tbuckley/cabot-search huggingface dataset:
STEM-18. A HIGH THROUGHPUT NEUROSPHERE BASED COLONY FORMATION ASSAY TO VALIDATE DRUG AND RADIATION EFFECTIVENESS IN PATIENT DERIVED XENOLINES
Authors: Manoj Kumar, Joshua Anderson, Hasan Alrefai, Lauren Nassour, Taylor Schanel, Patricia Hicks, Christopher Willey
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a primary malignant brain tumor developed from normal astrocytes. GBM patients’ median survival is less than 2 years despite safe surgical resection, fractionated conventional radiation, and temozolomide (TMZ) therapy. Few currently used drugs are successful in GBM although there are many FDA approved blood-brain barrier (BBB) penetrant drugs, for other uses that have not been screened in GBM. We utilized a panel of 734 of these BBB penetrant drugs in different GBM patient derived xenolines (PDX) along with acquired radio-resistant derivatives (-RT) including X1441, JX14P, JX14P-RT, JX39P, JX39P-RT and normal human astrocytes (NHA) as control and screened for viability with Cell Titer-Glo. We identified multiple candidate drugs that preferentially killed GBM PDX cells at 10 µM relative to NHA control. As we used stem cell media (serum free) in our drug screening study, it indicates that the potent drugs are also effective in killing cancer stem cells or brain tumor initiating cells. These drugs had targets ranging from PDGFR, DNA/RNA synthesis, as well as other kinase inhibitors. We developed a high throughput (HT), neurosphere based colony formation assay (CFA) in 96-well plate to screen multiple drugs and doses in combination with radiation. For visualizing the colonies, we use a Cytation 5 imager at 4X resolution and count the colonies based on parameters including object size, width, intensity and others. We plan on validating our drug screen and HT-CFA assay with high throughput PamChip kinase activity assays and with in vivo orthotopic tumor PDX models.
INNV-03. BEYOND ANALGESICS: PHOTOBIOMODULATION THERAPY AS A PARADIGM SHIFT IN PAIN MANAGEMENT
Authors: Olivier UWISHEMA
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pain constitutes a primary cause of medical care demand and disability among patients. The predominant method employed for pain management entails analgesic administration. Nonetheless, prolonged use of analgesics may lead to adverse effects, including cardiovascular and gastrointestinal complications. Photobiomodulation therapy (PBMT) emerges as a novel approach to pain treatment, demonstrating effective pain reduction and anti-inflammatory properties. This systematic review aims to elucidate the impacts of PBMT on pain modulation and assess its potential for widespread application. METHODS A systematic review was conducted utilizing Boolean operators combining terms such as “Photobiomodulation” AND “Pain Management”; “Photobiomodulation therapy” AND “pain”; “PBMT” AND “Pain”. Electronic databases including Cochrane Library, PubMed, and Scopus were searched. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement. RESULTS The systematic review revealed that PBMT is a non-invasive, safe, and cost-effective technique for pain management. It has demonstrated efficacy across various conditions, encompassing neurological and musculoskeletal disorders. PBMT can complement existing interventions such as exercise programs, transcutaneous electrical nerve stimulation (TENS), or surgical procedures. However, further research with long-term follow-up is warranted to validate these findings. CONCLUSIONS PBMT emerges as a promising modality for pain management, offering a non-invasive alternative with favorable safety profiles. Its efficacy in diverse conditions underscores its potential utility as an adjunctive or standalone treatment option. Nonetheless, additional studies with extended follow-up periods are necessary to confirm and further elucidate its therapeutic benefits.
DDEL-08. MEGADOSE BOSWELLIA SERRATA CAUSES SIGNIFICANT DECREASE IN CEREBRAL EDEMA WITH MINIMAL TOXICITY IN BRAIN TUMOR PATIENTS
Authors: Jose Carrillo, Naveed Wagle, Akanksha Sharma, Minhdan Nguyen, Judy Truong, Emmaline Mauritson, Janet Kong, Samuel Katz, Cole Carrillo, Yash Carrillo-Singh, Santosh Kesari
Journal: Neuro-Oncology (2024)

Abstract Boswellia serrata has been shown to reduce cerebral edema following radiation in brain tumors by Kirste et al in a prospective, randomized, placebo-controlled, double-blind pilot trial. In the study dose of Boswellia used was 4200mg/day, and was well tolerated. We report 2 patients who took doses 10x that which was recommended, after inadvertently buying much higher doses online. Both patients obtained significant reduction in cerebral edema and enhancing disease on MRI. The daily dose of 42000mg/day was tolerated well, with only mild dysphonia in one patient. The optimal dosing of Boswellia serrata to treat cerebral edema is not known, and should be studied further.
SURG-22. BRAIN METASTASIS FROM ADVANCED GASTRIC CANCERS: HIGH INCIDENCE OF LEPTOMENINGEAL DISSEMINATION AND ITS CLINICAL IMPACT ON SURVIVAL
Authors: Euihyun Kim
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Advanced gastric cancer is one of the most common and fatal cancers worldwide, and due to its highest incidence rate in Eastern Asian, it is steadily considered important. However, brain metastasis from advanced gastric cancer is very rare, and its incidence is reported as less than 1% of patients with primary advanced gastric cancer. There have been very few studies describing on the incidence and clinical outcome of patients with brain metastasis from advanced gastric cancers. METHOD We retrospectively analyzed 128 patients diagnosed as brain metastasis from advanced gastric cancers, and then underwent treatment from 2005 to 2021 April in our institution. Patients’ survival and its associated prognostic factors were evaluated. Especially, subgroup analysis on patients with leptomeningeal dissemination (LMD) was performed. RESULT Of total 128 patients of advanced gastric cancer with brain metastasis, 74 patients (58%) were diagnosed with LMD. Overall survival of LMD group was significantly shorter than that of non-LMD group (p&amp;lt;0.001). Patients treated with tumor removal (TR) followed by whole brain radiotherapy (WBRT) showed superior overall survival than patients with WBRT alone (p=0.002). Among 74 LMD patients, those who underwent WBRT combined with intrathecal methotrexate (IT MTX) showed better outcome than patients with WBRT alone (p=0.025). Specifically, for the 51 pure LMD patients without parenchymal brain metastasis, the superiority of adjuvant IT TMX on survival outcome was more apparent (p=0.011). CONCLUSION The incidence of LMD has been underestimated as 58% of patient with brain metastasis from advanced gastric cancers presented LMD on radiological and cytological studies. If the brain tumor is surgically resectable, TR followed by WBRT can be the first choice of treatment provides survival benefit. Patients with LMD are most benefited from IT MTX combined with WBRT.
BIOM-32. GENOMIC DETERMINANTS OF DIFFUSELY INFILTRATIVE GLIOMATOSIS CEREBRI PATTERN
Authors: Pushan Dasgupta, Samir Dagher, Xiaohan Chi, Zaid Soomro, Chetna Wathoo, Ruitao Lin, Max Wintermark, Melissa Chen, Vinay K Puduvalli, Nazanin K Majd
Journal: Neuro-Oncology (2024)

Abstract Gliomatosis cerebri (GC), though no longer a distinct pathological entity in WHO 2021, is a unique and aggressive phenotype of diffuse gliomas with extensive and widespread infiltration. GC can present as primary de novo or secondary after treatment. We aimed to study the genomic determinants of GC. We identified 72 GC cases from 2013-2023 at MD Anderson Cancer Center. Cases were confirmed by detailed radiographic review. This included 57 glioblastoma (79%), 13 IDH mutant astrocytoma (18%), 1 IDH mutant oligodendroglioma (1.4%), and 1 high-grade astrocytoma with piloid features (1.4%). 53/72 (73.6%) were primary and 19/72 (26.4%) were secondary GC. We used 40 patients without the GC pattern as controls. Among glioblastoma GC cases and in comparison with controls, mutations in PTEN and EGFR were significantly associated with the GC pattern: 18/57 (32%) vs 3/38 (7.9%), p-value=0.01 and 23/57 (40%) vs 6/38 (16%), p-value=0.013, respectively. This held true in primary but not secondary GC. Out of 20 most commonly mutated genes in GC, mutations in EGFR, TERT, and MDM4 were associated with worse PFS: p-value=0.004, p-value=0.007, p-value=0.013, respectively and mutations in TERT and MDM4, but not EGFR, were associated with worse OS: p-value=0.003, p-value=0.015, respectively. Secondary GC was associated with IDH mutation compared to control non-GC cases: 8/19 (42%) vs 2/40 (5%), p-value=0.001. As expected, IDH mutation was associated with improved PFS, p-value&amp;lt;0.001 and OS, p-value=0.003 in GC. No genes were significantly associated with laterality of GC. We found novel associations between PTEN and EGFR mutations and the GC phenotype and IDH mutation with the occurrence of secondary GC after treatment. While MDM4 is not associated with outcomes in gliomas, we show that MDM4 mutation is associated with poor survival in GC. These findings shed light into molecular basis of GC and need to be further validated in larger studies.
STEM-05. SHARED ONCOGENIC MUTATIONS IN THE SUBVENTRICULAR ZONE AND GLIOBLASTOMA: GENETIC AND CLINICAL IMPLICATIONS
Authors: Joo Ho Lee, Hyun Jung Kim, Jihwan Yoo, Jin Kyoung Shim, Eui-Hyun Kim, Jong Hee Chang, Jung Won Park, Xue Li, Jeong Ho Lee, Seok-Gu Kang
Journal: Neuro-Oncology (2024)

Abstract The subventricular zone (SVZ), a neurogenic niche in the adult brain, is suspected to harbor neural stem cells (NSCs) that can acquire cancer-driving mutations and give rise to glioblastoma (GBM). Nevertheless, the corroborating genetic data are restricted to a small patient cohort. This study aimed to validate the presence of low-level oncogenic mutations in the SVZ of GBM patients and assess their clinical implications.. We performed deep hybrid capture sequencing of 15 GBM-associated genes and TERT promoter amplicon sequencing on triple-matched samples from the SVZ, primary tumor, and blood of 60 GBM patients. Approximately 62% of patients (40 of 61 patients) showed shared oncogenic mutations between the tumor and tumor-free SVZ, including TERT promoter, PTEN, and TP53. While shared mutations did not affect overall clinical profiles, TERT promoter mutations were significantly enriched in the shared group (94.9% of patients, p ≤ 0.001). RNA sequencing revealed upregulation of proliferation-related genes in tumors with shared SVZ mutations, and these patients had worse progression-free and overall survival (p = 0.038 and 0.031, respectively). This study provides the largest-scale genetic validation of the SVZ as a potential cellular origin of GBM, highlighting the distinct genetic and clinical features associated with shared oncogenic mutations. These findings warrant further investigation into the role of SVZ mutations in GBM genesis and their potential as therapeutic targets.
NCMP-26. PATIENTS WITH ANTI-HU/ANNA1 PARANEOPLASTIC NEUROLOGICAL DISORDERS DEVELOP PROGRESSIVE DISABILITY BUT HAVE INCREASED SURVIVAL
Authors: Kimberly DiMauro, Nicolas Thompson, Glen Stevens, Amy Kunchok
Journal: Neuro-Oncology (2024)

Abstract ANNA-1/Hu-IgG paraneoplastic neurological disorders (PND) are rare and factors associated with disability and survival outcomes are unknown. We aimed to 1) examine disability and survival in ANNA1/Hu-IgG PND and 2) compare survival to a control group of small cell lung cancer (SCLC) without PND. METHODS This is a retrospective cohort study of ANNA1/Hu-IgG+ with PND and a control cohort of SCLC without PND (n=1513). Cox proportional hazard models examined clinical predictors of disability and survival. Kaplan-Meier curves examined time to mortality and mRS&amp;gt;2. Cox proportional hazard models compared survival between ANNA1/Hu-IgG PND and SCLC without PND, adjusting for age, sex, cancer stage, and brain metastases. RESULTS Forty-five patients with ANNA/Hu1-IgG PND were included (73% female, mean age=63 years [SD=13]). Phenotypes included; neuropathy (16, 36%), ataxia (11, 24%), encephalitis (10, 22%), myasthenic syndromes (3, 7%), myelopathy (2, 4%), enteric neuropathy (2, 4%), myoclonus (1, 2%). Cancers were identified in 78%; SCLC (26, 74%), non-SCLC (4, 11%), other (5, 14%). Immunosuppressive therapy for PND was given in 53%. At 5-year follow-up, 74% had mRS&amp;gt;2. Limbic encephalitis had greater hazard of mRS&amp;gt;2 at last follow-up (HR=7.76, [95% CI=2.20-27.39], p=0.001). At 5-year follow-up, 58% had died. Survival was not influenced by phenotype nor immunosuppressive treatment. Patients with SCLC and ANNA1/Hu-IgG (n=26) were compared to SCLC without PND (n=1513) and had 54% lower hazard of death (adjusted HR =0.46, [95% CI = 0.28–0.76], p=0.003). In ANNA-1/Hu-IgG PND, most patients experienced disability and greater disability was associated with limbic encephalitis, suggesting a potential modifiable factor. However, patients with SCLC and ANNA1/Hu-IgG PND survived longer than patients with SCLC without ANNA1/Hu-IgG PND, suggesting a possible survival advantage due to earlier cancer detection (lead time bias) and/or increased antitumor immunity.
RADT-24. WALLERIAN DEGENERATION OF THE CORTICOSPINAL TRACT IN GLIOMAS: A RETROSPECTIVE ANALYSIS AND A SYSTEMATIC REVIEW OF MOTOR FUNCTION IN ELOQUENT AREAS POST-RADIATION THERAPY. HOW IMPORTANT IS MOTOR FUNCTION FOR PATIENTS WITH GLIOMAS IN RADIATION THERAPY?
Authors: Monica Santos, Natasha Rodrigues, Franceliny Gibram, Julia Brunelli, Anselmo Mancini, Fábio Moraes, Gustavo Marta, Samir Hanna, Marcos Maldaun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The quality of life for patients with gliomas is significantly impacted by tumor characteristics, treatment modalities, and radiation dosages. Variability in radiotherapy protocols and differences in tissue tolerance necessitate a detailed risk-benefit assessment, especially in eloquent brain areas responsible for motor functions. METHODS A retrospective analysis of electronic medical records from a Brazilian Radiation Therapy Department (2018-2023) was conducted. Patients with gliomas who underwent surgical resection and adjuvant radiochemotherapy, subsequently developing Wallerian Degeneration of the Corticospinal Tract (WDCT), were included. Additionally, a systematic search was performed in PubMed, Embase, and Cochrane databases, focusing on radiotherapy in eloquent areas and evaluating motor function. Of the 1,064 studies identified, 11 underwent full-text review by two independent examiners. RESULTS Among 192 glioma patients, 13 (6.77%) developed WDCT, all with high-grade gliomas, including 3 post-reirradiation cases. Retrospective dosimetric analysis of the corticospinal tract was performed for two patients who had tractography. Patient 1, with right frontoparietal tumor, had an ipsilateral corticospinal tract volume of 10.6 cm³, a max dose of 62.81 Gy, and 0.5 cc receiving 62.2 Gy; the contralateral tract volume was 18.5 cm³, with 0.5 cc receiving 51 Gy. Patient 2, with right frontal tumor, had an ipsilateral corticospinal tract volume of 31.1 cm³, a max dose of 42.76 Gy, and 0.5 cc receiving 42.37 Gy; the contralateral tract volume was 30.3 cm³, with 0.5 cc receiving 24.19 Gy. The systematic review identified 5 studies reporting pre- and post-radiotherapy motor outcomes in eloquent areas, with 4 focusing exclusively on gliomas. However, heterogeneity in radiotherapy techniques and outcome assessments precluded a meta-analysis. CONCLUSION Motor function in glioma patients undergoing radiation therapy remains an underexplored area. Future studies should focus on standardized assessments of functional outcomes to establish dose constraints and optimize treatment protocols, thus improving the quality of life for glioma patients.
SURG-11. COMPARATIVE RISK ANALYSIS OF DEVELOPMENT OF ANEMIA IN RADIOTHERAPY-TREATED VS. NON-TREATED MULTIPLE SCLEROSIS PATIENTS: A MULTICENTER RETROSPECTIVE COHORT STUDY
Authors: Jinpyo Hong, Mason Stoltzfus, David Hallan, Elias Rizk
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION The use of RT in patients who are diagnosed with multiple sclerosis (MS) is controversial due to adverse effects such as inflammation. Simultaneously, the relationship between oncologic RT and worsening anemia is well established. However, there is not a clear understanding of the risk associated with undergoing RT due to their oncologic diagnosis in MS patients for developing anemia. OBJECTIVE This study aims to analyze the risk of developing anemia for patients with MS who have been treated with RT versus who have not. METHODS This retrospective study consists of analysis of the data acquired from TriNetX, a database that houses clinical data from 92 healthcare organizations. Cohort 1 included MS patients with history of RT, while cohort 2 included MS patients without any history of RT. The cohorts were propensity score matched for demographics such as age, sex, race, and ethnicity. All neoplasms were also matched to eliminate cancer as a confounding variable. The analysis included outcomes of interest, ICD-10 code D64 (Other anemia), up to 6 months after the first occurrence of the index event. RESULTS 4,844 patients were identified for each cohort post-propensity score matching. The mean age was 65.4 and 67.3 years old, and most patients were white at 76.3% and 77.0% for the MS with RT and without RT cohorts, respectively. Cohort 1 had 628 patients who developed anemia, while cohort 2 only had 511 patients. The odds ratio was 1.263 with 95% confidence interval of 1.116 to 1.430 showing the statistically significant difference between the cohorts. CONCLUSION This study demonstrates that there is a significant increase in the likelihood of developing broadly categorized anemia for multiple sclerosis patients with or without radiation therapy. Further study is warranted to understand other potential factors leading to an increased risk of developing anemia in the irradiated cohort.
IMMU-70. GLIOBLASTOMA DERIVED IL-8 INSTRUCTS IMMUNE CELL IDENTITY IN LATERAL VENTRICLE CONTACTING TUMORS
Authors: Stephanie Medina, Asa A Brockman, Claire E Cross, Madeline J Hayes, Bret C Mobley, Akshitkumar M Mistry, Silky Chotai, Kyle D Weaver, Reid C Thompson, Lola B Chambless, Rebecca A Ihrie, Jonathan M Irish
Journal: Neuro-Oncology (2024)

Abstract Adult IDH-wildtype glioblastoma (GBM) is an aggressive brain tumor with no established immunotherapy. Glioblastoma tumors that contact the ventricular-subventricular zone (V-SVZ) stem cell niche have especially poor clinical outcomes (PMC5771712, PMC5262526) and abnormal immune microenvironments filled with CD32+ HLA-DRhi macrophages that have displaced resident microglia (PMC10371245). Identifying the origin and role of these CD32+ macrophages is likely critical to developing successful GBM immunotherapies. Here, we present a mechanistic origin for these CD32+ cells as M_IL-8 macrophages. In ex vivo experiments with conditioned medium from primary human tumor cells, IL-8 was sufficient and necessary for tumor cells to instruct healthy macrophages, and inhibitory antibodies to IL-8 blocked the generation of CD32+ CD163+ M_IL-8 cells. Additionally, IL-8 protein was present in GBM tumor cells in vivo and especially common in tumors contacting the V-SVZ (p&amp;lt;0.0001, N=192 cores from 73 patients). Surface proteins CXCR1 and CXCR2, the primary receptors for IL-8, were detected on cells that were spatially separated from IL-8+ glioblastoma cells in tumors contacting the V-SVZ. These results suggest the hypothesis that glioblastoma-cell IL-8 instructs incoming CXCR1+ hematopoietic macrophages to adopt a suppressive M_IL-8 identity in V-SVZ-contacting GBM. Abundant HLA-DR (MHC II) observed on the CD32+ M_IL-8 cells closely matched the signature phenotype of cells in human tumors (PMC10371245) and contrasted with lower surface MHC II expression typically observed on human myeloid derived suppressor cells (PMC6608074). M_IL-8 cells might especially target CD4+ helper T cells required for effective cancer immunotherapy (PMC5312823). IL-8 and CD32+ macrophages should now be explored as targets in combination with GBM immunotherapies, especially for patients whose tumors present with radiographic contact with the V-SVZ stem cell niche. Some results here have been shared in a bioRxiv preprint by the these authors (PMC10996638).
STEM-03. TARGETING F-ACTIN DYNAMICS OF GLIOBLASTOMAS TO OVERCOME THERAPY RESISTANCE: IMPACTS ON DNA REPAIR AND GLIOMA STEM CELL PHENOTYPE
Authors: Yuli Magalhaes, Fabio Forti
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor with high recurrence and resistance to therapies. The F-actin cytoskeleton in GBM is related to cell invasion and the glioma stem cell (GSC) phenotype, affecting self-renewal and migration. Our research identifies a novel role for the F-actin pathway in DNA repair, impacting genomic stability and contributing to therapy resistance. Understanding F-actin’s role is crucial for developing targeted strategies to improve GBM treatment outcomes. This study examines the effects of pharmacological F-actin depolymerization on reversing resistance to ionizing radiation (IR) and temozolomide (TMZ) in GBM spheroids. We established resistant sublines of GBM U87-MG cells through IR and TMZ cycles, observing significant resistance increases via MTT assays. Also, resistant cells had enhanced spheroid formation capacity, with higher size and proliferation. Alterations in DNA repair and F-actin pathway were observed, with intensified and disorganized F-actin polymerization and efficient repair in resistant cells. Elevated expression of stemness markers (Nestin, CD133, and CD44) indicated a GSC-like phenotype in resistant cells, corroborated by increased tumorigenicity and de novo spheroid formation. These markers were further enhanced by DNA damage. Treating cells with actin polymerization inhibitors reduced resistance to TMZ and IR, partly due to impaired DNA repair capacity. Additionally, F-actin disassembly affected stemness marker expression, reinforcing the link between cytoskeletal dynamics and the GSC phenotype. Our findings suggest that F-actin dynamic is crucial for resistance in GBM. Targeting F-actin could resensitize recurrent GBM tumours by diminishing DNA repair capabilities and affecting the GSC-like phenotype, offering new therapeutic avenues.