tbuckley/cabot-search huggingface dataset:
MDB-80. PREVIOUS MANAGEMENT OF MEDULLOBLASTOMA IN A MIDDLE-INCOME COUNTRY: IDENTIFYING AREAS FOR IMPROVEMENT
Authors: Mauricio Sánchez, Yessika Gamboa, Mario Delgado, Karla Garita, Jessica Esquivel, Carlos Rodríguez, Adrian Caceres, Amanda Leis, Maria José Acuña, Monica Nuñez
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma stands as the most prevalent malignant brain tumor among the pediatric population. Diagnosis, staging, and treatment protocols are well-established in high-income countries. However, in low- to middle-income countries, management practices often deviate and frequently prove inadequate, potentially impacting final outcomes significantly. In Costa Rica, a middle-income country, a study was conducted to document the prevailing management approaches for patients at the Hospital Nacional de Niños. METHODS Data from 31 children under the age of 13, treated between 2009 and 2015, were retrospectively analyzed. All patients were included in the study. Demographic details, initial symptoms, staging procedures, surgical interventions, histologic subtypes, treatment modalities, and survival outcomes were scrutinized. Risk stratification relied on age, CSF analysis (when available), and the extent of resection as per the neurosurgeon’s assessment. Due to incomplete staging, all patients received high-risk chemo - radiotherapy protocol. RESULTS The study identified 31 patients. Median age of 6.1 years (range, 0 -12), 51.1% being male. The most prevalent symptoms included headache, vomiting, and ataxia, manifesting in 93% of cases. Histological subtype was unspecified in 45.2% of patients. High-risk status was assigned to 11 patients (35.5%), with 8 of them aged under 3 years, while 20 patients (64.5%) were categorized as low risk, yielding a 5-year overall survival (OS) of 27% and 80%, respectively. Complete resection achieved in 21 cases, resulting in a 5-year OS of 71.5%, compared to 25% for 4 patients with incomplete resection. The overall 5-year OS rate was 61.3%. CONCLUSIONS This study underscores suboptimal practices in the diagnosis, staging, and management of medulloblastoma at the time of assessment. While outcomes for patients classified as standard are acceptable, they received intensified chemo/radiotherapy, potentially leading to heightened long-term adverse effects. Importantly, identified deficiencies have since been addressed. The impact of these interventions will be evaluated in future studies.
MDB-70. SYSTEMATIC TRANSCRIPTOMIC ANALYSIS OF CHILDHOOD MEDULLOBLASTOMA IDENTIFIES M6A-LNCRNA SIGNATURES ASSOCIATED WITH PROGNOSIS, MOLECULAR SUBTYPE, AND IMMUNE CELL INFILTRATION
Authors: Kandarp Joshi, Menglang Yuan, Keisuke Katsushima, Olivier Saulnier, Selah Dean, Ernest Amankwah, Stacie Stapleton, George Jallo, Michael D Taylor, Charles G Eberhart, Ranjan J Perera
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the predominant pediatric brain tumor, subdivided into four molecular subgroups, with group 3 and group 4 tumors posing significant clinical challenges due to poor prognosis and classification. This study investigates the roles of N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) in MB, aiming to develop diagnostic and prognostic tools. METHODS We analyzed transcriptome from 1236 samples to identify m6A-associated lncRNA signature (M6LSig). A multivariate-cox analysis identified a gene signature significantly associated with overall survival (OS) of patients. Risk score was calculated based on the sum of weighted gene expression of these genes. Nomograms were calculated for predicting OS and PFS probability. We did feature selection with Boruta to identify minimum gene signature for subgroup classification. We performed correlation analysis of gene signature and risk score with immune-cell abundance. We depleted METTL3 and METTL14 in G3-MB cell-line (D425) to measure impact on cell proliferation and dysregulation of M6LSig genes as a result of loss of m6A. RESULTS Nomogram was constructed using risk score derived from 24 M6LSig significantly associated with OS and PFS of the patients. A 171 gene signature was identified that can accurately classify samples into one of four major subgroups of MB with more than 90% accuracy including between Grp3/Grp4 samples. M6LSig genes and risk score showed significant correlation with immune cell type abundance in MB tumors. Expression of CD155 and 4-1BB was significantly different between high and low risk samples. m6A writer genes knockdown in D425 cells resulted in decreased cell proliferation and upregulation of many M6LSig genes. CONCLUSION M6LSig based risk can accurately predict OS and PFS and 171 genes signature can classify patients into subgroups with more than 90% accuracy. Risk score can also be used for determining high risk versus low-risk patient and design tailor made immune-therapy for better survival.
MDB-72. BREFELDIN A (BFA) INDUCES CD133 PROTEOLYTIC PROCESSING IN MEDULLOBLASTOMA STEM CELLS (MBSCS)
Authors: Zaira Spinello, Martina Cese, Maurizio Ronci, Laura Giusti, Luana Abballe, Evelina Miele, Elisabetta Ferretti, Giuseppina Catanzaro
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is a malignant brain tumor occurring in children, characterized by elevated resistance to conventional chemotherapy. Medulloblastoma stem cells (MBSCs) represent a fraction of the tumor cell population which has been associated with poor prognosis and refractoriness to conventional therapies. CD133 (Prominin 1, PROM1) is a transmembrane protein serving as a cancer stem cell marker associated with cancer progression. Brefeldin A (BFA) is an antibiotic disrupting the Golgi apparatus, thus triggering Endoplasmic reticulum (ER) stress signaling pathways. BFA cancer-inhibitory properties have been already described in cancer of different tissue origin. However, the effects of BFA on MBCSs have not been investigated yet. Thus, the aim of this study was to characterize the response of MBSCs to BFA and the effects induced by BFA on CD133. METHODS Human group 3 MB (G3MB) cell lines were grown in stem selective medium (B27™) and treated with 0.3 uM BFA for 24h before collection. Apoptosis, clonogenicity and CD133 expression were evaluated. CD133 was immunoprecipitated and the corresponding bands were excised and analyzed by nanoLC-MS/MS. Raw data were processed using PEAKS XPro. RESULTS Our results show that BFA-treated cells induced the overexpression of a CD133 isoform that was missing the N-terminus region. Moreover, we found a downregulation of CD133 activated intracellular signalling together with a reduced exposition on cell membrane. CONCLUSIONS We report here for the first time, a N-terminus proteolytic processing of CD133, potentially associated to the cell trafficking effects induced by BFA. Finally, this study suggests a proof of principle for the design of novel molecules with similar structures and mechanism of action of BFA.
MDB-71. IDENTIFICATION AND DESCRIPTION OF A NOVEL TYPE OF MEDULLOBLASTOMA
Authors: Alicia Eckhardt, Chris Meulenbroeks, Neal Geisemeyer, Michael Bockmayr, Karoline Hack, Marthe F Sönksen, Christian Thomas, Melanie Schoof, Arend Koch, Sage Green, David Doss, Ekin Guney, Arie Perry, Stephan Frank, Peter Kuzman, Miriam Ratliff, Abigail Suwala, Stefan Rutkowski, Martin Hasselblatt, Michael D Taylor, David Jones, Marcel Kool, Ulrich Schüller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is one of the most frequent high-grade brain tumor types of childhood and adolescence. Based on biology, histology, and its clinical course, MB is a heterogeneous disease with four different molecular types (WNT, SHH, Group 3, and Group 4), which are most reliably distinguishable by their global DNA methylation pattern. METHODS We analyzed DNA methylation (n=47), copy number variants, transcriptomic data (n=7) and histology (n=28) of a previously unrecognized type of MB. RESULTS As a result of integrating DNA methylation data of &amp;gt;2,600 MB and screening of &amp;gt;140,000 data sets uploaded to the DKFZ brain tumor classifier (www.molecularneuropathology.org), we identified a small group of MB that displayed a homogeneous DNA methylation pattern, which was clearly distinct from previously known MB types. Tumors within this group have also been recognized as a separate methylation class by latest versions of the classifier, which has provisionally been named medullomyoblastoma (MB_MYO). Transcriptomic data were similarly distinct from other MB types. Comparison of these data to various cell types of the developing hindbrain revealed transcriptional similarities to precursor cells of the rhombic lip with signatures of WNT signaling and myogenic differentiation. In line with the latter findings, 2/11 cases with DNA sequencing data harbored hotspot CTNNB1 mutations and 5/28 cases showed a myogenic differentiation based on histology. MYC amplifications were present in 11/47 cases, corresponding to a higher fraction of MYC-amplified tumors compared to all known MB types. Median age at diagnosis in this cohort was 16 years, and five-year overall survival was ~75 %. CONCLUSIONS In summary, we describe a novel type of MB identified by DNA methylation profiling that likely needs to be addressed separately during the retrospective analyses of MB patient cohorts, for the design of future clinical trials, and when evaluating targeted therapies.
OTHR-11. TITLE: ELECTROGRAPHIC SEIZURES AND EEG BACKGROUND FEATURES IN PEDIATRIC NEURO-ONCOLOGY PATIENTS ADMITTED TO THE PEDIATRIC INTENSIVE CARE UNIT
Authors: Elizabeth E S Pickup, Julia S Keenan, Roger J Packer, Elizabeth M Wells, Caroline Conley, Katelyn Staso, Dana B Harrar, Arnold J Sansevere
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Electrographic seizures (ES) are common in critically ill children with the incidence of ES ranging from 10-50%. Continuous EEG (cEEG) is frequently obtained in children with brain tumors due to encephalopathy or concern for seizures. Despite this, little is known about the incidence of ES, EEG background features, or the impact of EEG on clinical management in this population. METHODS This is a prospective single center study of critically ill children with brain tumors admitted to the pediatric intensive care unit (PICU) from July 2021 to July 2023. Patients with new or known primary brain tumors and cEEG completed during their admission were included. We excluded patients with planned admissions for EEG. Clinical variables included age, sex, oncologic diagnosis, tumor grade and location, indication for EEG, EEG features, and changes in management. RESULTS Thirty-six patients were identified who met the inclusion criteria. 21 patients were female. The median age was 11.0 years (IQR 6.6– 15.4 years). The most common indication for EEG was encephalopathy in 42% followed by clinical seizure in 31%. ES were captured in 19% (7/36) with the majority being subclinical; in patients with acute encephalopathy, ES were captured in 20% (3/15). The EEG background was abnormal in 97% of cases. The most common EEG background was slow disorganized with background asymmetry seen in in 74%. EEG background features met criteria for the ictal-interictal continuum in 14%. A higher rate of ES was seen in patients with disseminated tumors (p=0.03) and severe encephalopathy on EEG (p=0.006). EEG led to a change in management in 31% of patients. CONCLUSIONS ES are common in critically ill children with brain tumors and would go undetected without cEEG. EEG findings often led to a change in clinical management and is a vital tool for the evaluation of this population.
OTHR-10. PILOT STUDY TO EVALUATE AUTOMATED LABORATORY DATA TRANSFER INTO MEDIDATA RAVE ACROSS THE NATIONAL CANCER INSTITUTE (NCI)-SUPPORTED PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) AND PEDIATRIC EARLY PHASE CLINICAL TRIAL NETWORK (PEP-CTN) COOPERATIVE GROUPS
Authors: Tamara P Miler, Richard Aplenc, Charles Minard, Shelly Lensing, Yu Wang, Prasanna Velamuru, Jennifer H Foster, Milena Silverman, Cheryl Sung, Karina Wong, Thalia Beeles, Brenda Weigel, Elizabeth Fox, Arzu Onar-Thomas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Electronic data capture (EDC) has the potential to improve data accuracy and efficiency in oncology. The PBTC and PEP-CTN cooperative groups conducted a pilot project to 1) assess the feasibility of automated transfer of laboratory data from participating institutions’ electronic health records (EHR) to the Medidata Rave EDC housed within each consortium’s Uniform Resource Locator (URL); 2) evaluate discrepancies between retrospective automated laboratory data extraction from the EHR and manual data ascertainment during the original conduct of the study (MANUAL). METHODS Data from patients treated on 7 completed PBTC or PEP-CTN trials at 7 hospitals were included. Each consortium created a Rave instance to receive data. Sites elected to use local methods or the ExtractEHR R package to map and extract laboratory data for designated patients. Post-extraction data were uploaded to the Rave Batch Uploader (BU)-associated file transfer protocol (FTP) and BU uploaded data into Rave. After successful upload, discrepancies between EHR and MANUAL data were categorized. Two hospitals reviewed discrepancies at their sites to identify reasons for discrepancies. RESULTS Automated extraction and upload required significant PBTC/PEP-CTN operational effort and close work with hospital technical teams to map and extract data. All sites successfully extracted specified laboratory data and had ≥1 complete upload via BU to Rave; 2 sites had 2 uploads. Discrepancies were most commonly due to more data in EHR datasets (&amp;gt;1 result on a given day, data on additional study window days) or mismatched values or units. Differences in percentages of discrepant results between hospitals were likely due to mapping differences for EHR extraction. CONCLUSIONS This study demonstrated that in the pediatric cooperative oncology group setting automated laboratory data ascertainment can be performed. Accomplishing this required upfront central operational and hospital-based effort to prepare for data upload and transfer. This effort varied by site.
OTHR-07. LIFE THREATENING CATATONIA AND THE USE OF ELECTROCONVULSIVE THERAPY IN A PATIENT WITH RELAPSED MEDULLOBLASTOMA
Authors: Stanley Chaleff, Roselyn Gerwin, Lee Wolfrum, Pamela Bokat, Nadav Kastle
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma is one of the most common malignant brain tumors in the pediatric population and with multimodal therapy the majority of patients will be cured, but patients experience significant morbidity related to the disease and therapy. Catatonia is a life-threatening psychomotor disorder that has rarely been described in the pediatric population and is likely under recognized. Catatonia is a treatable condition using benzodiazepines as first line with electroconvulsive therapy (ECT) used for patients who do not respond or have life threatening malignant catatonia. In the medical literature there are very few papers to inform on the safety of using ECT in patients who have received radiation in the past or are undergoing chemotherapy. We describe a patient in remission of his medulloblastoma who presented with refractory catatonia who needed lifesaving ECT, then had metastatic recurrence of his medulloblastoma. The patient was initially diagnosed with group 4 medulloblastoma at 14 – he was treated with high-risk therapy to metastatic sites of disease at diagnosis as per COG ACNS 0332 with a combination of surgery, chemotherapy and craniospinal radiation and a boost to the primary tumor and metastatic sites of disease. Approximately 18 months after the end of therapy he was diagnosed with treatment refractory catatonia and needed to be started on ECT with a good response. 6 months after presentation of catatonia, the patient unfortunately had a relapse of his medulloblastoma in his left temporal lobe and is now actively getting ECT and chemotherapy at the same time without complications. The description of this patient will add to the sparse body of evidence that it is likely safe to be able to deliver chemotherapy at the same time as ECT.
MODL-05. UNDERSTANDING THE METABOLIC VULNERABILITIES IN INFILTRATING GLIOMATOSIS CEREBRI CELLS
Authors: Hriday Bahadoor, Chinar Salmanli, Hassiba Outlifah, Clemence Hubsch, Marlène Deschuyter, Izzie Jacques Namer, Damien Reita, Sophie Martin, Monique Dontenwill, Natacha Entz-Werle
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gliomatosis cerebri (GC), a rare form of high-grade glioma, is characterized by a particularly invasive phenotype within multiple lobes of the brain and a dismal prognosis. This entity was removed in 2016 of the WHO brain tumor classification because of an absence of specific GC driving molecular signature. Its diffusive aspect on MRI is defined by an absence of cohesive tumor mass, a mild contrast enhancement and a rare neoangiogenesis. Based on those observations, our objectives were to understand how these cells are adapting to their brain environment without a physiological nutritive efflux associated to a reduced oxygen concentration and determine a metabolic signature of GC. METHODS Preliminary results in a large cohort of HGGs bearing several drivers (H3.3 G34V, NMYC amplified, BCOR positive) or a more “wildtype” phenotype with new entities (pedRTK 1 and 2) were underlining glucose and glutamine as major nutrients in cell metabolic suppliance. Therefore, epigenetic assessments, bulk metabolomics, and Seahorse technology, as well as labeled glucose and glutamine metabolites study, helped us in pediatric GC-derived cell lines (BT97 and BT139, PEDIAMODECAN program) to understand the role of both nutrients and their central role in GC in hypoxic microenvironment. RESULTS Both glucose and glutamine are involved in carbon fueling biosynthesis in those cells. Glutamine is much more involved in supplying nitrogen to fuel several specific amino acids and mitochondrial metabolisms. Meanwhile, we developed drug testing using Matrigel invasion aspects. The tested drugs were able to reduce invasiveness of GC cells and modify the intratumoral metabolism. CONCLUSION All those observations seem to explain GC cell adaptation into the hypoxic microenvironment, their plasticity and resistance through metabolic reprogramming based on glutaminolysis and glycolysis.
OTHR-04. HEALTH SYSTEM DELAYS IN DIAGNOSIS AND TREATMENT OF CHILDREN WITH CENTRAL NERVOUS SYSTEM (CNS) TUMOURS IN SRI LANKA
Authors: Mahendra Somathilaka, Ashika Jayathilaka, Dhanushka Jayasekera, Mohomad I M Azwer, Nilrukshan Jayaweera, Sanjeewa Garusinghe, Modhini Jayawickrama, Roshana Constantine, Tejpal Gupta, Girish Chinnaswamy, Santhosh Upadhyaya, Zeena Salman, Ibrahim Qaddoumi, Sanjeeva Gunasekera
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children with central nervous system(CNS) tumours have to navigate multiple layers of care to reach the only centre providing oncology care (chemotherapy and radiotherapy) in Sri Lanka. This can lead to significant delays and affect outcomes. METHODS This is a retrospective study of patients less than 19 years registered at the National Cancer Institute Sri Lanka(NCISL) from 1st January 2022 to 31st December 2023. Data was extracted from clinic records and interviewing caregivers. RESULTS From a total of 828 new children with cancer 135 had CNS tunours and data was available for 130 for analysis. Commonest cancers seen were low grade gliomas and medulloblastoma. Fifty-one percent were males and the median age was 6 years (Range 1-18). Most common presenting symptoms were headache and vomiting. Median time from onset of symptoms to first medical contact was 4 days (InterQuartile Range(IQR) 1-9.5) and to first imaging it was 44 days (IQR 3-151) for all symptoms. In the presence of neurological symptoms, the time to imaging was 26 days (IQR 2-141). Ninety-six(74%) had upfront surgery at a median time 14 days from first imaging (IQR 7-34.5) with a median time of additional 25 days to reach an oncology centre (Range 7-94). Patients who did not have upfront surgery took 13.5 days (IQR 2-36.5) for the same. After arriving at the oncology centre, radiotherapy (80/130, 62%) was initiated in 24 days. When calculated from date of surgery radiotherapy initiation time was 61 days. (Range 5-88) CONCLUSION Although there seem to be no significant delay in presentation of children with CNS tumours to the health system, there were significant delays in imaging and initiating adjuvant radiotherapy. Further studies are warranted to determine the attributing factors and corrective steps to be taken to expedite referral of affected children.
IMMU-16. LOCOREGIONAL DELIVERY OF MRNA CAR T CELL THERAPY INTO THE CEREBROSPINAL FLUID IN PRECLINICAL MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Kyra Harvey, Zein Al-atrache, Olivia McManus, Conor Dickson, Luke Patterson, Ezra Beaubien, Cullen Wilson, Sreehita Hajeebu, Samantha Keil, Molly Braun, Michael Meechan, Nicholas A Vitanza, Jeff Iliff, Peter Madsen, Jessica Foster
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND GD2-directed Chimeric Antigen Receptor (CAR) T cell therapy is a promising immunotherapeutic modality for diffuse midline glioma (DMG). We developed mRNA CAR T cells as a safe alternative to virally transduced CAR T cells and have shown that intra-tumoral (IT) infusions of mRNA GD2-directed CAR T cells result in significant tumor regression with improved toxicity in murine DMG models. For clinical translation, we sought to determine the optimal route and trafficking patterns of CAR T cells administered into the cerebrospinal fluid (CSF). METHODS NSG mice engrafted with DMG xenograft SU-DIPG13P* in the pons were treated with 5x106 mRNA CAR T cells either into the lateral ventricle (LV) or into the cisterna magna (CM), with brains harvested after 24 hours for analysis using confocal microscopy. RESULTS Both LV and CM treated mice showed higher GD2-directed CAR T cell migration to tumors compared to CD19-directed controls, with higher accumulation of GD2-directed CAR T cells in the parenchyma for LV treated mice compared to CM (p&amp;lt;0.001). To evaluate efficacy of delivery in the CSF, NSG mice engrafted with DMG xenograft 7316-6349 in the pons were treated with 5x106 mRNA CAR T cells IT, LV, or CM twice a week for 3 weeks totaling 6 doses. Mice were imaged weekly to monitor bioluminescent tumor signal, showing that mice treated with GD2-directed CAR T cells IT had significantly decreased tumor burdens compared to LV and CM GD2 CAR treated groups (p &amp;lt; 0.05 and p &amp;lt; 0.01 respectively), as well as compared to CD19 controls (p &amp;lt; 0.01). CONCLUSIONS Despite local infiltration, mRNA CAR T cells delivered into the CSF did not fully reduce tumor burden, and thus, future work is aimed at evaluating potential routes of priming tumors to attract subsequent cellular therapy doses delivered intra-ventricularly.