tbuckley/cabot-search huggingface dataset:
TMOD-36. NANOGLIOS: A MINIATURIZED PATIENT AVATAR ENABLING RAPID AND HIGH-THROUGHPUT PHENOTYPIC SCREENING FOR GLIOMAS
Authors: Zhaohui Wang, Wei Huang, Satoru Kawakita, Francisco Bustamante, Rene Larios, Chongming Jiang, Gregory P Lekovic, Richard G Everson, Linda M Liau, Albert Lai, Zhaohui Wang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Establishing pre-clinical patient derived orthtopical xenograft models for IDH-mutant and H3K27M-mutant gliomas has presented significant histological challenges. There is increasing interest in developing faithful patient-derived ex vivo 3D models to replicate these type of gliomas, aiming to accelerate drug screening efforts. METHOD We developed a rapid approach for establishing nanoliter-sized miniature glioma organoids, termed NanoGlios, by leveraging emulsion microfluidics. We tested the robustness of NanoGlios for neurosphere culture, glioma xenografts, and primary patient samples, focusing on H3K27M-mutant diffuse midline gliomas (DMGs) and IDH-mutant gliomas. We compared the morphological features of NanoGlios to their counterparts using high-content imaging, H&amp;E staining, and histological analysis. Additionally, we evaluated the mutation and gene expression profiles of NanoGlios relative to their counterparts. Furthermore, we conducted proof-of-concept drug screening of NanoGlios with various inhibitors and established an AI-enhanced high-throughput phenotypic imaging-based screening platform. RESULTS We successfully established NanoGlios from various sample sources, including neurospheres, xenografts, and primary tissues harboring H3K27M or IDH1/2 mutations. NanoGlios derived from xenografts or primary tissues captured more heterogeneous patterns as compared to the neuropsheres. We were able to generate thousands of NanoGlios and perform drug assays for hundreds of conditions at passage 0 within two weeks from both resected glioma tissues and xenografts. The AI phenotypic screening enabled us to identify differential responses of NanoGlios to ONC-201 treatment and drug responses to mutant IDH inhibitors Vorasidenib and Ivosidenib, which was not able to be detected by conventional cell viability bulk assays.
CNSC-01. PEDIATRIC GLIOMAS EXPRESS CIRCADIAN GENES AND DEMONSTRATE CIRCADIAN REGULATION OF TEMOZOLOMIDE SENSITIVITY
Authors: Ella A Nettnin, Cesar A Garcia, Ethan Schonfeld, Lindsey C Mehl, Maria Isabel Barros Guinle, Claudia K Petritsch, Erin M Gibson, Laura M Prolo
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Pediatric high-grade gliomas (pHGG) are highly invasive brain tumors with dismal survival rates, prompting the need for innovative therapeutic strategies. Previous research in adult glioblastoma patients revealed a correlation between the timing of Temozolomide administration and patient survival. There has, however, been limited exploration into circadian gene expression in pediatric gliomas. In this study, we investigate whether pHGGs exhibit rhythmic expression of circadian genes and whether the timing of drug administration influences Temozolomide sensitivity. METHODS A bioinformatics approach, immunocytochemistry and immunoblotting were used to assess key circadian genes in low- and high-grade gliomas. We then used timed qPCR to assess rhythmic expression in BMAL1 and REV-ERBα, two key circadian genes, across 48 hours in our pHGG cells following dexamethasone cell synchronization. Lastly, we used CyQuant Proliferation Assays to examine the effects of Temozolomide applied at peaks versus troughs in BMAL1 expression. RESULTS Using data from PedcBioPortal, we found significantly higher expression of BMAL1 in pHGGs compared to pLGGs (0.349 + 1.05 vs 0.0545 + 0.666, p &amp;lt; 0.001). We identified cellular localization of BMAL1 and REV-ERBα in pHGGs along with rhythmic expression of BMAL1 and REV-ERBα in our three pHGGs primary cell cultures across 48 hours (JTK_CYCLE, p &amp;lt; 0.005). Lastly, we demonstrated a chronotherapeutic response to Temozolomide in two of our pHGG cell lines, with significantly decreased proliferation when treatment occurred at trough versus peak BMAL1 expression (p &amp;lt; 0.01). CONCLUSION In this study, we found that circadian genes BMAL1 and REV-ERBα are expressed in pHGGs and expression patterns differ between pHGGs versus pLGGs. Circadian gene expression is rhythmic in pHGGs, and pHGGs can have differential Temozolomide-sensitivity based on circadian cycles. These findings suggest that circadian timing of chemotherapy may influence the efficacy of treatment, and next steps will be to explore the mechanisms underlying circadian regulation of Temozolomide sensitivity.
SURG-21. DEVELOPMENT AND VALIDATION OF A CLINICAL RISK SCORE FOR POSTOPERATIVE OUTCOME IN NEWLY DIAGNOSED GLIOBLASTOMA: A REPORT OF THE RANO<i>RESECT</i> GROUP
Authors: Philipp Karschnia, Jacob S Young, Gilbert C Youssef, Antonio Dono, Levin Häni, Tommaso Sciortino, Francesco Bruno, Stephanie T Juenger, Nico Teske, Jorg Dietrich, Michael Weller, Michael A Vogelbaum, Martin van den Bent, Juergen Beck, Niklas Thon, Jasper K W Gerritsen, Shawn Hervey-Jumper, Daniel P Cahill, Susan M Chang, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Raymond Y Huang, Patrick Y Wen, Mitchel S Berger, Annette M Molinaro, Joerg-Christian Tonn
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Following resection or biopsy, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aim to make use of our RANO classification for extent of resection (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool. METHODS The RANO resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model was prognostically verified in a separate external validation cohort. RESULTS Our training cohort compromised 1003 patients with newly diagnosed IDH-wildtype glioblastoma, including 744 patients who underwent adjuvant radiochemotherapy (TMZ/RT→TMZ). Residual tumor, MGMT promotor methylation status, age, and KPS were prognostic of overall survival and forwarded into regression tree analysis. By combining eleven terminal nodes and individually weighting the prognostic factors, an additive scale (range, 0-9 points) integrating these four variables distinguished patients with low (0-2 points), intermediate (3-5 points), and high risk (6-9 points) for poor postoperative outcome (median overall survival: 24 vs. 16 vs. 6 months; p&amp;lt;0.01). The presence of the three risk groups was confirmed in the subgroups of patients treated with or without RT/TMZ→TMZ. The prognostic value of the risk score was verified in a external single-center validation cohort of newly diagnosed glioblastoma (n = 258, p&amp;lt;0.01). Compared to previously postulated models, goodness-of-fit measurements were superior for our score. CONCLUSIONS The novel RANO risk score serves as an easy-to-use, yet highly prognostic tool for postoperative patient stratification prior to further therapy. The score may serve to guide patient management and reduce imbalances between study arms in prospective trials.
NCMP-29. BRAIN LESIONS IN A TEEN WITH NEWLY DIAGNOSED T-CELL ALL AND SARS-COV-2 INFECTION
Authors: Salvatore Aspromonte, Clinton Ehidom, Shama Khan, Julio Arevalo Perez, Juan Pascual, Jeffrey Greenfield, Tobias Hohl, Sofia Haque, Yasmin Khakoo, Tanya Trippett
Journal: Neuro-Oncology (2024)

Abstract T-cell Lymphoblastic Leukemia (T-cell ALL) accounts for up to 15% of all newly diagnosed cases of acute lymphoblastic leukemia in pediatric patients (0-18 years old). Patients are at risk of opportunistic infections during induction therapy with up to 2% developing blood stream infections when their absolute neutrophil count is above 1,500. We report a case of a 15-year-old female with High-Risk T-cell ALL, CNS1 (negative CNS disease), presenting with three days of headaches, photophobia, and non-neutropenic fever. She completed induction chemotherapy one week earlier with vincristine, daunorubicin, calaspargase and a 28-day course of dexamethasone. On physical exam, she had no focal deficits or changes in sensation or strength. CBC was notable for a white blood cell count: 7500, hemoglobin: 8.6, platelets: 328,000 and ANC (Absolute Neutrophil Count): 4700. The patient was also COVID positive on admission. A contrast enhanced MRI brain demonstrated multiple diffusion restricting and peripherally enhancing lesions, concerning for intracranial abscesses. Neurosurgery performed a burr hole craniotomy and aspirated 5 mL of purulent drainage, the culture of which grew Aspergillus fumigatus complex. The patient was started empirically on Voriconazole, in addition to broad spectrum antibiotic coverage pending culture results, due to excellent CNS penetration and proven superiority to amphotericin-based therapy for invasive aspergillosis. Micafungin was added due to CT chest demonstrating nodular infiltrates, suggesting primary pulmonary aspergillosis with CNS dissemination. The patient improved symptomatically without further sequelae. Patients with COVID-19 on prolonged courses of corticosteroids are at higher risk of developing fungal co-infections regardless of neutrophil count. While pulmonary aspergillosis is the most common location of a COVID-19 aspergillus coinfection, there have been documented reports of intracranial micro-abscesses. Contrast-enhanced brain MRI should be obtained in any patient with a recent history of COVID-19 presenting with new neurological symptoms, especially in a patient with a recent history of corticosteroids.
EPID-27. THE INCIDENCE OF BRAIN METASTASIS IN GASTROINTESTINAL CANCER ACCORDING TO PRIMARY SITE AND STAGE: A 15-YEAR SINGLE INSTITUTIONAL ANALYSIS
Authors: Marc Vincent Barcelona, Kaushik Jagannath Kataki, Fadwa Abdel Rahman, David Schultz, Barbara-Ann Millar, Tatiana Conrad, Mojgan Taremi, Paul Kongkham, Elena Elimova, Yangqing Deng, Michael Ming Yan
Journal: Neuro-Oncology (2024)

Abstract Gastrointestinal (GI) cancers are a diverse group of cancers including pancreatic, gastric/gastroesophageal junction/esophageal (G/GEJ/E), colorectal (CRC), hepatocellular (HCC), biliary tract (BT), and anal origin cancers. The risk of developing brain metastasis (BrM) is not well characterized. The aim was to determine the incidence of BrM among all GI cancer patients at Princess Margaret Hospital (PM). We included patients diagnosed with GI cancer presenting from 2005-2020, captured prospectively in our institutional registry. These patients were cross-referenced with our radiotherapy database, where radiotherapy for brain metastases (BrM) was used as a proxy for the brain metastases development. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk. Overall survival (OS) was estimated using the Kaplan Meier method. The registry accounted for 22,188 patients. The median age of the cohort was 64. Most common primary sites are CRC adenocarcinoma, pancreatic adenocarcinoma, G/GEJ/E adenocarcinoma were 31.52%/11.71%/10.25%. The 15-year CI for BrM for the entire cohort was 1.65%, and for CRC, small bowel, anal, pancreatic, G/GEJ/E, HCC, and BT cancers were 2.69%/2.49%/1.30%/0.5%/3.52%/ 0.05% /0.4% (p &amp;lt; 0.001) and Stage I-IV disease were 0.39%/0.81%/1.2%/3.1%, respectively (p &amp;lt; 0.001). 5 year CI for HER2 positive G/GEJ/E patients was 19.5%. Median OS from initial presentation for those with BrM was 25.13 months. On univariable analysis, chemotherapy receipt [HR 1.916, p &amp;lt; 0.001], Stage IV at presentation [HR 3.991, p &amp;lt; 0.001], and G/GEJ/E primary [HR 1.357, p &amp;lt; 0.001] predicted for higher risk of BrM. Multivariable analysis confirmed that receipt of chemotherapy and Stage IV disease predicted a higher risk for BrM and pancreatic, HCC, and BT cancers predicted for lower BrM. We observed that among patients diagnosed with GI cancers, Stage IV disease predicted higher risk for developing BrM and were more likely to receive chemotherapy.
CTNI-81. PROPOSAL FOR A PHASE IB PILOT CLINICAL TRIAL TO STUDY SAFETY AND IMPROVING ANTI-NEOPLASTIC ADVERSE EFFECTS BY ADDITION OF NATURAL MARINE PRODUCT FUCOIDAN TO THE STANDARD THERAPY FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Xiao-Tang Kong, Yoshiyuki Miyazaki, Chunxiao Ma, Geoffrey Winston Abbott, Daniela A Bota, Carlen A Yuen
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION GBM is the most aggressive primary brain tumor. Despite standard of care (SOC) with the Stupp protocol and tumor treating fields (TTFs), survival remains poor. In addition, SOC treatment is associated with 96% any adverse effects (AE) and 25% severe AEs (Chinot et al, NEJM 2014), which affects quality of life (QOL) and can lead to early treatment termination. Therefore, novel therapies are needed and minimization of chemoradiation-related AEs is crucial. Marine natural product, fucoidan, may have an important role in oncological management as tumor-directed therapy and as a protectant against chemoradiation-related AEs. Fucoidan is a seaweed-derived sulfated polysaccharide. Mounting evidence garnered from randomized clinical trials for colon, head and neck, and lung cancer patients suggests that fucoidan can improve certain AEs associated with chemoradiation. Furthermore, data gleaned from multiple studies have shown that fucoidan is tolerable with a good safety profile. HYPOTHESIS Fucoidan is safe in combination with chemoradiation and chemotherapy and improves treatment related AE profile. Fucoidan may improve survival outcome in GBM patients by augmenting cytotoxic effects, inhibiting angiogenesis, and improving the tolerability of SOC therapy. METHOD 12 newly diagnosed GBM patients will be enrolled. A Fucoidan-based product will be administered orally at the established dose for cancer patients daily with concurrent chemoradiation therapy and adjuvant chemotherapy over 6 months. Patients will be evaluated weekly to monthly for AEs and QOL scoring; laboratory and brain MRI monitoring will be performed per SOC guidelines. NK cell activity, proinflammatory cytokines, including interleukin (IL)-1β, will be measured. POTENTIAL OUTCOME This pilot study may establish a foundation for future larger randomized clinical trials to treat brain cancer more effectively by adding nature products.
EPCO-33. OMICON: A CLOUD PLATFORM FOR FAIR RESEARCH ON GENE COEXPRESSION NETWORKS IN NORMAL HUMAN BRAIN AND BRAIN TUMORS
Authors: Rebecca Eliscu, Divya Padmanabhan, Sanoj Sudhakaran, Sharat Nair, Shravan Suresh, Pratheeksh Joseph, Alex Jacob, Vineet Ravindran, Mizba Feroz, Akshay Ajayakumar, Renjith Reghuvaran, Shiny Raj, Aswathy Vijay, Gouri Lakshmi, Remya Vava, Carolina Escobar, Martin Thormann, Shawn Shamsian, Michael Oldham
Journal: Neuro-Oncology (2024)

Abstract Genome-wide coexpression analysis of bulk human brain samples is a powerful approach for identifying highly reproducible transcriptional signatures of cell types and cell states, since it can survey huge numbers of individuals, cells, and transcripts. However, it is difficult to optimize gene coexpression network construction, compare gene coexpression modules from independent datasets, or even locate gene expression datasets with similar attributes. To address these challenges, we have developed the OMICON platform (theomicon.ucsf.edu) to promote FAIR (Findable, Accessible, Interoperable, Reusable) research practices involving human brain gene coexpression networks. OMICON contains structured gene expression data for &amp;gt;17K bulk human brain samples (~10K normal and ~7K malignant glioma), which were collected from diverse public repositories and consortia (e.g., GEO, TCGA, CGGA, CPTAC, REMBRANDT, IvyGAP, GTEx, NABEC, the Allen Institute). To promote interoperability, we have standardized metadata for hundreds of dataset and sample attributes, including single-nucleotide and copy-number mutations. For each dataset, we have used the FindModules R function to construct dozens of gene coexpression networks by iterating over module detection parameters. These efforts have identified ~100K gene coexpression modules, which have been extensively characterized via enrichment analysis with thousands of curated gene sets. All datasets, metadata, gene coexpression networks, enrichment results, and analysis steps can be browsed with an interactive workflow visualization tool, which promotes accessibility, reusability, and reproducibility by maintaining complete data provenance with unique identifiers. To promote findability, we have built an advanced search engine to identify datasets, samples, modules, and more, by filtering standardized metadata (e.g., find gene coexpression modules in human glioblastoma datasets that are significantly enriched with markers of T-cells). A detailed description of OMICON’s functionality is described on our Help page: theomicon.ucsf.edu/home/help. Through this functionality, OMICON seeks to build community and focus therapeutic efforts around reproducible analyses of transcriptional variation in normal human brain and brain tumors.
EPID-30. THE COST OF HOSPITAL-BASED CARE AMONG CANADIAN PATIENTS WITH MALIGNANT CENTRAL NERVOUS SYSTEM TUMOURS IN COMPARISON TO THOSE WITH LUNG AND COLORECTAL CANCERS IN THE YEAR PRECEDING THEIR CANCER DIAGNOSIS
Authors: Linwan Xu, Keyun Zhou, Yan Yuan, Emily Walker
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Approximately 12% of the Canadian GDP was spent on healthcare in 2023. While hospital-based care (HC) constitutes a significant portion of this expenditure, the costs may vary depending on the cancer type. We investigate the HC cost of patients with malignant central nervous system tumours (CNS cancer) and compare it to patients with common cancers in Canadian provinces. METHODS We obtained data between 2010 and 2014 from the Canadian Institute for Health Information’s in-patient and ambulatory care datasets. HC cost was estimated using a 12-month look back period prior to diagnosis date for each patient, including cost related to cancer diagnosis and general healthcare. Choosing colorectal (CRC) and lung (LC) cancers to be the common cancers, patients who were 15 years of age or older and had a diagnosis of one of these cancers were included. We used quantile regression to investigate the factors associated with HC cost. RESULTS A total of 4,498 (CNS), 41,028 (CRC) and 29,747 (LC) patients were included from Alberta and Ontario, Canada. Encounter type (in-patient/out-patient), province (AB/ON), and comorbidities (Yes/No) were the top three factors contributing to HC cost. Adjusting for encounter type, comorbidities and age, the HC costs for CNS patients were $0.7k and $2.4k higher than CRC patients at 50th and 90th percentile, respectively, and $1.0k higher than LC patients at 90th percentile in Ontario. While in Alberta, HC costs for CNS patients were $0.2k and $0.8k higher than CRC patients at 50th and 90th percentile, respectively, and $1.0k lower than LC patients at both 50th and 90th percentiles. CONCLUSIONS We compared HC cost among Canadian patients with different cancer types; significant HC cost differences between patients with CNS and common cancer were observed. Further investigations are warranted to understand drivers of the cost differences.
EPCO-43. DECONVOLUTION OF GLIOBLASTOMA RNA-SEQ REVEALS IMMUNE SUBPOPULATIONS PREDICTING THERAPEUTIC RESPONSE
Authors: Asad Rauf, Manmeet Ahluwalia, Andrew Dhawan
Journal: Neuro-Oncology (2024)

Abstract Bulk RNA-seq is now among the standard of care for patients with newly diagnosed glioblastoma (GBM), but whether this data can predict therapeutic response is unclear. In silico deconvolution of bulk RNA-seq data allows for quantification of cell types comprising the tumor and its microenvironment. Our study tests whether cell type proportions predict therapeutic response in patients with GBM and high-grade glioma (HGG) enrolled in trials of investigational agents. 127 patients with GBM/HGG underwent post-resection/biopsy whole exome RNA-seq and reads were post-processed using standard computational pipelines. In silico deconvolution was performed using GBMDeconvoluteR, which generates cellular proportions comprising the RNA-seq reads. Multivariate Cox regression models were used to examine each cell proportion as a predictor of progression-free (PFS) and overall (OS) survival. Statistical significance was ascertained using Bonferroni correction for multiple comparisons. Among 54 patients treated with a PD-L1 inhibitor (nivolumab) and VEGF inhibitor (bevacizumab), the proportions of NK cells (p=0.0024), radial glial cells (p=0.0010), and mural cells (p=0.0025), was associated with increased PFS, while proportion of endothelial cells (p=0.0008) was associated with decreased PFS. Astrocyte (p=0.0022), macrophage (p=0.0015), NK cell (p&amp;lt;0.0001), and mural cell (p=0.0004) proportions were associated with longer OS, while endothelial cell proportion (p=0.0001) was associated with shorter OS. Among 21 patients treated with a tyrosine kinase inhibitor (ibrutinib) combined with radiation and temozolomide (RT/TMZ), cell proportions assessed at the time of diagnosis did not predict PFS or OS. In 52 patients with HGG treated with a JAK inhibitor (ruxolitinib) with RT/TMZ, only mural cell proportion was associated with a longer OS (p=0.0017). Our results highlight how bulk RNA-seq data can be used to predict therapeutic response. In GBM patients treated with immunotherapies, the proportion of NK cells may predict response. Further work will examine which gene programs are predictive of therapeutic response.
RBIO-05. IPAX-2: PHASE 1 SAFETY AND DOSE FINDING STUDY OF [131I]IPA PLUS STANDARD OF CARE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Hui Gan, Brenda Cerqueira, Daniela Divlianska, David Cade
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) overexpresses the L-type amino transporter (LAT) 1 &amp; 2, which supports internalization of the therapeutic small-molecule amino acid derivative, 4-L-[131I] iodo-phenylalanine ([131I]IPA) and its companion diagnostic, 18F-FET. Previous studies of [123I]IPA SPECT have shown uptake by &amp;gt;85% of gliomas. Results from a phase 1 trial (IPAX-1) that explored [131I]IPA + radiotherapy in patients with recurrent GBM demonstrated a favorable safety and tolerability profile and promising efficacy. The objective of IPAX-2 (NCT05450744) is to evaluate the safety and tolerability of [131I]IPA in patients newly diagnosed with GBM. METHODS IPAX-2 is a phase 1, multicenter, open-label, single-arm, parallel-group, dose-finding study to evaluate the safety of ascending radioactive dose levels of [131I]IPA + best standard of care in newly diagnosed patients with GBM. Eligible participants (N=12) will be 18-65 years of age with histologically-confirmed intracranial GBM following surgical resection; no prior systemic therapy or radiation for GBM; a Karnofsky Performance Status ≥70; a plan to begin chemoradiation 3-6 weeks after surgical resection with Stupp regimen; adequate organ function; and adequate tissue samples previously archived. Four cohorts will encompass a 3 + 3 dose escalation, with [131I]IPA administered in 2 fractions corresponding to ½ of full dose activity via intravenous infusion (2x3.0 GBq, 2x4 GBq, 2x5 GBq, 2x6 GBq). Dose 1 will be administered prior to external beam radiation therapy (EBRT), and Dose 2 will be administered following completion of EBRT. 18F-FET PET will be used to identify suitable candidates with LAT1/2 overexpression, establish a baseline, and provide quantitative follow-up information. Primary outcome measures are 1) incidence rate treatment-emergent adverse events and 2) safety and tolerability by determining the dose-limiting toxicity, maximum tolerated dose, and recommended phase 2 dose. DISCLOSURES: Telix Pharmaceuticals is the sponsor of this study.