tbuckley/cabot-search huggingface dataset:
CTNI-28. IN VITRO GLIOMA STEMLIKE CELL-BASED SCREENING TO PREDICT DRUG SENSITIVITY IN RECURRENTGLIOBLASTOMA: A CLINICAL SERIES AND SYSTEMATIC LITERATURE REVIEW
Authors: Mariachiara Buccarelli, Martina Offi, Silvia Chiesa, Ciro Mazzarella, Maria Laura Falchetti, Giovanni Maria Ceccarelli, Francesco Beghella Bartoli, Silvia Silvia, Rina Di Bonaventura, Giuseppe Maria Della Pepa, Sohum Rajesh Shetty, Giuliano Di Monaco, Francesco Doglietto, Roberto Pallini, Alessandro Olivi, Liverana Lauretti, Lucia Ricci-Vitiani, Quintino Giorgio D’Alessandris
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION There is no standard care for recurrent glioblastoma (GBM) after surgery and radiochemotherapy. Lomustine is commonly used in clinical trials, while regorafenib, a multikinase inhibitor, has shown a survival benefit in the randomized multicentric REGOMA trial, becoming the standard treatment in several countries, including Italy. However, due to nonnegligible toxicity, early identification of likely responders is crucial for personalized treatment. Various studies have explored putative molecular predictors of response with conflicting results. Glioma stem-like cells (GSCs), the most treatment-resistant subpopulation, are believed to drive GBM recurrence post-chemoradiotherapy. Thus, GSCs might provide valuable insights into the drug sensitivity of recurrent GBM. MATERIALS AND METHODS Between 2020 and 2022, nine patients enrolled in a prospective study to obtain GSC cultures from tumor tissue obtained at first surgery were treated with regorafenib upon tumor recurrence. Four patients underwent reoperation before starting regorafenib. GSC cultures were exposed to increasing regorafenib doses in vitro to determine sensitivity (IC50). RESULTS The median progression-free survival (PFS) was 3 months, consistent with REGOMA data. Only one patient achieved 6-month PFS (11.1%). GSCs from this patient were the only ones with an IC50 below the plasma range of regorafenib during treatment (IC50 4.6 μM, range 5.2-8.1 μM). Additionally, this patient had not undergone reoperation before starting regorafenib. Systematic literature review showed few but promising studies in which therapy personalization was based on in vitro drug screening. CONCLUSIONS Although preliminary, these findings suggest a potential paradigm shift in personalized treatment for recurrent GBM, utilizing a GSC-based approach rather than molecular profiling. Further evaluation of GSCs from recurrent tumor tissue is necessary to determine their utility.
NCOG-08. A RARE PRIMARY CNS T-CELL LYMPHOMA CASE: 12-YEAR FOLLOW-UP AFTER CHEMOTHERAPY
Authors: Amory Cheng, Daniela A Bota, Xiao-Tang Kong
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Primary central nervous system (CNS) T-cell lymphoma (PCNSTL) is a rare hematological malignancy. There is mere literature to guide the treatment. CASE REPORT This study is an update on our previously reported case at SNO in 2012 after a 12-year follow-up, detailing the long-term outcome of our chemotherapy treatment for a case of PCNSTL. In 2011, a 26-year-old immunocompetent patient presented with severe headache, vomiting, and lethargy. The brain MRI found more than a dozen masses on his bilateral cerebral hemispheres. Brain biopsy discovered T-cell lymphoma. The patient was started biweekly high-dose-methotrexate (HD-MTX) in 2011. After three doses, there was no noticeable improvement on his brain MRI. His treatment was switched to HD-MTX plus high dose cytarabine regimen (Ferreri et al, The Lancet, 2009). The patient could not tolerate cytarabine; thus, was changed back to HD-MTX. The patient responded to the rest of HD-MTX well. He completed 8 doses of biweekly HD-MTX induction therapy and 2 doses of monthly HD-MTX maintenance therapy. His brain MRI showed complete resolution of enhancement on one-year follow-up image. The patient has been off-treatment and monitored under surveillance of brain MRIs since 2012. He has had no lymphoma recurrence over the past 12 years. His physical functions have been preserved with a Karnofsky Performance Status scale of 80%. Neuropsychological evaluations in 2015, 2018, and 2023 showed mild cognitive impairment with gradual improvements in his working memory and semantic fluency. His Mini-Mental Status Exam scores have remained stable to mild improvement, recording 27/30 in 2015, 26/30 in 2018, 27/30 in 2023 and 28/30 in 2024. DISCUSSION The patient, who is now 38 years old, has surpassed a 12-year survival mark. Our experience emphasizes the feasibility of treating PCNSTL through chemotherapy only, which might be potentially beneficial in surviving and preserving major aspects of brain function.
NCOG-13. ASSESSING CAREGIVER OUTCOMES OF PRIMARY BRAIN TUMOR PATIENTS: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Tobias Walbert, David Cachia, Caroline Hertler, Paula Sherwood, Linda Dirven, Jacob Young, Macy Stockdill, Eduardo Rodriguez Almaraz, Karin Pill, Florien Boele
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Family caregivers in neuro-oncology are known to have high levels of unmet support needs. Intervention trials and effective support options are scarce. The Response Assessment in Neuro-Oncology (RANO-) Cares working group has been established to determine standards of caregiver outcomes (CO) research reporting in neuro-oncology. We present the current state of methodological quality of reporting on neuro-oncology caregiver outcomes in randomized controlled trials (RCTs). METHODS A systematic literature review (PubMed/Medline, Embase, Web of Science, Emcare, Cochrane Library, PsycINFO; July 2023) was performed to assess to what degree RCTs assessing outcomes of family caregivers of adult primary brain tumor patients adhere to established reporting standards. Using Covidence, screening and data extraction was independently performed by two researchers, with a third guiding consensus. A 33-item checklist (23 applicable to secondary analysis reports) based on the International Society for Quality of Life (ISOQOL) Research criteria for patient-reported outcome reporting was utilized to assess reporting standards. Risk of bias was assessed per RCT. RESULTS Fifteen publications (12 unique RCTs) included 684 neuro-oncology caregivers, with low overall risk of bias. Ten publications (66%) reported on COs as a primary aim and eight (80%) of these satisfied ≥2/3 of the key methodological criteria. Of the five secondary analysis reports (33%) two met ≥2/3 of applicable key criteria. Criteria often missed are related to sample size calculations, details on statistical approaches, discussion of limitations and clinical significance of studies. Only three of the 12 RCTs were definitive trials aimed at improving COs and five should be considered as pilot or feasibility studies. CONCLUSION RCTs investigating neuro-oncology COs have high reporting standards and risk of bias was low. Future studies should focus on specific caregiver interventions to reduce high caregiver burden and with that patients’ quality of life.
CNSC-28. BRAINSTEM NEUROMODULATORY NEURONS PROMOTE GLIOMA GROWTH LOCALLY AND VIA LONG-RANGE PROJECTIONS TO MIDLINE AND CORTICAL STRUCTURES
Authors: Richard Drexler, Antonia Drinnenberg, Avishai Gavish, Belgin Yalcin, Kiarash Shamardani, Abigail Rogers, Rebecca Mancusi, Kathryn Taylor, Yoon Seok Kim, Pamelyn Woo, Alexandre Ravel, Eva Tatlock, Rayyan Jokhai, Alberto Ayala-Sarmiento, David Rincon-Fernandez, Charu Ramakrishnan, ’Akea La Siverts, Tanya Daigle, Bosiljka Tasic, Hongkui Zeng, Joshua Breunig, Kyle Loh, Karl Deisseroth, Michelle Monje
Journal: Neuro-Oncology (2024)

Abstract Neuronal activity robustly drives glioma progression, mediated through paracrine and synaptic neuron-to-glioma interactions. Recent research has focused on glutamatergic and GABAergic neurons, while the impact of neuromodulatory neuron subpopulations and their long-range projections remain unexplored. Here, we explore the glioma-promoting effects of serotonergic and cholinergic brainstem neurons, which project to defined regions throughout the brain. By employing optogenetic stimulation of midbrain serotonergic or cholinergic neurons in mice bearing high-grade glioma allografts or xenografts, we observed robust, circuit-specific effects of each neuromodulatory neuronal subtype on proliferation. Concordant with the anatomy of serotonergic projections, we found that serotonergic neurons of the dorsal raphe nucleus promoted glioma proliferation in the neocortex and pons, while those from the median raphe nucleus increased proliferation in the thalamus. Similarly, stimulation of cholinergic neurons in the laterodorsal tegmentum nucleus enhanced thalamic glioma growth, and stimulation of the pedunculopontine nucleus promoted pontine tumor growth. The long-range neuronal activity-regulated effects on glioma cells were mediated by neurotransmitter secretion at axon terminals, and paracrine signalling protein release locally in the brainstem. The activity-regulated paracrine factor profiles are distinct between serotonergic and cholinergic neurons, illustrating neuron subtype-specific mechanisms affecting glioma cells beyond neurotransmitter differences. Co-culture with hESC/hiPSC-derived cholinergic or serotonergic neurons demonstrated synaptic structures between both neuromodulatory subpopulations and glioma cells, indicating a synaptic component to these neuron-glioma interactions. ScRNA-seq data integration revealed distinct receptor abundances between DMGs and IDH-WT glioblastomas correlating with specific cellular states. Inhibition of these targets – such as M1 or M3 cholinergic receptors in DMG – mitigated the proliferation-inducing effects of the relevant neuron subtype on glioma cells. In summary, these findings introduce brainstem cholinergic and serotonergic neuromodulatory neurons as drivers of high-grade glioma growth in a circuit-specific manner in midline structures and in neocortex, adding to the complexity with which gliomas integrate into brain-wide neural circuitry.
EXTH-01. EFFICACY OF PERAMPANEL AGAINST GLIOBLASTOMA CELLS
Authors: Shun Yamamuro, Takuma Nishide, Kaoru Nara, Yumi Aida, Genki Yazawa, Kentaro Ohyama, Yoshinari Ozawa, Sodai Yoshimura, Emiko Sano, Atsuo Yoshino
Journal: Neuro-Oncology (2024)

Abstract We investigated the antitumor effect of perampanel, which is the AMPA-type glutamate receptor antagonist widely used as an antiepileptic drug in Japan, on glioblastoma cells both in vitro and vivo. Commercially available glioblastoma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13) and newly established glioblastoma cell line 0125-DGC were used in the experiments. First, the antitumor effect of perampanel was evaluated by cell counting assay. The number of surviving cells after administrating drugs (perampanel, carbamazepine, sodium valproate, levetiracetam, and temozolomide) was counted. The cell proliferation inhibitory effect was observed in all cell lines after administration of perampanel and temozolomide. The antitumor effect was greater when perampanel and temozolomide were used together than when they were used alone. Next, we investigated the mechanism of the antitumor effect of perampanel on glioblastoma cells using FACS, western blotting, RT-PCR, and transwell assay. The expression levels of apoptosis-related proteins and mRNAs on glioblastoma cells were increased after administration of perampanel. Furthermore, perampanel demonstrated the inhibitory effect on the migration of glioblastoma cells. Finally, we evaluated the antitumor effect of perampanel in vivo. U-87MG cells were transplanted into the brains of immunodeficient mice, and these mice were treated by perampanel and/or temozolomide. The transplanted mice were divided into an untreated control group, a perampanel treatment group, a temozolomide treatment group, and a combination treatment group. As a result, survival times were significantly prolonged in all treatment groups compared to the untreated control group. Notably, survival times in the combination therapy group was significantly longer than in the monotherapy group. These results revealed that perampanel exhibits antitumor effects on glioblastoma cells by inducing apoptosis and suppressing cell migration ability. Furthermore, perampanel may enhance the antitumor effect of temozolomide for glioblastoma when it used as combination therapy.
BIOM-13. COMBINED MGMT PROMOTER METHYLATION AND LOW GENE BODY METHYLATION IS A SUPERIOR PREDICTOR OF ALKYLATING AGENT RESPONSE THAN PROMOTER METHYLATION ALONE IN GLIOBLASTOMA
Authors: Nicholas Nuechterlein, P J Cimino
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The DNA methylation status of the promoter region of O-6-methylguanine-DNA methyltransferase (MGMT) is a critical predictor of temozolomide response in newly diagnosed glioblastoma. However, MGMT-STP27, the dominant method for MGMT promoter methylation determination from methylation array data, considers only methylation probes located in the promoter region. In this study, we propose a robust MGMT classifier that considers MGMT methylation probes in both the promoter and gene body regions. METHODS We leveraged glioblastoma DNA methylation and/or gene expression data published by the TCGA (N=312), GLASS (N=276), and Capper et al. (N=535). We correlated MGMT gene expression and MGMT probe methylation in datasets with paired expression and methylation data. We formulated an MGMT methylation score that measured the difference between MGMT promoter probe methylation and gene body probe methylation. We then compared the prognostic utility of this score with the MGMT-STP27 model on patients treated with upfront alkylating agents in multiple datasets in both univariate and multivariate analyses. RESULTS We found that MGMT expression was prognostic in TCGA (OS HR=1.5, p=0.027, PFS HR=1.9, p=0.001) and GLASS (OS HR=1.4, p=0.088, PFS HR=1.6, p=0.03) glioblastomas among patients treated with alkylating agents. MGMT expression was negatively correlated with MGMT promoter methylation and positively correlated with MGMT gene body methylation. We defined an MGMT score as the difference between the average MGMT DNA methylation in negatively correlated promoter probes and the average methylation in positively correlated gene body probes. This score was prognostic in the TCGA (OS HR=1.6, p=0.003, PFS HR=1.6, p=0.001) and GLASS (OS HR=3.1, p=0.01, PFS HR=3.9, p=0.004) and was also superior to the MGMT-STP27 classifiers in multivariate analyses (TCGA p=0.03). CONCLUSION Overall, we defined an MGMT methylation score that considers promoter and gene body methylation and may be a superior predictor of glioblastoma response to alkylating agents compared to MGMT-STP27.
TMOD-03.<i>BRAFV600E</i> MUTATION INDUCES TWIST1 UPREGULATION ASSOCIATED WITH MIGRATION AND CEREBRAL FLUID DISSEMINATION IN GLIOBLASTOMA
Authors: Yohei Miyake, Frank Furnari
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION BRAFV600E-mutant glioblastoma (GBM) with epithelioid features frequently show cerebrospinal fluid dissemination (CSFD), which results in poor prognoses. BRAF mutation is worth investigating since BRAF or downstream MEK inhibitors show dramatic response for BRAFV600E-mutant GBM including CSFD. This suggests BRAF mutation could play a role for inducing the clinical manifestation of CSFD found in newly diagnosed and recurrent BRAFV600E-mutant GBM. Because, BRAFV600E-mutant GBM often recur with CSFD, elucidating the mechanism by which BRAFV600E-mutant GBM exhibits CSFD is important to improve prognosis. (Objective) To elucidate the molecular mechanism of CSFD involved in BRAFV600E-mutant GBM. METHODS We introduced the heterozygous BRAFV600E mutation in human induced pluripotent stem cells (iPSC) in the context of GBM genetic alterations, CDKN2A/2B, and PTEN deletion, TERT promoter mutation and with EGFRvIII overexpression. We implanted these iPSC-derived neural progenitor cells into immunodeficient mouse brains to establish a BRAFV600E-mutant GBM model. At the same time, we created a model with the same genetic background without BRAFV600E. We compared their gene expression, pathology, and migration patterns to identify BRAFV600E specific characteristics. RESULTS RNA sequencing revealed BRAFV600E-mutant tumors upregulated migration, and downregulated cell-to-cell adhesion genes. TWIST1 was one of the most upregulated genes, and was validated by qPCR. Concomitant with TWIST1 expression we detected downregulation of E-cadherin. The BRAFV600E GBM model histologically showed a cluster-like invasion phenotype, while non-BRAF tumors showed homogenous invasion with typical GBM pathological findings. Immunohistochemical staining showed relatively high TWIST1 expression in cluster-like tumor cells of BRAFV600E tumors. Upon re-engraftment of primary tumor-derived cells, secondary BRAFV600E tumors presented leptomeningeal dissemination. TWIST1 knockdown resulted in a decrease in the migratory ability of our BRAFV600E model in vitro, and is under investigation in vivo. CONCLUSION BRAV600E mutation induces TWIST1 upregulation, and might facilitate migration and CSFD. This work nominates TWIST1 and its regulated genes as targets for BRAFV600E-mutant GBM with CSFD.
TMIC-16. SPECIFIC TARGETING OF THE MRNA EXPRESSION OF TGFB2 LIGAND TO POTENTIALLY ENHANCE IMMUNE THERAPIES IN LOW-GRADE GLIOMAS
Authors: Sanjive Qazi, Wen-Han Chang, Anthony Maida, Vuong Trieu, Cynthia Lee
Journal: Neuro-Oncology (2024)

Abstract Low-grade glioma (LGG) tumors are characterized by a low infiltration of immune cells, requiring therapies augmenting the immune response in the tumor microenvironment (TME). The Transforming Growth Factor beta (TGFB) pathway contributes to an immunosuppressive environment. We propose targeting the specific inhibition of Transforming Growth Factor Beta 2, TGFB2 mRNA, as an attractive therapeutic strategy using antisense oligonucleotides. We conducted a bioinformatic-led investigation highlighting the ratio of TGFB2:TGFB1 mRNA expression levels in the cohort of 513 TCGA patients, revealing the TGFB2 ratio as a negative prognostic indicator through utilizing a multivariate Cox proportional hazards model that included the TGFB2 ratio and age at diagnosis as linear covariates to predict overall survival (OS). The model showed a 1.8-fold higher TGFB2 ratio relative to TGFB1 mRNA expression correlated to worse OS. Furthermore, the impact of the TGFB2 ratio was significantly affected by the age at diagnosis, in which older patients exhibited worse OS at increased TGFB2 ratios. Increasing the ratio of TGFB2 relative to TGFB1, TGFB3, TGFBR1, or TGFBR2 in LGG patients led to significant increases in multivariate Cox model determined hazards ratios, HR (HR (95% CI range)) of 1.372 (1.224-1.539), 1.434 (1.288-1.560), 1.327 (1.195-1.473), and 1.381 (1.233-1.547) respectively (P&amp;lt;0.0001 for all comparisons). Correlation of TGFB2:TGFB1/TGFB3/TGFBR1/TGFBR2 ratio across 1330 Reactome pathways using Gene Set Enrichment Analysis showed the most positively correlated genes were members of TME pathways including PD-1 signaling, Syndecan interactions, Non-integrin membrane-ECM interactions, EPH-Ephrin signaling, and Collagen biosynthesis and modifying enzymes. These results suggest that the specific targeting TGFB2 in LGG can remodel the TME for immune therapies to improve OS outcomes.
BIOM-10. CLINICAL PERFORMANCE EVALUATION OF A BRAIN CANCER LIQUID BIOPSY
Authors: James Cameron, Matthew Baker, Georgios Antoniou, Paul Brennan, Holly Butler, David Eustace, Ewan Gray, Asgeir Jakola, Michael Jenkinson, Senada Koljenovic, Alan Lazarus, Ryan Mathew, David Palmer, Isaac Phang, Alexandra Sala, Tobias Weiss
Journal: Neuro-Oncology (2024)

Abstract Diagnostic delays impact the quality of life and survival of patients with brain cancer. Currently, with no blood test to assist them, clinicians must make their referral decision based on symptoms. Existing symptom-based referral guidelines inadequately stratify patients for brain imaging based on suspicion of cancer. A simple, rapid liquid biopsy placed in a primary care setting would enable more efficient triage of patients with non-specific symptoms related to brain cancer. The Dxcover® Liquid Biopsy is a rapid multi-omic liquid biopsy that interrogates a blood sample with infrared radiation and produces a distinctive signature that represents the whole biomolecular profile of the sample, and is sensitive to the hallmarks of brain cancer. The nature of the technology also allows for the diagnostic models to be tailored towards higher sensitivity (or specificity) depending on clinical priorities and international healthcare markets. In initial feasibility studies, we recruited 988 patients prospectively with non-specific symptoms associated with a brain tumor, and the algorithm detected 96% of the patients with brain tumors and 100% of glioblastomas (GBM), when tuned for greater sensitivity. EMBRACE is a prospective, observational, multicenter study, currently recruiting patients across seven sites in the United Kingdom, Belgium, Sweden and Switzerland. The study duration is 24 months and will recruit a minimum of 2200 participants. The target population is comprised of patients presenting to primary care with non-specific symptoms that are associated with brain cancer, such as headache and new onset neurological defect. The primary objective is to determine the clinical performance of the liquid biopsy for patients with brain cancer, in terms of diagnostic sensitivity and specificity. The test performance will be determined by comparing the liquid biopsy result to diagnostic imaging. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain cancer. This simple, non-invasive liquid biopsy would facilitate the triage of brain tumor patients for rapid imaging.
TMIC-07. TRIPLE COCKTAIL IMMUNOMODULATION OF TUMOR DRAINING LYMPH NODES RESULTS IN SYNERGISTIC REVERSAL OF IMMUNOSUPPRESSION AND IMPROVED OVERALL SURVIVAL IN A MURINE GLIOBLASTOMA MODEL
Authors: John Choi, John Klich, Lily Kim, Ethan Schonfeld, Rohit Verma, Kwang Bog Cho, Gordon Li, Eric Appel, Michael Lim
Journal: Neuro-Oncology (2024)

Abstract Clinical trials involving anti-PD-1 fail to improve survival compared to standard of care in glioblastoma (GBM). Despite the advent of newer immunotherapies such as STING agonists and anti-CSF-1R, combination of these strategies is limited by necessitation of intracranial delivery (STING) or off-target side effects with systemic exposure (anti-CSF-1R + anti-PD-1). We have previously shown that delivery of anti-PD-1 to tumor draining lymph nodes via hydrogels decreases systemic exposure of anti-PD-1 and results in improved therapeutic response compared to systemic delivery. This study assesses the efficacy of combining STING agonist (STING), anti-CSF-1R (aCSF1r), and anti-PD-1 (aPD1) into a hydrogel nanoparticle that targets different components of immunosuppression in tumor draining lymph nodes. CT-2A murine glioma cells were orthotopically implanted into C57BL/6J mice with treatment on day 7 via deep cervical injection of hydrogel polymers loaded with either PBS (control), STING, aCSF1r, aPD1, or a combination of all three immunomodulators. Flow cytometry was used for immunophenotyping and Kaplan-Meier survival curves were generated to assess therapeutic efficacy. Each treatment strategy targeted a different component of immunosuppression. Compared to controls, aCSF1r resulted in the greatest decrease of immunosuppressive myeloid cells in the brain (P=0.0017) and cervical lymph nodes (P=0.0008); STING resulted in the greatest activation of intracranial dendritic cells (P=0.0001); and aPD1 resulted in the highest level of T cell activation of the monotherapies (P=0.0008) but also caused compensatory upregulation of regulatory T cells in the brain (P=0.0176). Combination therapy resulted in the greatest decrease in immunosuppression with increased T cell IFN-y production and dendritic cell activation, with resultant improvement in median and overall survival (P=0.0006). Triple combination therapy to tumor draining lymph nodes that specifically targets multiple components of immunosuppression is a safe and efficacious treatment that can be translated to clinical application.