tbuckley/cabot-search huggingface dataset:
PATH-39. AI-BASED IDENTIFICATION OF GLIOMA IDH MUTATIONAL STATUS FROM H&amp;E-STAINED WHOLE SLIDE IMAGES
Authors: Shubham Innani, Bhakti Baheti, MacLean P Nasrallah, W Robert Bell, Spyridon Bakas
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Isocitrate-dehydrogenase (IDH) mutational status is diagnostically critical in adult gliomas, with prognostic and therapeutic implications. IDH status cannot be determined by sole histologic assessment and requires molecular testing. We hypothesize that AI-based analysis can accurately predict IDH mutational status in glioma, by retrieving sub-visual cues in H&amp;E-stained digitized tissue sections. MATERIALS AND METHODS A retrospective discovery cohort of 1,534 cases (756/778 IDH-wildtype/IDH-mutant, including all available grades) from the TCGA-LGG/TCGA-GBM collections was used for model development with 10-fold cross-validation (CV). A replication cohort of 114 cases (82/32 IDH-wildtype/IDH-mutant) from the University of Pennsylvania Health System (UPHS) was used for independent hold-out evaluation. Each 20X magnification whole slide image (WSI) underwent comprehensive curation for elimination of artifactual content, followed by partitioning into 256x256 patches, and feature extraction using pre-trained i) ImageNet weights (baseline), and ii) self-supervised vision transformer (ViT). A weakly-supervised attention-based multiple-instance-learning framework distinguished cases as IDH-wildtype or IDH-mutant, while generating visually interpretable attention heatmaps. RESULTS Evaluation on discovery and replication cohorts with the ViT yield accuracy of 90.84% (AUCDiscovery=97.16%) and 93.94% (AUCReplication=97.36%), respectively, with high sensitivity (i.e., high confidence in correctly predicting IDH-wildtype glioma). Comparison of the ViT with the baseline model on the replication cohort indicates the ViT superiority by improvements of 8% and 9.5% in accuracy and AUC, respectively. Histologic assessment of heatmaps indicates IDH-wildtype tumors exhibiting distinct regions of significant pleomorphism and microvascular proliferation, while IDH-mutant tumors exhibit dense nodular cell concentrations, microcystic architecture, and gemistocytic cells. CONCLUSION Our accurate H&amp;E-based computational determination of glioma IDH status, with interpretations aligned with human-identifiable features, can contribute to obviating the need for molecular analyses and enable expedited diagnosis even in community healthcare settings. This study robustly identifies morpho-IDH correlates and could enable expedited patient prognostic stratification.
INNV-26. FEASIBILITY EVALUATION OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR BRAINSTEM GLIOMAS
Authors: Wenyin Shi, Brian Berger, Noe Urman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor Treating Fields (TTFields) therapy is a novel anti-mitotic therapy that is FDA-approved for use in patients with newly diagnosed and recurrent glioblastoma (GBM). However, TTFields therapy is currently only approved for supratentorial GBM, and the feasibility of TTFields therapy for treating infratentorial GBM remains unknown. TTFields values of average local minimum power density (LMiPD) &amp;gt;1.15 mW/cm3 and local minimum field intensity (LMiFI) &amp;gt;1.06 V/cm, were associated with improved OS and PFS based on a posthoc analysis of the EF-14 study. This is a dosimetric planning evaluation of the feasibility of TTFields therapy for brainstem gliomas. METHODS MRIs of patients with brainstem gliomas were used for this dosimetric evaluation, with planning conducted using MAXPOINT (Novocure, Switzerland). Gross tumor volume (GTV) for TTFields planning was defined as enhancing tumor on T1 post contrast MRI. Clinical target volume (CTV) was defined as GTV expanded by a 3 mm margin around sum total of resection cavity, necrotic core, and enhancing tumor. LMiPD and LMiFI to the GTV and CTV were evaluated. RESULTS A total of 5 patients with brainstem gliomas were included in this study. The median GTV volume was 8.2 cc (range: 3.8 – 13.5 cc), and median CTV volume was 18.6 cc (range: 9.1 – 23.4 cc). The median LMiPD for GTV and CTV were 1.9 (range: 1.1 – 2) and 1.9 (range: 1-2.1) mW/cm3, respectively. The median LMiFI for GTV and CTV were 1.3 (range: 1.1-1.6) and 1.2 (range: 1.1-1.6) V/cm, respectively. CONCLUSION LMiPD and LMiFI values for brainstem gliomas achieved levels that are consistent with those associated with improved OS and PFS in posthoc analyses in supratentorial GBM. This dosimetric planning study suggests feasibility and theoretical benefit of TTFields for brainstem gliomas. Further clinical evaluation is warranted to validate its efficacy.
EXTH-04. COMBINATION OF BEVACIZUMAB ENHANCES THE ANTI-TUMOR EFFICACY OF AD-SGE-REIC FOR GLIOMA
Authors: Yoshihiro Otani, Yasuhiko Hattori, Atsuhito Uneda, Nobushige Tsuboi, Keigo Makino, Shuichiro Hirano, Joji Ishida, Kentaro Fujii, Yusuke Tomita, Tetsuo Oka, Yuji Matsumoto, Yosuke Shimazu, Hiroyuki Michiue, Kazuhiko Kurozumi, Hiromu Kumon, Isao Date, Shota Tanaka
Journal: Neuro-Oncology (2024)

Abstract Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor gene and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we revealed the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC) and conducted the phase Ⅰ/Ⅱ a clinical trial for recurrent malignant glioma (jRCT2063190013). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic efficacy in patients with glioma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab in vitro and in vivo. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased β-catenin protein levels. In glioma-bearing mouse models, survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab showed anti-glioma effects by suppressing the angiogenesis and invasion of tumor cells. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.
SURG-02. ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA WITH LEPTOMENINGEAL DISSEMINATION PRESENTING WITH CRANIAL NEUROPATHY IN AN ADULT PATIENT: ILLUSTRATIVE CASE AND REVIEW OF THE LITERATURE
Authors: Simon Menaker, Andre Boyke, Serguei Bannykh, Lindsey Ross, Paula Eboli
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Anaplastic pleomorphic xanthoastrocytomas (APXA) are very rare, grade III malignant astrocytic glial neoplasms first described as a distinct entity in the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS). They are generally seen in pediatric and young adult patients as supratentorial lesions with both solid and cystic components and have a high propensity for recurrence despite local treatment. APXAs occasionally demonstrate leptomeningeal dissemination (LMD) but extremely seldom at the time of diagnosis. They are typically treated via surgical resection with adjuvant chemoradiation, although there is no standard of care for adjuvant therapy. Case Presentation: The authors describe the case of a 37-year-old male with a history of seizures since age 11 who presented with four months of worsening headache, increasingly frequent seizures, and diplopia with right cranial nerve III palsy. Imaging at the time of diagnosis of his seizure disorder as a child demonstrated a small left temporal lesion, which remained stable on imaging for over 20 years and was never biopsied, however MRI at current presentation showed significant interval enlargement with intralesional hemorrhage and leptomeningeal enhancement involving the left temporal and parietal lobes, left internal auditory canal, and right oculomotor nerve. He underwent surgical resection with gross total resection achieved and pathology revealed WHO Grade III pleomorphic xanthoastrocytoma with ATG7::RAF1 fusion, 9p21 deletion, and TERT promoter mutation on next generation sequencing. This was followed by adjuvant whole brain radiation with boost and treatment with MEK inhibitor cobimetinib. His postoperative course was remarkable for intermittent speech difficulty and improving right third nerve palsy. CONCLUSION We describe the unusual presentation of an already exceedingly rare primary CNS tumor, namely APXA in an adult patient with LMD and cranial neuropathy at the time of diagnosis, and detail tailored adjuvant therapy based on genomic profiling.
CNSC-49. ELUCIDATING THERAPEUTIC POTENTIAL OF USP1 INHIBITION IN DIFFUSE MIDLINE GLIOMAS
Authors: Monika Yadav, Adora Klinestiver, Garrett Gibson, Syed M Faisal, Dana Messinger, Carl Koschmann, Viveka Nand Yadav
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with the H3K27M mutation in the H3F3A or H3C2 gene. Despite treatment advances, radiotherapy is the only viable option, but 99% of patients die within 1.5-2 years. Therefore, there is an urgent need to identify potential novel therapeutic targets for the treatment of DMGs. Ubiquitin-specific protease 1 (USP1) is a key deubiquitinating enzyme involved in genome integrity, cell cycle regulation, and cell homeostasis. USP1 is overexpressed in various cancers, including gliomas, is linked to poor prognosis. It promotes glioma stem cell (GSC) self-renewal and radio-resistance by regulating ID1 and CHEK1. Our recent findings show that ID1 is crucial for DMG invasion and migration. Inhibiting USP1 suppresses malignant growth, enhances radiation sensitivity, and improves chemotherapy response, highlighting its potential for combined therapies. However, USP1’s role in DMGs and its feasibility as a therapeutic target remain poorly understood. In this study, we investigated USP1 in DMGs for the first time. RNA sequencing revealed high USP1 expression in DMG patient samples and cell lines, directly linked to the H3K27M mutation. Correcting this mutation reduced USP1 expression in DMG cell lines. Pharmacologic inhibition of USP1 with the specific inhibitor SJB3-019A significantly reduced DMG cell proliferation, triggered apoptosis, and altered cell cycle profile. SJB3-019A-mediated USP1 inhibition decreases migration and invasion in multiple patient-derived DMG cell lines. Additional in vitro experiments revealed that USP1 inhibition leads to a significant decrease in the expression of ID1 and pAKT, suggesting the ID1/AKT pathway as a potential mechanism underlying the observed effects. H3K27M-mediated activation of USP1 in DMG is a promising therapeutic target, with inhibition by SJB3-019A reducing tumor aggressiveness by inhibiting invasion and migration. We will next assess SJB3-019A’s efficacy in vivo using genetically engineered isogenic mouse models (GEMM) with DNp53/PDGFRA/H3.3K27M (PPK) alterations and evaluate USP1 inhibition combined with radiation therapy as a potential radiosensitizer in DMGs.
BIOM-72. INTEGRATION OF ULTRASENSITIVE ELECTROLUMINESCENT IMMUNOASSAY AND CELL-FREE DNAMETHYLATION ANALYSIS FOR NON-INVASIVE MONITORING OF ADULT DIFFUSE GLIOMAS
Authors: Andrew Ajisebutu, Miyo Chatanaka, Vikas Patil, Ioannis Prassas, Diamandis Eleftherios, Gelareh Zadeh
Journal: Neuro-Oncology (2024)

Abstract Gliomas are highly aggressive brain tumors with nearly universal recurrence rate. Despite this, the ability to accurately predict and identify tumor recurrence relies solely on serial MRI imaging, which is marred by treatment effects such as radiation necrosis, and necessarily identifies progression retrospectively. It is believe that tumor undergo molecular changes upon tumor progression, however the resampling of tumors upon recurrence imposes significant risks. This highlights the need for novel non-invasive biomarkers capable of identifying tumor recurrence. Due to the low accuracies of individual biomarkers, we have proposed the use of an integrated, multi-platform approach to biomarker discovery. A cohort of 107 glioma plasma samples, including 30 pairs, underwent plasma proteomic analysis, consisting of a panel of serum proteins (FABP4, GFAP, NFL, Tau and MMP3,4 &amp;7) quantified through ultrasensitive electrochemiluminescence multiplexed immunoassays, and plasma DNA methylation analysis, captured through cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Unsupervised hierarchal clustering revealed robust separation of primary and recurrent tumors through plasma proteomics, associated with a distinct plasma methylation signature. NFL, Tau and MMP3 levels differed between primary and recurrent samples; pair-wise analysis revealed increased in NFL and Tau concentrations upon recurrence. Tau levels predicted outcome independent of WHO Grade and IDH status. A predictive generalized linear regression model created through the integration of the proteomic and methylation signatures allowed for the discrimination of primary and recurrent samples in 83% of cases. This work suggests that the combination of DNA methylation and plasma proteomics may improve the ability of these techniques for the serial monitoring of gliomas patients.
PATH-54. HIGH-THROUGHPUT SINGLE NUCLEAR DNA SEQUENCING OF HUMAN SPORADIC<i>NF1</i> MUTANT IDH-WILDTYPE GLIOBLASTOMAS REVEALS PATTERNS OF TUMOR EVOLUTION AND RECURRENCE
Authors: Kanish Mirchia, Sixuan Pan, Emily Payne, Rachel Agoglia, Marc Arribas-Layton, Harish Vasudevan
Journal: Neuro-Oncology (2024)

Abstract The advent of single cell techniques has advanced our understanding of glioblastoma (GBM) evolution and cell lineage relationships. However, study of mutational co-occurrence and clonal phylogeny has been hampered by limitations in single cell genotyping. Here, we perform semi-automated, rapid single nuclear dissociation followed by targeted single nucleus DNA sequencing (snDNA-seq) of eleven retrospectively identified somatic NF1 mutant IDH-wildtype glioblastomas. Bulk DNA sequencing was performed as part of routine clinical care using a CLIA-certified targeted sequencing panel. For snDNA-seq, tissue cores with greater than 30% tumor were dissociated on a S2 genomics S100 Singulator followed by snDNA-seq using a targeted 361 amplicon panel (Tapestri, Mission Bio, USA) to sequence for recurrently observed single nucleotide substitutions and copy number alterations. A mean of 3,661 cells were recovered per sample with a mean of 96 reads per cell per amplicon and 87% mean panel uniformity. SnDNA-seq validated point mutations and copy number alterations observed in bulk DNA-sequencing and revealed novel alterations and subclonal copy number alterations not detected on bulk analysis. Within individual samples, snDNA-seq based phylogenetic reconstruction identified mutually exclusive patterns of mutation between NF1 and PI3K signaling alterations, suggesting these events may occur in distinct tumor subclones. With regard to copy number alterations (CNAs), snDNA-seq demonstrated intra-tumoral heterogeneity for chromosome 9p loss, chromosome 7 gain, and chromosome 10 monosomy. Subclonal CNA clones not detected by bulk sequencing were identified in 5 samples. Analysis of a matched primary-recurrent tumor pair revealed expansion of a specific mutational clone (loss of 9p, 10p, gains of 1p, 7, 15, and 19q) at recurrence. SnDNA-seq recapitulated bulk DNA sequencing alterations and identified distinct patterns of mutational co-occurrence, CNAs, and tumor evolution over time. Reconstructing GBM phylogeny at single cell resolution has potential translational implications for understanding tumor evolution and treatment resistance.
TMOD-10. ESTABLISHMENT OF ADULT AND PEDIATRIC BRAZILIAN PRE-CLINICAL MODELS FOR HIGH-GRADE GLIOMAS
Authors: Mirella Baroni, Raquel Megid, Leticia Tshikawa, Ana Carolina Martin, Terence Duarte, Flavia Escremim, Izabela Gomes, Daniel Moreno, Felipe Garcia, Gustavo Teixeira, Luiz Fernando Lopes, Bruna Mançano, Allan Polverini, Ismael Lombardi, Carlos Júnior, Rui Reis, Silvia Teixeira
Journal: Neuro-Oncology (2024)

Abstract High-grade gliomas (HGG) are the most aggressive brain tumors, necessitating robust and representative preclinical models for therapeutic research. We established primary cultures and patient-derived xenograft models from three pediatric high-grade gliomas (pHGG) and one adult IDH wild-type glioblastoma (GBM IDHwt) Brazilian patients. The first pHGG case, from an 11-year-old with PDGFRA (c.1977C&amp;gt;G) and TP53 (c.637C&amp;gt;T) mutations, led to the development of the HCB570 primary culture, PDX and patient-derived orthotopic xenograft (PDOX) OXP9. The second pHGG, from an 11-year-old with CMMRD syndrome and MSH6 germline mutation, resulted in the HCB589 primary culture, PDX and PDOX OXP22. The third pHGG case, from a 14-year-old with diffuse midline glioma harboring an H3F3A mutation, established the HCB604 primary culture and PDX OXP32. The HCB612 primary culture and PDX GBM1, were established from an adult patient with GBM IDHwt, TERT mutated, with no MGMT promoter methylated. The primary cultures showed varied proliferative rates, with an average doubling time of 55 hours. All cultures demonstrated colony-formating capability, with an average IC50 of 750µM for temozolomide (TMZ) exposure. Immunohistochemical and EPIC methylation profiles confirmed that the PDX models closely resemble the patient features. Our establishment of diverse preclinical models, including those derived from patients with rare genetic conditions such as CMMRD, provides valuable insights into HGG pathogenesis and potential therapeutic strategies. The present Brazilian patient-derived models enrich glioma research inclusion diversity and foster future personalized treatment approaches.
CTNI-05. A PROSPECTIVE STUDY OF TUMOR-TREATING FIELDS COMBINED WITH SYSTEMIC THERAPY IN RECURRENT GLIOBLASTOMA
Authors: Chengcheng Guo, Qunying Yang, Zhenqiang He, Hao Duan, Jie Lu, Xi Cao, Ke Sai, Chao Ke, Zhenghe Chen, Ruhua Liu, Xiangheng Zhang, Yonggao Mou
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor-treating Fields (TTFields) monotherapy was approved for recurrent glioblastoma. However, TTFields combined with systemic therapy has not been well studied in China. This study aims to explore the efficacy and safety of such combination therapy for recurrent GBM. METHOD This study is a prospective, single-arm, open-label clinical trial (NCT04689087) planning to enroll 40 recurrent supratentorial GBM patients and use TTFields combined with physician chose systemic therapy. Kaplan-Meier survival curve was used to estimate PFS, OS and survival rate. The primary endpoint was 6-months OS rate (OS6). Secondary endpoints were PFS, PFS6 and safety. OS and PFS were computed from the day of initiating TTFields. RESULT Fourty recurrent supratentorial GBM patients was enrolled from July 2020 to May 2023. The average age was 51 and median KPS score was 80. Sixty-eight percent (27/40) of them underwent total resection surgery and 5% (2/40) only experienced biopsy as their newly diagnosed GBM surgery. Eighty-eight percent (35/40) of patients started TTFields when they were first diagnosed as recurrence, while 12.5% (5/40) patients started TTFields at their second-time recurrence or latter. Median time from diagnosis of recurrence to initiating TTFields was 27 days. Median duration time of TTFields was 8.7 months and average compliance of TTFields was 87% (20.9 hours/day). As for molecular biomarkers, 50% (20/40) patients were MGMT protein positive and 32.5% (13/40) were TERT mutant. Chemotherapy was included in the systemic therapy in 80% (32/40) patients, antiangiogenic therapy in 60% (24/40) patients, BRAF inhibitor therapy in one patient and immune checkpoint inhibitor therapy in one patient. At data cut-off date of March 20, 2024, the median follow-up period was 20.8 months. The primary endpoint OS6 was 87.2%, the median OS was 20.2 months (95%CI 11.9-NR). Median PFS was 8.5months (95%CI 6.2-NR). PFS6 was 67.5% while the historical reference of physician’s best choice of active chemotherapy from EF-11 study showed a PFS6 of 15%. Scalp adverse events were the most common AE. Seventy-eight (31/40) of patients experienced grade 1 or 2 scalp adverse events which can be relieved by topical corticosteroids. CONCLUSION TTFields combined with systemic therapy showed favorable efficacy and safety in Chinese recurrent GBM patients. Key words: Recurrent GBM, TTFields, prospective study, systemic therapy
CNSC-07. OLIGODENDROGLIAL IMPAIRMENT IN WHITE MATTER TRACTS FOLLOWING NEUROFIBROMATOSIS TYPE 1 (NF1) GERMLINE MUTATION OR CARBOPLATIN TREATMENT
Authors: Benjamin Emoefe Aghoghovwia, Sama Alnassiry, Hana El-Toukhy, Ava Hamblett, Samer Sharafaldin, Momo Harris, Yuan Pan
Journal: Neuro-Oncology (2024)

Abstract Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome due to mutations in the NF1 gene. The disease affects 1 in 2500-3000 people worldwide and patients are predisposed to neoplasms such as optic pathway glioma, plexiform neurofibroma. In addition, NF1 patients often experience neurological issues such as learning difficulties. Unfortunately, there is no cure for NF1 yet. Chemotherapy (e.g., carboplatin) remains the first-line treatment for NF1-associated low-grade glioma; while effective in reducing tumor burden, it does not reliably restore neuronal function. In this study, we sought to determine how chemotherapy and Nf1 germline mutations influence neurological function, using genetically engineered mice of NF1. Nf1-heterozygous mice received carboplatin (60 mg/kg/day) or vehicle every other day for one week. Their optic nerves were collected and processed for immunofluorescence and transmission electron microscopy (EM). We found that carboplatin treatment reduces the density of oligodendrocytes in Nf1-heterozygous mice and impairs myelination. Moreover, a similar effect of carboplatin was observed in wild-type mice, suggesting that carboplatin impairs oligodendroglia independent of the NF1 status and the effect of carboplatin should also be evaluated in the non-NF1 context. In another set of experiments, we sought to understand how germline Nf1 mutations influences oligodendroglia. Whereas we did not observe a difference in optic nerve oligodendrocyte density in mice with an engineered mutation targeting the GTPase-activating protein-related domain (GRD) domain of the Nf1 gene, a reduction of oligodendrocyte density was observed in mice harboring a patient-derived mutation (R1809C), which localizes outside of the GRD. A similar effect was observed in the corpus callosum of Nf1+/R1809C mice together with myelin impairment, suggesting a RAS-independent mechanism of Nf1 regulation of oligodendrocytes. Together, these findings indicate that both Nf1 germline mutations and chemotherapy could contribute to oligodendrocyte and myelin deficits in white matter tracts.