tbuckley/cabot-search huggingface dataset:
EXTH-70. PRECLINICAL TRIALS OF THE ANTIBODY-DRUG CONJUGATE TISOTUMAB VEDOTIN IN ADULT-TYPE DIFFUSE GLIOMAS
Authors: Thomas Sears, Wenxia Wang, Dusten Unruh, Alicia Steffens, Matthew McCord, Craig Horbinski
Journal: Neuro-Oncology (2024)

Abstract The gene F3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Our previous work showed that, among adult-type diffuse gliomas, IDH wild-type (IDHwt) glioblastomas (GBM) express more TF than IDH mutant (IDHmut) gliomas (PMID: 27664011, 30266764, 31222125). Tisotumab vedotin (TisVed), an anti-TF antibody conjugated to monomethyl auristatin E, is a therapeutic designed to target cells expressing TF. We therefore sought to determine the therapeutic potential of TisVed in IDHwt vs. IDHmut gliomas. TisVed was more active against cultured IDHwt GBM cells than IDHmut glioma cells (P&amp;lt;0.0001). This activity was increased by 55% with daily washout of the soluble TF secreted by IDHwt GBM cells. TisVed extended the survival of mice intracranially engrafted with IDHwt GBM by 34% (37.5 days vs. 28 days for IgG control, P=0.006), but not mice with IDHmut glioma (30.5 days, P=0.88). TisVed also reduced the growth of IDHwt GBM flank xenografts by 58% (P=0.045). Unconjugated Tis had no antitumor effect intracranially or in the flank. All 12 flank-engrafted mice treated with Tis, and 9/12 mice treated with TisVed, developed large hematomas in and around the flank xenografts, compared to 0/12 IgG-treated mice (P&amp;lt;0.001). Similarly, a semiquantitative analysis showed that intracerebral hemorrhage was more extensive in Tis/TisVed- treated GBM12 mice than in IgG-treated GBM12 mice (P=0.046). These data indicate that TisVed targets high TF-expressing IDHwt GBM, but not low TF-expressing IDHmut glioma, that its activity is predominately through the vedotin conjugate rather than inhibition of TF signaling, and that it may have some effect against TF-expressing IDHwt GBM, but intracerebral hemorrhage may be a concern.
TMIC-71. ELUCIDATING IMMUNE MICROENVIRONMENTAL DISTINCTIONS BETWEEN IDH-MUTANT ASTROCYTOMA AND OLIGODENDROGLIOMA USING SINGLE-CELL TRANSCRIPTIONAL PROFILING
Authors: Benjamin Whitfield, Yang Liu, Pravesh Gupta, Shivangi Oberai, Krishna Bhat, Jason Huse
Journal: Neuro-Oncology (2024)

Abstract Despite exhibiting longer overall survival that IDH-wt counterparts, IDH-mutant gliomas remain uniformly deadly and impact patients in the prime of adult life. The immune microenvironment of IDH-mutant gliomas remains incompletely characterized, particularly with regard to distinctions between IDH-mutant astrocytoma and IDH-mutant, 1p/19q codeleted oligodendroglioma. To address this knowledge gap, we subjected dissociated tumor suspensions derived from 7 astrocytoma and 7 oligodendroglioma clinical samples to flow cytometry-based sorting for the pan-immune marker, CD45, and the microglial marker, P2RY12. This process yielded both microglial and non-microglial immune cell populations, which were then analyzed by scRNA sequencing. This workflow revealed a single large cluster of microglia, characterized by expression of Galectin-1 and lysosomal Lipase A, which was present at a significantly higher level in oligodendroglioma. While the biological significance of this cluster is unclear, gene set enrichment analysis exploring phenotypic differences between microglia in astrocytoma and oligodendroglioma revealed significant increases in expression of gene sets related to antigen presentation in astrocytoma. Parallel analysis of the non-microglial immune fraction showed an increase in the expression of pro-inflammatory gene sets, such as genes related to cytokine secretion, within the CD8 T-cell compartment of astrocytomas. We also observed upregulation of the expression of inflammatory gene sets within the dendritic cells of astrocytomas. Taken together, these changes suggest that the immune compartment of astrocytoma is more active and inflamed, and targeting the immune system in these tumors may represent a potential therapeutic avenue.
Transformative Therapies for Depression: Postpartum Depression, Major Depressive Disorder, and Treatment-Resistant Depression
Authors: Elizabeth Richardson, Riah Patterson, Samantha Meltzer-Brody, Robert McClure, Amanda Tow
Journal: Annual Review of Medicine (2024)

Depressive disorders present an enormous global public health burden. A notable treatment gap exists between the prevalence of depression and our ability to provide rapid-acting, effective treatment that achieves remission. Brexanolone and zuranolone, the first US Food and Drug Administration-approved drugs for postpartum depression, signify a critical advancement in addressing the unmet needs of a vulnerable patient population. Psilocybin shows promise for treatment-resistant depression and for those who have struggled to find relief with existing treatments. This review discusses transformative therapies that represent significant advancements in postpartum depression, major depressive disorder, and treatment-resistant depression.
EXTH-74. COOLING GLIOBLASTOMA WITH A NEURAL IMPLANT
Authors: Syed Faaiz Enam, Mahabad Barwari, Reed Chen, Aksharkumar Dobariya, Sourav Patnaik, Bret Evers, Ravi Bellamkonda, Toral Patel, Ankur Patel
Journal: Neuro-Oncology (2024)

Abstract Survival rates for glioblastoma (GBM) patients are low due to the difficulty in eradicating all tumor cells, leading to frequent recurrence. This recurrence is frequently within 2-cm from the original site. Studies indicate that supra-total resection improves survival, and non-destructive local therapies show promise in preventing GBM recurrence. Our research demonstrates that non-freezing, ‘cytostatic’ hypothermia is effective against GBM in rats and can be scaled to pig models. This method, unlike ablative cryogenic hypothermia, safely inhibits GBM growth without damaging healthy tissue. Using in vitro culture models and in vivo rat models via a Peltier device, we tested cytostatic hypothermia. This was followed by finite-element modeling (FEM) to simulate bioheat transfer in human and pig brains. The system consists of a neural implant with a multiprobe array, a Peltier chip, a water block, and an artificial internal circulation system with a piezoelectric pump. In vitro tests identified a cytostatic window of 20–25°C. Miniature Peltier devices were fabricated to achieve this in rats to inhibit GBM growth and extend survival. Rats whose tumors received cytostatic levels of hypothermia survived their full study period. FEM simulations confirmed that multiprobe arrays could cool brain tissue to 25°C without significantly raising skin temperature. Portable systems were successfully fabricated and tested in pigs, achieving safe target temperatures with minimal EEG and OCTA changes. Our findings suggest that cytostatic hypothermia can be scaled to larger animals and made implantable and portable, offering a promising non-destructive approach to halting GBM growth and prolonging survival, moving closer to becoming a viable treatment option for patients with GBM.
NIMG-44. ELEVATED TRANSLOCATOR PROTEIN 18KDA BINDING IN LOW MEAN DIFFUSIVITY CLUSTERS IS A FEATURE OF THE TRANSFORMING GLIOMA AND IDH MUTANT GLIOMA MICROENVIRONMENT
Authors: James Breese, Erjon Agushi, Daniel Lewis, Rainer Hinz, Bandar Alfaifi, Alan Jackson, Mueez Waqar, David Coope
Journal: Neuro-Oncology (2024)

Abstract Around 95% of low-grade gliomas undergo anaplastic de-differentiation into high-grade gliomas, a process only partially understood from in vivo clinical imaging. 11 patients with suspected transforming gliomas underwent a combined magnetic resonance imaging (MRI) and positron emission tomography (PET) protocol, incorporating post-contrast T1-weighted/FLAIR acquisition for tumour delineation and diffusion tensor imaging. The PET radiotracer [11C]-(R)-PK11195 assessed translocator protein 18kDa (TSPO) distribution, whose upregulation is associated with inflammation/glioma progression. [11C]-(R)-PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model, with the grey-matter cerebellar time-activity curve serving as the reference tissue input function. KMeans clustering of mean diffusivity (MD) intensity values defined spatially distinct “habitats” of high/low MD voxels within the glioma microenvironment. BPND values within high/low MD clustering habitats were evaluated, across glioma grades and isocitrate dehydrogenase (IDH) mutational status. Across all grade 2 and 3 gliomas (n= 6), mean TSPO BPND values in low MD habitats (0.0383 ±0.102) were significantly greater than high MD habitats (-0.045 ±0.142) (p= 0.003). In grade 4 gliomas (n= 5), no significant difference was observed in mean BPND values between low (0.514 ±0.176) and high (0.465 ±0.296) MD habitats (p= 0.543). IDH mutant gliomas (n= 7) exhibited significantly higher mean BPND in low MD habitats (0.116 ±0.225), relative to high habitats (0.052 ±0.287) (p= 0.021). IDH wildtype gliomas (n= 4) showed no significant differences between BPND values in low (0.498 ±0.199) and high MD habitats (0.424 ±0.325) (p= 0.467). Our novel findings demonstrate spatial heterogeneity in TSPO expression within 2/3/IDH mutant gliomas, a characteristic absent from grade 4/IDH wildtype varieties. Regions of restricted diffusion with high TSPO signal in grade 2/3/IDH mutant tumours indicate the heterogenous distribution of active TSPO-expressing immune/neoplastic cell populations, contrasting the homogenous distribution in grade 4/IDH wildtype gliomas, highlighting differences between their inflammatory profile and pathological features.
IMMU-56. THE TIGIT/CD155 AXIS PLAYS A CRITICAL ROLE IN EXTRACELLULAR VESICLE-MEDIATED PROGRAMMING OF THE GLIOBLASTOMA MICROENVIRONMENT
Authors: Mohamad Asad, Julio Inocencio, Stefan Mitrasinovic, Minori Aoiki, Ian Parney, Celina Crisman, Patrick Lasala, Emad Eskandar, Benjamin Himes
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM), the most common and deadly primary brain tumor, exerts profound local and systemic immunosuppressive effects through a variety of mechanisms. Tumor-derived extracellular vesicles (EVs) are increasingly appreciated as critical mediators of these effects. In surveying the tumor-immune microenvironment in samples of ultrasonic aspirate collected during surgical resection of GBM (n=13), we identified several key immunomodulatory markers expressed across a range of myeloid cell populations. Particularly, we found TIGIT, classically understood as a T cell inhibitory protein, expressed across a range of myeloid cell populations in patient samples, including in myeloid-derived suppressor cells (MDSCs, 46.84±16.78% of total monocytic MDSCs). Using EVs collected from patient-derived cell lines, we were able to recapitulate these effects upon co-culture with monocytes derived from the peripheral blood of healthy donors (n=7). Furthermore, Induced MDSCs significantly inhibit T cells proliferation (70.97±8.454%, compared to control 19.4±5.71; p&amp;lt;0.03), concomitant with a surge in Th2 immune responses via TIGIT/CD155 axis. This effect was reversed after TIGIT silencing, indicating a TIGIT-dependent immune suppression in the GBM microenvironment. Our study indicates EV-induced TIGIT upregulation in myeloid cells as a crucial immunosuppressive mechanism in glioblastoma, with potential therapeutic applications.
CTNI-33. EARLY COMPLETE RESPONSE MIGHT NOT BE AN INDICATOR OF LONGER PROGRESSION-FREE SURVIVAL IN NEWLY-DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH A COMPLETE RESPONSE BY MTX-BASED INDUCTION THERAPY
Authors: Motoo Nagane, Nobuyoshi Sasaki, Kuniaki Saito, Keiichi Kobayashi, Kazuha Kugasawa, Ryo Onoda, Hirofumi Nakatomi
Journal: Neuro-Oncology (2024)

Abstract Primary central nervous system lymphoma (PCNSL) is an extra-nodal non-Hodgkin lymphoma solely arising from the central nervous system including eyes. While 70% of patients with newly-diagnosed PCNSL achieve a complete response (CR) after R-MPV, the current standard of care MTX-based induction therapy, recurrence yet frequently occurs (~50%) and clinical factors related to failure are not well defined. Early complete response is associated with lower recurrence rate in various cancers. In this study, we conducted a retrospective, single-institution study to investigate whether early complete response was associated with recurrence in PCNSL. Newly-diagnosed PCNSL patients treated with R-MPV at the authors’ institution between 2011 and 2022 were identified, and progression-free survival (PFS), overall survival (OS) were analyzed along with number of chemotherapy cycles required to achieve a CR or CR unconfirmed (CRu). In total of 92 patients treated with R-MPV identified, 68 (75%) patients achieved a CR or CRu. Among patients who achieved CR or CRu, a median total of seven (1-8) R-MPV cycles were delivered. The median cycle required to achieve CR or CRu was five (1-8). Consolidation whole brain radiation therapy (WBRT) was given to 29 younger patients (median age: 63), while 39 older patients (median age: 74) were treated without WBRT. The number of chemotherapy cycles required to achieve CR or CRu was not associated with PFS or OS in all ages. However, requiring six or more chemotherapy cycles to achieve CR or CRu was associated with longer PFS (p=0.046) in patients treated without WBRT. These data suggest that early complete response might not be indicative of superior survival outcome in newly-diagnosed PCNSL treated without consolidation WBRT. Persisting enhancing lesions during chemotherapy could lead to treatment intensification through delivering greater number of chemotherapy cycles, which might have conferred longer PFS in these patients.
PATH-56. LOSS OF HETEROZYGOSITY OF CDKN2A/B DEFINES AN AGGRESSIVE SUBSET OF RECURRENT, HIGH-GRADE MENINGIOMAS
Authors: Alper Dincer, Shaila Ghanekar, Emre Kocakavuk, Joanna Tabor, Miri Kim, Jennifer Moliterno
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Loss of heterozygosity (LOH) occurs when one gene allele is lost, leaving the cell with a single functional copy. This genetic alteration drives tumor progression by disabling critical regulatory pathways. Currently, CDKN2A/B homozygous loss is a criterion for WHO Grade 3 meningiomas. However, the impact of CDKN2A/B LOH and other copy-number alterations remains unclear. This study investigates the effects of LOH in the CDKN2A/B tumor suppressor gene on progression-free survival (PFS) and overall survival (OS) in meningiomas. METHODS The study included adult patients with sporadic primary or recurrent meningiomas who underwent resection and whole exome sequencing. LOH and copy-number alterations were confirmed on visual inspection of b-allele frequency and mean ratio graphs. Samples of unsuitable quality for evaluation were excluded. CDKN2A/B copy number and LOH were associated with PFS and OS. RESULTS The sample included 333 meningiomas (64.6% female [n=215], 18.8% recurrent meningiomas [n=61], and 50 cases of postoperative recurrence [15%]). CDKN2A/B was intact in 88.5% of samples (n=295), while 38 samples (11.4%) exhibited CDKN2A/B LOH. This included homozygous deletions (n=2, 5.2%), heterozygous deletions (n=11, 28.9%), amplifications (n=12, 31.6%), and copy-neutral LOH (n=13, 34.2%). All copy-number alterations were associated with an increased risk of recurrence compared to CDKN2A/B intact samples, so CDKN2A/B LOH was used for subsequent analysis. CDKN2A/B LOH was more frequently associated with prior recurrence (22.9% vs. 8.8%; p=0.004), prior radiation (46% vs. 15.6%; p&amp;lt;0.0001), and WHO Grade 2 and 3 tumors (63.2% vs. 42.7%; p=0.02). CDKN2A/B LOH was associated with worse PFS (HR 3.97 [1.3-11.9]; p=0.01) and worse OS (HR 2.9 [1.03-8.2]; p=0.0429) only in recurrent, high-grade meningiomas, independent of the fraction of the genome altered, mutation count, and Simpson grade. Postoperative radiation therapy did not improve PFS (HR 3.24 [1.06-9.85]; p=0.038). CONCLUSION CDKN2A/B LOH is enriched in high-grade, recurrent meningiomas and confers worse PFS and OS despite postoperative radiotherapy. CDKN2A/B LOH is a high-risk biomarker that predicts tumor behavior and patient outcome.
NCOG-32. RELATIONSHIPS BETWEEN INTRAOPERATIVE TASK-BASED GAMMA BAND ELECTROCORTICOGRAMS, DIRECT ELECTRICAL STIMULATION, AND COGNITIVE-LINGUISTIC OUTCOME FOLLOWING AWAKE BRAIN TUMOR RESECTION
Authors: Kyle Noll, Israt Tasnim, Priscella Asman, Chandra Swamy, Katherine Connelly, Matthew Muir, Matthew Hall, Guiseppe Pellizzer, Nuri Ince, Sujit Prabhu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND As an adjunct to direct electrical stimulation (DES), intraoperative electrocorticography (ECoG) can aid detection of language-eloquent cortex. However, it is unclear how surgical impact upon mapping findings relates to cognitive-linguistic outcomes. METHODS Ten patients underwent awake craniotomy for tumor resection with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to an electrode array capable of both recording ECoG activity and delivering DES. Time-frequency gamma band activations were visualized (Early, Long, Late, Double Peak) for 3 naming paradigms (Object, Action, Auditory). DES was also conducted for each task. Mapping results were overlayed on postoperative MRI to examine proximity to parenchymal trauma (cavity, sulcal displacement). Patients completed cognitive-linguistic testing [WAB-R (N=3) or Neuropsychological Assessment (N=7)] prior to surgery and &amp;lt;2 months postoperatively. Patients with persisting aphasia at 6-month follow-up were also identified. RESULTS Postoperative language decline was found in 50% of patients, with 30% showing worsening (&amp;gt;1SD) in Naming and Phonemic Fluency, and 60% in Semantic Fluency. Surgery impacted ECoG features in 60% of patients and DES arrest sites in 30%. A trend was observed where Early and Late Object naming ECoG features were associated with Semantic Fluency decline [rpb(5)=-.69, p=.067]. Arrest during Auditory naming DES &amp;lt;1 cm of surgical effect was associated with decline in Abstraction [rpb(5)=-.83, p=.042; FET, p=.029] and Semantic Fluency [rpb(5)=-.87, p=.012; FET, p=.024]. Excluding the 3 transsulcal surgeries, arrest during Auditory naming DES &amp;lt;1 cm of resection was associated with general language decline [FET, p=.047]. All 3 patients with persisting aphasia had Auditory naming arrest &amp;lt;1 cm of resection and 2/3 patients had Object naming ECoG features resected. CONCLUSIONS While preliminary, results suggest that surgical proximity to ECoG and DES mapping results may inform risk of surgically-acquired cognitive-linguistic decline. Findings support the potential of multimethod-multitask intraoperative language mapping.
PATH-67. THE ROLE OF STATUS OF HER-2, ESTROGEN-RECEPTOR, BRCA 1, AND BRCA 2, IN THE INCIDENCE OF BRAIN METASTASIS IN BREAST CANCER
Authors: Ahmed Altaf, Ahmed Gilani, Ali Azan, Ather Enam
Journal: Neuro-Oncology (2024)

Abstract Breast cancer (BC) is the most diagnosed tumor in women and the second-leading cause of brain metastasis (BM), with a prevalence ranging from 10-36%. According to the Epidemiological Strategy and Medical Economics research program, advanced BC patients face an estimated 25% risk of developing BM within 2-3 years after the initial diagnosis. The frequency of BM is significantly increased by the primary tumor profile, including larger tumors, higher nuclear grade, HER-2 positivity, estrogen-receptor negativity, and triple-negative status. A gap remains in the classification of the BM site relative to primary tumor biomarkers, and the absence of multimodality treatment methodologies poses challenges to survival rates and quality of life in BC patients. This retrospective cross-sectional study at Aga Khan University Hospital identified 52 cases of brain metastasis secondary to breast cancer over a 10-year period. The median age of patients was 55 years, ranging from 32 to 78 years. Primary breast tumors were predominantly high-grade ductal carcinomas (65%), followed by lobular carcinomas (25%) and other rare histological types (10%). Secondary brain metastases were primarily located in the cerebrum (60%), cerebellum (25%), and brainstem (15%). Tumor profiles indicated a significant correlation between HER-2 positivity and the development of brain metastasis, with 70% of HER-2 positive patients presenting with extensive brain metastasis. Tumor progression varied, with a median time to brain metastasis of 2.5 years from the initial breast cancer diagnosis. Despite aggressive multimodality treatments, including surgery, radiation, and chemotherapy, the overall prognosis remained poor. The study found that early detection of HER-2 positive and triple-negative tumors could potentially delay the progression of brain metastasis through targeted therapies. Mortality rates in this cohort were high, with a median survival of 8 months following the diagnosis of brain metastasis. These findings underscore the need for improved diagnostic, preventive, and therapeutic strategies to manage brain metastasis in breast cancer patients.
PATH-66. MOLECULAR FEATURES RELATED TO LONG-TERM SURVIVAL IN GLIOBLASTOMA
Authors: Michal Nisnboym Ziv, Itay Raphael, Jan Drappatz, Daniel F Marker
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor in adults, with a dismal prognosis that rarely exceeds beyond 2 years of survival despite multimodal treatment. While small fractions of GBM patients seem to display extended survival, the underlying mechanisms for this peculiarity remain largely unknown. Previously published investigations of long-term survivors (LTS) usually incorporate small numbers of patients, non-uniform definition of LTS and rarely provide a comprehensive molecular analysis. With advances in multi-omics technologies and their integration with disease diagnostics, numerous prognostic molecular markers have been proposed. So far, only O6-methylguanine-DNA-methyltransferase (MGMT) gene promotor hypermethylation was linked to outcome and therapy response. We aim to investigate omics characteristics associated with LTS. Molecularly confirmed Isocitrate Dehydrogenase (IDH) wildtype GBM patients, &amp;gt;18 years old, operated and treated at our institution between 2013 and 2020 and living ≥5 years post-diagnosis (LTS = 62) or 1-2 years (STS = 62) were identified. Clinical and demographic characteristics were matched. Tumor tissues was analyzed with targeted next generation sequencing (NGS) and compared between LTS and STS. In addition, methylation analysis was done for all LTS. Results will be presented. We hope to shed a broader light on the molecular drivers behind the LTS in GBM patients, that will provide prognostic markers and potential targets for novel treatments.