bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-19. SEX DIFFERENCES IN GLIOBLASTOMA TREATMENT AND ADVERSE EVENTS
Authors: Dmukauskas Mantas , Cioffi Gino , Neff Corey , Price Mackenzie , Waite Kristin , Kruchko Carol , Ostrom Quinn , Barnholtz-Sloan Jill 
Published: November 2023

Abstract
Despite aggressive therapies, the survival rates for gliomas remain complex and accumulating evidence indicates that there are sex differences in patient response to treatment and the development of adverse events (AE). We utilized the Surveillance, Epidemiology and End. RESULTS: Program (SEER)-Medicare dataset to examine sex differences in treatment patterns and AEs in patients 65 years and older diagnosed with glioblastoma. We identified 15,693 individuals (≥65 years) diagnosed with glioblastoma between 2004-2017. Sex differences were assessed based upon their treatment modality: no-treatment (NT), standard treatment (ST) (surgery + radiation + chemotherapy), or other treatment (OT) (any other combination of surgery, radiation and/or chemotherapy). Multivariable models were used to determine the odds of males versus females experiencing an AE by treatment group. Sex differences in survival were assessed using Kaplan-Meier and Cox proportional hazards models. There was a significant sex difference in the type of treatment received by glioblastoma patients, with males receiving more ST than females (38% v 34%; p&lt; 0.001). Females treated with ST had increased odds of rheumatoid arthritis or collagen vascular disease (OR=0.42; 95%CI, 0.30-0.59; p&lt; 0.001). Females receiving OT had an increased odds of rheumatoid arthritis or collagen vascular disease (OR=0.59; 95%CI, 0.44-0.78; p&lt; 0.001), and mood disorders (OR=0.81; 95%CI, 0.72-0.90; p&lt; 0.001). Males receiving NT had an increased odds of blood disorders (OR=1.48; 95% CI, 1.12-1.96; p=0.006), cardiac events when treated with ST (OR=1.24; 95%CI, 1.10-1.41; p&lt; 0.001), and respiratory events when treated with OT (OR=1.20; 95%CI, 1.07-1.35; p=0.002). Females with glioblastoma, receiving ST had an increased adjusted overall survival compared to males (p&lt; 0.001), whereas no sex difference were observed in those receiving OT or NT. Our analysis demonstrates that there are sex differences in odds of AE and overall survival associated glioblastoma treatment, which could impact clinical treatment decisions.
NCOG-25. SINGLE-INSTITUTION SERIES OF SPINAL EPENDYMOMA IN CHILDREN WITH NF2-RELATED SCHWANNOMATOSIS
Authors: Burket Noah , Koenig Jenna , Tailor Jignesh 
Published: November 2023

Abstract
NF2-related schwannomatosis (NrS) is a tumor predisposition syndrome that results in the development of multiple central nervous system tumors, including spinal ependymomas (SP-EPN). SP-EPN are intramedullary tumors that are slow growing but can displace critical nerve pathways in the spinal cord, resulting in motor and sensory deficits that contribute to patient morbidity. Although surgery is the mainstay of treatment, it can also result in high morbidity, resection of sporadic SP-EPN is often curative; however, SP-EPN in NrS patients will often regrow, possibly resulting in additional surgeries and a lifetime of deficits, especially impacting pediatric patients. Yet, natural history and clinical outcomes for pediatric NrS patients with SP-EPN have not been well described. We reviewed 27 pediatric NrS patient cases from 1993 to 2023 at our institution and identified 10 patients with a diagnosis of SP-EPN, with a range of 1-3 tumors present at patient diagnosis. Demographic, clinical, pathologic, and radiologic data were collected from electronic medical records. Median age of diagnosis of NrS was 12 years old (range: 5-17) and median time from NrS diagnosis to SP-EPN diagnosis was 31 days (range: -1-1636). 14 out of 16 (87.5%) initial tumors were in the cervical spine region, with C2 being the most frequently involved level. Two patients underwent resection of their tumors, with both experiencing progression of their disease and one developing paraplegia. The most common symptoms from SP-EPN were pain (30%), motor deficits (30%), and sensory deficits (30%). 40% of the patients had progressive disease at last follow up, with median time from diagnosis to progression of 3.33 years. Median time from SP-EPN to last follow-up was 4.08 years. This series showcases the burden of SP-EPN in pediatric NrS patients, emphasizing the need for further exploration into clinical outcomes and novel treatments for this debilitating condition.
NCOG-33. GLIOBLASTOMA AND PARKINSONISM, IS DEPLETED DOPAMINE A PROTECTIVE SURVIVAL FACTOR? A CASE SERIES OF 3 GBM PATIENTS
Authors: Carrillo Jose , Wagle Naveed , Sharma Akanksha , Nguyen Minhdan , Truong Judy , Mauritson Emmaline , Singh Iryna , Juarez Tiffany , Kesari Santosh 
Published: November 2023

Abstract
Glioblastoma multiforme (GBM) is the most common malignant brain tumor, and carries a grave prognosis with a median survival of 15 months. The pathophysiologic hallmark of Parkinson’s disease is neuronal loss of dopamine producing cells in the substantia nigra. Dopamine has been shown to modify cell-cycle status in neural progenitor cells. Dopamine agonism is adequate to increase progenitor proliferation in the subventricular zone (SVZ). Dopamine receptor antagonists have antiproliferative effects. A few clinical trials use selective dopamine receptor D2 (DRD2) inhibitors. Parkinsonism can have organic etiologies like stroke or neoplasm, while idiopathic Parkinsonism is known as Parkinson’s disease. While uncommon to have dual diagnoses, we identified three patients with both GBM and Parkinsonism, all were IDH wildtype, 2 patients were MGMT methylated, mean age was 67 years. Our 3 patients have a combined median PFS of 23.4 months, mean PFS of 25.4 months, which compares favorably to historical control median PFS of 6.9 months. Our 3 patients with dual diagnosis have a median OS of 47.3 months, and mean OS of 43.7 months, which compares favorably to historical median OS of 14.6 months. One might expect a patient with a neurodegenerative disease like Parkinson’s disease and a highly malignant tumor like GBM to have an extremely poor prognosis, yet our patient cohort reveals the opposite. The improved overall survival in GBM patients with Parkinsonism supports further clinical research into selective dopamine receptor inhibitors.
EXTH-01. STEM CELL THERAPY FOR LEPTOMENINGEAL DISEASE
Authors: Kitamura Yohei , Kanaya Nobuhiko , Moleirinho Susana , Tamura Ryota , Ueda Ryo , Sasaki Hikaru , Toda Masahiro , Shah Khalid 
Published: November 2023

Abstract
Leptomeningeal disease (LMD), known as carcinomatous meningitis, occurs in approximately 5% of all cancer patients. LMD presents an extremely poor prognosis, with an average life expectancy of 4-6 weeks. Although, whole brain/spinal cord irradiation and intrathecal injection of anticancer drugs are sometimes performed, the effects are limited, so new therapeutic strategies for LMD are urgently needed. We have reported that treatment using engineered stem cells (SCs) may be effective treatment option against LMD of breast cancer, lung cancer, and malignant melanoma, which are types of cancer that tends to metastasize to the central nervous system. Specifically, we reported that engineered allogeneic SCs simultaneously targeting epidermal growth factor receptor (EGFR) and death receptor (DR) has efficacy for LMD of triple negative breast cancer. Also, we reported that twin SCs releasing oncolytic herpes virus, granulocyte-macrophage colony-stimulating factor (GM-CSF), and single-chain variable region fragments (scFv) against PD-1 has efficacy in LMD of malignant melanoma. The greatest advantage of SC based therapeutic strategy for LMD is summarized by these facts: (1) LMD is a condition in which cancer cells spread within a single closed space through cerebrospinal fluid, and the SCs characteristic of homing to tumor cells has an advantage; (2) Repetitive intrathecal injection of drugs for patients is an invasive procedure, but SCs can continuously secrete/release therapeutic agents into the spinal cavity after a single injection. We believe that stem cell therapy has the potential to become a new therapeutic option for LMD in the future.
EXTH-02. A TERT-SPECIFIC TCR-LIKE ANTIBODY CAR T CELL APPROACH FACILITATES KILLING OF GLIOBLASTOMA
Authors: Zhu Eric , Gladney Susan , Ritchey Julie , Livingstone Alexandra , O'Neal Julie , Johanns Tanner 
Published: November 2023

Abstract
Glioblastoma (GBM) is a difficult form of brain cancer to treat as GBM cells utilize various strategies to evade host immune responses. Prior studies have shown autologous cytotoxic T cells (CTL) modified to express chimeric antigen receptors (CAR) facilitating host CTL responses against cancers. This study investigates the ability of T-cell receptor (TCR)-like antibody clones against TERT to facilitate specific CAR T cell mediated killing of GBM. Lentiviral vectors were created for five TCR-like antibody CAR constructs recognizing an HLA-A*02:01-restricted TERT-derived antigen. Nur77-GFP Jurkat reporter cell lines and 3 healthy donor-derived CTLs transduced with these vectors were used in flow-based and in vitro killing assays to assess specificity and functionality. K562 cells that did, and did not, express HLA-A*02:01 were targets in the flow-based assay. Flow cytometry captured activation of transduced Jurkat cells via GFP and CD69 upregulation. Three luciferase-transduced GBM cell lines were targets in the cytotoxic killing assay and visualized via bioluminescence imaging (BLI). Increased GFP and CD69 expression was seen on Jurkat cells transduced with clones 3A12 and 3H2 only when co-cultured with TERT antigen and A*02 positive K562 suggesting specific recognition of the TERT:HLA complex. Furthermore, healthy donor-derived CTL transduced with 3A12 and 3H2 CAR constructs demonstrated in vitro killing of tumor cells by BLI. Interestingly, the 3H2 construct only showed cytotoxicity in the presence of exogenous TERT antigen. However, when the heavy and light chains of the 3H2 clone were flipped in the lentiviral construct (3H2F), specificity to the TERT:HLA complex was preserved but the CAR T cells now demonstrated cytotoxicity of GBM without needing exogeneous peptide. TCR-like antibody clones 3A12 and 3H2F specifically recognize an HLA-A*02:01-restricted TERT-derived antigen, facilitating effective in vitro cytotoxicity of GBM cells. Ongoing experiments will evaluate the in vivo activity of these TERT-specific CAR constructs and assess potential off-target toxicity.
EXTH-04. CYTOSTATIC HYPOTHERMIA AGAINST GLIOBLASTOMA AND THE DEVELOPMENT OF A NEURAL IMPLANT FOR RODENTS AND SWINE
Authors: Enam Syed Faaiz , Chen Reed , Barwari Mahabad , Dobariya Aksharkumar , Patel Ankur , Patel Toral , Bellamkonda Ravi 
Published: November 2023

Abstract
Survival rates for patients with glioblastoma (GBM) remain discouraging due to the near-impossibility of eradicating all tumor cells, resulting in frequent recurrence. However, studies have shown that recurrence is predominantly localized (80% of cases) and that survival outcomes are improved with supra-total resection. Consequently, non-destructive local therapies hold promise for preventing GBM recurrence. We have demonstrated that non-freezing, 'cytostatic' hypothermia is a unique and effective approach against GBM. Unlike ablative cryogenic hypothermia, which kills both neoplastic and healthy infiltrated tissue, this method safely and effectively inhibits GBM growth. Through extensive investigations, we have previously identified a cytostatic window of 20–25°C and examined its impact on multiple pathways. By implementing hypothermia, we successfully inhibited GBM growth, doubling median survival in two rodent models. Notably, all rats subjected to cytostatic hypothermia survived the study period. To further advance towards translation, we conducted computer simulations to demonstrate the feasibility of a scaled and implantable system. Subsequently, we designed and fabricated a multiprobe array capable of uniformly extracting heat from a small volume of brain tissue in swine. This heat would then be transferred to the dorsal flank through an innovative artificial internal circulation system (AICS). The system underwent iterative testing in vitro and validation in vivo using live, anesthetized swine. Unlike targeted therapeutics that often show promise in preclinical models but fail in clinical trials, cytostatic hypothermia capitalizes on fundamental physics that broadly influence biology. It has the potential to reduce brain tumor recurrence, limit tumor evolution, and simultaneously offer time to patients as other cytotoxic therapies are developed.
EXTH-08. IMMUNOTHERAPEUTIC TARGETING OF FIBROBLAST ACTIVATION PROTEIN (FAP) IN TREATMENT REFRACTORY GLIOBLASTOMA USING NOVEL CAR-T CELL THERAPY
Authors: Tatari Nazanin , Hedad Hayget Mohamed Seid , Zingg Andreas , Bartoszek Ewelina M , Tschan Viviane J , Schenker Timo , Ritz Marie-Françoise , Miletic Petar , Venugopal Chitra , Etter Manina M , Singh Sheila K , Läubli Heinz , Hutter Gregor 
Published: November 2023

Abstract
Glioblastoma (GBM), the most common malignant primary adult brain tumor, is characterized by extensive cellular and genetic heterogeneity. The standard of care therapy and clinical trials have not been successful in improving patients’ survival which underscores an urgent need for developing new effective therapies. In silico and in vitro analysis have revealed high level of Fibroblast Activation Protein (FAP) expression in GBM tissue by multiple cell populations including endothelial cells, fibroblasts, stromal and tumor cells, but not normal brain tissue, making FAP a safe and suitable therapeutic target. As chimeric antigen receptor (CAR) expressing T cells have shown promising results against multiple cancers, we aimed to target FAP in GBM by FAP specific CAR-T cells generated using a novel GMP-ready FAP-CAR construct produced based on a virus-free CAR gene transfer using advanced sleeping beauty transposon technology and pre-clinically test their anti-tumor efficacy. Our data revealed that co-culturing CAR-T cells with FAP+ GBM cells (U87) resulted in increased surface expression of T-cell activation markers. Moreover, FAP CAR-T mediated cytotoxicity against FAP+ GBM cells was also observed in the co-culture of GBM and CAR-T cells. For further validation, the effect of FAP CAR-T cells will be tested on patient-derived GBM organoids. The in vivo efficacy of FAP CAR-T cells is currently under investigation and we anticipate that the treatment of GBM tumor-bearing mice with FAP CAR-Ts results in extended survival and tumor burden reduction. These rigorously obtained data show high level of efficacy for FAP-specific CAR-T cells against GBM suggesting that clinical development of this therapeutic modality can provide a novel therapeutic strategy for GBM patients. Therefore, upon successful completion of the preclinical study, we plan to conduct a phase I dose-escalation trial of autologous FAP-CAR T cells for patients with recurrent Glioblastoma.
EXTH-14. MRNA-LOADED EXOSOMES FOR TARGETED GLIOBLASTOMA IMMUNOTHERAPY
Authors: Dong Shiyan , Antony Abin , Wang Yifan , Kim Betty , Jiang Wen 
Published: November 2023

Abstract
Recent successes of mRNA therapeutics against pathogenic infections have increased interest in their investigations for other human diseases including cancer. However, precisely delivering the genetic cargo to cells and tissues of interest remains challenging. Extracellular vesicles such as exosomes have gained increased interest recently as potential nucleic acid and drug carriers given their favorable immunogenic profile, long circulatory half-life, and ability to cross biological barriers such as blood-brain barrier. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded exosomes. This was achieved using a microfluidic electroporation approach where a combination of nano- and milli-second pulse electroporations produced a large quantity of IFN-γ mRNA-loaded exosomes with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic exosomes (imExo) selectively targeted glioblastoma cells and generated potent antitumor activities in vivo, including against tumors intrinsically resistant to immunotherapy. Together, these results provide a new adaptive approach to engineering mRNA-loaded exosomes with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.
EXTH-17. TARGETING CTPS1 AND NUCLEOTIDE BIOSYNTHESIS PATHWAYS AS A NOVEL THERAPEUTIC APPROACH IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Hathaway Matthew , Jagana Hawa , Meechan Michael , Rajendran Ashmitha , Slusher Barbara , Evans II Myron 
Published: November 2023

Abstract
MYC-amplified medulloblastoma (MB) tumors are the deadliest of all subgroups with a &lt; 50% 5-year overall survival rate. High risk patients receive large doses of chemo- and radio- therapy (CT/RT) with most survivors experiencing debilitating neurological and cognitive sequelae making the identification of novel targets of the utmost importance. Recent whole-genome CRISPR screening identified the enzyme CTPS1 and other components of the de novo pyrimidine metabolism cascade as a possible cancer-specific vulnerability in MYC-amplified MB. Our study tested targeted inhibitors of this pathway to identify rational combinations for translation to pre-clinical models. A stable of treatment-naïve, patient-derived models of MYC-amplified MB were used and treated with various de novo pyrimidine synthesis inhibitors alone and in novel combinations. Analysis of proliferation, cell survival, and downstream signaling were performed both in vitro and in vivo. Inhibition of CTPS1 led to a significant decrease in cell proliferation and alterations in cell cycle with minimal increases in cell death, suggest a cytostatic mechanism. Previous work has shown de novo pathway inhibition results in reduction of the dNTP pool, leading to activation of the DNA damage response (DDR), seizing the cell cycle. Interestingly, the DDR inhibitor prexasertib (CHKi) robustly targets MYC-amplified MB tumors in pre-clinical models. Combining CHKi and CTPS1 inhibitors yields significant tumor cytotoxicity both in vitro and in vivo. We further demonstrated robust synergy of CHKi with other clinically relevant de novo pyrimidine metabolism inhibitors. The results of this investigation confirm CTPS1 and the de novo pyrimidine metabolism pathway as targets in MYC-amplified MB and identifies a novel rational combination for treatment in patients.
EXTH-18. DEVELOPMENT OF A TRANSGENIC MOUSE MODEL ENABLING COMPARATIVE ANALYSIS OF CHIMERIC ANTIGEN RECEPTOR (CAR)-EXPRESSING IMMUNE CELL POPULATIONS FOR CANCER IMMUNOTHERAPY
Authors: Hatae Ryusuke , Watchmaker Payal , Yamamichi Akane , Kyewalabye Keith , Okada Kaori , Phyu Su , Goretsky Yitzhar , Chen Tiffany , Chuntova Pavlina , Terabe Masaki , Okada Hideho 
Published: November 2023

Abstract
We reported the creation of C57BL/6J-background transgenic (Tg) mice carrying the anti-epidermal growth factor receptor (EGFR)vIII-CAR with CD3z-CD28-4-1BB downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. Breeding these mice with CD4-Cre Tg allows rigorous and reproducible evaluation of CAR-T cell therapy in syngeneic models (Chuntova et al. Neuro-Onc 2022). As the extension of the approach, we crossed the EGFRvIII-CAR Tg mice with mice carrying Vav-Cre, which allowed the expression of anti-EGFRvIII CAR in all hematopoietic cells. In particular, we evaluated CAR-T, CAR-NKT, CAR-NK cells, and CAR-macrophages. CAR-NK cells displayed a robust antigen-specific cytolytic activity against EGFRvIII-expressing SB28 cells, comparable to CAR-T cells in vitro and mice bearing intracerebral EGFRvIII-expressing SB28 gliomas. Remarkably, CAR-NKT cells produced higher levels of inflammatory cytokines when co-cultured with EGFRvIII-expressing SB28 cells, such as IFN-g, Perforin, IL4, and IL17. On the other hand, despite their in vitro cytotoxic effects against SB28 cells, CAR-NK cells failed to mediate a therapeutic response in mice bearing intracerebral glioma. Future studies will be directed at improving the in vivo persistence of CAR-NK cells using engineered cytokines, such as IL-2 superkine. In addition, we extensively investigated CAR-macrophages in vitro and in vivo. Unfortunately, we did not observe significant CAR-specific anti-tumor effects. Consequently, we modified the intracellular domain of CAR from CD3z-CD28-4-1BB to CD3z alone. This alteration led to increased TNF-α production through CAR signaling. This transgenic mouse model offers rigorous and reproducible evaluations of CAR-expressing hematopoietic cells. Furthermore, the model provides a platform for developing combination therapies, such as CAR-T plus CAR-NKT or CAR-T plus CAR-NK cells, with potential implications for enhanced cancer treatment strategies.
EXTH-25. IN VIVO TWO-PHOTON TUMOR IMAGING IN AN ORTHOTOPIC MEDULLOBLASTOMA MOUSE MODEL
Authors: Teske Nico , Kutlu Nayad N , Herold Julika J , Dengler Laura , Eberle Constantin , Nikolaishvili Elene , Karschnia Philipp , Blobner Jens , Müller Katharina , Langer Sigrid , Buschinger Vincenz , Warmuth Linda , Busch Dirk H , Buchholz Veit , Thon Niklas , Tonn Joerg-Christian , Feuchtinger Tobias , von Baumgarten Louisa 
Published: November 2023

Abstract

BACKGROUND
Medulloblastoma represents the most common primary brain malignancy in pediatric patients and is associated with neuro-cognitive impairment and frequent relapses after aggressive multimodal therapy. Adoptive immunotherapies such as CAR T-cell therapy are currently being investigated, showing promising results in preclinical models but lacking efficacy in first-in-human trials. Refined in vivo models to investigate reasons for treatment failures are therefore urgently needed.

METHODS
We developed a xenogeneic orthotopic medulloblastoma (MB) model in mice by combining a chronic cerebellar window with repetitive intravital two-photon laser scanning microscopy. Red tdTomato-fluorescent DAOY (SHH MB) tumor cells expressing B7-H3 were implanted intracranially into the cerebellum of immunodeficient mice (n = 7), and tumor cell formation was followed by in vivo-microscopy. Intravenous fluorescein isothiocyanate (FITC)-dextran was used for intravascular plasma staining. B7-H3-directed CAR T-cells were injected into the adjacent brain parenchyma.

RESULTS
Chronic cranial window implantation was well tolerated and allowed repetitive visualization of the mouse cerebellum. After intracranial tumor cell implantation, continuous tumor growth could be evaluated with epifluorescence as well as 2-photon laser scanning microscopy. Tumor formation was identified as early as day 5 in every mouse and could continuously be followed up to 35 days until mice succumbed due to tumor burden. Window quality and fluorescence intensity remained high until the end of the experiments. Studies on GFP-expressing CAR T-cell injection directed against B7-H3 are currently ongoing.

CONCLUSIONS
We herein establish a robust orthotopic medulloblastoma mouse model that allows repetitive in vivo tracking of fluorescence-expressing tumor cells, CAR T-cells and blood vessels over weeks. Such models may be used to study medulloblastoma tumor growth under the influence of different immunotherapies and reveal interactions between tumor cells and CAR T-cell therapies on a single-cell level.