tbuckley/cabot-search huggingface dataset:
BIOM-49. PATIENT-CENTRIC INTEGRATED GRAPH DATABASE REVEALS CRITICAL BIOMARKERS IN THE RECURRENCE OF IDH WILD-TYPE GLIOMA
Authors: Yang Liu, Kasthuri Kannan, Jason Huse
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND IDH wild-type glioblastoma (GBM) represents a formidable therapeutic challenge due to its consistent recurrence and progression despite standard treatments. Understanding the molecular and cellular mechanisms driving GBM recurrence through data integration is crucial. This study employs a novel graph database strategy to uncover insights into these tumors and identify functional biomarkers through graph algorithms-based pathway enrichment analysis. METHOD We developed a stand-alone graph database using Neo4j for primary-recurrent paired GBMs, integrating clinical and gene expression data from the Glioma Longitudinal AnalySiS (GLASS) Consortium and internal MD Anderson cohort. Based on log2 fold-change, we used hierarchical trees for differentially expressed genes to decompose the expression profile. Nodes in the database represent patients with considerable absolute log2 values determined by hierarchical trees, while shared patients define the edges. We applied graph algorithms such as degree centrality and community detection to identify potential biomarkers and supplemented these analyses with pathway identification to refine the biomarker list. Further, we divided the data set into 80% training and 20% testing sets. We evaluated the predictive performance of these biomarkers using machine learning models, including logistic regression, random forest, SVM, and neural networks. RESULTS DEG analysis revealed 33 down-regulated and 418 up-regulated genes in recurrent tumors. The top enriched pathways included neuroactive ligand-receptor interaction and GPCR ligand binding. Our database approach implicated 35 out of 451 genes as significant drivers of recurrence in IDH wild-type GBM. The prediction performance of these biomarkers was comparable to features selected through methods such as mRMR and logistic lasso and target identification methods like WGCNA. CONCLUSION Our innovative systems biology approach reveals that ligand-receptor interactions are crucial in driving recurrence in IDH wild-type GBM. This method also yielded promising mechanistic targets for recurrence, prompting focused and therapeutically relevant functional analyses. Moreover, this methodology is not limited to our study but can be applied in other multi-omics settings, offering a robust tool for biomarker discovery and validation.
INNV-27. TEMOZOLOMIDE FOR PATIENTS WITH AGGRESSIVE PITUITARY TUMORS: A CASE SERIES
Authors: Jessica White, Duru Baykal, Hazal Ser, Joon Uhm, Michael Ruff, Daniel Lachance, Bryan Neth, Jamie Van Gompel, Caterina Giannini, Aditya Raghunathan, Dana Erickson, Ugur Sener
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pituitary adenomas are often effectively managed with medical therapy, surgery, and radiation therapy. However, up to 15% of pituitary neoplasms exhibit rapid growth, invasive behavior, or, rarely, metastasize despite optimal standard treatments. Temozolomide is associated with a survival benefit for patients with these aggressive pituitary tumors. METHODS We present a case series of 8 patients with an aggressive pituitary tumor (APT) or pituitary carcinoma (PC) treated with temozolomide. RESULTS Eight patients (3 female, median age at diagnosis 44) with APT (n=6) or PC (n=2) were treated. A variety of pituitary tumor types were represented (1 prolactinoma, 5 corticotroph adenomas, 1 gonadotroph adenoma, 1 thyrotropinoma). Prior to temozolomide initiation, patients underwent a median 5 treatments including medical management (n=4), surgery (n=7), radiation therapy (n=7). Temozolomide was started at median 3.5 recurrence. Median treatment duration was 6 cycles (n=6, 150-200 mg/m2 days 1-5, 28-day cycles; n=1, 75 mg/m2, days 1-21, 28-day cycles). Seven patients experienced progression after temozolomide treatment, median progression-free survival (PFS) was 4 months. One patient remains on treatment, progression-free at 5 months. MGMT methylation status was assessed for 3 tumors. Among 2 patients with MGMT promoter methylated tumors, PFS was 4 months for one patient, the other remains on treatment. For one patient with MGMT promoter unmethylated corticotroph adenoma, PFS was 9 months. No ≥ grade 4 toxicities were noted. Most common toxicities were nausea (n=5), thrombocytopenia (n=3), and fatigue (n=2). CONCLUSION In this group of heavily pretreated patients, temozolomide monotherapy was well-tolerated and associated with median PFS of 4 months. Interestingly, PC patients had longer PFS at 9 months and 24 months. Our findings support use of single-agent temozolomide chemotherapy for patients with APT/PC, but further prospective analysis is needed to identify patients more likely to benefit from treatment and optimal timing of chemotherapy initiation.
SURG-07. QUANTIFYING THE RISK OF SHORT TERM SEIZURES FOLLOWING LASER INTERSTITIAL THERMAL THERAPY
Authors: Ethan Srinivasan, Ann Marie Flusche, Aden Haskell-Mendoza, Joshua Woo, Ariel Gonzalez, Ellery Reason, Joshua Jackson, Emily Lerner, Ryan Edwards, Allison Schwalb, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor-related epilepsy is a common sequela of both primary and metastatic brain tumors, as well as radiation necrosis (RN). Laser interstitial thermal therapy (LITT) is an effective option for lesional cytoreduction but induces transient peritumoral edema that typically resolves within 3 months of the procedure. Accordingly, we quantified the risk of seizure development early post-LITT in patients with tumors or RN of diverse histologies. METHODS Patients treated with LITT for brain tumors or radiation necrosis at a high-volume center from 2015 – 2021 with at least 3 months of clinical follow-up were evaluated for seizure risk and time to discontinuation of anti-epileptic drugs (AEDs) for at least 4 weeks, with censoring at death or last follow-up. RESULTS One-hundred and seventeen patients met inclusion criteria, and 22 (19%) experienced a post-LITT seizure within 3 months of surgery. Those with pre-LITT seizures (P = 0.03), prior whole-brain radiation (WBRT) (P = 0.0099), or lower pre-operative KPS (P = 0.04) were more likely to have a post-LITT seizure. Frontal lobe tumors appeared to be more frequently associated with seizures (68% vs 45%, P = 0.06). Prior WBRT, odds ratio (OR) 4.27 (95% CI 1.01 – 18.55), P = 0.047 and pre-LITT seizure, OR 5.39 (95% CI 1.87 – 16.31), P = 0.002 remained predictive on multivariate analyses. Successful AED weaning occurred at a median of 1.68 months (no seizure within 3-months group) versus undefined for patients experiencing seizures (P = 0.015). Post-LITT seizures within 3 months were associated with worsened post-LITT overall survival, 5.95 vs 17.2 months, P &amp;lt; 0.0001. DISCUSSION Prior seizure history or previous WBRT pose a risk of breakthrough seizures following laser ablation. Neurosurgeons should consider extended AED treatment or referral for management of tumor-related epilepsy in patients with these neurologic risk factors.
PATH-12. CLINICAL AND NEUROPATHOLOGICAL MARKERS FOR DISTINGUISHING BETWEEN IDH-MUTANT ASTROCYTOMAS OF WHO GRADE 2 AND 3
Authors: Jens Blobner, Patrick N Harter, Jonathan Weller, Nico Teske, Viktoria Ruf, Stephan Schoenecker, Robert Forbrig, Nathalie L Albert, Louisa von Baumgarten, Joerg-Christian Tonn, Niklas Thon, Philipp Karschnia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The neuropathological criteria of anaplasia to distinguish between IDH-mutant astrocytomas of WHO grade 2 and 3 are ill-defined by the WHO 2021 classification. Following the positive phase III trial results and the expected approval of Vorasidenib for grade 2 astrocytomas, identifying prognostic markers distinguishing grade 2 and 3 tumors remains crucial. METHODS We retrospectively searched our institutional database for patients meeting the diagnostic criteria for IDH-mutant astrocytomas per the WHO 2021 classification. Clinical, neuropathological, and molecular data were collected, and outcomes compared using log-rank analysis. Centralized slide review is ongoing to exclude inter-rater variability due to the study’s retrospective nature. RESULTS We identified 99 patients with IDH-mutant astrocytomas in which detailed neuropathological and clinical information were available for review, including 63 tumors (63.6%) which were assigned to WHO grade 2 and 36 tumors (36.4%) assigned to WHO grade 3. At a median follow-up of 7.5 years, median progression-free survival was 5.7 years for WHO grade 2 tumors and 4.4 years for WHO grade 3 tumors. Median overall survival for WHO grade 2 and WHO grade 3 tumors was not reached. On univariate analysis, higher WHO grade, an increased number of mitoses, elevated Ki67 indices and the presence of contrast-enhancement on pre-operative imaging were associated with less favourable outcome. However, only the presence of contrast-enhancement retained its prognostic significance when forwarded into a multivariate model (p = 0.034 for overall survival, p = 0.012 for progression-free survival). The findings on the association between contrast-enhancement and outcome were confirmed in treatment-based subgroups, including individuals treated with a watch-and-scan approach (n = 30), radiotherapy (n = 25), or chemotherapy (n = 33). CONCLUSION While our findings await confirmation in larger prospective cohorts, neuropathological criteria for anaplasia might need to be accompanied by clinical information including contrast enhancement to prognostically distinguish grade 2 from grade 3 tumors particularly in patients undergoing biopsy given the risk for undersampling.
CNSC-52. OLIGODENDROGLIOMA SPATIAL TRANSCRIPTOMIC SEQUENCING REVEALS THERAPY-DEPENDENT EVOLUTION OVER TIME
Authors: Kanish Mirchia, Jacob Young, Minh Nguyen, Harish Vasudevan, John de Groot, David Raleigh
Journal: Neuro-Oncology (2024)

Abstract Oligodendroglioma evolution is incompletely understood. Here we analyze serial oligodendroglioma samples to define genomic and cellular mechanisms underlying treatment resistance. RNA sequencing was performed on 53,406 spatial transcriptomes from 31 oligodendrogliomas (IDH mutant, 1p/19q-codeleted) that were resected from 16 patients. There were 15 CNS WHO grade 2 and 16 grade 3 oligodendrogliomas, which were stratified for temporal progression across grades (n=5 grade 2 to 2, n=5 grade 2 to 3, n=6 grade 3 to 3) and treatments between serial resections (n=2 TMZ/RT, n=2 TMZ, n=1 mTOR inhibition, n=1 IDH inhibition, n=10 surgical monotherapy). Spatial transcriptomic clusters were defined using cell signature gene sets, cell cycle analysis, differentially expressed marker genes, immunohistochemistry, spatial copy number alterations (CNAs), and deconvolution of 18,628 oligodendroglioma single-cell transcriptomes from 16 independent patients. Specificity was tested using immunofluorescence on independent oligodendrogliomas that did not recur after surgical monotherapy (n=8 samples, median follow-up 8.4 years) and spatial transcriptomic sequencing on 8 matched-paired astrocytomas from 4 patients. Integrated uniform manifold approximation and projection revealed a proneural/NPC-like cluster that was enriched in grade 3 oligodendroglioma samples and represented the starting point in oligodendroglioma lineage differentiation using RNA velocity, Monocle, and subclonal spatiotemporal CNA evolution. Comparison across treatment regimens showed (1) enrichment of the proneural/NPC-like cluster in recurrent versus primary tumors that were treated with surgical monotherapy, (2) enrichment of a proneural/OPC-like cluster and depletion of an oligodendrocyte-like cluster after TMZ/RT, (3) enrichment of proneural/NPC-like and immediate-early response clusters after TMZ/RT, (4) enrichment of the oligodendrocyte-like cluster following mTOR inhibition, and (5) enrichment of cancer associated fibroblasts (CAFs) following IDH inhibition. These data show the spatiotemporal landscape of oligodendroglioma is associated with branched lineage differentiation that is modified by postoperative therapy, and suggest that therapy-dependent druggable dependencies may exist to treat oligodendrogliomas that are resistant to standard interventions.
CTIM-24. PHASE II TRIAL OF RHIL-7-HYFC IN PATIENTS WITH HIGH-GRADE GLIOMA DEMONSTRATED ACCEPTABLE SAFETY PROFILE AND REDUCED LYMPHOPENIA
Authors: Yuping Derek Li, Jingqin Rosy Luo, Cierra Grote, Leslie Nehring, Ruth Katumba, Kelsey Etter, Kaiden Barozinsky, Sara Ferrando-Martinez, Kristina Stermer, Byung Ha Lee, Tanner Johanns, Omar Butt, Jiayi Huang, Jian L Campian, Milan G Chheda
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Lymphopenia, a common finding in patients with high-grade gliomas (HGGs), is associated with poor outcomes including worse survival, fatigue, and in some cases, increased opportunistic infections. Interleukin-7 (IL-7) is a cytokine crucial for lymphocyte survival and proliferation. We previously demonstrated long-acting IL-7 (rhIL-7-hyFc, efineptakin alfa, NT-I7) increases absolute lymphocyte counts (ALCs) and extends survival in preclinical murine models of HGG. Here, we report results using rhIL-7-hyFc to effectively reduce lymphopenia in patients with HGG. METHODS We performed a phase II randomized, placebo-controlled, double-blind study of rhIL-7-hyFc in patients with newly diagnosed HGGs (82% IDH-wildtype glioblastoma in both groups). Patients received rhIL-7-hyFc (720mcg/kg) or placebo one-week post-radiation and temozolomide, with subsequent doses at weeks 13, 25, and 37. The primary endpoint was ALC four weeks post-initial administration; exploratory endpoints included CD4 count, progression-free survival (PFS), and overall survival (OS). RESULTS We enrolled 22 patients (median age 59.5 years, range 33-74; 40.9% female) with HGG. Both groups exhibited comparable demographics, including MGMT methylation status, and received a median of 2 doses of rhIL-7-hyFc or placebo. At 4 weeks, the pre-specified primary endpoint, ALC significantly increased relative to baseline in the treatment group, compared to placebo (median percent change=148% vs. 16.7%, p=0.007), as did CD4 count (121% vs. 10.5%, p=0.011). There were no treatment-related grade 4/5 adverse events. Exploratory endpoints of PFS and OS will be reported at time of conference. CONCLUSIONS rhIL-7-hyFc is safe and effective in improving ALC and CD4 count in patients with newly diagnosed HGG undergoing temozolomide and concurrent radiation therapy. This study was powered to meet the primary endpoint; larger trials will likely be required to demonstrate clinical efficacy. Nevertheless, these data support the continued exploration of rhIL-7-hyFc as an adjunct to standard therapy to mitigate lymphopenia and potentially extend survival for patients with HGG.
CNSC-27. INTRATUMORAL CANCER CELL NETWORKS IN BRAIN METASTASES
Authors: Niels Olshausen, Nils R Hebach, Joana S Schlag, Calvin Thommek, Yvonne Yang, Dirk C Hoffmann, Chanté Mayer, Dana Westphal, Michael O Breckwoldt, Wolfgang Wick, Frank Winkler, Matthia A Karreman
Journal: Neuro-Oncology (2024)

Abstract Recently, we have shown that primary brain tumors form highly organized, small-world scale-free networks, reminiscent of early networks in neurodevelopment and highly resistant to therapy. Such putative cancer-cell intrinsic neural mechanisms are becoming an increasing focus in the field of Cancer Neuroscience, but it has not yet been shown whether tumors of non-CNS origin also have the ability to form multicellular networks which sustain proliferative signaling and increase resistance to therapy. We observed synchronized calcium activity using longitudinal microscopy both in vivo and in vitro that were reminiscent of gap junction coupled networks. Indeed, dye transfer experiments verified functional coupling of brain metastases cells in vitro. Similarly, inhibition of gap junctions with different pharmacological agents significantly reduced calcium oscillations and tumour proliferation in vitro. Furthermore, gap junctions are significantly upregulated in brain-tropic sublines compared to parental cells. To understand the functional relevance of these gap-junction coupled tumor cell networks, we performed bulk RNA-Sequencing of two melanoma metastasis models in monoculture under gap junction inhibition and control: We observed reduced calcium communication and a concordant downregulation of neurodevelopmental and synaptic pathways within the tumor cells upon network disconnection, highlighting a potential recapitulation of neural-like features in metastases to the brain. To investigate the therapeutic potential of targeting these networks, we treated mice with brain metastases with two brain-penetrant gap junction blockers and observed significantly reduced tumor burden. Finally, we investigated the presence of heterotypic networks between brain metastases cells and the brain microenvironment with our SR101 dye transfer pipeline. Contrary to our findings in primary brain tumors, no gap junction connections to cells of the brain microenvironment in those models with reduced tumor growth upon network inhibition could be detected, supporting a cancer cell intrinsic gap junction mediated network and highlighting a selectivity of these homogenous tumor networks and potential therapeutic vulnerability.
NCMP-09. SPONTANEOUS RESOLUTION OF PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) DEVELOPED AFTER RITUXIMAB TREATMENT FOR LOW-GRADE B-CELL LYMPHOMA
Authors: Anas Alshawa, Shadi Latta, Karan Dixit
Journal: Neuro-Oncology (2024)

Abstract Progressive multifocal leukoencephalopathy (PML) is a rare viral infection caused by the reactivation of the JC virus, which causes significant morbidity and mortality. Rituximab, a CD20 inhibitor used for B-cell neoplasms as well as autoimmune diseases, is associated with the development of PML. Here, we report a case of a 74-year-old woman with a history of low-grade B-cell lymphoma with biopsy-proven PML with spontaneous immune reconstitution with clinical and radiographic improvement. For her low-grade B-cell lymphoma, she received six cycles of rituximab and bendamustine, followed by one cycle of maintenance rituximab, which was discontinued due to intolerance. Ten months later, she developed progressive left-sided paresthesias, paresis, and incoordination. Brain MRI revealed a large right subcortical frontal-parietal FLAIR hyperintense and peripherally enhancing lesion with leading-edge diffusion restriction. CSF studies revealed elevated protein (385 mg/dL) and negative JCV PCR. A brain biopsy was performed with tissue staining positive for SV40, consistent with PML. Her CD4 count was 88 cells/mm3. A repeat CSF sample one month later showed near normalization CSF protein (47 mg/dL) and negative CSF JCV PCR. MRI of the brain one month later demonstrated complete enhancement resolution and decreased FLAIR abnormality, which correlated with subjective and objective clinical improvement. Her serum CD4 also increased to 134 cells/mm3. This highlights a rare case of PML related to rituximab with spontaneous improvement, which may help guide clinicians in counseling patients who may also develop this complication. Furthermore, this supports the biological rationale for continued investigation of T-cell therapies to achieve immune reconstitution.
CTIM-25. PHASE2B/3 STUDY OF NEOANTIGEN-SPECIFIC T CELL IMMUNOTHERAPY IN NEWLY DIAGNOSED O6 – METHYLGUANINE METHYLTRANSFERASE UNMETHYLATED (MGMT -) GLIOBLASTOMA
Authors: Tolga Tuncer, Michael Salacz, Brian Milligan, Andrew Sloan, Aaron Mammoser, John Yu, Jean Aguiar, Barry Skikne, Wayne Carter, Gary Wood
Journal: Neuro-Oncology (2024)

Abstract MGMT- glioblastoma (GBM) is the most common malignant primary brain tumor, yet outcomes have not improved in decades despite intensive investigations. TVI-AST-008 is a randomized clinical trial of a novel neoantigen-specific T cell immunotherapy regimen proven invariably curative in rodent models and clinically effective in trials of patients with relapsed/resistant GBM. TVAX neoantigen-specific T cell immunotherapy exploits the fact that cancer cells express neoantigens, and adoptive transfer can bypass the immunosuppressive milieu near the resection cavity. In this manner, TVAX effector T cells initiate apoptosis in any residual GBM. After pathologic confirmation, autologous GBM tumor tissue sent to the TVAX GMP manufacturing facility is irradiated and utilized for proprietary vaccine production. Patients are vaccinated with a series of two intradermal injections and the resulting cancer neoantigen-specific T cells are harvested by leukapheresis. These T cells are activated and proliferated ex vivo by TVAX manufacturing to generate effector T cells. These are re-infused following standard radio-chemotherapy, followed by low-dose interleukin-2 to further stimulate T cell proliferation. In the study, MGMT- GBM patients are randomly assigned to treatment or control arms. Patients in the treatment arm undergo vaccination, then standard concurrent IMRT-chemotherapy, followed by re-infusion of TVAX autologous effector T cells. Patients in the control arm undergo standard IMRT-chemotherapy followed by adjuvant chemotherapy with temozolomide. TVI-AST-008 is an ongoing, randomization-controlled study with Fast Track designation from the FDA. The primary end point is overall survival. Additional end points include progression free survival, safety and immune response. Patients are followed with physical exams and surveillance MRI for evidence of disease progression. The trial is targeted for 15 centers in the US.
TMIC-27. PDPN ACTIVATION OF CLEC5A IN THE PERI-NECROTIC NICHE DRIVES TAM POLARIZATION AND TME IMMUNOSUPPRESSION IN GLIOBLASTOMA
Authors: Jiabo Li, Xuya Wang, Ling-kai Shih, Bo Feng, Tomasz Gruchala, Xuejun Yang, Daniel Brat
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma, IDH-wildtype (GBM, WHO grade 4) is the most common malignant glioma of adults and is characterized by a severely hypoxic and immunosuppressive tumor microenvironment (TME). CLEC5A regulates immune responses in inflammatory and infectious diseases. However, its role in GBM immune regulation remain unclear. Here, we found that CLEC5A has the strongest association with poor clinical outcomes among all immune-related genes in GBM. Tumor-associated macrophages (TAMs) account for the majority of immune cells in the GBM and CLEC5A expression in this population is highest in hypoxic, peri-necrotic zones. Both hypoxia and GBM conditioned media cause increased CLEC5A expression by THP-1 cells, and overexpression of CLEC5A enhanced TAM polarization, migration toward glioma cells, and increased secretion of cytokines that mediate immunosuppression. We show that CLEC5A is a cell surface receptor activated by podoplanin (PDPN) and induces TAM polarization through Syk-JAK-STAT3 signaling. Co-IP assay showed that CLEC5A and PDPN could be binded together using antibodies for CLEC5A, Flag-CLEC5A or PDPN when we cocultured control THP-1 cells and THP-1 cells overexpressing Flag-CLEC5A with primary GBM cells (NU02068). PDPN blocking antibody (α-PDPN) reduced the specific binding between PDPN and CLEC5A, as well as inhibited the TAM-IM polarization. Overexpression of CLEC5A significantly upregulated the expression of p-Syk, Jak2, p-Jak2, STAT3, p-STAT3, CD163, CD206 and PD-L1. Moreover, Bay 61-3606, a selective Syk inhibitor, rescued CLEC5A overexpression-mediated TAM-IM polarization and Syk-JAK-STAT3 activation in THP-1 cells. In vivo, both silencing CLEC5A in TAMs and silencing PDPN in GBM cells, as well as pharmacologically targeting Syk delayed glioma growth, prolonged survival and was associated with diminished immunosuppressive TAMs. Collectively, we found that PDPN-CLEC5A-Syk-JAK-STAT3 signaling causes TAM polarization and enhances TME immunosuppression in GBM and can be targeted to suppress growth.