tbuckley/cabot-search huggingface dataset:
CTIM-09. INB-200: FULLY ENROLLED PHASE 1 STUDY OF GENE-MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)
Authors: Mina Lobbous, Trishna Goswami, Larry Lamb, Kate Rochlin, Thiru Pillay, Mariska ter Haak, Louis B Nabors
Journal: Neuro-Oncology (2024)

Abstract IN8bio’s DeltEx drug resistant immunotherapy (DRI), comprising TMZ-resistant γδ T cells engineered to express methylguanine-DNA methyltransferase (MGMT), enables γδ T cells to target upregulated NKG2D ligands on tumor cells in real time during alkylating chemotherapy exposure. Updated results from the fully enrolled Phase 1 trial evaluating DRI in adult newly diagnosed GBM subjects with IDH wild type and mutant tumors, adequate organ function and KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107 DRI cells/dose) into the resection cavity with 150 mg/m2 of IV TMZ on Day 1 of each of 6 Stupp maintenance cycles. The primary endpoint is safety and secondary endpoints include survival; immunologic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. A total of 23 subjects were enrolled and 13 dosed (61% male; median age 68 (range: 21-74); 92% IDH-WT, 54% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS), neurotoxicity (ICANS) or treatment related deaths were reported. The most common adverse events were decreased WBC/platelet count, asthenia, fatigue, hydrocephalus, headache, decreased appetite, urinary tract infection, thrombosis and balance disorder with ≥G3 platelet count decreased in 23% and WBC/ neutrophil/ lymphocyte count decreased in 7.7% each. Peripheral TMZ-based lymphodepletion was maintained for up to 1 year evidenced by near or below normal range T, B, and NK subsets. With median follow-up of 10.8 months, 83% of subjects exceeded the median 7 month Progression Free Survival (PFS) of the Stupp regimen alone, had manageable toxicity with a continued encouraging trend in PFS. Subject with IDH mutant tumor remains progression free for &amp;gt; 35 months. Long-term follow-up for durability of PFS and OS continues.
CTNI-68. UPDATES ON A POTENTIALLY PIVOTAL TRIAL CNS-201: A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM)
Authors: Sandra Silberman, Zena Muzyczenko
Journal: Neuro-Oncology (2024)

Abstract Berubicin, derived from doxorubicin (Dox), appears to cross the BBB and has shown significant central nervous system (CNS) uptake and anti-tumor activity. A current, potentially pivotal trial for patients with recurrent GBM after first-line therapy has completed enrollment in the US and Europe: a total of 252 patients were randomized 2:1 (Berubicin:Lomustine) after failure of prior therapy. All patients had to have certification of progression by a central reader, were Grade 4 IDH WT, and were stratified by MGMT methylation status. The primary endpoint, overall survival (OS), is maturing in this blinded trial; however, data will be presented that will document the demographics of the Berubicin and Lomustine arms, and provide a comparison of safety profiles and disposition of the patients enrolled on the study. Recently, a pre-planned non-binding futility analysis of the primary endpoint, OS, was evaluated when the trial reached ~30% of expected events (44 events). This interim analysis was performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB), which was additionally comprised of two oncologists. The DSMB’s charter mandated that they review the primary endpoint, OS, as well as secondary endpoints and safety data to determine whether these data for the risk-benefit profile warranted modification or discontinuation of the study. The DSMB recommended that the study continue as it was currently planned, with no modifications required, having met a pre-determined conditional endpoint. After the results of this interim analysis, CNS Pharmaceuticals completed enrollment with 252 patients evaluable for efficacy based on OS evaluations. Based on the decision of the DSMB, as well as the data presented herein, which includes comparative safety and balanced randomization of the arms, we will provide our recommendations and highlight our further development of Berubicin as a therapeutic option for patients with recurrent GBM as well as other CNS malignancies.
NIMG-07. GLIOBLASTOMA AS A MIMIC OF ACUTE ISCHEMIC STROKE: AN UNDERRECOGNIZED PHENOMENON AND THE IMPACT ON PATIENT OUTCOMES
Authors: Sima Vazquez, Eris Spirollari, Sauson Soldozy, Jose Dominguez, Fawaz Al-Mufti, Robert Aiken, Simon Hanft
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma may present similarly to acute ischemic stroke. This study aims to determine characteristics and outcomes of patients with glioblastoma presenting with stroke-like symptoms. Our objective is to characterize patients with glioblastoma who present as mimics of acute ischemic stroke and identify differences in outcomes when compared to those diagnosed with glioblastoma only. METHODS The 2016-2019 National Inpatient Sample (NIS) database was queried for all patients who had a new diagnosis of glioblastoma. Patients with new glioblastoma who carried an admission diagnosis of acute ischemic stroke, but did not undergo thrombectomy, chemical thrombolysis, or hemicraniectomy were categorized as “GBM-Stroke Mimic”. The characteristics and comorbidities between GBM-Stroke Mimic and new glioblastoma patients were compared. Primary outcomes analyzed were discharge disposition and mortality. RESULTS Of 61,755 patients newly diagnosed with glioblastoma, 1,000 (1.6%) were GBM-Stroke Mimics. GBM-Stroke Mimic patients more commonly presented with aphasia (P &amp;lt; 0.001) and hemiplegia (P &amp;lt; 0.001). Age greater than 65, atrial fibrillation, diabetes mellitus, hypertension, hyperlipidemia, and long-term anticoagulation/antiplatelet therapy were more commonly associated with GBM-Stroke Mimic patients (all P &amp;lt; 0.001). GBM-Stroke Mimic patients were more likely to be discharged to skilled nursing facility, (p &amp;lt; 0.001), and a diagnosis of GBM-Stroke Mimic was an independent risk factor for inpatient death (P &amp;lt; 0.001). CONCLUSION To our knowledge, this is the first study formally investigating the clinical outcomes of glioblastoma when initially diagnosed as stroke. When this misdiagnosis is made, we found an association with increased inpatient mortality, delays of care, and inappropriate resource allocation.
NIMG-59. COMPARATIVE ANALYSIS OF LONG-TERM GLIOBLASTOMA SURVIVORS USING MACHINE LEARNING GENERATED RADIO-PATHOMIC METRICS
Authors: Daniel Aaronson, Samuel Bobholz, Savannah Duenweg, Fitzgerald Kyereme, Allison Lowman, Biprojit Nath, Aleksandra Winiarz, Jennifer Connelly, E Kelly Mrachek, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) remains the most devastating central nervous system malignancy with poor overall survival (OS), even with gross total resection (GTR) and chemoradiation. Identifying factors associated with long-term survival (LTS) in GBM patients is challenging but crucial for improving prognostic models. This study compares an internal dataset of the top 10% long-term survivors of GBM (n=14) against a combined external cohort of 528 GBM patients who underwent GTR. METHODS We used a previously published machine learning-generated radio-pathomic model based on autopsy tissue as ground-truth to generate whole-brain maps of cell density and tumor probability maps (TPM) using conventional preoperative MRI sequences in both our internal dataset and a combined external cohort of GBM patients who underwent GTR from the UCSF-PDGM-v2 and UPenn-GBM databases. We then analyzed clinical and radio-pathomic metrics, including cell density and TPM values within contrast-enhancing (CE) and FLAIR hyperintense regions. Statistical comparisons were performed using t-tests. RESULTS Cell density metrics showed significant differences, with lower cell density in contrast-enhancing regions (t-value: 4.709, p&amp;lt;0.001; median: 1559 vs. 1959) and in FLAIR hyperintense regions (t-value: 3.585, p&amp;lt;0.001; median: 1356 vs. 1568) within the LTS group. TPM metrics also showed significant differences, with lower TPM values in contrast-enhancing regions (t-value: 3.312, p&amp;lt;0.001; median: 0.71 vs. 0.72) and in non-enhancing regions (t-value: 2.606, p&amp;lt;0.01; median: 0.68 vs. 0.69) in the LTS group. CONCLUSION Our comparative analysis reveals distinct radio-pathomic characteristics associated with long-term survival in GBM patients. Reduced cell density and lower TPM values in both contrast-enhancing and FLAIR hyperintense regions are significantly correlated with long-term survival. These findings suggest that integrating radio-pathomic data may enhance prognostic models and warrants further studies evaluating the relationship of these markers and OS.
NCMP-13. EXPLORING THE PATHOPHYSIOLOGY OF HYDROCEPHALUS IN CHOROID PLEXUS PAPILLOMA
Authors: Stuart Harper, Ashna Prabhu, Travis Perryman, Lindsey Dudley, Alondra Delgadillo, Aidan Gor, Kunal Patel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Choroid plexus papilloma (CPP) is a benign intraventricular lesion associated with hydrocephalus and ventricular outflow obstruction. However, the molecular mechanism by which cerebrospinal fluid (CSF) is produced by choroid plexus (CP), or by which CSF production is altered in the setting of CPP to cause hydrocephalus, is unknown. METHODS A PRISMA systematic literature review was conducted to identify gene targets associated with CSF production. Primary tissue samples of CP and CPP from the same patient were obtained, and expression of target genes was assessed using immunohistochemistry and quantified using QuPath software H-scoring. Single-nucleus sequencing of both CP and CPP was also completed, and differential expression of identified target genes was evaluated by calculating log fold change. RESULTS Systematic literature review yielded 25 studies in animal models and 18 unique gene targets. 16 targets were expressed in primary CP and CPP tissue samples upon immunohistochemistry staining. 11 of 18 targets revealed significant differential expression between CP and CPP on single-nucleus sequencing. Genes with notable expression increases in CPP included ion transporters NKCC1 (Na-K-Cl cotransporter) and TRPV4 (non-selective cation channel), as well as carbonic anhydrase II. CONCLUSIONS We present evidence that choroid plexus papilloma has altered expression of genes previously implicated in CSF production. Upregulation of membrane transporters and cytoplasmic enzymes involved in Na+, K+, Cl-, and HCO3- transport may provide a mechanistic explanation for the development of hydrocephalus in CPP. Pharmacologic inhibition of CSF production may offer a route for non-surgical management of CPP, as well as other pathologies causing hydrocephalus.
TMIC-18. ROLE OF NEUROTRANSMITTERS IN GLIOBLASTOMA PATHOPHYSIOLOGY: EMERGING INSIGHTS
Authors: Khushboo Irshad, Sanjay Singh, Khalil Ali Ahmad, Kechen Ban, Benjamin Aghoghovwia, Rajasekaran Mahalingam, Momo Harris, Sama Alnassiry, Renae Bertrand, Aishani Gargapati, Nathan Bui, Truc Kuo, Frederick Lang, Yuan Pan
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glioblastoma (GBM) are the most common primary brain tumor in adults associated with a dismal patient outcome. While it is well-known that glutamatergic neurons can form functional synapses with glioblastoma cells to enhance tumor growth, lesser is known about the effects of activity of other neuronal types on glioblastoma biology, especially among different glioblastoma molecular subtypes. Here, we examined the effects of various neurotransmitters on the growth of glioblastoma cells characterized as classical, proneural and mesenchymal subtypes. METHODS Patient-derived glioblastoma cell lines were exposed to varying concentrations of different neurotransmitters and assessed for cell viability using CCK-8 assay. Transcriptomic data from TCGA (The Cancer Genome Atlas) database was analyzed for correlation of expression of neurotransmitter receptors (NTRs) with patient survival. Using IVY-GAP database, we compared the expression of NTRs at leading-edge versus tumor core of tumors to assess their possible involvement in cell migration and microenvironmental interactions. RESULTS Consistent with previous findings, we observed an increase in cell viability in all GBM cell lines after being incubated with L-glutamate. The classical subtype has a stronger growth response to L-glutamate compared to the other two subtypes. TCGA data revealed the expression of GRIK4 (glutamate ionotropic receptor kainate type subunit 4) as highest in the classical subtype as well as inversely correlated with worse patient survival in this GBM subtype, as opposed to proneural or mesenchymal patient groups. CCK8 assay also suggested that acetylcholine and dopamine increase glioblastoma cell growth. A subset of cholinergic and glutamatergic receptors (CHRM1, GRM2) was found upregulated in infiltrating/leading-edge regions of glioblastoma tumors compared to the tumor core, suggesting possible involvement in glioblastoma-neuron interactions. CONCLUSION Our findings suggest that GBM subtypes may differentially leverage neuro-modulatory mechanisms to support their growth. Future studies will investigate the differential neuronal responses in GBM subtypes using pharmacological/genetic approaches.
CNSC-50. PRIMARY INTRACRANIAL CONGENITAL GLIOBLASTOMA (PICG): A SYSTEMATIC REVIEW OF CASE REPORTS FROM 2000 TO 2023
Authors: Haseeb Mehmood Qadri, Asif Bashir
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND AND OBJECTIVE The most commonly reported congenital intracranial space occupying lesions are teratoma, glioma and neuroblastoma. Primary intracranial congenital glioblastoma (PICG) is one of the most lethal and extremely rare neoplasms. Most pediatricians and gynecologists are unable to detect it congenitally, posing an ominous risk of spread and disease severity. We aim to determine the clinical manifestations, number of reported cases, radiological findings and neuro-oncological management of PICG. MATERIALS AND METHODS A comprehensive literature search using PubMed Central and Google Scholar was done, retrieving 17 case reports and five case series of 31 patients with PICG and included using the Preferred Reporting items for Systematic Reviews and Meta-Analyses guidelines, published between 2000 and 2023. RESULTS The mean age at presentation was 86.00 ± 88.36 days, with both genders affected equally, i.e. 45.16%. The most common symptoms and signs at presentation were seizures (38.70%) and hydrocephalus (51.61%), respectively. Left hemispheric (48.38%), with frontoparietal involvement (16.12%) was the frequently affected site. MRI findings were suggestive of low intensity signal significant of hemorrhage or calcification and a heterogenous mass in 35.58% and 32.25% cases, respectively. Gross total resection (GTR) was achievable in 48.38% patients. Glial fibrillary acid protein and vimentin were positive in 45.16% and 29.03% cases, respectively. Intraoperative mortality and recurrence were noted in 25.80% and 9.68% of patients, respectively. The average follow up duration was 20.57 months. CONCLUSION PICG has an extremely aggressive course of natural progression. Congenital presentation and its lack of awareness among clinicians is itself a challenge for disease management. Adjuvant chemo-radiotherapy has proven fruitful along with GTR. Post-operative CSF diversion is warranted.
TMIC-10. GENETIC LANDSCAPE OF BRAIN METASTASIS IN TRIPLE-NEGATIVE-BREAST CANCER: COMPARISON OF PAIRED PRIMARY AND METASTATIC TUMOR USING SPATIAL TRANSCRIPTOMIC ANALYSIS
Authors: Jihwan Yoo
Journal: Neuro-Oncology (2024)

Abstract The survival rate of individuals diagnosed with breast cancer has shown improvement over time, primarily attributed to advancements in early detection methods and the implementation of proactive treatment strategies. However, it is concerning that the incidence of breast cancer continues to rise, thereby leading to a corresponding increase in mortality rates among female breast cancer patients. Among these, the presence of brain metastasis is associated with a worse prognosis in individuals with breast cancer. Notably, triple-negative breast cancer exhibits a heightened propensity for the development of brain metastasis. Furthermore, there has been a notable rise in the duration of breast cancer survival, leading to a concomitant increase in the occurrence of metastatic cancer throughout the course of the disease. Presently, a greater number of patients are experiencing brain metastases, surpassing the figures reported in current statistical data. In instances of metastatic cancer, a distinct microenvironment that is particular to the tumor is formed in a distant location. The comprehension of the molecular genetic and immunological mechanisms involved in the several phases of brain metastasis, including tumor cell invasion, engraftment, and proliferation, has significant importance in the context of patient treatment and prognosis prediction. However, it is worth noting that a well-defined scientific foundation in this area is currently absent. The objective of this study was to analyze the molecular genetic characteristics of triple-negative breast cancer primary tumors and brain metastasis tumors. This was achieved by utilizing spatial transcriptome analysis technology to compare the differences in genetic profiles between the tumor cells and the surrounding tumor microenvironment. The findings of this study allowed for a comprehensive comparison of the tumor microenvironment at each site. In order to validate alterations in gene expression of various constituents and elucidate the mechanisms behind metastasis, it is imperative to conduct spatial confirmation.
TMIC-24. BICARBONATE RECEPTOR SLC4A4 SENSITIZES INFILTRATING GLIOBLASTOMA CELLS TO CHANGES IN EXTRACELLULAR PH
Authors: Kunal Patel, Travis Perryman, Ashna Prabhu, Stuart Harper, Lindsey Dudley, Alondra Delgadillo, Aidan Gor, Aparna Bhaduri, Harley Kornblum
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma progression involves changes in extracellular pH (pHe) related to rapid cell turnover and growth. There exist differences in pH between contrast-enhancing solid tumor and non-enhancing infiltrating tumor. SLC4A4 is a two-way bicarbonate transporter used in cortical astrocytes to buffer intracellular pH. METHODS In patients undergoing surgery for newly diagnosed IDH wild-type glioblastoma, we obtained tissue from solid tumor and infiltrating tumor. Single-nucleus RNA sequencing (n=15), immunohistochemistry (n=20) were carried out to identify SLC4A4 in infiltrating tumor beyond the contrast enhancing edge. SLC4A4 knock-down models were used to evaluate functional biology of this bicarbonate receptor using our tumor – cortical organoid model of infiltrating glioma and gliomaspheres. pH measurements were recorded using pH sensitive microelectrodes to evaluate changes on pH buffering ability of tumor cells during acid titration assays. RESULTS Single-nucleus RNA sequencing (n=15) and spatial RNA sequencing (n=3) showed SLC4A4 to be the highest expressed transmembrane receptor on infiltrating glioblastoma cells but not solid tumor. IHC (n=20) confirmed higher protein expression in infiltrating tumor (p=0.0390). Infiltrating cells were specifically sensitive to decreasing pHe (p=0.0105). In the infiltrating glioma cortical-organoid model, the slc4a4- had increased proliferation (GFP+ cell quantitation; n=10, p=0.0410). There was also increased proliferation in wild-type cells treated with SLC4A4 inhibitor DIDS (n=10, p=0.0016). Immunostaining of these models showed that downmodulation of SLC4A4 was associated with increased Ki67 and decreased caspase staining. CONCLUSIONS SLC4A4 plays a role in pH buffering in glioblastoma. We hypothesize that loss of SLC4A4 in solid tumor allows for desensitization of these cells to an acidic extracellular environment and allows for increased tumor growth and density while infiltrating tumor remains sensitivity to changes in pHe. An understand of pH regulation may lead to therapeutic efficacy through pH modulation of tumor.
RADT-23. MOLECULAR PROFILING OF GLIOMAS: INSIGHTS INTO RADIONECROSIS AND PSEUDOPROGRESSION THROUGH NEXT-GENERATION SEQUENCING
Authors: Monica Santos, Felipe Restini, Sayonara Fagundes, Fábio Moraes, Gustavo Marta, Samir Hanna, Marcos Maldaun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gliomas, the most common primary tumors of the CNS, presenting diagnostic and therapeutic challenges due to their heterogeneity. Next-generation sequencing (NGS) enhances diagnostic precision by identifying genetic alterations, guiding accurate diagnosis and personalized treatment strategies. Post-treatment complications such as radionecrosis and pseudoprogression present additional diagnostic difficulties, often mimicking tumor recurrence. This study aimed to evaluate the association between genetic alterations detected by NGS and treatment-related complications. METHODS This retrospective study analyzed data from electronic medical records at a Brazilian Radiation Therapy Department (2018-2023). The study included patients with gliomas who underwent surgical resection followed by adjuvant radiochemotherapy and subsequently developed complications such as radionecrosis and pseudoprogression. Genetic alterations detected by the HSL 500 (NGS) test were evaluated for their association with these complications using Fisher’s Exact Test. RESULTS Out of 192 patients treated for glioma, 46 (23.96%) experienced treatment-related complications, with 20 patients having available NGS test results. Among these, eight cases were identified as pseudoprogression, fifteen as radionecrosis, with three patients presenting both conditions. All 20 patients with NGS results were diagnosed with high-grade gliomas, eight of whom underwent reirradiation, resulting in two cases of radionecrosis post-reirradiation. Although no statistically significant association was found between genetic alterations and radionecrosis or pseudoprogression, specific mutations were prevalent in each group. In radionecrosis cases, the most common mutations were TERT promoter (c.1-124C&amp;gt;T) (n=9, p=0.613) and EGFR amplification (n=8, p=1.0). In pseudoprogression, frequent mutations included TERT promoter (c.1-124C&amp;gt;T) (n=6, p=0.642), EGFR (n=5, p=0.67), PTEN (n=4, p=1.0), NF1 (n=2, p=0.537), and P53 (n=2, p=0.197). CONCLUSION Molecular testing for glioma characterization is crucial for diagnosis and prognosis, aiding in understanding treatment-related complications. Strategies to avoid radionecrosis and pseudoprogression are vital to improve patient quality of life, especially in high-grade gliomas. Further studies are needed to confirm these trends and explore clinical relevance of mutations.