project aimed to characterise these infant tumours.

METHODS
We collected DNA methylation (n=570) and gene expression (n=56) profiles of PF-EPN-A tumours, and single-cell RNA sequencing data of human fetal cerebellum from published studies.

RESULTS
Analysis of copy number profiles derived from DNA methylation arrays showed that infants with PF-EPN-A have relatively quiescent genomes when compared to children aged four to eighteen years (mean fraction of changes in infants (n=300) = 0.018 and children (n=270) = 0.055; p-value &lt; 2.2 × 10-16). No recurrent focal amplifications or losses were detected, however, copy number loss involving chromosome arms, 12q (12%), 7q (9.7%), 5p (8.3%), and 16p (6%) were relatively common in infants, while 1q gain, 6q loss, and 22q loss were more frequent in children. When we stratified PF-EPN-A based on copy number alterations, infants with altered genomes were associated with poor outcomes compared to infants with stable genomes (fraction of changes = 0), which in turn showed poor overall survival compared to children with stable genomes. Gene set enrichment analysis using data from microarrays showed that infant tumours were specifically enriched with genes involved in the extracellular matrix organization, interferon gamma signaling, neuronal system, autophagy, and signaling by Interleukins, VEGF and PDGF. Integration with single-cell data from the human fetal cerebellum revealed that infants in PF-EPN-A had significantly higher proportions of glial progenitor cells and decreased granule cell progenitor subpopulations.

CONCLUSIONS
Together, our study identifies distinct genetic and transcriptional programs among infants in PF-EPN-A tumours, representing opportunities to refine future treatment.
EPEN-13. PRE-IRRADIATION CHEMOTHERAPY EXPERIENCE FOR PEDIATRIC EPENDYMOMA POLISH PROTOCOL
Authors: Filipek Iwona , McGlynn Mary Claire , Drogosiewicz Monika , Tarasińska Magdalena , Perek-Polnik Marta , Kowalczyk Paweł , Święszkowska Ewa , Grajkowska Wiesława , Abdelbaki Mohamed S , Dembowska-Bagińska Bożenna , Trubicka Joanna 
Published: June 2024

Abstract

BACKGROUND
Pediatric ependymomas are aggressive central nervous system malignancies arising from the ependymal linings of ventricles and spinal canal. Despite better understanding of tumor biology ependymomas remain therapeutic challenge in pediatric neurooncology. The role of chemotherapy remains controversial. Herein, we describe the outcomes of patients treated at the largest center in Poland who underwent surgery, pre-irradiation chemotherapy and irradiation regardless of extent of surgical resection.

METHODS
This retrospective review includes pediatric patients with ependymoma treated according to national protocol at the Children’s Memorial Health Institute. We reviewed histology, disease extent, treatment, and report on overall survival (OS) and progression free survival rates (PFS). Descriptive statistics were analyzed using SPSS software.

RESULTS
Forty-nine patients were included (median age: 84 months). Most patients (96%) had cranial ependymomas (43% supratentorial and 57% posterior fossa lesions). Disseminated disease was found in 16% of cases. Complete resection was achieved in 43%. All patients received pre-irradiation chemotherapy; 6.1% had progressive disease and 41% achieved complete response (CR). All patients, except one, underwent irradiation (67% focal, 2% focal/ventricular, 29% craniospinal, and 2% whole brain). Thirty-five percent of patients relapsed. Five-year PFS and OS were 69% and 80% respectively. Comparing posterior fossa to supratentorial lesions, there was no difference in response after surgery and pre-irradiation chemotherapy (CR 37% versus 50% (p=0.51)) or irradiation (CR 42% versus 55% (p=0.37)). However, relapse was more likely in posterior fossa ependymomas (OR 0.30 IQR (0.70, 1.29), p=0.03) with lower 5-year PFS (56% versus 85%, p=0.03) and 10-year PFS (52% versus 85%, p=0.02). The benefit of chemotherapy was marked in patients with Grade 3 (5-year OS 82% versus 69%)

CONCLUSIONS
We describe a large cohort of pediatric ependymoma patients who received pre-irradiation chemotherapy. This strategy did not negatively impact the incidence of progression before irradiation.
EPEN-17.IN VITRO MODELLING OF PEDIATRIC SUPRATENTORIAL EPENDYMOMAS USING CEREBRAL ORGANOIDS
Authors: Roosen Mieke , Morscio Julie , Stathi Phylicia , Mack Norman , Schwalm Benjamin , Polychronopoulos Panagiotis A , Kranendonk Mariëtte E G , Hoving Eelco , Bunt Jens , Kool Marcel 
Published: June 2024

Abstract

BACKGROUND
Ependymomas (EPN) are glial tumors of the central nervous system occurring in children and adults. ZFTA-fusion positive and YAP1-fusion positive EPN are the main supratentorial (ST) subgroups in children. While most ST-EPN-YAP1 patients survive, only 50% of ZFTA positive patients survive longer than 5 years. Improving survival of ST-EPN patients requires a better understanding of tumor biology. Human embryonal stem cell-derived (hESC) brain organoids provide a novel opportunity to model ST-EPN and study the impact of oncogenic fusions on tumor development within a healthy brain environment.

METHODS
hESC-derived cerebral organoids were genetically modified with YAP1 or ZFTA fusion genes and histologically and molecularly analyzed using antibody stainings, bulk and single cell RNA sequencing.

RESULTS
scRNA-seq analyses showed that our cerebral organoids mimic embryonal brain development and that radial glia, the presumed cell-of-origin of ST-EPN are abundant in 11-day old organoids. At this timepoint, electroporation of oncogenic ZFTA-RELA or YAP1-MAMLD1/YAP1-FAM118B fusions led to ectopic tumor outgrowth. Histological and molecular analyses showed that ZFTA and YAP1 EPN tumor organoids displayed different phenotypes and fusion-specific gene signatures, closely resembling human ZFTA and YAP1 EPN patient samples. ScRNA-seq data of organoid tumors showed a skewed differentiation compared to normal development with ZFTA tumors being more neuronal and YAP1 tumors having a more extracellular matrix-like phenotype. Analysis of the healthy compartment showed that YAP1 tumors influence the differentiation of the healthy cells and in both subtypes a new cell cluster was identified with high expression of tumor associated markers. Intercellular interactions revealed potential targetable tumor(specific) interactions such as YBX1-NOTCH1 in ZFTA or GNAI2-CAV1 in YAP1 tumor organoid models, as well as CD99-CD81 in both.

CONCLUSIONS
These models contribute to a better molecular and biological understanding of ependymomas and can be used to identify targeted therapies, especially those targeting the tumor microenvironment.
EPEN-27. GAINING A CLUE FROM 1Q: A HIGH-RISK CHROMOSOMAL GAIN IN PEDIATRIC POSTERIOR FOSSA EPENDYMOMA
Authors: Richman Cory M , Rasnitsyn Alexandra , Przelicki David , Diaz Jacob Torrejon , Macleod Graham , Varadharajan Srinidhi , Lee John , Angers Stephane , MichealRaj Antony , Ayrault Olivier , Taylor Michael D 
Published: June 2024

Abstract

BACKGROUND
Ependymomas are neuroepithelial tumours that can be classified into distinct molecular subgroups, each exhibiting a unique clinical outcome. Therapeutic efforts against the most aggressive and abundant subgroup of pediatric ependymoma (posterior fossa group A, PFA) have traditionally been hampered by a lack of known recurrent driver mutations. However, approximately 25% of PFA tumours exhibit gains of the chromosome arm 1q which is associated with an extremely poor prognosis despite aggressive treatment. By interrogating the multi-omic landscape of PFAs harbouring this copy number variation, we aimed to uncover genetic dependencies from which actionable therapeutics could be derived.

METHODS
Transcriptomic (bulk/single-cell RNA sequencing), proteomic (LC-MS/MS) and phosphoproteomic analyses were conducted on patient tissues and primary patient-derived cell lines to gain insight into the pathways that drive 1q gain pathogenesis. Chromatin immunoprecipitation sequencing of H3K27me3 and H3K27ac marked histones was carried out to profile the epigenetic landscape of these tumours, and whole genome CRISPR knockout screens were performed to reveal the contribution of essential genes unique to tumours harboring 1q gains.

RESULTS
Through the comparison of 1q gain and balanced PFA samples, our multi-omic analyses identified the up-regulation and essentiality of known glioma oncogenic drivers previously uncharacterized in PFA. The investigation of essential candidate genes showed a convergence on pathways related to ciliogenesis, with genetic vulnerabilities informing in vitro drug screening. Candidate genes were further validated by in vivo knockdown using established xenograft mouse models for pre-clinical testing.

CONCLUSIONS
This combined approach has allowed for the derivation of a functional cancer signature underlying 1q gains in PFA and presents novel therapeutic targets for this high-risk subgroup. PFA ependymoma is a deadly malignancy whose complex biology has so far eluded therapy, and new insights from this project will help to identify the first effective therapies for this vulnerable patient population.
EPID-02. A CLINICALLY RELEVANT SURVIVAL COMPARISON OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS FOR 31 EUROPEAN COUNTRIES – POPULATION-BASED RESULTS FROM THE EUROCARE-6 PROJECT
Authors: Hoogendijk Raoull , Capocaccia Riccardo , van der Lugt Jasper , Kranendonk Mariëtte , Hoving Eelco , Wesseling Pieter , Visser Otto , van Vuurden Dannis , Gatta Gemma , Karim-Kos Henrike ,   EUROCARE Working Group
Published: June 2024

Abstract

BACKGROUND
Survival outcomes of pediatric central nervous system (CNS) tumors have been reported to vary largely across countries and regions in Europe. This is the first time the EUROCARE-6 database was used to study survival outcomes for clinically relevant groups of pediatric CNS tumors in Europe.

METHOD
Survival data of 14,689 children (&lt;15 years) diagnosed with a CNS tumor between 2008 and 2013 from 31 European countries was analyzed. Multivariable cox regression model was used to compare adjusted risks of dying (HR) from major groups of CNS tumors between countries using Germany as reference.

RESULTS
Five-year observed survival (OS) of low-grade gliomas (LGGs) for most countries was &gt;90%. Three countries with comparable hazard ratios (2.6-2.7) showed to have a significantly higher risk of dying compared to Germany. Large variation in survival was seen for high-grade gliomas (HGGs); 0%-70%. When analyzing HGGs, six countries had a significantly higher risk of dying with hazard ratios ranging from 1.2 to 4.2. When excluding malignant gliomas, NOS (ICD-O-M9380/3) from the HGGs the risk of dying became comparable for two out of the six countries. For HGGs, only one country had a significant lower risk of dying. For Medulloblastomas, 5-year OS within the majority of countries ranged between 40-70% but with some countries having no patients surviving their disease. Seven countries had significantly worse survival outcomes with hazard ratios ranging from 1.7-3.2. No countries were found to have better survival outcomes.

CONCLUSIONS
This population-based study provides an insightful comparison of survival from CNS tumors in children between European countries corrected for potential incompleteness of non-malignant CNS tumors and misclassification of NOS tumors. Survival disparities were still seen for all tumor groups.