bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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 (<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 >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.
EPID-06. PEDIATRIC BRAIN TUMOUR DIAGNOSTIC DELAY DURING COVID-19 PANDEMIC IN A REGIONAL NEURONCOLOGY CENTRE
Authors: Mucelli Martina Pozzi , Toniutti Maristella , Pedicini Sara , Liguoro Ilaria , D’Agostini Serena , De Colle Maria Cristina , Tuniz Francesco , Vindigni Marco , Pegolo Enrico , Coassin Elisa , Mascarin Maurizio , Cogo Paola Elisa , Pilotto Chiara
Published: June 2024

BACKGROUND

The Pediatric Central Nervous System (CNS) tumors incidence has increased in the last decades. A diagnostic delay could be related to adverse effects involving neurosurgical approach. Moreover, many studies report that Coronavirus-19 pandemic has even increased the diagnostic delay of solid tumors, in particular CNS types.

METHODS

We conducted a retrospective study including all pediatric patients who received a diagnosis of CNS tumor at Udine Hospital between January 2020 and December 2021. Our first aim was to assess if there has been a variation in the incidence rate and a possible diagnostic delay of CNS pediatric tumors during 2020-2021. As a secondary objective we evaluated if the Coronavirus-19 pandemic has affected our ability to identify tumor relapses caused by delays in planning follow-up exams and imaging. Data of every patient were recorded and compared with data from a historical cohort recruited between 2000 and 2011.

RESULTS

25 patients were enrolled in the study: 19 (11 males) were diagnosed with a primitive CNS tumor, 7 (3 males) with a secondary lesion. Incidence rate during 2020-2021 was 5.17 per 100.000 inhabitants (age 0-18 years) and median diagnostic interval was 6.7 weeks, both higher than in the historical cohort (but not statistically significant). Median age was 10 +/- 4,7 age (IQR 25°-75°5,9-13,7). No substantial variation of clinical presentation was detected, although some symptoms were found to be more frequent than in the past. A significant rise in the number of high histological grade tumors was recorded (63% vs 12%, p value < 0.001), but there was no difference in tumor relapses diagnostic delay (median 6,7 weeks compared with 5 weeks in historical cohort).

CONCLUSIONS

Coronavirus-19 pandemic had no impact in diagnostic delay, planning and execution of follow-up exams in children with CNS tumors.
EPID-08. PEDIATRIC GLIOMA IN INDONESIA: CLINICAL PROFILES AND OUTCOMES
Authors: Rahmartani Ludi Dhyani , Budiarso Michael Nathaniel , Susanto Eka , Amal Mohamad Yanuar ,   Handoko., Nuryadi Endang , Gunawan Kevin
Published: June 2024

BACKGROUNDS

Gliomas are the most common form of pediatric brain tumor. The primary obstacle to optimizing pediatric brain tumor health services, particularly in LMICs, is the lack of comprehensive epidemiological data. We aim to compile comprehensive data on pediatric gliomas, focusing on clinical profiles and outcomes within a national general hospital in Indonesia.

METHODS

A retrospective observational longitudinal study was performed at Cipto Mangunkusumo National General Hospital, focusing on glioma patients’ profiles and outcomes, registered under the pediatric CNS tumor service from January 2022 to December 2023.

RESULTS

Out of 50 suspected glioma patients, 28 patients (56%) underwent biopsy, 28% underwent other modalities (brainstem location), 12% were scheduled for surgery but had already died, 2% were in a watchful waiting mode, and 2% were scheduled for surgery but were lost to follow-up. Glioma-confirmed patients were predominantly female (57.1%), with a mean age of 7.11 ± 4.98. Low-grade gliomas predominated at 57.1%, a trend we attribute to Cipto Mangunkusumo’s status as a referral national hospital, where low-grade glioma cases may have been managed more frequently at lower-level hospitals. The majority of tumors were supratentorial (53.6%) compared to infratentorial (39.3%) and supra-infratentorial (7.1%). The most common symptoms were seizures (25%), followed by headaches (21.4%), disequilibrium (14.3%), and vomiting (10.7%). Moreover, the latter three symptoms exhibited a longer mean delay between symptom onset and medical consultation, potentially impacting prognosis. In the last follow-up, higher-grade gliomas demonstrated a significantly higher mortality rate at 28.6% compared to low-grade gliomas at 3.6% (P < 0.001).

CONCLUSION

Given the variable clinical characteristics of glioma tumors, these results underscore the urgent need for comprehensive epidemiological data on pediatric gliomas in Indonesia, particularly regarding prognosis-related factors. Such data could serve as a crucial step towards future research and clinical strategies aimed at improving outcomes for children with gliomas.
METB-03. SOLID PEDIATRIC TUMORS IN MICE REVEAL MODEL-SPECIFIC GLOBAL DNA METHYLATION AND CNV PROFILES CORRESPONDING TO HUMAN COUNTERPARTS
Authors: Schoof Melanie , Zheng Tuyu , Sill Martin , Imle Roland , Hofmann Nina , Ernst Kati , Vonficht Dominik , Chan Chun Ho , Cais Alessia , Holland-Letz Tim , Postlmayr Andreas , Shiraishi Ryo , Wang Wanchen , Morcavallo Alaide , Spohn Michael , Göbel Carolin , Niesen Judith , Peter Levke-Sophie , Eckhardt Alicia , Bourdeaut Franck , Han Zhi-Yan , Pei Yanxin , Murad Najiba , Swartling Fredrik J , Taylor Jessica , Gilbertson Richard J , Dottermusch Matthias , Kerl Kornelius , Glass Rainer , Cheng Jiying , Horstmann Martin A , Nollau Peter , Wolters-Eisfeld Gerrit , Zhao Haotian , Sturm Dominik , Chesler Louis , Haas Simon , Weiss William A , Northcott Paul A , Kutscher Lena M , Stücklin Ana Guerreiro , Ayrault Olivier , Neumann Julia E , Kawauchi Daisuke , Jones David , Pfister Stefan M , Pajtler Kristian , Banito Ana , Schüller Ulrich , Zuckermann Marc
Published: June 2024

BACKGROUND

The analysis and comparison of global DNA methylation patterns has become a gold standard in modern neuropathology. For human central nervous system (CNS) tumors and other cancers, the research community has collected thousands of methylation profiles, leading to the discovery and definition of numerous molecularly distinct tumor types and subtypes. Although reliable preclinical mouse models are essential for the understanding of tumor development and the validation of therapeutic approaches, such DNA methylation analyses have so far not been systematically performed for murine tumors owing to technical limitations.

METHODS

We employed the Illumina Bead Chip 285k mouse methylation array to profile ~500 samples covering 90 different mouse models representing 33 pediatric solid tumor types, including CNS tumors and sarcomas from 18 laboratories. We compared DNA methylation profiles of these models between each other and to human CNS tumors, performed immune cell deconvolution and conducted an in-depth analysis of copy number variants (CNVs) during tumor evolution.

RESULTS

Unsupervised clustering showed that mouse models form groups of their presumed tumor types. Using a tailor-made cross-species analysis based on syntenic CpG sites, we found that most tumors also group with their corresponding human counterparts. Immune cell deconvolution revealed distinct tumor microenvironments that showed clear similarities to human tumors. We further identified recurrent, model-specific CNVs that are syntenic to genomic aberrations in respective human tumors, suggesting an essential role of CNVs during tumor initiation or maintenance.

CONCLUSION

We provide a global resource of well characterized pediatric solid cancer models representing numerous different tumor types. Our comparative analyses reveal novel molecular model characteristics and validate their reliability as human disease models. Our data provide new biological insights into immune composition, tumor cell identities and tumor development by identifying model-specific CNV profiles.
METB-06. PEDIATRIC BRAIN TUMOURS: A SINGLE INSTITUTIONAL EXPERIENCE OF NEXT GENERATION SEQUENCING-BASED TARGETED PANEL EVALUATION
Authors: Epari Sridhar , Bapat Prachi , Gurav Mamta , Shetty Omshree , Shah Aekta , Sahay Ayushi , Prasad Maya , Sahu Arpita , Singh Vikash , Shetty Prakash , Moiyadi Aliasgar , Dasgupta Archya , Chatterjee Abhishek , Chinnaswamy Girish , Gupta Tejpal
Published: June 2024

BACKGROUND

Pediatric brain tumours (pBT) are molecularly diverse and with the advent of targeted-therapies it is important to decipher molecularly.

METHODS

Single institutional non-consecutive pBT (<18 years) cohort include – a. high-grade glial tumour (HGG; H3-wildtype, IDH1/2-wildtype, immunohistochemically MMR-protein-proficient, negative for NTRK/ALK-rearrangements by FISH in <3 years), b. high-grade CNS neuroepithelial tumour, NOS (cNET), c & d. pilocytic astrocytoma (LGG-PCA), and low-grade glial/glioneuronal tumour LGG-LGGNT), histologically not typical of PCA nor any defined entity that were negative for BRAFV600mutations, KIAA1549- BRAF (16-9, 15-9, & 16-10) fusions, e. low-grade glial tumour with diffuse architecture (LGG-DLGG) that were negative for IDH1R132/IDH2R172-mutations. These were evaluated for NGS-based-panel (42 genes, 137 RNA fusions, and 24 genes for amplification – STS-plus-panel Sophia Genetics).

RESULTS

41 cases (HGG: 12, cNET:2, LGG-PCA: 10 & 1, LGG-LGGNT: 13 & LGG-DLGG: 3) formed the study-cohort. a. HGG: 5 were <3 years (supratentorial [ST]: 3; posterior-3rd-ventricular [p3v]: 1 & posterior-fossa [PF]: 1), 2 showed mutations in TP53-exons 5 & 6 respectively, one ST case showed SND1-AKT2 (9:7) fusion. Of 6-18 years (all ST location), 3 showed TP53-mutations, one showed PDGFA & KIT-amplification with SF3B1-mutation and one showed BRAFV600E-mutation. b. cNET: BRAFV600E and TP53-mutation was observed in each of the case respectively. c. LGG-PCA: one case showed FAM131B-BRAF (2:9) fusion. One KIAA1549- BRAF (15-9) fusion case was evaluated as it progressed, showed additional TP53-mutation. d. LGG-LGGNT: one (4/F; PF location) showed EGFR-gains with TERT-promoter (C228T) mutation (like adult-type glioma), one showed NF1-exon 12 mutation with KIAA1549-RAD51 (18:4) fusion, one showed CDKN2A-exon 2 mutation and one (midbrain) case showed BRAFV600E-mutation. e. LGG-DLGG: one (11/M, occipital-SOL) showed KEAP1-exon 5 mutation with KIAA1549- BRAF (15:9) fusion.

CONCLUSIONS

TP53-mutations is common in HGG, infantile HGG can show non-ALK/NTRK fusions. LGG can show non-BRAF/KIAA1549-fusions, rarely can show KEAP1 mutations and adult-type-like alterations. Target-panel NGS-based assay can help to molecularly decipher to a certain extent, especially for instituting targeted-therapies.
METB-09. VARIANT WORKBENCH IN THE KIDS FIRST PROGRAM FACILITATES GENOMIC DISCOVERIES IN PEDIATRIC NEURO-ONCOLOGY RESEARCH
Authors: Guo Yiran , Li Qi , Rozowsky Jare , Costanza Jeremy , Mattioni Michele , Thibert Jean-Philippe , Brown Miguel , Higgins David , Zhu Yuankun , Heath Allison , Resnick Adam , Ferretti Vincent
Published: June 2024

The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer and structural birth defects, including the discovery of shared genetic pathways between these disorders. Kids First Data Resource Center developed the Kids First Data Resource Portal (KFDRP), which is a centralized data platform for both Kids First and collaborative cohorts. Currently, KFDRP facilitates data access for 40 studies with over 35,500 participants. To assist researchers and clinicians in identifying potential disease-causing germline variants in the human genome, KFDRP released the Variant WorkBench (VWB), which facilitates variant querying, manipulation, analysis, and visualization. Cavatica is a widely used bioinformatics analysis platform developed by Velsera. Compared to a previous version, the Cavatica-based VWB has better support for data import/export, more convenient sharing of notebooks and data, and easier billing details, with the same level of scalable, cloud-based computing. Additionally, Cavatica-based VWB has incorporated multiple public reference databases, including Cancer Hotspots, ClinVar, COSMIC, dbNSFP, gnomAD, TOPMed, as well as gene-phenotype links provided by OMIM, HPO, Orphanet, and the Deciphering Developmental Disorders Project. These databases have been converted to parquet files, reducing process time and memory usage compared to regular text files, thus speeding up data retrieval and querying. Furthermore, Cavatica empowers users to create and share custom analysis workflows tailored to specific research questions and datasets, enhancing data utility and analysis accuracy. Here we present a gene-based variant filtering workflow that aggregates information from dbNSFP, HGMD, TOPMed, gnomAD, and ClinVar. We identified 1202 pathogenic/likely pathogenic variants in NF1, a gene that helps regulate cell growth, across 582 pediatric brain tumor samples within 6 mins. Among the variants, there are 21 protein-altering variants. Overall, the upgraded VWB is more powerful, user-friendly, and adaptable.
METB-12. GIFT FROM A CHILD POSTMORTEM SPECIMEN DATASET EXTENSION OF THE PEDIATRIC BRAIN TUMOR ATLAS EMPOWERS PEDIATRIC BRAIN TUMOR RESEARCH
Authors: Koptyra Mateusz P , Diarra Noni , Rokita Jo Lynne , Chroni Antonia , Frenkel Beth , Anthony Ciana , Kraya Adam , Baubet Valerie , Biluck Ian , Sullivan Catherine , Coleman Noel , Seip Lauren , Lilly Jena , Santi Mariarita , Viaene Angela , Storm Phillip B , Resnick Adam C , Child On Behalf Of Gift From A
Published: June 2024

BACKGROUND

Pediatric brain and spinal cord tumors are the leading cause of cancer-related mortality in children. An incomplete understanding of brain tumor biology and associated limited access to high-quality biological samples for research are the main factors driving the lack of clinical therapeutic development for pediatric brain tumors that recur or progress. Post-mortem tissue donation provides an unprecedented resource for addressing some of these limitations.

METHODS

The Gift from a Child (GFAC) program by the Swifty Foundation has a unique mission to increase post-mortem pediatric brain tissue donations through advocacy as well as the education of clinicians and families. Through GFAC’s strategic collaboration with the Children’s Brain Tumor Network (CBTN), CBTN has leveraged postmortem tissue to expand the Pediatric Brain Tumor Atlas (PBTA), a cross-histology multi-omics atlas resource. As part of the effort CBTN has sequenced and released data for over 350 post-mortem pediatric brain tumor specimens including multiple brain region sampling cases with specimen and sequencing quality metrics.

RESULTS

Here we present an assessment of postmortem samples and available multi-omic data on postmortem samples within the PBTA dataset. Data have been harmonized and released with no publication embargo. To access data, researchers can utilize existing open source data resources and platforms including PedCbioPortal and OpenPedCan to: (1) Identify tumor spatial and temporal specific alterations (2) Establish tumor evolution trajectory leading to therapeutic resistance and tumor progression; (3) Understand tumor heterogeneity longitudinally across multiple ‘omics layers; and (4) Identify and request specimens and derived tumor models.

CONCLUSIONS

Together, we present the largest deeply characterized cohort of postmortem pediatric brain tumor samples as powerful expansion of the PBTA cohort of >3,000 pediatric brain tumors. CBTN’s open-science model supported by the GFAC mission highlights the value and utility of autopsy-based specimen collection on behalf of improving outcomes for children with brain tumors.
METB-15. ROLE OF DNA METHYLATION PROFILING IN THE MANAGEMENT OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS: A SINGLE INSTITUTIONAL SERIES
Authors: Sato Mariko , Sharma Prachi , Navalkele Pournima , Pathare Jody , Abdullae Zied , Aldape Ken , Crawford John
Published: June 2024

BACKGROUND

DNA methylation profiling has now been integrated into the WHO classification of CNS tumors and serves as confirmatory means to diagnose CNS tumors in conjunction with genetic sequencing/microarray analysis. The practical impact on patient care in the retrospective and prospective settings is less known.

METHODS

Methylation analysis was performed on a cohort of previously and newly diagnosed children with CNS tumors at Children’s Hospital Orange County from 2022-2023. Data regarding histologic diagnosis, integrated molecular diagnosis, methylation classification, timing of result completion and functional impact of methylation results on patient diagnosis/management was evaluated.

RESULTS

Forty patients (21 boys, ages 5 weeks-17 years) with previously diagnosed (N=11) or newly diagnosed (N=21) CNS tumors were evaluated by methylation analysis at one or more institutions. The most common tumor types were diffuse type pediatric high-grade glioma (N=6) and ependymoma PFA (n=4). Methylation analysis revealed no match in two cases (ALK-EML4 fusion embryonal tumor and recurrent low grade glioneuronal tumor) and had insufficient DNA extraction in one patient with low grade glioneuronal spinal cord tumor. Among the 5 tumors with duplicate methylation analyses at two institutions, three Ependymoma PFA subgroups were concordant while two showed differing classifications (diffuse type pediatric high-grade glioma RTK1 subtype vs. non- classifiable and medulloblastoma group 4 vs. non-WNT, non-SHH). In patients with previously diagnosed CNS tumors, methylation either led to a change in classification or modification of diagnosis in 7 out of 11 patients. The average time from surgery to the receipt of methylation results for newly diagnosed patients was 24 days (range 4-90 days).

CONCLUSION

Methylation analysis was beneficial in both the previously diagnosed and newly diagnosed setting in patients with previously difficult to classify tumors following conventional molecular analysis. Changes in tumor classification or modifications in diagnosis were observed in the majority of patients.
GCT-10. OUTCOME OF CHILDREN AND ADOLESCENTS DIAGNOSED WITH GERMINOMA WITH HCGΒ VALUES BETWEEN 100-200 MUI/ML TREATED ACCORDING TO THE BRAZILIAN CNS GCT PROTOCOL
Authors: Aguiar Carol S , Dassi Natália , Mançano Bruna , Epelman Sidnei , Aguiar Simone S , Silva Nasjla S , Finlay Jonathan L , Cappellano Andrea M
Published: June 2024

BACKGROUND

Primary central nervous system (CNS) germ cell tumors (GCT) are rare tumors, classified according to histological components and tumor markers (TM) as Germinomas and Non-Germinomatous Germ Cell Tumors (NGGCT). The aim of this study is to assess the outcome of patients with Germinoma and HCGβ levels between 100-200mIU/ml treated according to the Brazilian CNS GCT Consortium Protocol.

METHODS

From 2013 to 2021, forty-three patients presented with histological and/or TM (serum and CSF) consistent with the diagnosis of germinoma, five of them with HCGβ levels between 100-200mIU/ml. The treatment plan performed was four cycles of carboplatin/etoposide followed by whole ventricular field irradiation (WVFI) of 18Gy with a boost to primary site(s) up to 30Gy and 24Gy craniospinal irradiation (CSI) for disseminated disease.

RESULTS

Average age 13.7 years (6.3-20.3 years), four males and one female. Diagnosis was made by TM (n=2), and biopsy +TM (n=3). The primary tumor location was pineal (n=2), suprasellar (n=1), and bifocal (n=2) with 1 case presenting ventricular spread at diagnosis. Three patients achieved complete response (CR) after two cycles of chemotherapy and one after four cycles. One patient showed partial radiological response (PR) with negative TM after four cycles and was submitted to a second-look surgery, with pathological report of residual scar tissue. Radiotherapy was performed as described in all patients with four patients receiving WVFI (18Gy+30Gy) and one CSI (24Gy+30Gy). In a mean follow-up of 64 months, overall and event-free survival was 100%.

CONCLUSION

Despite the small sample, the present study shows effectivity with excellent results and a possibility of increasing the cutoff and therefore reducing treatment for patients with HCGβ at levels up to 200mlU/ml currently treated in some protocols as NGGCT cases.
GCT-12. OUTCOMES OF INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOURS (NGGCT) TREATED AT A SINGLE UK PROTON CENTRE ACCORDING TO UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) GUIDANCE, INCLUDING EARLY IMPROVED OUTCOMES USING WHOLE VENTRICULAR RADIOTHERAPY (WVRT) FOR LOCALISED DISEASE
Authors: Goyal Love , France Anna , Gaito Simona , Colaco Rovel J , Pan Shermaine , Saunders Daniel , Thorp Nicola , Murray Matthew J , Nicholson James C , Ajithkumar Thankamma V , Whitfield Gillian A
Published: June 2024

BACKGROUND

After SIOP-CNS-GCT-II closed in 2018, the CCLG recommended, with caveats, following standard trial arms: 4 Cisplatin-Etoposide-Ifosfamide (PEI) cycles, then focal radiotherapy (FRT) (54Gy/30fractions) to primary site(s) for localised NGGCT and craniospinal-irradiation (CSI) (30Gy/20fr) + boosts (24Gy/15fr cranial, 20.8Gy/13fr spinal) for metastatic disease. Since 04/2021, the CCLG formally recommended adding WVRT (24Gy/15fr) for localised NGGCT, and considering 2x standard, 2x high-dose PEI for high-risk (HR) cases (diagnostic AFP>1000ng/ml).

METHODS

Retrospective review of all CNS-NGGCT patients referred 12/2018-06/2023. We collected patient, tumour and treatment factors, acute toxicities (CTCAE grade≥3), and event-free survival (EFS) from radiotherapy until 09/2023.

RESULTS

Twenty-four patients (21M:3F) included, 14 localised (4xHR), 10 (including 2 incompletely staged) treated as metastatic (3xHR). Median age 11 years, median follow-up 16 months (m). Primary sites: 13 pineal, 5 pituitary/suprasellar, 6 bifocal. Patients were treated according to CCLG guidance. One received FRT without WVRT. One incompletely staged bifocal standard-risk (SR) NGGCT after partial response to PEI had surgery, local+metastatic progression, then second-line chemotherapy before CSI. All seven HR patients received intensified chemotherapy. Nine had post-chemotherapy surgery for residual, two showing necrosis/inflammation, three mature teratoma, two mixed viable GCT. Three relapses (1/17 SR, 2/7 HR) made early EFS 0.875. Of 13 localised patients receiving WVRT, 2 progressed. One bifocal SR patient developed spinal metastases at 5.0m and died despite chemotherapy+spinal irradiation. One unifocal HR patient developed posterior parafalcine metastasis at 3.9m, received GemPOx (Gemcitabine-Paclitaxel-Oxaliplatin), surgery, high dose Carboplatin-Etoposide-Thiotepa with stem-cell rescue, and photon CSI and remains disease-free at 13.2m. One metastatic HR patient progressed at 0.9m and died at 3.0m despite chemotherapy. Acute toxicities were grade 3 lymphopenia in two CSI patients.

CONCLUSIONS

Despite short follow-up, initial EFS is excellent in SR disease. No localised WRVT-receiving NGGCT patient progressed within the ventricular volume, suggesting benefit of low-dose WVRT.
GCT-29. MULTI-INSTITUTIONAL ANALYSIS OF PEDIATRIC RELAPSED/REFRACTORY CENTRAL NERVOUS SYSTEM GERMINOMAS
Authors: McGlynn Mary Claire , Abu-Arja Mohammad H , Zaghloul Mohamed Saad , Bertrand Kelsey , Gajjar Amar , Alias Hamidah , Cappellano Andrea , Graham Richard T , Baglivo Sofia Jares , Bhadri Vivek , Govender Dinisha , Dassi Natalia , Czogala Malgorzata , Ronsley Rebecca , Knowles Truman , Mueller Sabine , Dhall Girish , Nagabushan Sumanth , Abdelbaki Mohamed S
Published: June 2024

BACKGROUND

Relapsed central nervous system germinomas are rare with no universal agreement regarding management. We explored the prognostic factors that may impact the treatment of patients with relapsed CNS germinoma.

METHODS

We collected data on relapsed/progressive germinomas from nine large international sites. Data was summarized using descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fischer’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI).

RESULTS

Twenty-seven patients with relapsed (24) and progressive (3) germinomas were included (3.7% metastatic). Median age at diagnosis was 15.8 years (interquartile range (IQR): 11.9-18.5). Complete remission (CR) after initial treatment (chemotherapy 63.9% and radiotherapy 88.9%) was achieved in 15 patients (55.6%). The median time from diagnosis to relapse/progression was 20.0 months (range: 10.8-65.1 months) with 55.6% occurring within 24 months. Twenty-five patients (92.6%) underwent chemotherapy, 15 (55.6%) received high-dose chemotherapy with stem cell support (HDCx), and 16 received (59.3%) radiotherapy. At last follow-up, 86.6% of HDCx and 87.5% of radiotherapy recipients were alive. Median time to last follow-up was 41.8 months (IQR: 19.6-132.1). Fifteen children (55.6%) achieved CR after therapy and 21 (77.8%) were alive at last follow-up. Of patients receiving irradiation, 12.5% received whole ventricular irradiation, 81.3% craniospinal irradiation, and 6.3% focal irradiation. Chemotherapy at relapse was associated with improved 5-year OS (OR=1.32 95%CI: 1.06-1.64) Re-irradiation at relapse (OR=2.6, 95%CI: 0.36-19.2) and HDCx at relapse (OR=2.17, 95%CI: 0.30-15.71) did not reach statistically significant difference. CR after initial therapy (OR=1.25, 95%CI: 0.97-1.61) was not associated with improved 5-year OS, CR after relapse therapy was associated with increased 5-year OS (OR=3.50, 95%CI: 1.08-11.24)

CONCLUSIONS

Relapsed CNS germinomas are salvageable at relapse. This ongoing multi-institutional study will contribute to existing knowledge about relapsed/progressive CNS germinomas and inform prospective clinical trials to improve outcomes for children with relapsed/progressive disease.
HGG-06. MOLECULAR PATTERNS OF PEDIATRIC HIGH-GRADE GLIOMAS IN SOUTHEAST ASIA
Authors: Aw Sze Jet , Merchant Khurshid , Goh Jian Yuan , Mok Yingting , Tan Char Loo , Tan Enrica Ee Kar , Low Sharon Yin Yee , Chang Kenneth Tou En
Published: June 2024

BACKGROUND

Molecular characteristics of pediatric high-grade gliomas are largely based on cohorts derived from North America and Europe. In this study, we compare the molecular findings of a Southeast Asian cohort of pediatric high-grade gliomas with published data.

METHODS

We collated clinical, histopathological, and molecular data from pediatric high-grade gliomas diagnosed in our laboratory over the past 5 years. Molecular testing methods used included Illumina’s Childhood Cancer Panel (26 cases), FoundationOne’s CDx panel (2 cases), and Archer FUSIONPlex Pan Solid Tumour v2 panel (2 cases). 7 cases had no molecular data. 11 cases underwent additional DNA methylation analysis using Illumina’s Infinium MethylationEPIC v1.0 kit.

RESULTS

37 cases of pediatric high-grade gliomas from 34 patients were identified. Patient age ranged from 2 to 26 years (median 14 years). The male-female ratio was 1.1:1. Diffuse midline gliomas, H3K27-altered (DMG, H3K27-altered) constituted 51% of the cases (19/37), followed by diffuse pediatric-type high-grade gliomas, H3-wildtype and IDH-wildtype (32%; 12/37) and diffuse hemispheric gliomas H3G34-mutant (16%; 6/37). The commonest genes with pathogenic single nucleotide variants were TP53 (79%;22/28), followed by H3F3A (54%;15/28). The commonest amplified genes were MYCN and EGFR (both 4/28; 14%). Three gene fusions were detected, none of which arose from infants – 2 were found in diffuse pediatric-type high-grade gliomas, H3-wildtype and IDH-wildtype (CSTF3::ALK and PRCC::NTRK1 fusions), and one occurred in a DMG, H3K27-altered (ERC1::RET fusion). The most common methylation groups identified were DMG, H3K27-altered and diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, MYCN subtype (both 3/11; 27%).

CONCLUSIONS

Although small, our Southeast Asian cohort comprised a higher percentage of TP53-mutant high-grade gliomas amongst all pediatric high-grade gliomas as a group. The commonest amplified genes were MYCN and EGFR. We detected gene fusions in non-infant gliomas. These findings suggest geographical differences in the biology of pediatric high-grade gliomas.
HGG-07. INVESTIGATING THE ROLE OF SENESCENCE IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Chang Timothy H , Nassar Alexander , Kleinman Claudia , Bandopadhayay Pratiti
Published: June 2024

Cellular senescence has expanded well past the original definition of just proliferative exhaustion and tumor suppression. Today, senescence is considered a “Hallmark of Cancer” and the senescence-associated secretory phenotype (SASP) secretes molecules that can promote oncogenesis, angiogenesis, and an immunosuppressive tumor microenvironment (TME). Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors with dismal outcomes and limited therapeutic options. Accumulating evidence suggests potential therapeutic vulnerabilities in targeting senescence in adult solid and brain tumors. Furthermore, senescent immune cells in the TME appear to play an important role in the initiation and progression in adult solid tumors. The role of senescence in pHGGs, however, has not been well described. Here, we show evidence of senescent glial and immune cells in pHGG tumors. Using patient-derived cell lines, we also investigate triggers of senescence and further characterize SASP in pHGGs. By understanding the role of senescence in gliomagenesis, we hope to open new approaches in treating pHGGs.
HGG-16. PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA OF METHYLATION-BASED RTK2A AND RTK2B SUBCLASSES PRESENT DISTINCT RADIOLOGICAL AND HISTOMOLECULAR FEATURES
Authors: Tauziède-Espariat Arnault , Friker Lea L , Nussbaumer Gunther , Alice Métais , Antonelli Manila , Benesch Martin , Bison Brigitte , Dangouloff-Ros Volodia , Garrè Maria Luisa , Giangaspero Felice , Grabovska Yura , Grill Jacques , Jones David T W , Jones Chris , Karremann Michael , Kramm Christof M , Mackay Alan , La Madrid Andrés Morales , Perwein Thomas , Pietsch Torsten , Sumerauer David , van Vuurden Dannis , von Bueren André O , Warmuth-Metz Monika , Wesseling Pieter , Zamecnik Josef , Castel David , Gielen Gerrit H , Varlet Pascale
Published: June 2024

BACKGROUND

Diffuse pediatric-type high-grade gliomas (pedHGG), H3-wildtype and IDH-wildtype, encompass three main methylome-based subclasses: pedHGG-MYCN, -RTK1A/B/C, and -RTK2A/B. Since their first description in 2017, tumors of pedHGG-RTK2A/B have not been further characterized and their clinical significance is unknown.

METHODS

A not yet published cases series on pedHGG with a gliomatosis cerebri (GC) growth pattern showed an increased incidence of pedHGG-RTK2A/B (n=18/40). We assembled a cohort of 14 additional methylation-based pedHGG-RTK2A/B tumors and pooled them with the GC tumors providing centrally reviewed radiological, histological, and molecular characterization.

RESULTS

Our cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 RTK2A (78%) and seven RTK2B (22%) cases. The median age was 11.6 years (4-17) with an overall survival of 15.9 months (interquartile range 12.1-25.8). Of the additional unselected cases with available imaging (10 of 14), seven showed a GC phenotype at diagnosis or follow-up. In addition, pedHGG-RTK2B tumors exhibited bithalamic involvement (6/7, 86%). Histopathology confirmed a diffuse glial neoplasm in all cases with prominent angiocentric features in both subclasses. Most tumors (24/29, 83%) diffusely expressed EGFR, notably with a focal perivascular enhancement. Cells of pedHGG-RTK2A lacked Olig2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed Olig2. Loss of ATRX expression occurred in four pedHGG-RTK2B samples (57%). In sequencing analyses (RTK2A: n=18, RTK2B: n=5), EGFR alterations (n=15/23, 65%; predominantly point mutations) were commonly found in both subclasses. Mutations in BCOR (n=14/18, 78%), SETD2 (n=7/18, 39%), and TERT promoter (n=6/18, 33%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 mutations (4/5, 80%).

CONCLUSIONS

In conclusion, genotype-phenotype correlations in a multicenter series of pedHGG-RTK2A/B tumors revealed a highly diffuse-infiltrating tumor frequently exhibiting a GC phenotype. The two subclasses share particular histomolecular features (EGFR alterations, angiocentric pattern), whereas they differ in specific characteristics (pedHGG-RTK2A: Olig2 negativity, BCOR and SETD2 mutations; pedHGG-RTK2B: ATRX and TP53 alterations).
HGG-18. ONC201 COMBINED WITH THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD AS A NEW THERAPEUTIC REGIME FOR PEDIATRIC HIGH-GRADE AND DIFFUSE MIDLINE GLIOMAS
Authors: de la Nava Daniel , Ausejo-Mauleon Iker , Nazarian Javad , Mueller Sabine , Allen Joshua E , Koschmann Carl , Venneti Sriram , Dun Matthew D , Gomez-Manzano Candelaria , Fueyo Juan , Patiño-Garcia Ana , Alonso Marta M
Published: June 2024

BACKGROUND

Pediatric high-grade (pHGGs) and diffuse midline gliomas (DMGs) patients have the worst survival rates in childhood cancer. The oncolytic adenovirus Delta-24-RGD and the imipridone ONC201 are two of the most promising therapeutic agents in the field, having demonstrated safety and effectiveness in clinical trials. Therefore, we evaluated whether the Delta-24-RGD/ONC201 combination could increase the therapeutic benefit in pHGGs and DMGs.

METHODS

A battery of human pHGG, DMG, and murine DMG cell lines was used for the study. Viral replication was assessed by hexon titration. Characterization of combination response was assessed by MTS, RNAseq, Seahorse, and immunofluorescence. In vivo experiments were performed to assess the efficacy of the proposed combination. The tumor microenvironment infiltration was evaluated by flow cytometry.

RESULTS

ONC201 cotreatment with Delta-24-RGD did not affect the virus replication capability in vitro. Cytotoxicity studies showed that cotreatment was either synergistic or additive. Importantly, cells treated with the combination maintain the mitochondrial damage caused by ONC201, showed a significant reduction of IGF1/IGF1R and PDGF pathways, and increased nuclear DNA damage. Remarkably, Delta-24-RGD/ONC201 treatment in human pHGG and DMG xenograft-bearing mice showed a safe toxicity profile and a significant increase in the median overall survival compared to each agent alone. Combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment towards a proinflammatory phenotype. We observed an increase in both lymphoid and myeloid lineage in the combined treatment versus either single treatment. Interestingly, Delta-24-RGD/ONC201 produces a higher activation in CD8+ T cells, higher activation and proliferation in CD4+ T cells, and less immunosuppressed regulatory T cells.

CONCLUSIONS

Our data supports that the Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone by potentiating nuclear DNA damage and improving the antitumor (immune) response. Altogether, our results reveal the potential of this combination for future clinical trials.
HGG-29. INTEGRATED MOLECULAR PROFILING OF >2000 PAEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA TUMOURS AND >100 PATIENT-DERIVED MODELS
Authors: Mackay Alan , Grabovska Yura , Carvalho Diana , Burford Anna , Pereira Rita , Temelso Sara , Sejdiu Drenusha , Crampsie Shauna , Molinari Valeria , Rogers Rebecca , Kessler Ketty , Bjerke Lynn , Bridges Les , Reisz Zita , Al-Sarraj Safa , Singh Navneet , Stapleton Simon , Bleil Cristina , Hittite Samantha , Debian Bassel , Cockle Julia , Carceller Fernando , Clarke Matthew , Jones Chris
Published: June 2024

BACKGROUND

Paediatric-type diffuse high-grade glioma (PDHGG) is recognised in the WHO2021 CNS Tumour Classification as biologically distinct from ‘adult-types’, and comprises four major categories based on distinct biology and clinical presentation, though sub-types within these are less well-defined.

METHODS

Published and unpublished genome/exome/targeted sequencing from n=1593 cases were integrated with n=2027 cases with methylation array profiling, with an overlap of n=761. These were supplemented with varying availability of bulk/single-cell RNAseq, ChIP-seq and ATAC-seq, and analysed alongside data from ~100 patient-derived models representing 16 PDHGG sub-types.

RESULTS

Around half of cases were diffuse midline glioma with H3K27 alterations (DMG-H3K27), which can be split into sub-types based upon either the specific histone alteration (DMG-H3.3K27M/-H3.1K27M/-EZHIP) or co-segregating pathway activating mutations (DMG-EGFR/-MAPK/-ACVR1). These showed distinct copy number, transcriptomic and epigenetic signatures depending on the anatomical location, replicated in ~50 models established as 2D/3D cultures and CDX/PDX. By contrast, diffuse hemispheric glioma with H3G34 mutations (DHG-H3G34) presented a homogenous genomic landscape (TP53/ATRX/PDGFRA) but with a higher degree of transcriptional diversity in both tumours and models. In high-grade glioma, H3/IDH-wild-type (HGG-WT) samples, receptor tyrosine kinase (RTK) subtypes are split by the presence or absence of co-segregating mutations (BCOR/SETD2/NF1) and copy number changes. Across methylation-based subtypes, genetic drivers are associated with distinct phenotypes or drug responses independent of location. EGFR mutations are largely confined to the highly infiltrative pedHGG_RTK2 hemispheric (enriched in gliomatosis cerebri) and DMG-EGFR (bithalamic glioma) subtypes, whilst PDGFRAmutations span DMG-H3.3K27M, DHG-H3G34, and pedHGG-RTK1, and exhibit a differential drug response to targeted therapies depending on the nature of the alteration. Hypermutant tumours are split between pedHGG-RTK1A and the emerging ‘HGG-E’ subtype.

CONCLUSIONS

These data aim to catalogue the diversity of PDHGG subtypes in order to identify biologically rational targets, and credential patient-derived models which can be exploited for mechanistic/preclinical studies.
HGG-41. COMBINATORIAL BH3-MIMETIC STRATEGY FOR OVERCOMING RADIORESISTANCE IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Madhavan Krishna , Donthula Sahiti , Walker Faye M , Sobral Lays Martin , Balakrishnan Ilango , Pierce Angela , Karam Sana D , Serkova Natalie J , Venkataraman Sujatha , Dahl Nathan A
Published: June 2024

BACKGROUND

High-grade gliomas (HGGs) are a leading cause of cancer-associated death in children. Radiation therapy (RT) continues to be the only standard-of-care treatment across HGG subtypes, but disease frequently recurs following only a transient response. We have recently identified that HGGs utilize the pro-survival BCL-2 family of proteins to evade cell death after radiation, and we demonstrated that effective inhibition of BCL-2 with the CNS-penetrant drug venetoclax could be utilized to disrupt this resistance and augment radiation-induced cell killing. While this treatment significantly prolonged survival in orthotopic mouse models of pediatric HGG, tumors invariably developed resistance to single-agent venetoclax and recurred.

METHODS

We profiled tumors from venetoclax-resistant animals for alternate BCL-2 family binding. We then assessed susceptibility to MCL1 inhibition in venetoclax-treated or treatment naïve culture models. Synergy was tested in vitro, and mitochondrial ROS production and induction of apoptosis was assessed using the MCL1-specific agent S63845. Finally, venetoclax and S63845 were tested in combination following fractionated radiotherapy in orthotopic models of DIPG.

RESULTS

MCL1 is an acquired dependency following treatment with RT + venetoclax. S63845 synergizes with venetoclax following RT to drive mitochondrial ROS production and apoptosis. The combination of venetoclax and S63845 significantly prolongs survival in xenograft models of DIPG.

CONCLUSIONS

Combinatorial targeting with BH3 mimetics augments radiation-induced cell killing and may open new therapeutic avenues for pediatric HGG.