tbuckley/cabot-search huggingface dataset:
METB-10. GENOME-WIDE DNA METHYLATION PROFILING OF PRIMARY CELLS FROM PEDIATRIC BRAIN TUMORS IS AN INFORMATIVE TOOL TO ASSESS CELL CULTURE RELIABILITY AND IN VITRO SELECTION
Authors: Lucia Pedace, Luana Abballe, Simone Pizzi, Maria Vinci, Celeste Antonacci, Claudia Nardini, Sara Patrizi, Francesca Del Bufalo, Sabrina Rossi, Giulia Pericoli, Francesca Gianno, Zein Mersini Besharat, Luca Tiberi, Angela Mastronuzzi, Elisabetta Ferretti, Marco Tartaglia, Franco Locatelli, Andrea Ciolfi, Evelina Miele
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recent genomic and epigenomic profiling analyses have provided remarkable insights into biology of pediatric brain tumors (pBTs). Nonetheless, pBTs represent the deadliest childhood cancer worldwide and are associated with high morbidity. In vitro models of pBT are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. METHODS We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples from medulloblastomas, high-grade gliomas, low-grade gliomas, ependymoma, and meningiomas. The cohort included 155 tumors and 86 pBT-derived cell cultures. For the analysis of pBT-derived cell cultures, we have considered the most significant variables: i) cultured medium (serum vs serum-free), ii) passages (late vs early), and iii) dimensionality (2D vs 3D cultures). As a complementary approach, the global relationships between the 241 samples based on the DNAm information were visualized using fast interpolation-based t-distributed stochastic neighbour embedding (t-SNE) and differentially methylated regions in tumors compared to cell models were identified. RESULTS Our findings showed that cell cultures cultured under stem-like cells enriching conditions (serum-free, 3D) and maintained in culture early passages are characterized by a higher degree of faithfulness to the parental tumors, in terms of methylation class and CNV profile, than the counterparts maintained in 2D cultures, in presence of serum, and maintained for extended passages. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. CONCLUSIONS DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.
LGG-23. INHIBITORS IN THE TREATMENT OF LOW GRADE GLIOMAS- A SINGLE CENTER EXPERIENCE, BRATISLAVA, SLOVAKIA
Authors: Stanislava Hederova, Andrea Mocna, Denisa Slezakova, Estera Bublakova, Boris Rychly, Marian Svajdler, Alexandra Kolenova
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric LGGs are the most common CNS tumors in children. They are a very heterogeneous group of tumors of different histological types, according to the WHO classification of grade 1- 2. The major molecular pathway affected in these tumors is the mitogen-activated protein kinase (MAPK) signaling cascade. The frequency of MAPK pathway activation makes this pathway an attractive candidate for targeted therapy, and direct inhibition via BRAF and/or MEK inhibitors is emerging as a clinically relevant strategy. METHODS We performed a retrospective analysis of patients treated with inhibitors at the Department of Pediatric Hematology and Oncology in Bratislava since 03/2020. Currently 9 patients, 5 boys and 4 girls, are treated with inhibitors. They are pLGG patients, two of them with concomitant genetically confirmed neurofibromatosis type 1. Six patients are treated with the MEK inhibitor trametinib in monotherapy and three patients with BRAF V600-mutated LGG with a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. In our cohort with a small number of patients, with a median follow-up of 13 months, we did not observe disease progression in even one patient on inhibitor therapy. Tolerance to treatment is reasonable. CONCLUSIONS In recent years, our understanding of the molecular biology of pediatric brain tumors has improved significantly. Alterations in the mitogen-activated protein kinase (MAPK) pathway are generally the most common molecular alterations in cancer, and dysregulation of this pathway also dominates the development of pediatric LGGs. The introduction of targeted drugs not only allows to improve the disease prognosis and survival of children with CNS tumors, to improve their quality of life on treatment, but also to reduce toxicity caused by e.g. radiotherapy, and at the same time to reduce the incidence of late sequelae of treatment.
HGG-48. THE BLOOD-BASED TELOMERIC DNA C-CIRCLE ASSAY CAN DETECT ALTERNATIVE LENGTHENING OF TELOMERES (ALT) IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Tenley E Lehman, Jenna L Deal, Jihyun Lee, Jessica B Foster, Mateusz P Koptyra, Trevor A Burrow, Balakrishna Koneru, Kristina A Cole, C Patrick Reynolds
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGG) comprise ~10% of pediatric brain tumors; 40% of pediatric HGG use the alternative lengthening of telomeres (ALT) mechanism to maintain replicative immortality. ALT cancers share a unique biology providing potential therapeutic targets. Extrachromosomal telomere DNA repeats, termed C-circles, can be detected by a unique PCR assay, providing a sensitive and specific biomarker for ALT cancers. C-circles have been detected in ALT tumors and serum of ALT patients. We have adapted the C-circle assay (CCA) to provide a sensitive and specific assay with cfDNA in patient plasma. Here we determined if cfDNA in plasma can be used to detect patients with ALT-positive HGG. METHODS Frozen plasma samples were collected in Streck tubes at time of surgery prior to resection from patients with HGG. DNA was extracted and quantified. Isothermal rolling C-circle amplification and real-time telomere PCR was performed followed by analysis. The C-circle positive neuroblastoma cell line, CHLA-90, and C-circle negative neuroblastoma cell line, CHLA-20, served as the positive and negative controls respectively. CCA values in plasma of 2 and above indicate positivity for C-circles. RESULTS Plasma samples were analyzed by CCA from three pediatric patients whose brain tumors were previously biopsied and identified as ATRX mutation positive. ATRX mutation indicates ALT however, not all ALT cancers have ATRX mutations. All plasma samples were above the 2.0 cutoff at 3.37, 3.13, and 4.59 and thus classified as C-circle positive. CONCLUSIONS This preliminary cohort shows that the CCA has potential for identifying ALT pediatric brain tumors using cfDNA from plasma. As novel therapies effective against ALT HGG are developed, the plasma CCA may allow accelerated initiation of neoadjuvant therapy to shrink tumor prior to surgical resection and lessen or prevent the need for tumor biopsy. Expansion of the initial test cohort is underway. Supported by NCI UO1 CA63988.
METB-11. HOW METHYLATION PROFILING HELPS IN DIAGNOSING AND TREATING PEDIATRIC BRAIN TUMORS IN INDONESIA
Authors: Ludi Dhyani Rahmartani, Michael Nathaniel Budiarso, Kevin Gunawan, Eka Susanto, Felix Sahm, Olfat Ahmad, Stefan Pfister
Journal: Neuro-Oncology (2024)

Abstract BACKGROUNDS Pediatric brain tumors (PBT) exhibit extensive heterogeneity, impacting treatment outcomes. While traditionally classified based on histopathological features, recent WHO classifications have integrated DNA methylation array profiling amongst other molecular characteristics, which improves diagnostic accuracy and thus treatment decisions. However, access to this technology is limited in low- and middle-income countries (LMICs) like Indonesia. As part of the MNP Outreach Consortium, we aimed to introduce methylation profiling in Indonesia to aid in diagnosing and stratifying PBT patients. METHODS In 2023, we conducted a case series involving seven challenging PBT cases from Cipto Mangunkusumo National General Hospital, re-assessing them with methylation profiling. RESULTS Through collaboration with the Institute of Neuropathology Heidelberg and the DKFZ, our centre adopted a discerning approach to re-evaluate histopathological samples from complex cases. This endeavour yielded notable results, reaffirming four initial diagnoses and altering three others Amongst the findings, one case initially diagnosed as anaplastic ependymoma, CNS WHO grade 3, was reclassified as a supratentorial ependymoma with YAP1 fusion gene, based on methylation class. Noteworthy within this latter group, one case initially categorized as low-grade pilocytic astrocytoma was reclassified as high-grade diffuse midline glioma, H3 K27 altered. Moreover identifying the copy number plot could indicate a KIAA1549::BRAF fusion to reclassify a case from diffuse pediatric glioma WHO grade 2 to pilocytic astrocytoma WHO grade 1. The recurrent pigmented neuroectodermal tumor of infancy (MNTI) was reclassified as Medulloblastoma, non-WNT/non-SHH, group 3 subtype II on methylation profiling, highlighting molecular similarities and potential treatment insights. These findings offer insights into genetic mechanisms and guide treatment strategies. CONCLUSION Accurate diagnosis, facilitated by advanced molecular profiling, enhances prognostication and enables personalized treatment plans, even in LMICs. This underscores the importance of expanding access to advanced diagnostic technologies in resource-limited settings.
HGG-51. INTRANASAL DELIVERY OF PDGFRA-IMMUNOLIPOSOMAL SN-38 FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Savneet Kaur, Jun Watanabe, Eita Uchida, Peng Zhang, Rintaro Hashizume
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION pHGGs are the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the braistem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of liposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the specificity of anti-PDGFRA monoclonal antibody conjugated immunoliposome (PDGFRA-iLS) in pHGG cell lines. METHODS PDGFRA signals were assessed in pHGG cells using western blotting. Cells with high and low expression of PDGFRA were treated with rhodamine (Rho) labeled PDGFRA-iLS and imaged with fluorescent microscope. RESULTS DIPG007, SF7761 and KNS42 expressed high levels of PDGFRA, while SF8628 and DIPG36 cells showed low expression. Fluorescence microscopy revealed high PDGFRA-rhodamine (Rho)-iLS expression in DIPG007 cells (PDGFRA high), relative to SF8628 and DIPG36 cells (PDGFRA low). CONCLUSION PDGFRA-Rho-iLS shows increase cellular uptake in DIPG cells. Work is underway to determine the biodistribution, host toxicity, and anti-tumor activity of IND of PDGFRA-iLS-SN- 38 alone and in combination with radiation therapy in pHGG xenograft models.
OTHR-02. ONE-YEAR FOLLOW-UP OF THE NEW ERN PAEDCAN CNS TUMOR BOARD: LESSONS LEARNT AND FUTURE PROSPECTS
Authors: Marthe Sönksen, Brigitte Bison, Lisa Bußenius, Jelena Rascon, Denise Obrecht-Sturm, Barry Pizer, Katrin Scheinemann, Martin Schalling, Ruth Ladenstein, Martin Mynarek, Stefan Rutkowski
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND European Reference Networks (ERN) are collaborative networks connecting healthcare professionals across Europe. A virtual tumor board for pediatric patients with central nervous system (CNS) tumors was established within the ERN for pediatric oncology (ERN PaedCan) in September 2022. We report the feasibility, the implementation of recommendations and satisfaction of the participants. METHODS A web-based questionnaire was distributed to physicians presenting cases between November 2022 and November 2023. Questions addressed the implementation of recommendations, satisfaction and basic information about the local institution. Basic data of the presented cases were taken from anonymized tumor board protocols. RESULTS In the first year, 19 patients from 11 institutions located in nine European countries were discussed in 21 tumor boards. Median age at diagnosis was 10 (1-17) years. Demonstration of MRI findings by the German national reference center for neuroradiology was conducted in 19/21 conferences. 18/21 questionnaires (86%) were answered by physicians from eight countries. Main reason to request the discussion were questions about therapy (78%, n=14/18). Inquiring institutions treated a median of 10 (5-150) neuro-oncological pediatric patients per year. All hospitals conducted own institutional tumor boards. National central review was available in 3/8 countries (38%). Recommendations were followed, at least partly, in all cases except for one patient experiencing unexpected clinical deterioration. Recommendations were deemed helpful in 89%. All participants would recommend the tumor board to colleagues. Technical issues regarding data provision were reported as the main obstacle in 50 %. CONCLUSIONS A European virtual tumor board for pediatric patients with CNS tumors is feasible and perceived as useful by the participating institutions. Recommendations were followed frequently. Optimization of privacy-compliant data exchange is crucial for continuance of the format. This project has been supported by ERN PaedCan, which is funded by the European Union within the EU4Health Program 2021-2027. Funded by EU-grant 101085543.
MDB-64. NOVEL TRANSCRIPTS ASSOCIATE WITH SURVIVAL IN CHILDHOOD MEDULLOBLASTOMA
Authors: Marion K Mateos, Daniel Williamson, Marina Danilenko, Jack Goddard, Stephen Crosier, Anya Fletcher, Edward Schwalbe, Debbie Hicks, Simon Bailey, Steven C Clifford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the commonest malignant brain tumour in childhood, with progression-free survival (PFS) &amp;lt;65% in high-risk disease. Novel biomarkers, independent of current clinicopathological risk factors, could enhance understanding of biology and support improved treatment approaches. METHODS Using high-depth RNA sequencing of 217 patients, we identified novel multi-exonic medulloblastoma transcripts using a de novo analysis. We evaluated these alongside known/curated gene transcripts, including correlative survival analysis for 170 patients (aged 3-16 years and treated with curative intent). Multivariable survival analyses of the overall cohort (n=145) and a MBGroup3/MBGroup4 (Group3/Group4)-specific subcohort (n=95) was undertaken to identify prognostic transcripts, adjusting for current risk criteria and correcting for multiple testing. RESULTS From 3,150 novel transcripts identified, expression of 217 varied significantly and were further assessed. One was prognostic for PFS independent of subgroup (located on chromosome 20) while three were independently prognostic within Group3/Group4 (located on chromosome 1, 4 and 21 respectively). Transcript presence was validated by qPCR. From &amp;gt;60,000 known transcripts identified, 9693 were assessed. Four were independently prognostic for PFS in the whole-cohort (MRPS12, SLC25A34, MLYCD and ROGD1). In Group3/Group4, the top upregulated canonical pathways associated with PFS were: polo-like kinase, cyclin/cell cycle regulation, BRCA1/ DNA damage response, and glutamate receptor signalling. MELK and NQO2 were among the top 10 transcripts most highly associated with Group3/Group4 PFS. The prognostic significance of six transcripts (MRPS12, MLYCD, MELK, CDK4, NQO2, ROGD1) was validated in an independent Group3/Group4 dataset (n=470) while ROGD1 was prognostic independent of subgroup. Immunohistochemical validation showed low CDK4 expression, low MLYCD expression and high CHK1 expression were independent prognosticators in Group3/Group4. CONCLUSION De novo transcripts represent a significant component of the medulloblastoma transcriptome, providing prognostic information, and enhancing biological understanding of Group3/Group4 disease. CHK1 and MELK represent promising validated candidates for further evaluation as prognostic biomarkers in Group3/Group4 medulloblastoma.
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: Raoull Hoogendijk, Riccardo Capocaccia, Jasper van der Lugt, Mariëtte Kranendonk, Eelco Hoving, Pieter Wesseling, Otto Visser, Dannis van Vuurden, Gemma Gatta, Henrike Karim-Kos
Journal: Neuro-Oncology (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 (&amp;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 &amp;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.
QOL-38. PSYCHOSOCIAL OUTCOMES OF CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG) –PROSPECTIVE, LONGITUDINAL PROMIS ASSESSMENTS OF PATIENTS ENROLLED ON CONNECT PHASE I CLINICAL TRIALS
Authors: Mariah L Wright-Nadkarni, Emily L Moscato, Joseph R Stanek, Megan R Schaefer, Cynthia A Gerhardt, David M Ashley, Patricia A Baxter, Susan N Chi, Kathleen Dorris, Michael J Fisher, Trent R Hummel, Eugene I Hwang, David Gass, Sarah E S Leary, Natasha Pillay-Smiley, Ashley S Plant, Mythili Murala, Leonie Mikael, Maryam Fouladi, Margot A Lazow
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Given poor prognoses, children with DIPG/HGG may experience psychosocial sequelae throughout their illness journey, negatively impacting quality of life (QOL). We prospectively assessed caregiver-proxy and patient-reported psychosocial outcomes of children with DIPG/HGG enrolled on two early-phase CONNECT trials. METHODS Patient-Reported Outcomes Measurement Information System (PROMIS) short forms were administered monthly to patients ≥8 years and caregivers of patients aged 5-17 years while enrolled on two phase I clinical trials for newly-diagnosed DIPG/HGG involving upfront radiotherapy (RT) and concurrent and/or adjuvant oral agents. T-scores (M=50, SD=10) were calculated relative to the general population for emotional distress (Anxiety and Depression) and relationship quality (Peer Relationships and Family Relationships). Linear mixed modeling compared scores at pre-RT, post-RT, 1 month pre-progression, and end of therapy (EOT). Spearman’s correlations were calculated. RESULTS Twenty-eight patients (median age=10 years; DIPG [n=23]; HGG [n=17]) and 40 caregivers participated. Patient and caregiver-proxy reports demonstrated comparable levels of emotional distress and relationship quality to norms and were stable over time. The proportion of patients endorsing mild or greater impairment in emotional distress (T-score &amp;gt;55) was relatively comparable at pre-RT (Anxiety &amp; Depression=26%), post-RT (Anxiety=36%, Depression=23%), and 1 month pre-progression (Anxiety=23%, Depression=36%), with more patients endorsing impairment (Anxiety=58%, Depression=67%) at EOT, often corresponding to disease progression; though differences were not statistically significant. Caregiver-proxy and patient-reported scores were similar across all timepoints and domains, with a pattern of higher caregiver-reported versus patient-reported emotional distress (Spearman’s Rho range: 0.62-0.67;p&amp;lt;0.0001). CONCLUSIONS Children with DIPG/HGG and their caregivers reported comparable emotional functioning and relationship quality to the general population. Caregivers slightly overestimated psychological distress compared to youth self-reports. Findings may reflect resilience of this population when faced with adversity, while highlighting benefit of psychosocial supports and low therapy toxicity on QOL. Future analyses will compare psychosocial, physical, and functional symptoms.
MDB-54. GENOMIC VARIANCE OF MATCHED PRIMARY AND RECURRENT HUMAN MEDULLOBLASTOMA
Authors: Yu N/A Su, Hailong N/A Liu, Jiankang N/A Li, Xiaoguang N/A Qiu, Tao N/A Jiang, Yu N/A Tian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To investigate the difference between matched primary and recurrent human medulloblastoma across four molecular subgroups and to further expand the existing mutational spectrum in the recurrence or dissemination lesions. METHODS We analyzed the whole-exome sequencing (WES) data of 56 matched samples from 28 pairs with primary and recurrent/disseminated medulloblastoma. WES was performed using the Illumina HiSeq 2500 system, and the sequencing data were then subjected to variant detection, genome annotation, GO functional enrichment analysis, and GWAS. RESULTS All tumor samples were classified as four subgroups, including 4 cases of WNT-MB, 8 cases of SHH-MB, 20 cases of G3-MB and 24 cases of G4-MB. Conical and non-conical chromosomal variations were observed in each subgroup. Recurrent G3-MB cohort exhibited the loss of chr1p and chr22q and gain of the chr16p. The gain of chr2p, 2q, and 9p, as well as the loss of chr9q were found in the recurrent lesions of G4-MB. Recurrence of SHH-MB exhibited the loss of chr19q and chr4p, and loss of chr5p was found in the WNT-MB recurrences. CTNNB1, IDH1, and ARID1A were only observed in recurrent tumors of G3-MB; MYC was only observed in the recurrent tumors of G4-MB; IDH1 and TERT were only observed in recurrent tumors of the SHH-MB. Compared to primary medulloblastoma, recurrent tumor samples obtained a higher level of tumor mutation burden. The mutant gene profiles were mainly enriched in cell adhesion function. CONCLUSIONS When relapsing, medulloblastoma subgroup generally remains consistent, but exhibits the specific CNV, SNV and mutated gene profiles.