bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-16. A PROSPECTIVE OBSERVATIONAL STUDY OF CLINICAL PROFILE, COURSE AND OUTCOME OF PRIMARY BRAIN TUMOR AT A TERTIARY CARE CENTER
Authors: Patel Monik , patel Vivek , Parikh Ankita 
Published: November 2024

Abstract
Primary brain tumors include tumor arising from neuro-epithelial cells, cranial nerves, meninges, germ cells, pituitary gland, and blood-forming organs. These tumors can present with either generalized or focal signs and symptoms.General symptoms are due to raised intracranial pressure (headache, vomiting). Focal symptoms are due to the compression of a structure or destruction (focal neurological deficits). The aim of this study is to analyze the clinical profiles of pediatric and adult brain tumor patients. Data of primary brain tumor patients who were diagnosed from 1st December 2019 to December 2021 were prospectively collected and analysed. In our study of 61 patients, the majority of patients had GBM (32.8%) and astrocytoma (31.1%) and medulloblastoma (11.5%). Less common histologies ependymomas (9.8%), meningioma (6.6%), brain stem glioma (3.3%), oligodendrogliomas (3.3%) and germinoma (1.6%). Out of 19 astrocytomas, 10 were of low grade (1 or 2), while 9 were of high grade (3 or 4).The majority (61.7%) of gliomas were of high grade, while the remaining 38.3% were of low grade. The majority (57.5%) of patients received multimodal treatment,26.2%received dual modality (surgery and RT), while the remaining 16.3% received single modality, either surgery or RT. Most (86.9%) of the patients treated with radiotherapy as a part of a single or multimodal treatment. A significant percentage of patients (77.1%) received concurrent and adjuvant temozolamide-based chemotherapy. Primary brain tumors have a different profile in pediatric patients. Among pediatric patients, the median age was 11.8 years, with male predominance. This study concludes that primary brain tumors have a different profile among adults and pediatric patients, with the majority of patients achieving a response to the first line therapy with an overall good tolerance for therapy.
NCOG-26. THERAPEUTIC POTENTIAL OF FECAL MICROBIOME TRANSPLANT TO IMPROVE COGNITIVE DYSFUNCTION INDUCED BY CRANIAL IRRADIATION IN MICE
Authors: Bekal Mahesh , Das Tushar , Blasco-Conesa Maria P , Jagadeesan Gayathri , Ballester Leomar , Ganesh Bhanu Priya , Esquenazi Yoshua 
Published: November 2024

Abstract
Radiation therapy (RT) is a crucial treatment for brain tumors, but radiation-induced cognitive dysfunction (RICD) affects 50-90% of patients, significantly impacting their quality of life. Evidence suggests that gut microbiome dysfunction may contribute to progressive cognitive dysfunction (CD). Prior studies in aging and stroke models show that fecal microbiome transplants (FMT) from healthy hosts can promote recovery and improve cognition. To investigate the link between RICD and the gut microbiome, we subjected mice to Sham/9Gy/15Gy cranial irradiation, followed by cognitive tests using the Y-maze and Novel Object Recognition Test (NORT) at various time points. Both 9Gy and 15Gy irradiation resulted in significant cognitive dysfunction, as indicated by altered performance in both tests at 7 and 30 days post-irradiation. Fecal samples were collected before irradiation and at 10 and 30 days post-RT. Microbial DNA was extracted, and the 16S rRNA gene was sequenced and analyzed using the bioinformatics visualization toolkit, ATIMA. Significant gut dysbiosis was observed in both 9Gy and 15Gy irradiated mice compared to pre-irradiation samples, with the 15Gy group showing more pronounced and consistent changes in fecal microbiome diversity, particularly at 30 days post-RT. We hypothesized that FMT from healthy hosts (non-radiated mice) could prevent or ameliorate RICD by modulating microbial, metabolomic, and immunologic profiles. To test this, a separate cohort of mice received 15Gy cranial irradiation and FMT via oral gavage. After a 20-day post-irradiation period, cognitive and gut permeability tests were conducted. The FMT group exhibited significantly improved gut permeability and cognitive performance compared to controls. Our findings suggest that gut dysbiosis plays a crucial role in RICD and that FMT may be a potential strategy to mitigate RICD and improve the quality of life in brain tumor patients undergoing cranial RT.
NCOG-38. LAMOTRIGINE MONOTHERAPY ASSOCIATES WITH IMPROVED PROGRESSION-FREE AND OVERALL SURVIVAL IN HIGH-GRADE GLIOMA
Authors: Rilinger Ryan , Sharma Akshay , Feldman Marina , Guo Lydia , Volovetz Josephine , Grabowski Matthew , Lobbous Mina 
Published: November 2024

Abstract

BACKGROUND
High-grade gliomas (HGG) are aggressive brain tumors with notoriously poor prognoses and high symptomatic burden, including seizures in 30-60% of HGG cases. Despite negative impacts to quality of life, positive seizure history at presentation and during the disease course has been shown to associate with improved overall survival. Further, recent preclinical studies have suggested a link between neuronal hyperexcitation and more rapid glioma progression. We hypothesized anti-seizure medication (ASM) therapy may suppress neuronal excitation and therefore help prolong survival. To this aim, we characterized the association of various ASM therapies with survival and seizure control.

METHODS
Retrospective review of 413 patients with co-occurring HGG and clinically diagnosed epileptic activity. Multivariable linear regression was used to assess the impact of ASM quantity (monotherapy versus polytherapy) and type (specific ASMs as well as ASM class) on progression-free survival (PFS) and overall survival (OS). Logistic regression was used to assess the impact of ASM quantity and type on likelihood of achieving seizure remission. Additional variables in the regressions included age, treatment exposure (radiation therapy, cytotoxic chemotherapy, or targeted chemotherapy), and extent of surgical resection (gross total resection versus all other surgeries). Kruskal-Wallis tests were used to compare median survival between multiple groups.

RESULTS
ASM monotherapy and polytherapy demonstrated comparable survival outcomes. Among patients who received ASM monotherapy, only lamotrigine demonstrated a significant association with improved survival with PFS and OS (P = &lt;0.001 for both). No specific drug or drug class demonstrated greater likelihood of achieving seizure remission.

CONCLUSION
Lamotrigine demonstrates a unique association with improved outcomes that is neither shared by other ASMs nor explained by ASM drug class, without any decline in likelihood of achieving seizure remission. Optimization of ASM therapy may enhance survival outcomes without compromising seizure control.
EXTH-03. CAR T-CELLS TARGETED TO B7-H3 OR HER2 FUNCTION INDEPENDENTLY OF ANTIGEN DENSITY IN XENOGRAFT MODELS OF EPENDYMOMA
Authors: Mehta Sanya , Ibanez Jorge , Houke Haley , Ippagunta Siri , Emanus Erik , Mack Stephen , Krenciute Giedre 
Published: November 2024

Abstract

BACKGROUND
Targeted treatment options are desperately needed for ependymomas (EPN). Chimeric antigen receptor (CAR) T-cells have immense potential to positively transform treatment outcomes; however, little is known regarding antitumor efficacy of CAR T-cells against EPNs. Specifically, antigen density has emerged as a major influencer of CAR T-cell potency. However, the specific high and low antigen density thresholds governing CAR T-cell efficacy for EPN are unknown. The goal of this project is to determine the role of antigen density in CAR T-cell potency against EPN.

METHODS
Using quantitative flow cytometry, we determined antigen density of B7-H3 and HER2 (the two CAR targets currently in pediatric EPN clinical trials), on EPN patient derived cell lines (1425, ST1, CPITT, ST2, EPI, L46SJ). We generated B7-H3 and HER2-CAR T-cells with CD28z signaling domain and compared long-term cytolytic activity, expansion, and cytokine production against EPNs.

RESULTS
We found that all EPN cell lines express remarkably high yet variable density of B7-H3 (62,700 – 335,440 molecules/ cell). In contrast, surface density of HER2 was consistently and significantly lower (860 – 24,488 molecules/ cell). In repeated-stimulation assays, B7-H3-CAR T-cells killed 7-10 times and expanded up to 325,360-fold when cultured against EPN. However, we observed no significant difference in total expansion or correlation with antigen density against EPNs. Surprisingly, expansion of HER2-CAR T-cells against EPNs was drastically higher and greatly exceeded that of B7-H3-CAR-T cells against the same EPN cells despite much lower antigen density.

CONCLUSIONS
Our work shows that both B7-H3 and HER2 are good targets against EPN, despite drastic differences in antigen density. Results suggest that lower antigen density of HER2 may be superior for CAR T-cell activity. Future work will validate whether HER-CAR T-cells have superior antitumor efficacy in vivo to further delineate role of antigen density thresholds in CAR T-cell potency.
EXTH-18. ADAPTER CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY TARGETING SSTR2 IN MENINGIOMA
Authors: Chen Jiawei , Pellegrino Christian , Mastall Maximilian , Szulzewsky Frank , Bijnen Mitchell , Van Hove Hannah , Favalli Nicholas , Bassi Gabriele , Moisoiu Vlad , Vasella Flavio , Padevit Luis , Neidert Marian , Cimino Patrick , Reimann Regina , Roth Patrick , Manz Markus , Greter Melanie , Holland Eric , Neri Dario , Weller Michael , Wirsching Hans-Georg 
Published: November 2024

Abstract
Effective treatment options for meningioma patients beyond surgical resection and radiotherapy are limited. This study presents preclinical and translational evidence supporting the efficacy of an adaptor CAR-T cell system targeting Somatostatin Receptor (SSTR) 2 in otherwise untreatable meningiomas. Tissue microarray analysis revealed that SSTR2 expression was generally heterogeneous but high or intermediate in most World Health Organization (WHO) grade 2 (87.8%) and grade 3 (87.5%) meningiomas. The fluorescein-linked, SSTR2 antagonist peptide octofluo was used in conjunction with adaptor FITC (AdFITC) CAR-T cells to treat experimental meningiomas. In vitro, 10 nM octofluo induced tumor cell killing within 72 hours at effector-target cell ratios (E:T) as low as 1:100. This was observed in two human meningioma cell lines, Ben-Men-1 (CAR-T cells vs. untransduced T-cells [UTT]: 47.9% vs. 4.7%, P &lt; 0.001) and IOMM-Lee (CAR-T cells vs. UTT: 40.2% vs. 4.9%, P &lt; 0.001). In vivo, the AdFITC CAR-T cell system inhibited meningioma growth (P = 0.002) and prolonged survival (P = 0.003) in the IOMM-Lee orthotopic model compared to PBS. In a genetically engineered murine meningioma model, the AdFITC CAR-T cell system not only restricted tumor growth (P = 0.0018) and improved survival (P &lt; 0.0001), but cured a substantial proportion of meningioma bearing mice. This treatment also induced the expansion of both CD8+ CAR-T cells (P = 0.0041) and a host T-cell response. Preliminary ex vivo killing assays, involving co-culture of the AdFITC CAR-T cell system with patient-derived meningioma tissue, showed specific lysis rates of 15-20% (ET 1:1) within 12 hours. Targeting SSTR2 with the AdFITC CAR-T cell system emerges as a promising therapeutic approach for meningioma, an early phase clinical trial is warranted.
EXTH-23. NEW DNA-CROSSLINKING CHEMOTHERAPY IS EFFECTIVE AGAINST POST-TEMOZOLOMIDE MISMATCH REPAIR-DEFICIENT PATIENT-DERIVED HYPERMUTANT GLIOMAS
Authors: McCord Matthew , Wang Wenxia , An Shejuan , Sears Thomas , Sarkaria Jann N , James C David , Ruggieri Bruce , Bindra Ranjit S , Horbinski Craig 
Published: November 2024

Abstract
The DNA mismatch repair (MMR) pathway triggers glioblastoma (GBM) apoptosis when base mismatches induced by the alkylating agent temozolomide (TMZ) cannot be repaired. GBMs often develop hypermutation and resistance to TMZ through acquired inactivation of DNA MMR enzymes (MSH2, MSH6, MLH1, PMS2). A newly developed therapeutic, KL-50, fluoro-ethylates DNA bases, leading to DNA inter-strand cross-links. This form of DNA damage triggers MMR-independent apoptosis. Thus, KL-50 can target MMR-deficient tumor cells. Previous work showed that KL-50 is effective against GBM cell lines that were rendered TMZ-resistant through shRNA knockdown of MMR genes (PMID 35901163). In those studies, KL-50 was most effective when used in combination with an MGMT enzyme inhibitor, or in MGMT-deficient cells. Here, we extend those findings with a preclinical trial of KL-50 in GBM patient-derived xenografts (PDX), including PDX models of post-TMZ GBM that acquired MMR mutations and hypermutation through serial TMZ exposure (PMID 31852831). Among TMZ-naïve PDX, KL-50 extended survival of engrafted mice by 24 days for GBM6 (partially MGMT-deficient), and by 38 days for GBM12 PDX (fully MGMT-deficient) compared to vehicle (p&lt;0.0001, Log-Rank). Combining KL-50 with 4.0 Gy radiation further extended survival of GBM12 mice (9 days, p=0.02), but not GBM6 mice. With engraftments of GBM6R-m185, a post-TMZ, MMR-deficient derivative of GBM6, 14/14 (100%) of KL-50 treated mice are still alive 60 days post-engraftment compared to 0/13 (0%) of vehicle control mice (median survival 37 days, p&lt;0.0001, experiment ongoing). Complementary in vitro studies showed that GBM6R-m185 cells are more sensitive to KL-50 than TMZ at matched concentrations of 50µM (p=0.001, one-way ANOVA) and 100µM (p=0.047). These data demonstrate the potential of KL-50 in treating post-TMZ MMR-deficient recurrent gliomas.
EXTH-26. EXPLORING THE ROLE OF ANDROGEN RECEPTOR SIGNALING IN GLIOBLASTOMA IN AN ORTHOTOPIC ANIMAL MODEL
Authors: Mason Sofia R E , Chung Sylvia , Satgunaseelan Laveniya , McCool Cerys , Juan Beatriz Perez-San , Gupta Shabarni , Zaman Ashraf , Day Bryan W , Dear Rachel , Sim Hao-Wen , Holst Jeff , Chaffer Christine L 
Published: November 2024

Abstract

OBJECTIVE
Gliomas, particularly glioblastoma which is the most common and deadly type, frequently express androgen receptors (AR). We systematically characterized AR expression in low- and high-grade gliomas to investigate whether disrupting AR signaling with readily available blood-brain-barrier penetrant drugs could improve treatment.

METHODS
Low- and high-grade glioma samples were stained for AR by immunohistochemistry, with AR-expression correlated to grade and sex. Localization of AR and the influence of dihydrotestosterone (DHT) and anti-androgens in glioblastoma cell line (U251) were determined by immunofluorescence and immunoblot. Building on previous in vitro data, we used an orthotopic AR-positive patient-derived model (RN1) to test the efficacy of seviteronel, a blood-brain-barrier penetrant anti-androgen.

RESULTS
Two thirds of biopsy samples were positive for AR expression by IHC (n=25/39). AR expression correlated with increasing tumor grade (p&lt;0.05) but was similar between sexes (p=0.94). Anti-androgens enzalutamide and seviteronel prevented DHT-induced nuclear translocation of AR; however, seviteronel did so to a lesser extent, as measured by immunofluorescence and immunoblot. In the mouse model, seviteronel significantly improved survival compared to vehicle (n=12, 36.0 vs 27.5 days, p=0.03), and demonstrated reduced Ki67 expression in tumors at the endpoint (68.9% vs 85.0%, p&lt;0.001). Combining seviteronel with temozolomide limited tumor growth as measured by bioluminescence imaging, but did not significantly extend survival compared to temozolomide alone (n=16, 63.5 vs 56.5 days, p=0.37). Adding seviteronel to radiotherapy did not extend survival compared to radiotherapy alone (n=16, 33.0 vs 39.0 days, p=0.19).

CONCLUSIONS
Targeting AR signaling with blood-brain-barrier penetrant anti-androgens may represent a promising biomarker-directed therapeutic strategy. The mechanisms underlying the effects of seviteronel are being further investigated through affinity-purification mass spectrometry analysis and CUT&RUN sequencing of untreated and treated glioma cells. Additional animal experiments are underway to examine the role of biological sex and the glioma immune microenvironment on the efficacy of anti-androgens in vivo.
EXTH-29. EVALUATION OF THE ANTITUMOR EFFECT OF A CHEMOTHERAPY-LOADED DEVICE FOR THE TREATMENT OF PRIMARY BRAIN TUMORS
Authors: Déry Laurence , Charest Gabriel , Guérin Brigitte , Akbari Mohsen , Fortin David 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Tumor recurrence is therefore inevitable, and median survival is just over 14 months. Currently available treatments are inadequate and do not provide optimal tumor control. We believe that treatment localized directly at the tumor site will eliminate a greater number of infiltrating tumor cells while significantly reducing systemic toxicity. For this project, we are collaborating with a team specializing in bioengineering, who have produced a biomaterial enabling the gradual release of various chemotherapeutic agents. Our aim is to use this biomaterial to deliver chemotherapeutic agents to the tumor site through the surgical cavity. Cell-based assays were carried out using glial tumor cells in the presence of the biomaterial containing chemotherapeutics. A survival study was realized with the Fischer F98 rat model, which underwent partial tumor resection followed by injection of biomaterial containing chemotherapy. Histological studies of brains and resected tissues were also carried out to assess the effect of the biomaterial on the brain environment. In vitro assays showed a strong cytotoxic effect against glial tumor cells at 24h, 48h and 72h of biomaterial-drug incubation. The combination of two chemotherapeutic agents showed the best cytotoxic effect on glial tumor cells. We also performed a partial tumor resection and insertion of the chemotherapy-loaded biomaterial into the surgical cavity of the F98 glioma bearing rat. Similar to in vitro studies, the combination of two antineoplastic agents shows a significant improvement in animal survival. In conclusion, the in vitro and in vivo results of this study show that the combination of chemotherapy has the greatest antitumor effect. We hope that these exciting results will lead to the development of a new treatment for patients with glioblastoma and potentially other diseases where complete tumor resection is impossible.
EXTH-37. ALLOSTERIC MITOCHONDRIAL CLPP AGONIST ONC206 ALTERS STRESS RESPONSE, METABOLIC AND EPIGENETIC PROFILES TO ELICIT ANTI-CANCER EFFICACY IN HIGH-GRADE GLIOMAS
Authors: Prabhu Varun V , Maranto Cristina , Lee Andrew , Foster Scott , Allen Joshua E 
Published: November 2024

Abstract
Dordaviprone (ONC201) is a dopamine receptor D2/3 (DRD2/3) antagonist and allosteric ClpP agonist that has demonstrated durable responses in recurrent H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201 with nanomolar potency that also targets DRD2/3 and ClpP, is in Phase I trials for central nervous system tumors. We characterized target relevance, human ClpP binding, in vitro efficacy, downstream signaling and response determinants associated with ONC206 in high-grade gliomas (HGG). Co-crystallization with ClpP that assembles as a tetradecameric complex revealed an allosteric ligand interaction with distinctions in the ONC206-ClpP overall conformation relative to the ONC201-bound or apo complex, including an increase in the resolved pore size and decreased complex height. ONC206 was more potent than ONC201 in cell-free human ClpP casein/peptide degradation assays). Accordingly, HGG cell lines and patient-derived cells exhibited increased sensitivity to ONC206 relative to ONC201 and generally required a shorter duration of exposure. Unlike DRD2, CRISPR-mediated ClpP knockout in HGG cell lines blunted ONC206 sensitivity. Metabolomics revealed elevated α-ketoglutaric acid, α-hydroxyglutaric acid, and glutaric acid. Proteomics indicated inhibition of multiple mitochondrial pathways including OXPHOS and TCA cycle. TCA cycle enzyme α-ketoglutarate dehydrogenase (KGDH) was inhibited in a ClpP-dependent manner. Western blotting showed downregulated ClpX, and upregulated ATF4/CHOP, H3 K27me3 and H3 K36me3. Next-generation sequencing of acquired resistance cell lines, which exhibited cross-resistance to ONC201 and ONC206, revealed diverse ClpP missense mutations distributed across various monomer interfaces. Both intrinsic and well as ONC206-stimulated ClpP proteolysis were mitigated by these mutations, which was congruent with an absence of the tetradecameric assembly. These ClpP mutations recapitulated resistance and, conversely, wildtype ClpP overexpression restored sensitivity. Thus, allosteric ClpP agonism is a key determinant of ONC206 activity in HGG by altering stress response, metabolic, and epigenetic profiles.
EXTH-38. EVALUATION OF STORAGE CONDITIONS ON SERUM-DERIVED EXTRACELLULAR VESICLES IN BRAIN TUMOR SAMPLES
Authors: Goel Pallavi , Kumari Neha , Kaur Inderjeet , Ghanekar Yashoda , Sadasivam Subhashini , Pawar Vikas , Madiraju Surya , Ray Amit 
Published: November 2024

Abstract
Tumor-derived Extracellular Vesicles (EVs) are emerging as potential liquid biopsy tool in the field of cancer diagnosis and therapeutic targets. The functionality of EVs depends on its diverse cargo, which is known to alter host-receipient cells. Nevertheless, extracting EVs while preserving its integrity and functionality of its contents is challenging, specifically in Low-middle Income countries (LMIC) countries. Our study focussed on extraction of serum derived EVs analysis from brain-tumor samples encompassing Oligodendrogliomas, Astrocytomas and Glioblastomas. The stability of EVs were examined in serum stored for 2 years at -80°C to understand the effect of preservation and storage in different conditions, that were left exposed to room temperature for variable periods of time before freezing. To explore the optimal suitable conditions, EVs were isolated from serum samples using IZON column size-exclusion based-method, and evaluated for structural integrity and stability through nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) technology. Interestingly, the majority of isolated vesicles exhibited round, intact structure with bilayer membrane of size varying between 30 - 250nm. Moreover, protein content of EVs positive markers (CD63, CD81 and CD9) was also detected with minimal contaminations evidenced by weak bands for negative marker (ApoB), as determined by Western blot analysis. Further, column-based EV-derived RNA demonstrated optimal yield and purity was confirmed by RNA integrity number (RIN) using Qubit. While cryopreservation had minimum detrimental effects on mRNA sample quality, leaving it exposed to room temperature before freezing had a significant effect on EV isolation, as samples were often haemolyzed. This will provide insights in optimizing pre-analytical and analytical procedures for more effective outcomes in the clinical setting