tbuckley/cabot-search huggingface dataset:
BIOS-08. CISD: A NOVEL, USER-FRIENDLY MULTIFACETED ALGORITHM FOR DETECTING STITCHING ARTIFACTS IN LARGE-SCALE CODEX IMAGING DATASETS
Authors: Afrooz Jahedi, Aliya khan, Pravesh Gupta, Jason Huse, Kasthuri Kannan, Krishna Bhat
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CODEX (CO-Detection by indEXing) imaging has emerged as a pivotal tool in cellular biology, providing unprecedented insights into cellular distributions and interactions within the tissue microenvironment, crucial for advancing computational pathology. Despite its advantages, CODEX is susceptible to stitching errors during the merging of image tiles, which can significantly distort spatial analysis by introducing artifacts that obscure true cellular architecture. METHODS Addressing this challenge, we introduce CISD (CODEX Image Stitch Detection), a novel, user-friendly algorithm optimized for the detection of stitching artifacts in large-scale CODEX datasets. Developed and validated using a comprehensive dataset from 7 matched glioblastoma patients—encompassing over 2800 images across 29 immune protein markers—CISD utilizes a combination of image preprocessing, statistical measures, and thresholding to detect stitching errors. RESULTS CISD demonstrates robust performance, achieving a median Area Under Curve (AUC) value in the gold standard dataset where 73% of markers exceed 70% AUC, and 17% surpass 90%. Further validation shows that in a secondary dataset, 45% of markers maintain AUC values over 70% with 38% exceeding 90%, validating the algorithm’s consistent efficacy across varied datasets. CONCLUSION CISD’s significance lies not only in its computational achievements but also in its accessibility, facilitating high-quality analysis of extensive datasets without complex pattern recognition requirements. This democratizes high-precision computational pathology, enabling more researchers to accurately analyze spatial data. By reducing technical barriers, CISD sets a new benchmark in CODEX imaging, enhancing data reliability and accelerating research discoveries in cellular biology. This innovation stands to substantially refine spatial analysis in digital pathology, ensuring dependable interpretation of complex biological data.
TMOD-32. MURINE MODELLING OF THE STING PATHWAY IN GLIOMAS
Authors: Justin Low, Patrick Lang, Michelle Bowie, Eric Baker, Virginia Wertman, Rebecca Fuller, Emiley Gibson, David Ashley
Journal: Neuro-Oncology (2024)

Abstract The stimulator of interferon genes (STING) pathway is a critical component of innate antitumor immunity through the recognition of pathogenic cytosolic DNA and stimulating the production of type 1 interferons and pro-inflammatory cytokines. We have previously shown that STING signaling is silenced in the neoplastic compartment of the GBM tumor microenvironment, but remains intact in vascular and immune cells. In human patient derived cell lines, such silencing appears to be mediated by hypermethylation of a region of the STING promoter and can be reversed by treatment with both the DNA methyltransferase (DNMT) inhibitor Decitabine and DNMT1-selective inhibitor GSK-3685032. These results suggest that neoplastic cell STING promoter methylation represents a therapeutic vulnerability that can be exploited by epigenetic therapies to inflame the glioma tumor microenvironment. Murine models are critical tools for exploring the translational implications of STING silencing in vivo. Distinct mouse models have been developed to optimally represent specific aspects of human glioma biology. Here we characterize the STING pathway in commonly used syngeneic murine glioma models, including CT2A, GL261, SB28, and SMA560. We show that the expression of STING pathway components varies significantly across these lines. Importantly, unlike in humans, murine STING (mSTING) expression is not suppressed by promoter methylation and does not respond to decitabine treatment. Additionally, the mSTING protein is expressed in neoplastic cells in vivo. These results demonstrate a fundamental difference in epigenetic regulation of STING between human and murine glioma cells, and suggest that murine modeling of STING epigenetics requires the use of patient derived cell lines implanted in immunodeficient mice. Meanwhile, immune competent syngeneic models are appropriate for exploring the tumor immune microenvironment but would require non-epigenetic approaches (e.g. genetic knock-outs/knock-ins) for modulating STING expression. Humanized mice represent a promising emerging approach for faithfully recapitulating both epigenetic control and immune environment of human gliomas.
SURG-59. A RARE CASE OF COMBINED OCCURRENCE OF GLIOBLASTOMA MULTIFORME AND PHEOCHROMOCYTOMA: A CASE REPORT AND LITERATURE REVIEW
Authors: YaJui Lin
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is most common and malignant primary brain tumors. However, combined other solid organ malignancies sometimes occurred. To our knowledge, the combination of glioblastoma multiforme and pheochromocytoma is an exceedingly rare occurrence. As a result, we present the case of a 61-year-old male patient who suffered from slurred speech and unsteady gait due to left frontal glioblastoma with concurrent pheochromocytoma. The clinical course was retrospectively collected from medical records, including the lab data, imaging, surgical procedure and neurological examination results. We also provide a comprehensive review and discussion of the association between pheochromocytoma and glioblastoma, including genetic disorder the management strategy. The fluctuated blood pressure during brain surgery implied suspicious concurrent endocrine tumor in this patient. The patient was ultimately diagnosed with adrenal pheochromocytoma after left adrenalectomy and radical nephrectomy by urologist. No other malignancies or genetic disorders were found in this patient. Subsequently, this patient recovered well without any neurologic deficit and with effectively controlled blood pressure. The presence of a concomitant pheochromocytoma may precipitate paroxysmal catecholamine surges, fluctuations in cerebral perfusion, and an elevated risk of significant intra-cranial blood loss during neurosurgery. Once patient of brain tumors presented with uncontrolled or fluctuated blood pressure occurred, concurrent endocrine tumor should be considered.
CTNI-61. PRELIMINARY RESULTS OF A PHASE I/II TRIAL OF SELINEXOR AND TEMOZOLOMIDE IN RECURRENT GLIOBLASTOMA
Authors: Frances Chow, Michael Berens, Joycelynne Palmer, Miguel Villalona-Calero, Douglas Ney, Macarena De La Fuente, Kurt Jaeckle, Sani H Kizilbash, Ruham Alshiekh Nasany, Maya Hrachova, Alyx B Porter, David Piccioni, Kimberly Hoang, Lindsay Lipinski, Roy Strowd, Pierre Giglio, Megan Mantica, David Schiff, Steven Gore, Jana Portnow
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity through the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogenes, and decreased expression of anti-apoptotic proteins. As a single agent, SEL has demonstrated brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS Through an NCI Project Team, we developed a multi-institutional phase I/II clinical trial which opened across the NCI Experimental Therapeutics Clinical Trial Network. Eligibility included histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. We evaluated safety, tolerability, and dose finding with an IQ 3 + 3 design of TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. RESULTS From October 2022 to March 2024, we enrolled 12 patients (n=11 evaluable) into phase I of the study. Patient characteristics included 82% male, median age 62 (range 50-77), 64% white. The median number of cycles administered was 6 (range 1-12). Two dose levels (SEL 60mg and SEL 80mg) were evaluated. No dose-limiting toxicities (DLTs) were observed. The most common treatment related adverse events were nausea (58%), decreased platelet count (50%), fatigue (50%), constipation (42%), vomiting (25%), decreased lymphocyte count (25%), and decreased neutrophil count (25%). Grade 3+ treatment related adverse events included nausea, grade 3 (n=1); decreased lymphocyte count, grades 3-4 (n=2); and anorexia, grade 3 (n=1). Phase I has completed enrollment and the recommended phase II dose will be SEL 80mg. Additional results will be presented. CONCLUSION Results suggest that a sequential dosing regimen of SEL+TMZ is feasible, well-tolerated, and may minimize the cumulative toxicity of SEL. The phase II randomized portion of this trial is enrolling nationwide and will investigate efficacy and candidate molecular signatures of vulnerability (NCI #10505, NCT05432804).
IMMU-24. GLIOBLASTOMA ENRICHED GLYCOSPHINGOLIPIDS MODULATE THE FUNCTION OF HUMAN INKT CELLS
Authors: Morgan Coombs, Tyrone Dowdy, Md Masud Alam, Guzal Khayrullina, Vibhuti Joshi, Seketoulie Keretsu, Jinkyu Jung, Ayaka Hara, Emily Steffke, Laila Latifi, Hye Kim, Jo Spurgeon, Nargis Malik, John Hancock, Kelsey Smith, Jenny Gumperz, Mioara Larion, Masaki Terabe
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is an aggressive primary brain tumor highly resistant to currently available immunotherapies. A deeper understanding of its underlying immunoregulatory mechanisms is paramount to developing future immunotherapeutic treatments. Invariant natural killer T (iNKT) cells are unconventional T cells that recognize lipid antigens presented by an MHC-like molecule called CD1d. Although iNKT cells have been shown to regulate tumor immunity in other cancer types, their role in glioblastoma is not well characterized. Given the lipid-rich nature of the brain and the unique metabolic activity of glioblastoma cells, we hypothesized that interactions between glioblastoma and iNKT cells through glioblastoma-produced lipids could contribute to the immunosuppressive nature of the disease. We report multiple lipid species enriched in aggressive human glioblastoma stem-like cell (GSC) lines that activate human iNKT cells and modulate their functions. Lipidomic LC-MS analysis of GSCs, low-grade glioma stem-like cell lines, and normal human astrocytes revealed various glycosphingolipid species, including sulfatides, highly enriched in the GSCs. Multiple enriched sulfatide species, when presented by CD1d, were recognized by and activated iNKT cells in a dose-dependent manner. Additionally, cytokine analysis of stimulated human PBMC-derived iNKT cells demonstrated that the enriched sulfatides did not induce Th1 cytokine production, but rather many non-Th1 cytokines that potentially counteract Th1-type immune responses. This modulation of iNKT cell function by glioblastoma-enriched glycosphingolipids may contribute to the immunosuppression of glioblastoma and could highlight sulfatide production as a potential therapeutic target for glioblastoma treatment.
INNV-11. DELIVERY OF TTFIELDS TO THE INFRATENTORIAL BRAIN USING HFE ARRAYS
Authors: Oshrit Ze’evi, Ariel Naveh, Doron Manzur, Nadav Shapira
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Tumor Treating Fields (TTFields) therapy is a noninvasive, locoregional treatment comprising alternating electric fields delivered to the tumor via two pairs of skin-placed transducer arrays. TTFields physically disrupt cancer cell viability through a multimodal mechanism that includes antimitotic and antitumor immune effects. TTFields therapy is FDA-approved for glioblastoma (GBM) and CE marked for WHO grade 4 glioma. While clinically approved array layouts for GBM target supratentorial tumors, TTFields distribution depends on the arrays’ locations and dedicated layouts are needed to target infratentorial tumors. To increase patient comfort, Novocure developed HFE arrays that are thinner and lighter than existing INE arrays. Here, we evaluate innovative HFE array layouts for TTFields delivery to infratentorial tumors at therapeutic intensities (~1 V/cm). METHODS TTFields delivery was simulated using Sim4Life v6.2 in a male computational model. 32 layouts of HFE arrays were placed on the model’s scalp, neck, and scapulae, with one placed at a standard cerebral location. Local Average Field Intensity (LAFI) and Local Minimum Power Density (LMiPD) were calculated in the cerebrum, cerebellum and brainstem. RESULTS Standard cerebral layout provided LAFI of 2.47 V/cm to the cerebrum, while providing 1.50 and 1.10 V/cm to the cerebellum and brainstem, respectively (LMiPD 2.22, 1.34 and 0.64 mW/cm3). Layouts comprising arrays on the scapulae (right and left) paired in cross configuration with arrays on either the temples or forehead, provided LAFI of 1.87-2.17 V/cm (LMiPD 1.05-2.20 mW/cm3) to the cerebrum, while providing 1.64-2.13 V/cm (LMiPD 1.77-2.26 mW/cm3) to the cerebellum and 1.74-1.89 V/cm (LMiPD 2.28-2.89 mW/cm3) to the brainstem. CONCLUSION Lower array placement provides higher levels of field intensity in the cerebellum and brainstem versus standard cerebral layout, while still providing adequate field intensity to the cerebrum. This simulation-based study suggests feasibility of delivering therapeutic TTFields intensities to infratentorial tumors using dedicated HFE array layouts.
TMIC-52. DECODING METABOLIC INTERACTIONS IN GLIOBLASTOMA TUMOR MICROENVIRONMENT THROUGH COMPREHENSIVE SPATIAL TRANSCRIPTOMIC AND PROTEOMIC ANALYSIS
Authors: Avirup Chakraborty, Changlin Yang, Diana Feier, Aryeh Silver, Miruna Anica, Avinash Pittu, Illeana West, Olusegun Sobanjo, Ethan Hodge, Mia Engelbart, Srabasti Sengupta, Nagheme Thomas, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Within the GBM microenvironment, distinct micro-niches arise from independent cancer cell lineages with unique metabolic needs, characterized as Fast Cycling Cells (FCCs) and Slow Cycling Cells (SCCs). FCCs preferentially utilize aerobic glycolysis for energy, whereas treatment-resistant SCCs depend on lipid metabolism. Our study decodes the molecular and spatial heterogeneity within the GBM microenvironment, focusing on the dichotomy of immune infiltrates and the metabolic interactions between SCCs and the immune compartment in human GBM patients. METHODS We performed spatial transcriptomics and proteomics combined with geospatially resolved single-cell neighborhood analysis of IHC-stained GBM tissues using CellProfiler and the SNAQ algorithm that we developed to investigate the specific immune microenvironment of SCCs and FCCs. Holotomography and fluorescence-based time-lapse imaging coupled with flow cytometry were used to study lipid transfer between immune cells and GBM cells. Finally, the effects of pharmacological and genetic targeting of lipid transfer were investigated both in vitro and in vivo. RESULTS Our study establishes a connection between spatial metabolic heterogeneity and immune diversity, highlighting how specific tumor cell lineages correlate with characteristic immune micro-niches. In particular, SCCs exploit the metabolic properties of recruited immunosuppressive myeloid-derived cells, which metabolically support tumor cells by facilitating lipid transport and supporting SCC metabolism. Our results show that inhibiting lipid transfer affect SCCs, remodels the immune microenvironment, delays tumor growth and improves disease outcome. Our study also demonstrates a correlation between predicted sensitivity to lipid-modifying drugs, such as statins, and the SCC phenotype. This correlation could enable stratification and selection of patients most likely to benefit from such treatments. CONCLUSIONS This study establishes critical connections between the TME, cellular metabolism, anti-tumor immunity, and treatment vulnerabilities. Our research provides novel insights into how metabolic exchanges contribute to tumor progression and suggests that targeting metabolic interactions could be an effective therapeutic strategy for GBM.
QOL-23. MEASURING BODY FUNCTIONALITY APPRECIATION IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Sarah Cook, Alexandria Davies, Emilie Cheng, Autumn Lanoye, Ashlee Loughan, Sarah Braun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Body image is a multifaceted construct consisting of thoughts, feelings, and perceptions about one’s body and its functioning. Perception of one’s own physical functioning and capabilities may be an important consideration in neuro-oncology given the sequalae of brain tumors and associated treatment; however, it is understudied in this population. One brief measure of body image, the Functionality Appreciation Scale (FAS) is a comprehensive tool, focused on one’s perceived physical functioning and capabilities, rather than perceived appearance. We aimed to examine the psychometric properties of the recently developed Functionality Appreciation Scale (FAS) among patients with primary brain tumors. METHODS Adult patients with primary brain tumors (N=237) completed the FAS and other measures of psychological distress as well as medical and demographic characteristics. An exploratory variance factor analysis (EFA) using principal axis factoring and a Promax rotation was conducted. Convergent validity was examined via correlations to measures of psychological distress. RESULTS The EFA supported the single-factor structure, which accounted for 62.71% of the variance with all items loading significantly onto this factor. The FAS had good internal consistency (Cronbach’s a=.90). Convergent validity was demonstrated by negative associations (ps&amp;lt;.05) with symptoms of depression (r=-.30), generalized anxiety (r=-.21), and death anxiety (r=-.17). CONCLUSION Results confirmed the single factor structure of the FAS in primary brain tumor patients. Furthermore, the expected negative relationships with measures of psychological distress provide evidence of convergent validity. The FAS is valid and reliable in patients with primary brain tumors. Our findings suggest that body functionality and appreciation may be important to target in psychosocial interventions for those with primary brain tumors.
RBIO-04. OUTCOMES OF RADIOSURGERY FOR WHO GRADE 2 MENINGIOMAS: THE ROLE OF KI-67 INDEX IN GUIDING THE TUMOR MARGIN DOSE
Authors: Ying Meng, Kenneth Bernstein, Elad Mashiach, Brandon Santhumayor, Nivedha Kannapadi, Jason Gurewitz, Matija Snuderl, Donato Pacione, Chandra Sen, Bernadine Donahue, Joshua Silverman, Erik Sulman, John Golfinos, Douglas Kondziolka
Journal: Neuro-Oncology (2024)

Abstract The management of WHO grade 2 meningiomas is complicated by their diverse clinical behaviors. Stereotactic radiosurgery (SRS) can be an effective management option. Literature on SRS dose selection is limited, but suggests a higher dose is better for tumor control. We aimed to characterize the predictors of post-SRS outcomes that can help guide planning and management. We reviewed a cohort of consecutive patients with pathologically-proven WHO grade 2 meningiomas who underwent SRS at a single institution between 2011 and 2023. Ninety-nine patients (median age 62 years) underwent SRS, eleven of whom received hypofractionated SRS in 5 fractions. Twenty-two patients had received prior irradiation. The median follow-up was 49 months. The median overall survival (OS) was 119 months (95%CI 92–NA) with estimated 5- and 10-year survival of 83% and 27% respectively. The median progression-free survival (PFS) was 40 months (95%CI 32–62) with 3- and 5-year rates at 54% and 35% respectively. The median locomarginal PFS was 63 months (95%CI 51.8-NA) with 3- and 5-year rates at 65% and 52%. Nine (9%) patients experienced adverse events, 2 CTCAE grade 3 and 7 grade 2, consisting of worsening neurologic deficit from edema. In the single-session SRS cohort, Ki-67 was a significant predictor of both OS and intracranial PFS. Tumors with Ki-67 &amp;gt;10% had ~10 times risk of locomarginal progression compared to Ki-67 ≤10% (p&amp;lt;0.001). In tumors with Ki-67 &amp;gt;10%, margin dose ≥14 Gy was associated with significantly better tumor control, but not for tumors with Ki-67 ≤ 10%. Other significant predictors of tumor control were prescription dose, tumor volume, and location. The management of WHO grade 2 meningiomas requires a multi-modality approach. This study demonstrated the value of a targeted SRS approach in patients with limited disease, and further establish predictive biomarkers that can guide planning through a personalized approach.
CTNI-04. DECODING GLIOBLASTOMA SURVIVAL: UNRAVELING THE PROGNOSTIC POTENTIAL OF OLFACTORY FUNCTION IN A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Christoph Oster, Aylin Matyar, Thomas Hummel, Elke Hattingen, Teresa Schmidt, Martha Jokisch, Daniel Jokisch, Yahya Ahmadipour, Ulrich Sure, Martin Stuschke, Tobias Tertel, Bernd Giebel, Christoph Kleinschnitz, Björn Scheffler, Cornelius Deuschl, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Olfactory impairment is a common neurologic deficit among glioblastoma patients.We have previously shown that glioblastoma patients with reduced smell sensitivity had lower overall survival rates compared to those with normal olfactory function.A notable limitation in that study was the unequal distribution of prognostic factors between the two groups,and the absence of continuous olfactory assessments during treatment to investigate if therapy-associated neurotoxicity could be a contributing factor to diminished olfactory acuity.In this trial olfactory function will be evaluated in glioblastoma patients as a prognostic marker with regard to overall survival,neurocognition and quality of life. METHODS This prospective,multicenter study is set to recruit 64 glioblastoma patients alongside 64 healthy controls.Stratification of participants is based on prognostically relevant variables such as resection status,MGMT-promoter-methylation-status,radiographic involvement of olfactory brain areas,olfactory function,age,and Karnofsky performance status scale.We utilize Sniffin´ Sticks to evaluate olfactory function through identification and threshold tests,and this assessment is carried out longitudinally throughout the therapy starting from tumor diagnosis.Infiltration of the olfactory nerves or olfactory brain are scrutinized using a high-resolution coronal T2-weighted sequence which is added to a dedicated brain tumor protocol.MRI images are independently reviewed by two board-certified radiologists from distinct institutions,who are blinded to the patients’ olfactory function status.Furthermore,quality of life data,neuropsychological testing,and psychosomatic screening are performed at specific intervals throughout the study.Also,we examine next-generation-sequencing results to investigate potential genetic associations with hyposmia in glioblastoma patients. RESULTS The first participant was enrolled in May 2023.Currently,16 patients and three controls are already enrolled(May 2024).Plans are underway to open a second study site in 2024,with the aim to complete recruitment by December 2025.Follow-up assessments will continue until December 2027.We anticipate that the final results of the study will be available in 2028. CONCLUSIONS In the process,this study is the first prospective study which investigates the olfactory function systematically as prognostic factor in glioblastoma patients.