tbuckley/cabot-search huggingface dataset:
DDEL-16. MICROMESH FOR REVAMPING THE ‘COLD’ TUMOR MICROENVIRONMENT IN GLIOBLASTOMA IMMUNOTHERAPY
Authors: AnnaLisa Palange, Irene Guerriero, Ana Maria Lopez Estevez, Cristiano Pesce, Raffaele Spano’, Daniele Di Mascolo, Paolo Decuzzi
Journal: Neuro-Oncology (2024)

Abstract High-grade gliomas have poor prognoses with limited treatment options, typically maximal safe resection and adjuvant radiochemotherapy. Novel therapies often face challenges due to low brain penetrance and poor bioavailability. To address these issues, a conformable, compartmentalized polymeric implant called microMESH has been developed. microMESH provides localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines, enabling novel therapeutic combinations. When applied to the tumor margins, microMESH adheres to the tissue, releasing its therapeutic cargo over weeks and reducing systemic toxicity. Its biocompatibility, cytotoxicity, and anti-tumor efficacy were tested on murine cancer cells (CT-2A) and orthotopic glioblastoma syngeneic models. Exposing primary bone marrow-derived monocytes (BMDM) to CT-2A conditioned medium increased the expression of anti-inflammatory cytokines (IL-10 and IL-4) by 2 times without significantly affecting the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), indicating that CT-2A cells tend to establish an immunosuppressive ‘cold’ tumor microenvironment. Next, the co-incubation of CT-2A cells with BMDM followed by the administration of the immune checkpoint inhibitor aCD47 resulted in a cancer cell viability drop by 50% already at 50 μg/ml aCD47 after 1 day. Additionally, pre-treatment with docetaxel (DTXL) further decreased cell viability, suggesting a synergism between aCD47 and the chemotherapeutic drug. Flow cytometry showed that 50 nM DTXL at 3 days post-incubation was responsible for a strong translocation of the ‘immunogenic dell death’ protein calreticulin on the cell membrane, potentially explaining the synergism. Over 2 months, the intracranially deployed microMESH biodegraded without inducing any toxic effect. In orthotopic CT-2A tumors, aCD47/DTXL–microMESH (0.75 mg/kg, single intracranial application) showed a 40-day survival compared to 22 days for iv DTXL (3 mg/kg qod), 24 days for ip aCD47 (5 mg/kg qod), and 18 days for untreated mice. microMESH helped identify and enabled novel combination therapies directly at the tumor bed, demonstrating superior efficacy over systemic therapies.
INNV-25. POST-OPERATIVE LOW DOSE VERSUS STANDARD DOSE DEXAMETHASONE FOR MANAGEMENT OF CEREBRAL EDEMA: A RANDOMIZED, DOUBLE-BLINDED FEASIBILITY STUDY IN PATIENTS WITH PRIMARY OR METASTATIC BRAIN TUMORS UNDERGOING CRANIOTOMY FOR TUMOR RESECTION
Authors: Jana Portnow, Aleksandr Filipov, M Suzette Blanchard, Tracey Stiller, Julie Kilpatrick, Danalle Kelii, Lisa Feldman, Behnam Badie
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Although dexamethasone is effective for controlling cerebral edema during the peri-operative period, its immunosuppressive properties can inhibit responses to immunotherapy. We hypothesized that patients with mild to moderate cerebral edema could be safely managed post-operatively with lower doses of dexamethasone. METHODS Eligible patients with brain tumors who had less than 10 mm of midline shift on their pre-operative brain MRIs were randomized 1:1 to the standard or low dose dexamethasone arm, each tapering double blinded through post-op day 8. The double blind was maintained using equivalent volumes for IV doses and capsules containing dexamethasone or placebo. By post-op day 9, participants received the same dose of dexamethasone and continued tapering to off by day 14. Additional doses of dexamethasone were allowed if needed, based on specified symptom criteria. Lack of feasibility was defined as a participant requiring 18 mg or more of dexamethasone in addition to the planned total dose of dexamethasone (low dose: 49 mg; standard dose: 112 mg). Brain MRIs were performed on post-operative days 1, 3, and 8 to evaluate changes in cerebral edema. Manual segmentation and computer-assisted techniques were used to quantitatively measure cerebral edema volume. RESULTS Twenty-six patients were randomized and treated within tumor type strata (primary versus metastatic), of which 25 were evaluable. None of the participants on the low dose dexamethasone arm met the criteria for lack of feasibility. The quantitative assessment of differences in cerebral edema between the arms is ongoing and will be presented. CONCLUSIONS Administration of lower doses of dexamethasone post-operatively to brain tumor patients with mild to moderate cerebral edema is feasible. Treatment with lower doses of dexamethasone post-operatively should be considered in this patient population when peri-operative administration of immunotherapy is planned.
DDDR-04. PRECLINICAL INVESTIGATION OF A NOVEL BRAIN PENETRANT COMBINATION THERAPY TARGETING RAF AND MEK FOR MELANOMA BRAIN METASTASIS
Authors: Erika Yamazawa, Naema Nayyar, Nazanin Ijad, Consuelo Torrini, Christian Migliarese, Elizabeth Summers, Braxton Marion, Richard Williams, Rowena Suriben, Michelle Perez, Brooke Grandinetti, Hiroaki Wakimoto, Priscilla Brastianos
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Up to 75% of patients with advanced melanoma develop brain metastases. BRAF mutations are found in 50-55% of melanoma brain metastases. Current BRAF/MEK inhibitors, such as dabrafenib and vemurafenib, have shown responses on the order of 50-60% in patients with BRAF-mutant melanoma; however, responses are not durable. Better therapies are needed with improved penetration of the blood brain barrier. This study aims to evaluate the efficacy of two novel brain-penetrant inhibitors, KIN-7136 (MEK inhibitor) and KIN-8391 (RAF inhibitor), in preclinical mouse models of melanoma brain metastases driven by aberrant BRAF-MEK signaling. METHODS CellTiter-Glo® 2.0 Cell Viability Assay (Promega) was used for in vitro cell viability assays. Intracranial A375 melanoma models were generated in athymic nude mice to assess the pharmacodynamics, safety, and efficacy of combination therapy of KIN-7136 and KIN-8391. RESULTS In mice, the brain-to-plasma unbound partition coefficients (Kpuu) of KIN-7136 and KIN-8391 were 0.67 and 0.7 respectively, higher than the comparators binimetinib and belvarafenib, demonstrating improved brain exposure. The IC50s of KIN-7136/ KIN-8391 in melanoma cell lines were 27.0/36.5 nM in A375 (BRAF V600E), 78.6/35.4 nM in HMV2 (BRAF G469V), 183.0/699.0 nM in SK-MEL-2 (NRAS Q61R), and 53.9/110.0 nM in SK-MEL30 (BRAF D287H and E275K), respectively. KIN-7136 and KIN-8391 synergistically inhibited HMV2, SK-MEL-2, and SK-MEL-30 cells. Pharmacodynamic studies showed that both KIN-7136 and KIN-8391 suppressed phospho-ERK, a downstream component of BRAF-MEK signaling, in A375 xenografts in mice. Daily oral treatment with a combination of KIN-7136 and KIN-8391 was well-tolerated and extended overall survival to 64 days (median survival), compared to the vehicle control and monotherapies with KIN-7136 or KIN-8391 (28, 58, and 46.5, respectively) in the A375 intracranial tumor model. CONCLUSION These preclinical data confirm the synergistic effect of KIN-7136 and KIN-8391 in BRAF-mutant melanoma brain metastases models, supporting further research to advance its clinical translation.
DDDR-01. TUMOR ASSOCIATED MACROPHAGES VIS-À-VIS TMZ RESISTANCE IN PTEN-DEFICIENT GLIOMA
Authors: Xiang-rong Ni, Ji Zhang, Yan-jiao Yu, Jing Wang, Fu-rong Chen, Zhong-ping C hen
Journal: Neuro-Oncology (2024)

Abstract Drug resistance is one of the most important obstacles during chemotherapy. Currently temozolomide (TMZ) is still first line chemotherapy agent for gliomas, while drug resistance is one of the main reasons for chemotherapy failure. It has been reported that tumor-associated macrophages (TAMs) could be related to drug resistance, and thus we have investigated the association between TAMs and TMZ response in gliomas. Firstly, our study have found that PTEN-deficient glioma can specifically induce a large number of M2 phenotype TAMs, which can attenuate the TMZ-mediated the killing effect on glioma cells. Further search for the possible mechanism, we have found TAMs may secrete cytokine IL-6 in PTEN-deficient gliomas, which in turn mediate TMZ resistance. We also revealed that IL-6 highly secreted by TAMs can enhance the stemness of glioma cells through activation of the JAK-STAT3 signaling pathway in PTEN-deficient glioma cells. Secondly, have found valproic acid (VPA) can promote the transformation of TAMs from M2 to M1, reduce its IL-6 secretion, and in turn enhancing sensitivity of TMZ in PTEN-deficient gliomas. Our study revealed that TMZ resistance may modulated through soluble factors released by TAMs. Conventional anti-epilepsy drug- VPA may enhance TMZ sensitivity in PTEN-deficient gliomas, and worth to further clinical investigation. Keywords: PTEN-deficient gliomas; tumor-associated macrophages; valproic acid; temozolomide resistance
EPCO-55. SPATIAL HETEROGENEITY IN THE TUMOR CORE AND INFILTRATING MARGIN OF<i>IDH</i>WT GLIOBLASTOMA
Authors: Saad Khan, Anthony Wang, Rupen Desai, Jennifer Foltz, Eric Leuthardt, Bhuvic Patel, Sonika Dahiya, Albert Kim, Gavin Dunn, Allegra Petti
Journal: Neuro-Oncology (2024)

Abstract We integrated single-cell RNA-sequencing, Visium spatial transcriptomic, and Xenium in situ transcriptomic data to identify differences in cell composition between the tumor core and infiltrating edge in IDHWT glioblastoma (GBM). Using CellTrek, an algorithm that maps single cells to their most-likely locations in spatial transcriptomic data, we identified extensive spatial organization in GBM. Cell mapping revealed distinct regions enriched for tumor, immune, endothelial, neuronal, and glial cells. These were associated with the location of the tissue sample – edge regions were enriched for neurons and glia (as expected), while core regions were enriched for tumor cells and infiltrating immune cells, particularly macrophages. Within the core samples, the tumor and immune cells tended to occupy distinct spatial niches. Spatial clustering of mapped tumor cells across all samples revealed five spatially segregated tumor cell states, each associated with specific biological processes, including (1) histone methylation, (2) proliferation, (3) wound-healing, EMT, and antigen presentation, (4) hypoxia response, and (5) stem cell differentiation. These tumor cell states exhibited preferential colocalization with specific non-malignant cell types. For instance, antigen-presenting/wound-healing tumor cells tended to colocalize with diverse immune cells, while stem-like tumor cells tended to reside in neuron-rich regions at the tumor edge. Next, to identify ligand-receptor interactions governing this spatial organization, we analyzed known ligand-receptor pairs within all three data types. This revealed known and novel mediators of tumor cell interactions with vasculature, lymphoid cells, myeloid cells, neurons, and glia. While some interactions were shared across all tumor cell states (e.g. all tumor cell states interacted with myeloid cells via APP/CD74 interactions), others were specific to particular tumor cell states (e.g. wound-healing/antigen-presenting tumor cells interacted with macrophages via CSF1/CSF1R, while proliferating and stem-like tumor cells interacted with neurons through multiple known NRXN/NLGN interactions). These interactions suggest potential targets for clinical disruption of the tumor ecosystem.
CTNI-37. INTERIM SAFETY ANALYSIS OF THE PHASE IB/II RANDOMIZED ANTI-GLUTAMATERGIC DRUG REPURPOSING TRIAL GLUGLIO IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NCT05664464)
Authors: Hans-Georg Wirsching, Patrick Roth, Angela Fischer, Thomas Hundsberger, Denis Migliorini, Lorenz Romagna, Heinz Läubli, Katharina Seystahl, Lukas Imback, Tibor Hortobagyi, Leonhard Held, Andrea Bink, Michael Weller
Journal: Neuro-Oncology (2024)

Abstract The advent of cancer neuroscience has significantly advanced our understanding of brain tumor biology, yet the clinical implications remain largely unexplored. Glutamate, the most abundant excitatory neurotransmitter, presents a potential therapeutic target in brain tumors. Glioblastoma cells synthesize and secrete large amounts of glutamate, driving epilepsy, neuronal death, tumor growth, and invasion. Several brain-penetrating drugs, approved for other conditions, can inhibit glutamate synthesis, secretion, and signaling. These drugs include: (i) gabapentin, an anti-seizure medication that inhibits the glutamate synthesis enzyme branched-chain amino acid transaminase 1; (ii) sulfasalazine, an anti-inflammatory drug that blocks the cystine-glutamate exchanger system Xc, reducing glutamate secretion; and (iii) memantine, a cognitive enhancer that prevents glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate type glutamate receptors. The multi-center, open-label, parallel-group, two-arm, 1:1 randomized phase Ib/II trial GLUGLIO is investigating the efficacy of a daily oral anti-glutamatergic triple combination of gabapentin, sulfasalazine, and memantine until tumor progression, in conjunction with standard chemoradiotherapy, compared to chemoradiotherapy alone. The primary endpoint is progression-free survival at 6 months (PFS-6). A sample size of 120 patients was determined to detect an increase in PFS-6 from 50% to 70%, with 80% power, using exploratory hypothesis testing at a one-sided significance level of 10%. Secondary endpoints include overall survival, seizure-free survival, response rate, quality of life for patients and caregivers, symptom burden, cognitive functioning, tumor glutamate levels (measured by magnetic resonance spectroscopy), and the use of anti-convulsants and steroids. Each drug is dosed up to the maximum approved amount. Results from the phase Ib part of the trial, including an interim safety analysis, will be presented at the conference.
EPID-08. PATTERN OF EPIDEMIOLOGICAL DISTRIBUTION OF INTRACRANIAL NEOPLASMS IN NIGERIA FROM 1960: A SYSTEMATIC REVIEW AND POOLED ANALYSIS
Authors: Kehinde Alare, Samson Alare, Busayo Adetunji, Chukwunonso Chukwumaeze, Emmanuel Oluwumi, Abdulazeez Periola, Taiwo Omoniyo, Okikioluwa Odesanya, Precious Adedokun, Stephen Adedokun, Nenkimun Bakwa
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Intracranial neoplasms, encompassing a range of benign and malignant tumors, pose significant health challenges worldwide. This study systematically reviews the epidemiological patterns of intracranial neoplasms in Nigeria from 1960 to the present, providing a comprehensive analysis of their distribution, demographic characteristics, and temporal trends. METHODS A systematic review was conducted following PRISMA guidelines, encompassing studies published from 1960 onwards. Databases including PubMed, Google Scholar, and African Journals Online were searched using relevant keywords. Eligible studies were those that reported on the incidence, prevalence, or demographic details of intracranial neoplasms in Nigeria. RESULTS A total of 45 studies met the inclusion criteria, encompassing 3,517 cases of intracranial neoplasms. The pooled analysis revealed a significant increase in the incidence of intracranial neoplasms over the study period. The pooled prevalence between the year 1960 to presences is 3.22 (95% CI: 1.66 – 5.22), while the pooled 10-yearly incidence was 3.66(95% CI: 1.67 – 6.32), the incidence rose from 2.18% in 1960-1969 to 4.08% in 2000-2009, and eventually to 4.84% in 2010 – 2019. The most common types of intracranial neoplasms identified were gliomas, meningioma pituitary adenomas; meningioma was the leading type found in adults followed by glioma and pituitary adenoma, while in pediatric age group glioma was leading followed by medulloblastoma, and craniopharyngioma. The demographic analysis indicated a higher prevalence in males compared to females with male-to-female ratio of 1.17:1, with the majority of cases occurring in the fourth to sixth decades of life. Geographic distribution showed higher incidence rates in southern Nigeria especially south east and south west compared to Northern Nigeria, potentially reflecting disparities in diagnostic facilities and healthcare access. CONCLUSION This review highlights an increasing trend in the incidence of intracranial neoplasms in Nigeria, with distinct demographic and geographic patterns. The findings underscore the need for improved diagnostic capabilities, enhanced public health strategies, and targeted interventions to address the burden of intracranial neoplasms in Nigeria.
BIOM-25. MOLECULAR PROFILING PREDICTS EARLY AND LATE PROGRESSION IN GLIOBLASTOMA
Authors: Marina Nikolopoulos, Megan Wu, Alexander Bahcheli, Sorcha Kellett, Sten Myrehaug, Arjun Sahgal, Melanie Spears, Shraddha Pai, Jane Bayani, Sunit Das
Journal: Neuro-Oncology (2024)

Abstract Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 6% surviving more than 5 years. To date, there are few non-invasive clinical biomarkers to predict response to first – line treatment. Chemical exchange saturation transfer (CEST) MRI may have the potential to fill this gap. CEST MRI is sensitive to treatment-induced changes and changes in tumor metabolism. Our team has obtained CEST data for patients before, during and after the end of standard chemoradiation treatment, and found that CEST provides markers of early response and can identify early, standard and late progressors before treatment initiation. In this study, we aimed to establish molecular profiles of early, standard and late progressors with IDH wild-type glioblastoma. Patients (n=180) with primary, IDH wild-type glioblastoma were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from matched normal and tumour pairs and processed for whole genome sequencing, enzymatic methyl-seq and gene expression analysis using Nanostring. Clinical variables such as age, extent of resection, sex, ECOG status and MGMT promoter methylated were also collected. A survival analysis was conducted using the Kaplan-Meier method with log-rank tests. Univariate and multi-variate hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models. Early progressors reported a median progression-free survival (PFS) of 142 days compared to 832 days in late progressors (p&amp;lt;0.0001). Early progressors also harbored distinct and statistically significant differences in gene expression and genomic alterations, namely in DNA damage repair, glucose transport and arginine metabolism pathways. A gene signature was prognostic of PFS and overall survival. Collectively, this data has the potential to serve as a radiogenomic biomarker to assess treatment response before or within early phases of treatment and allow for individual tailoring of the treatment plan.
NCMP-28. CASE REPORT: REFRACTORY MYASTHENIA GRAVIS FLARE INDUCED BY IMMUNE CHECK POINT INHIBITOR
Authors: Sepideh Mokhtari, Kelly Nguyen, Andrew Brohl, Muhammad Jaffer, Edwin Peguero, Tyra Gatewood, Tuan Vu
Journal: Neuro-Oncology (2024)

Abstract Immune checkpoint inhibitors (ICIs) are used for treating many types of cancers. Neurological adverse effects are uncommon (incidence of 7.2%), however these effects can have life-threatening outcomes when they occur. We present a case of a 78-year-old male with an existing diagnosis of Myasthenia Gravis (MG) with metastatic Basal Cell Carcinoma (BCC). He was diagnosed in 2015 with ocular myasthenia gravis that was acetylcholine receptor antibody positive. He developed an exacerbation with double vision, fatigue, and upper extremity weakness that resolved with intravenous immunoglobulin (IVIG). During this year, he also had a thymectomy and he was controlled on Mestinon. Five months after his MG diagnosis, he was diagnosed with BCC and was given Vismodegib, however he had metastasis to the spine and lymph nodes. Unfortunately, he had no other treatment options besides immunotherapy, thus Cemiplimab was given in 2023. Ten days after receiving his 2nd dose, he developed left eye ptosis, neck weakness, shortness of breath, dysphagia, bilateral lower extremity weakness, and urinary retention. Workup additionally revealed concern for myocarditis and myositis. He received IVIG and intravenous methylprednisolone initially, and then had maintenance IVIG 1g/kg every 2 weeks with a prednisone taper. Due to ongoing symptoms, he got Rituximab which improved most of the symptoms except for dysphagia. He then received Efgartigimod alfa-fcab (Vyvgart) but had no improvement in dysphagia. Later, plasmapheresis (PLEX) was trialed but there was a partial response. Unfortunately, he obtained a PEG tube for dysphagia and declined significantly due to disease progression and multiple medical comorbidities. Myasthenia Gravis crisis from ICI therapy is a rare but serious treatment complication. In addition to the challenging nature of treating this condition, our case highlights the importance of a comprehensive work up to include consideration of overlap syndromes, such as myocarditis and myositis as identified in this case.
NIMG-73. FALSE POSITIVE INTRA-OPERATIVE MAGNETIC RESONANCE IMAGING DURING HIGH GRADE GLIOMA RESECTION
Authors: Daniel Kreatsoulas, Andrew George, Samuel Kolawole, Mark Damante, Santino Cua, Guilherme Finger, Brad Elder
Journal: Neuro-Oncology (2024)

Abstract Intraoperative magnetic resonance imaging (iMRI) allows assessment of extent of resection during surgery for high-grade glioma (HGG). In most cases, contrast-enhancing areas noted on iMRI indicate residual tumor. However, false positives may occur, leading to inappropriate additional resection and patient morbidity. The rate and pattern of false positive findings in iMRI have not been fully described. We analyzed surgical and imaging findings in patients undergoing iMRI during resection of HGG to determine factors linked with potential false positive contrast enhancement. A single-center analysis retrospectively assessed consecutive patients undergoing resection of newly diagnosed high-grade glioma using iMRI guidance. Preoperative, intraoperative and postoperative imaging, as well as pathologic findings were assessed. One hundred seventy-four consecutive patients who underwent surgery from 2016-2023 were included. All patients had preoperative MRI showing contrast-enhancing tumor and all underwent one iMRI during surgery to assess extent of resection. 124/174 cases (71.3%) demonstrated contrast enhancement on iMRI that prompted inspection and additional resection using updated neuronavigation. Enhancement corresponding to residual tumor was identified with or without additional removal in 120/124 cases (96.8%). No residual tumor was found in 4/124 cases (3.2%, false positives). All false positive cases were the result of contrast accumulation in hematomas (2), hemostatic agents (1) or dependent portions of the resection cavity (1). Both hematomas were located in the walls of the resection cavity and confirmed as hematoma, rather than tumor, by separate pathology analysis. False positives were not associated with patient positioning, tumor sub-type, anatomic location of tumor or extent of resection. Gross total resection (GTR) was confirmed in 163/174 (93.7%) cases on postoperative imaging. False-positive iMRI during HGG surgery can mimic residual tumor. This occurs at a low rate due to contrast pooling in the cavity or accumulation within hemostatic agents or hematomas along the cavity wall. Meticulous hemostasis when preparing the patient for iMRI may help prevent false positives and prevent unnecessary additional resection.