tbuckley/cabot-search huggingface dataset:
IMG-01. LONGITUDINAL SIGNAL CHANGES IN THE DENTATE AND INFERIOR OLIVARY NUCLEI IN PATIENTS WITH CEREBELLAR MUTISM SYNDROME
Authors: Soniya N Pinto, Matthew Scoggnis, Jia Liang, Yimei Li, Raja B Khan, Giles W Robinson, Paul Klimo, Charles A Wheeler, Samuel S McAfee
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cerebellar mutism syndrome (CMS) is a complication of posterior fossa surgery with an acute impairment in speech, and long-term neurocognitive deficits. Lesion mapping studies suggest the cognitive symptoms are associated with dentatorubrolivary damage1. We hypothesize that CMS patients will demonstrate more longitudinal MRI signal abnormalities in the dentate and inferior olivary nuclei as compared to non-CMS patients. METHODS MRI brains on 40 pediatric medulloblastoma patients between 2013-2015 were retrospectively reviewed by a neuroradiologist blinded to the diagnosis at pre-operative and immediate, 6-month, 12 month and most recent post-operative time points. The dentate and inferior olivary nuclei were scored for restricted diffusion, T1 and T2 hypo-and hyperintensity. A linear regression with different scores on CMS status (YES vs NO) was applied, after adjusting for age. RESULTS In the dentate nuclei, there was significantly higher T2 hypointensity in the CMS group on immediate (difference is 0.4084, p=0.0467) and most recent (difference is 0.7190, p=0.0386) post-operative MRIs. The CMS group had significantly higher T1 hyperintensity on the 1-year (difference is 0.9254, p=0.0108) and most recent (difference is 1.3291, p&amp;lt;0.001) post-operative MRIs. In the inferior olivary nuclei, there was significantly higher T2 hyperintensity on the 6-month (difference is 0.71, p=0.0045) and 1-year (difference is 0.6356, p=0.0162) post-operative MRIs. CONCLUSION The immediate post-operative findings are suggestive of a hemorrhagic, rather than an ischemic process in the dentate nuclei. On long-term follow up, the signal changes in the dentate and the inferior olivary nuclei represent dystrophic mineralization and hypertrophic degeneration, due to inflammation and axonal degeneration within the dentatorubroolivary tract2 References: 1. Albazron, Fatimah M., et al. “Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.” Neurology 93.16 (2019). 2. Perreault, Sebastien, et al. “Time-dependent structural changes of the dentatothalamic pathway in children treated for posterior fossa tumor.” American journal of neuroradiology 35.4 (2014).
EPEN-20. LEVERAGING ABERRANT EXTRACELLULAR VESICLE SIGNALING FOR TARGETED DRUG REPURPOSING IN PEDIATRIC EPENDYMOMA
Authors: Kendra K Maass, Johanna Rettenmeier, Julia K Sundheimer, Mieke M Roosen, Stefanie Volz, Tatjana Wedig, Paula Ertel, Cornelia Gansert, Karsten Richter, Michelle Nessling, Heike Peterziel, Aileen Friedenauer, Sonja Herter, Ina Oehme, Sophia Scheuermann, Christian Seitz, Daniel Senfter, Julia Benzel, Torsten Mueller, Konstantin Okonechnikov, Geraldine Genard, Jeroen Krijgsveld, Stefan M Pfister, Kristian W Pajtler
Journal: Neuro-Oncology (2024)

Abstract Increasing evidence highlights the diverse functions of extracellular vesicles (EVs) as intercellular messengers in all facets of cancer progression, pointing towards a potential new avenue in cancer treatment. Limited understanding of tumor-specific deregulations and lack of suitable drug compounds have hampered clinical translation of targeted interference with EV signaling. The most aggressive types of intracranial ependymoma (EPN) in children and adults are resistant to chemotherapy. Despite enormous diagnostic advancements in classification and stratification, EPN lack recurrent effective molecular targets precluding access of affected patients to precision-based oncology therapeutics. Here, we characterized the proteome of ninety-five EPN and five matching healthy control brain tissue samples. Employing a mulit-omic data integration approach, we identified EVs as an excessively augmented pathway on the functional level. Isolation and molecular characterization of EPN EVs combined with single cell sequencing analysis, and ultra-high content imaging unraveled perivascular mesenchymal cell populations as predominant EV originators. Targeting EV pathways through chemical inhibition of sphingomyelinases (SMPD1, SMPD2, SMPD3) including re-purposed FDA approved compounds revealed growth inhibition, reduced invasion capacity in vitro and significant survival probability in vivo. Transcriptomic analysis and scanning electron microscopy delineated transition of mesenchymal-to neuroepithelial subpopulations in cells and patient-derived xenograft (PDX) models of EPN upon reduction of EV release. This study showcases the inhibition of EV signaling as a promising therapeutic strategy against mesenchymal tumor persister cells, which are the suspected origins of repeated EPN relapses. Our study provides a framework to leverage cell state-specific vulnerabilities and drug repurposing to attack the most aggressive cell populations in cancers with unfavorable prognosis.
DIPG-16. THE BIG AND SMALL OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS: TARGETING SUMOYLATION AND CITRULLINATION IN DIFFUSE MIDLINE GLIOMA
Authors: Benjamin S Rayner, Arjayeeta Samadder, Holly Holliday, Yongjuan Chen, Hieu Nguyen, Alvin Lee, Jie Liu, Elisha Hayden, Oluwaseyi S Ogunmodede, Kerry-Anne Rye, Maria Tsoli, Jean B Bertoldo, David S Ziegler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Protein post-translational modifications (PTMs) alter the properties of protein through proteolytic cleavage, or the addition of modifying groups to one or more amino acids. Histones are major targets of PTMs, including through SUMOylation of lysine residues and citrullination of arginine residues, with both processes able to regulate gene transcription. We aimed to delineate the potential role of SUMOylation and citrullination in the epigenetic dysregulation that drives Diffuse Midline Glioma (DMG) tumorigenicity. METHODS AND RESULTS DMG tumours demonstrated an upregulation of SUMOylation machinery pathway components and increased expression of peptidylarginine deiminases (PADs), the enzymes responsible for citrullination. Nanomolar doses of the SUMOylation inhibitor TAK-981 blocks DMG cell cycle G2/M transition and results in potent decreases in cell viability and clonogenic potential, triggering ‘viral mimicry’ in DMG cells, resulting in increased expression of interferon stimulated genes and inflammatory mediators including IL-1β, IL-6 and TNFα, whilst also causing a pro-inflammatory M1 macrophage response. These data suggest that SUMOylation inhibition may lead to a double-punch effect against DMG by inhibiting tumorgenicity and stimulating an immune response. In further studies, we have shown that pharmacological inhibition of PAD activity in DMG decreases histone citrullination and restores histone methylation – considered the Achilles heel of DMG. This was accompanied by induction of reactive oxygen species and an unfolded protein response, resulting in DMG cell death in a dose dependent manner. In addition to fully characterising the epigenetic and global changes within DMG initiated through SUMOylation or PAD inhibition, we are currently performing preliminary drug efficacy studies in orthotopic DMG models, providing the necessary pre-clinical research pipeline towards an effective treatment for DMG. CONCLUSIONS Protein SUMOylation and citrullination are previously unrecognised therapeutic targets in DMG and potentially play key roles in tumour initiation and pathogenesis. Our data suggests a novel therapeutic approach for children with DMG.
BIOM-02. DISSECTING CDK4/6 INHIBITOR RESISTANCE MECHANISMS IN RECURRENT PEDIATRIC BRAIN TUMORS WITH LONGITUDINAL CSF LIQUID BIOPSIES FROM THE SJDAWN CLINICAL TRIAL
Authors: Katie Han, Anna Kostecka, Kyle S Smith, Sandeep Dhanda, Hong Lin, Margit Mikkelsen, Giles W Robinson, Paul A Northcott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND SJDAWN (NCT03434262) is a St. Jude Children’s Research Hospital phase 1 trial that assessed the safety and benefit of CDK4/6 inhibitor-based therapy in patients with relapsed CNS tumors. To capture tumor evolution dynamics and arising resistance mechanisms in response to treatment, 143 longitudinal CSF samples were collected from 34/68 (50%) patients for cell-free DNA (cfDNA) analysis. METHODS cfDNA was extracted from CSF liquid biopsies and analyzed using a novel methylation-based platform that integrates copy number, tumor classification, and deconvolution of methylation signatures into normal vs. disease fractions. Samples with measurable residual disease (MRD) were further characterized by deep whole-genome sequencing to discover mutation-driven resistance mechanisms. When available, pre- and post-SJDAWN tumor tissues were processed for single-nucleus multi-omics to track tumor evolution at single-cell resolution. RESULTS In the context of CDK4/6 inhibitor-based therapy, longitudinal cfDNA assessment revealed treatment-induced selection for subclones with focal amplification of positive cell cycle regulators CDK6, CCND2, and MYCN. Emergence of these resistance mechanisms notably preceded disease progression on MRI and CSF cytology by up to 6 months. Of the 68 patients enrolled on SJDAWN, 4 patients (3 Group 3/4, subtype III medulloblastomas and 1 anaplastic ependymoma) achieved &amp;gt;2-year progression-free survival. Interestingly, serial cfDNA profiling of 1 long-term survivor (Group 3/4, subtype III medulloblastoma) exhibited undetectable MRD status for &amp;gt;1.5 years prior to reemergence, suggesting tumor senescence by CDK4/6 inhibition may impede circulating tumor DNA (ctDNA) release kinetics. CSF liquid biopsies were further evaluated in comparison to matched tumor tissues, and changes in CSF-specific subclones were observed in response to treatment. CONCLUSIONS In addition to early MRD detection, liquid biopsies capture tumor evolution dynamics and can inform developing resistance mechanisms. Focal amplification of CDK6, CCND2, and MYCN facilitates CDK4/6 inhibitor resistance. In responders, treatment-induced senescence may inhibit ctDNA release kinetics.
DIPG-03. VENTRICULAR CEREBROSPINAL FLUID SAMPLING IN PEDIATRIC DIFFUSE MIDLINE GLIOMA PATIENTS: INSTITUTIONAL EXPERIENCE AND REVIEW OF THE LITERATURE
Authors: Daphne Li, Wendy Stellpflug, Kathy Romanski, Stacy Speck, Amanda Saratsis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Increasing evidence suggests that circulating biomarkers may serve diagnostic and longitudinal monitoring purposes in pediatric neuro-oncology. Mutant tumor DNA is detectable in the cerebrospinal fluid (CSF) of pediatric diffuse midline glioma (DMG) patients and quantity can reflect disease burden. CSF sampling (“liquid biopsy”) via a CSF access device could therefore play a role in DMG management. Therefore, we set to evaluate the incidence of hydrocephalus (HCP) in DMG patients, and to characterize ventricular reservoir placement and access practices. METHODS A single institution retrospective review of DMG patients &amp;lt;21-years-old was performed (1984-2019). MEDLINE searches for reports of ventricular reservoir or shunt placement in DMG, and reservoir access for intraventricular chemotherapy (IVC) were performed. RESULTS At our institution, 62.6% of DMG patients (67/108) required intervention for HCP: 19.4% provided transient CSF access (ETV alone n=3, EVD n=8, unspecified n=2), and 80.6% permanent CSF access (ETV + reservoir n=13, shunt n=41). Further, 22/34 patients with initially transient CSF devices required conversion to a permanent device. Five devices were revised for malfunction, one for infection. Seventeen articles cited HCP in 22% to 100% of DMG patients. IVC administration was described in 632 patients (seven articles), with 42 infectious and 63 non-infectious complications. CONCLUSIONS Management of HCP is often necessary in children with DMG. Given the low rate of clinical risk associated with VAD placement and access, and the potential utility of longitudinal disease monitoring via CSF analysis, VAD placement could be considered in future clinical trials to guide DMG treatment.
ATRT-07. PRC1/BMI1 ACTIVITY ALTERS CHROMATIN ACCESSIBILITY TO REGULATE DIFFERENTIATION IN ATYPICAL TERATOID RHABDOID TUMORS
Authors: Irina Alimova, Gillian Murdock, Angela M Pierce, Etienne Danis, Dong Wang, Natalie Serkova, Nicholas Foreman, Nathan Dahl, Sujatha Venkataranman, Rajeev Vibhakar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive pediatric brain tumor and characterized by SMARCB1 deletion. METHODS Genome wide RNAi screen, RNA-seq and ChIP-Seq analysis, colony formation assay, cell cycle, western blotting, immunoprecipitation, mass spectrometry analysis, mouse xenograft model, IVIS and MRI imaging. RESULTS We performed an RNAi-based functional genomic screen to identify key epigenetic regulators that co-operate with SMARCB1 loss and contribute to tumorigenesis in ATRT. 406 genes associated with epigenetic regulation in patient-derived ATRT cell lines were targeted. This screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as one of the top targets essential for ATRT cell growth. Using RNA-seq and ChIP-Seq analysis we demonstrated that BMI1 co-operates with SMARCB1 deletion to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. We found that genetic inactivation of BMI1 suppresses ATRT cell clonogenicity and neurosphere formation, leads to S-phase arrest and induces ATRT cell differentiation in vitro. In vivo BMI1 inhibition induces apoptosis, leading to significantly increasing survival of treated mice. By Doxycycline-inducible SMARCB1 re-expression system we revealed activation of proapoptotic proteins p16 and p21. With immunoprecipitation for BMI1, followed by mass spectrometry analysis we demonstrated that re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. Moreover, SMARCB1 re-expression significantly prolongs mice survival and decreases tumor size as evaluated by IVIS imaging system and T2-MRI. CONCLUSION Thus, we demonstrated that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex and that PRC1/BMI1 inhibition is a novel therapeutic approach in ATRT.
EPEN-30. PROTON THERAPY FOR PEDIATRIC INTRACRANIAL EPENDYMOMA: A SYSTEMATIC REVIEW, META-ANALYSIS AND META-REGRESSION
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric intracranial ependymoma (IE) represents a challenging subset of tumors necessitating tailored therapeutic strategies. Conventional treatments, including surgery and conventional radiation therapy, have shown limitations in achieving optimal outcomes, particularly in preserving neurocognitive function and mitigating long-term sequelae. Proton therapy (PT) has emerged with its ability to offer precise tumor targeting with reduced irradiation of healthy surrounding tissues. METHODS A systematic search was conducted using the electronic databases PubMed, CENTRAL, and EMBASE from inception through February 2024 following the PRISMA statement. Statistical analysis was conducted using R (R Foundation for Statistical Computing; Vienna, Austria) with the packages ‘meta’ and ‘metafor’. The random effects model of proportions was estimated using the generalized linear mixed-effects model (GLMM) method. RESULTS A total of 7 studies were included comprising 943 patients, with a mean age of 4 years, 543 boys (57.58%) and a mean dose of 56.94 Gy. The local control (LC) rate at 3 years was 83% (95% CI = 0.80 to 0.86, p=0.65) and a 5-year rate was 81% (95% CI = 0.72 to 0.89, p=0.35). Progression-free survival (PFS) was 75% at 3 years (95% CI = 0.68 to 0.82, p=0.17) and 71% at 5 years (95% CI = 0.56 to 0.87, p=0.07). Overall survival (OS) rates were notably high, with 93% at 3 years (95% CI = 0.89 to 0.97, p=0.11) and 85% at 5 years (95% CI = 0.83 to 0.87, p=0.96). Meta-regression analysis revealed that total dose significantly influenced 3-year OS (p=0.04), indicating a dose-dependent effect on survival rates. CONCLUSIONS This meta-analysis supports the effectiveness of PT through the outcomes LC, PFS and OS in pediatric IE. The significant correlation between total dose and 3-year OS underscores the importance of dose optimization in treatment planning. These findings highlight the importance of PT in pediatric neuro-oncology management, offering evidence-based guidance for enhancing therapeutic strategies and patient outcomes.
LGG-25. ADVANCING RESPONSE ASSESSMENT OF LOW-GRADE GLIOMAS: IDENTIFYING VOLUME CORRELATIONS OF BI-PERPENDICULAR DIAMETER CHANGES WITH MACHINE LEARNING
Authors: Gabe Dumbrille, Silu Zhang, Giles W Robinson, Thomas E Merchant, Asim K Bag
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Assessing brain tumor response is key for effective management and clinical trial benchmarks. Traditionally, bi-perpendicular diameter (BPD) measurements have been used to estimate tumor size. However, recent studies suggest volumetric assessment yields a more accurate measure of response and estimate of tumor burden. Advances in technology enable rapid volume assessments. Integrating volumetric analysis into clinical settings is challenged by the absence of volume-based standards aligned with traditional RAPNO bi-dimensional criteria. Our goal was to correlate volume change percentages with bi-perpendicular diameter changes using machine learning. METHODS In this project, we compared 2 machine learning models to establish a correlation between percentage change of sum of products of BPD and percent change in volume using a generalized linear model (GLM) and an artificial neural network (ANN). We analyzed 49 patients with low grade glioma, treated with focal irradiation (NCT04065776) (n=27) or mirdametinib (NCT04923126) (n=22). We trained and validated the models at train-test split ratios of 80/20, 75/25, and 70/30, incorporating a proportionate split of tumors from each group. The models were compared on the validation data set using mean-squared error (MSE). RESULTS At percentage changes of +25%, -25%, -50%, and -75% in the sum of BPDs, the GLM predicts changes in volume to be +33%, -31%, -59%, and -83%, respectively. For the ANN, the predicted changes are +20%, -29%, -53%, and -78%. The ANN demonstrated a lower MSE compared to the GLM. The two models showed higher concordance in their volume predictions at negative percentage changes in the sum of BPDs: -25% (p=0.15), -50% (p=0.03), and 75% (p=.08) CONCLUSION We identified volume percentage changes matching BPD changes per RAPNO criteria using two machine learning methods, both agreeing on negative values. Further testing with a larger dataset is needed to reliably correlate percentage changes.
ATRT-04. RETROSPECTIVE ANALYSIS OF 271 RELAPSED AND REFRACTORY ATYPICAL TERATOID RHABDOID TUMORS – COMBING DATA FROM INTERNATIONAL COHORTS IN A COLLABORATIVE EFFORT
Authors: Mona Steinbügl, Tom Rosenberg, Kavita Desai, Dinisha Govender, Anthony Pak Yin Liu, Nicolas André, Patricia O’Hare, Karsten Nysom, Franck Bourdeaut, Michael J Fisher, Ashley Margol, Alyssa T Reddy, Michael C Frühwald
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Relapse or refractory (r/r) disease is common in atypical teratoid rhabdoid tumors (ATRT), yet little is known about clinical patterns, prognostic factors, and outcomes beyond individual case reports. Large representative cohorts are missing, impeding the interpretation and design of clinical trials for r/r ATRT. METHODS We retrospectively collected data on r/r ATRT from centers in the US, Europe, Hong Kong, and Australia, including patients previously enrolled in clinical trials (e.g., COG ACNS0333, DFCI 02-294) or the prospective EU-RHAB registry. Inclusion criteria were relapse (recurrence after complete remission (CR)) or progression (tumor growth or new metastasis without previous CR) following at least one course of chemotherapy. RESULTS 271 patients were analyzed; median age was 16 months (m) at diagnosis (0-233). Molecular subgroup status was available in n=118. Relapse (44%) or progression (54%) occurred after a median of 8m. Only 34% of events were localized at the primary tumor site; distant metastasis only (31%) and combined events (31%) were more common. Salvage treatment was multimodal with systemic pharmacotherapy (n=176), surgery (n=71), high-dose chemotherapy (n=19), and/or radiotherapy (n=110). Targeted treatment included epigenetically targeted drugs (n=45), alisertib (n=11), immunotherapy (n=10) and metronomic therapy (n=45). 1-year overall survival (OS) following an event was 29.6±2.8%. Log-rank test suggested subgroup status as a prognostic factor. (TYR vs. non-TYR: 30 vs. 21w OS, p&amp;lt; 0.05; MYC vs non-MYC: 14 vs. 25w OS, p&amp;lt;0.05). OS was significantly inferior after progression compared to relapse (19 vs. 33w, p&amp;lt;0.05) and in patients with rhabdoid tumor predisposition syndrome (18 vs. 25w, p&amp;lt;0.05). CONCLUSION Our data confirm the poor prognosis of r/r ATRT. However, intense multimodal treatment is feasible, and molecular characteristics are potentially clinically relevant. Results from this analysis offer a robust foundation for prospective clinical trials and therapeutic algorithms for r/r ATRT.
DIPG-48. PRECISION GUIDED THERAPY PROVIDES CLINICAL BENEFIT IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Campbell McKay, Phoebe Power, Jordan Staunton, Shampavi Sriharan, Sophie Jessop, Nataliya Zhukova, Sarah Trinder, Dinisha Govender, Paulette Barahona, Andrew J Gifford, Cristina Mignone, Angela Xie, Gabor Tax, Maria Tsoli, Emmy Dolman, Chelsea Mayoh, Marie Wong, Mark Cowley, Glenn Marshall, Toby Trahair, Richard B Lock, Paul Ekert, Michelle Haber, Vanessa Tyrell, Loretta Lau, Neevika Manoharan*, David S Ziegler*, Dong-Anh Khuong-Quang*
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The utility of precision-guided therapeutic approaches to H3K27-altered diffused midline glioma (DMG) remains uncertain. The Australian Zero Childhood Cancer (ZERO) program combines molecular profiling (whole-genome sequencing (WGS), whole-transcriptome sequencing (RNAseq), and DNA methylation profiling), with in vitro high-throughput drug screening (HTS) and patient-derived xenograft (PDX) drug-efficacy testing in patients with high-risk cancer. METHODS We report on the cohort of patients enrolled with a DMG in the ZERO clinical trial between 2017 and 2023. RESULTS 68 patients were enrolled, predominantly at diagnosis (87%), with pontine lesions (66%) at a mean age of 8.7 years. 59 (87%) patients had WGS + RNAseq successfully performed. Most tumors harbored an H3F3A mutation (n=50), followed by HIST1H3B (n=11), HIST1H3C (n=2), HIST2H3C (n=1) and EZHIP overexpression (n=4). 37 samples were suitable for cell culture, with HTS successfully performed in 25 cases, and PDXs established in 7. Precision-guided therapy (PGT) was recommended by the ZERO multidisciplinary tumor board for 53 patients (78%), including 5 recommendations guided by HTS. PI3K/mTOR inhibitors and MEK inhibitors were the most recommended PGTs. 21 patients (31%), receiving 24 PGTs, were eligible for survival analysis. The clinical benefit rate (per RAPNO) was 52% for patients receiving PGT, with 5 patients exhibiting PR and 6 patients SD &amp;gt;6 months. Notably, the 5 PR included: a PR in a patient with BRAFV600E mutation to dabrafenib/trametinib, a near-CR in a patient with germline BRCA2 mutation to olaparib/durvalumab, a sustained PR in a patient with FGFR1 mutation to trametinib/bevacizumab and 2 patients with PIK3CA mutations who received PGT in the context of recent radiotherapy. Median overall survival of the PGT group was 21.2 months versus 11.8 months for the rest of the cohort (hazard ratio 0.67 [95%CI 0.39-1.1]). CONCLUSIONS These results, for the first time, highlight the potential clinical benefit of PGT in H3K27-altered DMG.