tbuckley/cabot-search huggingface dataset:
SURG-50. CLINICAL EXPERIENCE AND PATHOLOGICAL FEATURES IN AUTOPSY CASES TREATED WITH TUMOR TREATING FIELDS
Authors: Sho Tamai, Masashi Kinoshita, Kosuke Nambu, Shingo Tanaka, Mitsutoshi Nakada
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Since 2017 Tumor Treating Fields (TTF) was approved for primary glioblastoma in Japan. In this study, we reviewed clinical experience and the pathological characteristics of autopsy cases treated with TTF. METHODS From March 2018 to April 2022, 67 patients (36 males and 31 females, median age 68 years) with primary glioblastoma, IDH-wild type treated at our institution were included in the analysis. RESULTS Twenty-eight patients (19 males and 9 females, median age 66 years) met the TTF indication criteria for induction, 19 cases (67.9%) were 65 years or older, and 14 cases (50.0%) indicated MGMT promoter methylation. The mean duration of TTF treatment was 7.2 months. The main reasons for discontinuation were tumor recurrence in 11 patients (40.7%), skin symptoms in 8 patients (29.6%), and psychological distress in 6 patients (22.2%). Only 12 patients (42.9%) underwent TTF treatment over 18 hours per day, because of discomfort of wearing pad and concern about srrounding. Median PFS and OS in the used patients were 9.9 and 17.7 months, respectively. Autopsies were performed in 3 of the 16 deaths. Histopathological examination of tumor specimen indicate that the Ki-67 labeling index was higher in brainstem (33.6%) than in the supratentorial primary lesion (23.6%). DISCUSSION Comparing to the previous report (Stupp R et al., JAMA. 2017), our cases contained a large number of patients over 65 years old with shorter mean duration of TTF treatment, and shorter OS. After TTF treatment, the Ki-67 labeling index was higher on infratentorial than on supratentorial in the autopsy specimens, suggesting the anti-tumor effect of TTF for the supratentorial lesion. RESULTS High proliferative activity of infratentrial lesion was suggested as a typical form of progression for TTF treatment.
NCOG-40. RARE ADVERSE EFFECT OF TEMOZOLOMIDE IN A 65-YEAR-OLD FEMALE WITH GLIOBLASTOMA MULTIFORME: A CASE REPORT
Authors: Ujjwala Jain, Prashant Desai
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Temozolomide, an antineoplastic agent is primarily used to treat certain brain tumors, including glioblastoma multiforme (GBM). Common side effects include nausea, vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue, convulsions and rash. A rare (less than 1%) adverse effect includes aplastic anemia refractory to treatment. Herein we present a case of Temozolomide induced severe bone marrow suppression in a 65-year-old woman with GBM refractory to any treatment CASE PRESENTATION A 65-year-old female presented with dizziness and left-hand numbness. Imaging revealed a right hemisphere mass and she underwent partial resection with pathology showing GBM, IDH wildtype, with CDKN2A/B deletion. She was started on radiation therapy with concurrent temozolomide. After nearly 5 weeks of temozolomide/RT, she developed severe thrombocytopenia/neutropenia with onset of neutropenic fever and severe CMV infection, leading to her demise within a week. DISCUSSION Life threatening refractory cytopenias is a very rare side effect of Temozolomide with a high rate of morbidity/mortality. In the case of our patient, she initially had weekly CBC’s which were stable and hence was switched to a monthly schedule. The patient’s ANC and platelets showed a precipitous drop within a month and ended up with aplastic anemia. The development of this rare complication underscores the importance of increased awareness about this often-fatal adverse event and possibly more frequent monitoring to recognize it early, especially in these patients with an already limited life expectancy. A more tailored approach to monitoring blood work may be needed depending on patient factors. CONCLUSIONS Aplastic anemia refractory to treatment is a rare and life threating adverse effect of temozolomide. The frequency of checking blood work for patients on Temodar has not been definitively established with protocols ranging from once weekly to monthly. Given the potential for this fatal adverse event, it is important to develop better tools to help identify patients in whom more frequent monitoring may be necessary.
EPID-34. THE EFFECT OF ANTIDEPRESSANT THERAPY ON GLIOBLASTOMA SURVIVAL: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Yifei Sun, Mohammad Hamo, Emma O’ Hagan, Travis Atchley, Dagoberto Estevez-Ordonez
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Symptoms of depression are highly prevalent among patients with glioblastoma (GBM) and have been associated with poor outcomes. In addition to managing depression symptoms, preclinical and clinical studies suggest that antidepressants may inhibit GBM progression and may be associated with improved outcomes. However, the effect of antidepressants on survival is unknown and results from existing studies are conflicting. OBJECTIVE We conducted a systematic review and meta-analysis to investigate the effect of antidepressant therapy on GBM survival. METHODS We searched PubMed, Embase, Scopus, PsycINFO, and Web of Science from inception to March 2024 for studies assessing the overall survival of patients with GBM treated with antidepressants. Prespecified Hazard ratios (HR), 95% confidence interval (CIs), median overall survival, and patient characteristics were extracted. Results were combined using a restricted maximum-likelihood estimation random-effects model. RESULTS We identified 6 observational studies meeting inclusion criteria with 8269 patients. Of these, 1093 (13%) were treated with antidepressant therapy at some point after their GBM diagnosis. Antidepressant therapy was not significantly associated with overall survival (HR 1.27, 95% CI 0.90-1.79, p=0.17). In a sub-analysis of studies that specified whether SSRIs were utilized, SSRI usage specifically was also not associated with overall survival (HR 1.08, 95% CI 0.58-2.03, p=0.81) We observed considerable heterogeneity (I2 = 92.7%, p&amp;lt;.001). CONCLUSIONS Antidepressants were not significantly associated with overall survival in patients with GBM. However, our meta-analysis was limited by significant heterogeneity observed across studies. The effect of antidepressants on outcomes in patients with GBM remains uncertain. We observed conflicting results in the literature, with some studies suggesting decreased survival. Therefore, the role of antidepressants in patients with GBM warrants further investigation.
BIOM-56. HEAT SHOCK PROTEINS PREDICT CLINICAL RESPONSE AND POTENTIATE LOCAL IMMUNOGENICITY AFTER LITT FOR GLIOBLASTOMA
Authors: Jay Chandar, Chandler Berke, Deepa Seetharam, Vasundara Govindarajan, Shovan Bhatia, Mynor Mendez Valdez, Jelisah Desgraves, Emade Jaman, Victor Lu, Jesus Castro, Anna Hudson, Christian Ramsoomair, Michael Ivan, Ricardo Komotar, Ashish Shah
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) remains one of the deadliest cancers despite advances in therapies. Laser interstitial thermal therapy (LITT) is a minimally invasive technique used to ablate intra-axial brain tumors. Non-ablative LITT-induced hyperthermia (33-43˚C) increases intra-tumoral mutational burden and neoantigen production, promoting neoantigen presentation via heat shock proteins (HSPs). HSPs are protein-folding chaperones that present novel intracellular antigens for immune recognition. We investigated HSPs as predictors of local immune response and clinical outcomes of GBM patients undergoing LITT. We conducted immune deconvolution of bulk RNA-sequencing data from The Cancer Genome Atlas to determine the correlation between 97 unique HSPs and tumor infiltration of CD8+, CD4+, B, macrophage, neutrophil, and dendritic cells. We evaluated the association between HSP expression and overall survival (OS). Pre-LITT biopsies from 9 patients (responders and non-responders) were analyzed via immunohistochemistry (IHC) to identify spatial HSP expression. Next-generation sequencing was utilized to validate findings and identify other predictive biomarkers. We identified two HSPs for further investigation: SACS and HSPA5. SACS was associated with improved survival based on TCGA data (14.9 vs. 11 months, HR:1.3, p&amp;lt;0.0001). HSPA5 was associated with worse outcomes (12.1 vs. 15.0 months, HR:0.73, p&amp;lt;0.0001). Immune deconvolution showed HSPA5 positively correlated with dendritic cell infiltration (r=0.50, p=6.1E-27) and SACS with CD8+ infiltration (r=0.31, p=6.8E-11). IHC of 9 patients demonstrated high SACS expression was associated with improved OS (p&amp;lt;0.05) after LITT. Multiplex IHC illustrated that immune cell infiltration was associated with therapeutic response post-LITT. Our ongoing immunohistochemical and genomic analyses aim to clarify the role of HSPs in enhancing immunogenicity in GBM. Further investigation into SACS and immune cell infiltration may reveal how hyperthermia via LITT improves response through neoantigen presentation.
CTIM-16. SAFETY AND PRELIMINARY EFFICACY OF AZD1390 + RADIATION THERAPY FOR GLIOBLASTOMA
Authors: Patrick Wen, Jonathan T Yang, Brandon S Imber, Jan Drappatz, Rajesh Jena, Deborah Forst, Alicia Zukas, Susan C Short, Chunling Fan, William Trigg, Alvin Milner, Urszula M Polanska, Colin Glover, Chara Stavraka, Darshan Dalal, Djuro Karanovic, Anthony J Chalmers
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma is an aggressive cancer; intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide is the first-line standard of care. AZD1390, an ataxia telangiectasia mutated kinase inhibitor, aims to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood–brain barrier penetration, confirmed in healthy volunteers (NCT03215381) and patients with glioblastoma (Phase 0; NCT05182905). This Phase 1, open-label study (NCT03423628) evaluated safety and efficacy of AZD1390 and IMRT in patients with glioblastoma. METHODS Adult patients received escalating once-daily AZD1390 doses with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent glioblastoma) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly-diagnosed O-6-methylguanine-DNA methyltransferase unmethylated glioblastoma). Patients received 2 additional weeks of adjuvant AZD1390 post-IMRT. Primary objective was safety; secondary objectives included efficacy and pharmacokinetics. RESULTS As of Feb 6, 2024, 115 patients (Arm A=75; Arm C=40) received AZD1390 10–900 mg/day. Pharmacokinetics were linear, with a slightly more-than dose-proportional increase and mean elimination half-life ~9–11 hours. Most patients had ≥1 treatment-emergent adverse event (AE), most commonly fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade ≥3 AZD1390-related AEs occurred in 18/115 patients. The maximum tolerated dose was 400 mg (Arm A) and 300 mg (Arm C). Dose-limiting toxicities included creatinine kinase elevation (Arm A) and radiation skin injury (Arm C). AEs led to AZD1390 discontinuation in 15/115 patients. Safety profiles were mostly consistent across Arms despite different radiation schedules. At target-engaging doses, median overall survival was 12.7 months (95% CI: 10.7–18.9; Arm A) and still maturing (Arm C). CONCLUSIONS Concurrent AZD1390 and IMRT demonstrated manageable safety at doses with known target engagement. Preliminary efficacy is encouraging (Arm A). AZD1390 can potentially act as a radiosensitizer for glioblastoma treatment. Clinical investigation is ongoing.
IMMU-05. TNFR2 IS A NOVEL MARKER OF EXHAUSTION AND TNFR2 BLOCKADE IMPROVES SUBCUTANEOUS TUMOR CONTROL
Authors: Alexandra Hoyt-Miggelbrink, Jessica Waibl Polania, Aditya Mohan, Lucas Wachsmuth, Selena Lorrey, Emily Lerner, Daniel Wilkinson, Andrew Hardigan, Emily Blandford, Kelly Hotchkiss, Saskia Hemmers, Sarah Cook Quackenbush, Katayoun Ayasoufi, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract Checkpoint inhibitors have been successful in various tumors. However, these treatments have failed in glioblastoma. Approaches harnessing the immune response are hindered by multiple factors, including T cell exhaustion. TOX is particularly important for the transcriptional and epigenetic reprogramming of exhausted T cells. While it is known that NFAT is upstream of TOX, our understanding of the upregulation of TOX remains incomplete. We hypothesized that tumor necrosis factor (TNF) could be involved in the upregulation of TOX as TNF can lead to the translocation of NFAT into the nucleus. We observed significant upregulation of the anti-inflammatory TNF receptor type II (TNFR2) in tumor-infiltrating T cells. This local upregulation mimics expression patterns of canonical exhaustion markers. TNFR2 expression is correlated with markers of exhaustion, including PD1, TIM3, and TOX. Furthermore, TNFR2 knock out (KO) CD8 T cells have significantly lower TOX expression, without the concomitant decrease of TIM3. Whereas previous studies have linked TIM3 and TOX expression, these data suggest that TIM3 and TOX are regulated independently. We utilized bulk RNA-sequencing to assess transcriptional regulation of WT and KO T cells and detected a significant reduction of T cell exhaustion and immune checkpoint pathways in TNFR2 KO T cells. Various exhaustion-related transcription factors and coinhibitory markers were significantly reduced. In contrast, a significant increase in AP1 transcription factors, commonly associated with T cell effector functions, was detected. Given this reduced exhaustion profile, we subsequently investigated the influence of TNFR2 on tumor burden. TNFR2 KO mice had significantly lower tumor burdens following subcutaneous tumor challenges. We subsequently treated mice with a TNFR2 antagonist. While the antagonist alone was not sufficient to improve tumor control, combination with anti-PD1 significantly reduced tumor volumes. These data provide evidence for a novel marker of exhaustion that could result in a unique therapeutic strategy.
DISP-05. SUPERVISED MACHINE LEARNING PREDICTION OF THERAPEUTIC CLINICAL TRIAL ENROLLMENT FOR MINORITY PATIENTS AND WOMEN IN NEURO-ONCOLOGY
Authors: Mulki Mehari, Gayathri Warrier, Abraham Dada, Aymen Kabir, Aden Haskell-Mendoza, Sheantel Reihl, Joshua Jackson, Ariel Gonzalez, Ellery Reason, Ann Flusche, Tara Dalton, Mikias Negussie, Cesar Nava gonzales, Ugonma Chukwueke, Annette Molinaro, Alyx Porter, Peter Fecci, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite changes in national policy, women and minority patients remain under-accrued in glioma clinical trials. Supervised machine learning may serve as a novel approach to understanding which variables and their complex interplay most influence enrollment for underrepresented patients. We aimed to design and externally validate machine learning models to predict therapeutic clinical trial enrollment for a) all patients, b) women, and c) NIH-designated minority patients with low- and high-grade glioma. METHODS In a 20-year retrospective cohort of 1042 adult patients with low- and high-grade glioma, boosted neural network (BNN) models for the whole, women, and minority cohorts were used to analyze the combined effects of demographic, socioeconomic, and oncologic variables on clinical trial enrollment. These models were validated using an external cohort (n=103). RESULTS In the development cohort (445 [42.7%] women; 151 [14.5%] minorities; median age, 51.5 [interquartile range: 39.4-62.5] years), 350 patients (33.6%) enrolled in a therapeutic clinical trial. The whole cohort BNN (AUC: 0.827, misclassification rate (MR): 0.175), the women cohort BNN (AUC: 0.895, MR: 0.125), and the minority cohort BNN (AUC: 0.983, MR: 0.053) models accurately predicted trial enrollment on external validation. For the whole cohort and women models, several demographic (race, ethnicity, minority status, sex), socioeconomic (insurance, employment status), and oncologic variables (seizure, chemotherapy, KPS, WHO grade, tumor lobe) were equally influential (Main effect (ME): 1.000, Total effect (TE): 1.000) on enrollment. For the minority model, socioeconomic variables including insurance status (ME: 0.089, TE: 0.417) and occupation classification (ME: 0.087, TE: 0.381) drove enrollment. CONCLUSION We designed and externally validated the first machine learning model for predicting therapeutic clinical trial enrollment for patients with diffuse glioma. Model features driving trial enrollment varied for underrepresented patients. These results may help prioritize personalized patient-specific initiatives to address barriers to equitable patient accrual.
CNSC-10. WHEN GOOD THINGS GO OFF TRK: THE INTERSECTION OF NEUROSCIENCE &amp; ONCOLOGY
Authors: Siobhan Pattwell
Journal: Neuro-Oncology (2024)

Abstract How and why do processes and molecular players that were once an integral part of normal neurodevelopment go awry in pathological conditions, such as cancer? Embryogenesis, and neurodevelopment in particular, comprise an elegant and well-orchestrated series of tightly regulated events, culminating in an organized and highly functioning organism. Cancer, on the other hand, can often be viewed as an uncontrolled, unrestrained, genetically chaotic disease, lacking the precise spatial and temporal rigidity associated with normal development. While appearing to be on opposite sides of the organizational spectrum, the similarities between early neurodevelopment and oncogenesis are numerous. The link between developmental signaling and cancer initiation, maintenance, and metastasis has long been known for several members of the Wnt, Hedgehog, and Notch pathways and years of gene-level analyses have provided a wealth of knowledge and mechanistic insight. As advances in next generation sequencing allow for deeper characterization of genetic programs, it is increasingly possible to explore various isoforms of cancer associated genes. It is widely known that neurotrophins and their receptors (TrkA, TrkB, TrkC) are instrumental for neurodevelopment and that they remain critical for proper neuronal functioning throughout life. Our work highlights a previously unidentified role for an alternatively spliced neurotrophin receptor in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in humans and mice. This specific isoform, TrkB.T1, is the predominant NTRK2 isoform across embryonic organogenesis, and forced overexpression of this embryonic pattern causes multiple solid and nonsolid tumors in mice. TrkB.T1 also emerges as the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring various NTRK fusions. This work hopes to address the fundamental question of how neurodevelopmental processes can go awry in cancer, while seeking to better characterize the role of TRKs, in normal developmental processes and oncogenesis.
NCOG-14. THE ROLE OF POSTOPERATIVE BLOOD PRESSURE MANAGEMENT IN EARLY POSTOPERATIVE HEMORRHAGE IN AWAKE CRANIOTOMY GLIOMA PATIENTS
Authors: Johannes Kerschbaumer, Matthias Demetz, Aleksandrs Kriger, Daniel Pinggera, Julia Klingenschmid, Claudius Thomé, Christian Freyschlag
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Awake surgery is widely used to maximize the extent of resection and enhance neuro-oncological outcome in gliomas. Postoperative hemorrhage can severely deteriorate the patients’ neurological outcome. Higher postoperative blood pressure can increase the risk of postoperative hemorrhage, but optimal perioperative patient and blood pressure management is unclear. The aim of this study was to investigate the role of postoperative blood pressure and other common radiological and epidemiological features with the incidence of postoperative hemorrhage. MATERIAL &amp; METHODS In this retrospective analysis, we included all patients who underwent awake surgery between 2010 and 2023 at our institution. We assessed the blood pressure both intra- and postoperatively as well as the heart rate for the first 12 hours. We compared a cohort with postoperative hemorrhage, who required further treatment (surgical revision or intravenous antihypertensive therapy), with a cohort with no postoperative hemorrhage. RESULTS We included 48 patients with a median age of 39 years. 9 patients (19%) showed a preoperative history of arterial hypertension, 8 of them were on antihypertensive treatment. 23 patients (48%) showed signs of a hemorrhage on early postoperative MRI, of whom 9 (19%) required further treatment, which was surgery in 2 cases and conservative therapy in 7 cases. Patients with postoperative hemorrhage showed significantly higher postoperative systolic blood pressure during the hours 3-12 (p&amp;lt;0.05) as well as intraoperatively during the hours 1-5 (p&amp;lt;0.05). In ROC and Youden Test, a strong impact of systolic blood pressure over 140 mmHg during the early postoperative course could be shown. DISCUSSION Postoperative hemorrhage is a serious complication in awake surgery glioma patients. However, with early treatment, no significant difference in Performance scores at follow-up could be found. To avoid postoperative hemorrhage, treating physicians should aim strictly on systolic blood pressure of under 140 mmHg for the postoperative course.
NCOG-06. FACTORS ASSOCIATED WITH SOCIAL DISABILITY IN THE CHRONIC POSTOPERATIVE PERIOD IN PATIENTS WITH GLIOMAS
Authors: Riho Nakajima, Masashi Kinoshita, Hirokazu Okita, Mitsutoshi Nakada
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with low-grade gliomas may have no obvious problems during hospitalization or their initial return to social life; however, social life difficulties may gradually become more apparent long after the surgery. We investigated factors associated with social disabilities in patients with low-grade gliomas in the postoperative chronic phase. METHODS The study included 114 patients with WHO grade 2 or 3 gliomas who underwent surgery (mean age, 44.3±13.2 years). Seventy-six patients underwent an initial surgery and 38 underwent a second surgery. All patients underwent various brain functional assessments and interviews about their social lives over 1 year after the surgery (median, 23 months). Factors associated with social disabilities were determined using logistic multiple regression analysis and chi-square tests. Voxel-based lesion symptom mapping was used to examine the brain regions associated with social disabilities. RESULTS Social disabilities were observed in 12.3% of the patients. Factors associated with social disabilities were the number of surgeries (first vs. second, p=0.0052) and tumor location (left vs. right, p=0.0091). Patients with recurrence and right cerebral hemispheric lesions had a higher probability of social disability (42.1%, p&amp;lt;0.0001) than that of other patients. The reasons for social disability after right hemispheric recurrence were social behavior disorder (62.5%) and neuropsychological dysfunctions (37.5%). Social behavioral disorders include interpersonal problems, such as job switching owing to problems with others, poor interpersonal relationships, and sexually deviant behavior. No other apparent neuropsychological abnormalities were found in patients with social behavior disorders. Surgical resection of the deep part of the right prefrontal area is associated with social behavior disorders and right supplementary motor cortex resection is associated with neuropsychological disorders. CONCLUSION In lower grade glioma, patients with right hemispheric recurrence were more likely to develop social disabilities in the chronic phase, which was caused by social behavioral disorders and neuropsychological dysfunctions.