bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-47. HUMAN MICROBIOTA INFLUENCE THE GLIOMA-IMMUNE LANDSCAPE AS DETERMINED BY SINGLE CELL RNA-SEQUENCING IN A MURINE MODEL OF GLIOMA
Authors: Green George , Cox-Holmes Alexis , Marlow Gillian , Potier Anna Claire , Wang Yong , Zhou Lianna , Chen Dongquan , Morrow Casey , McFarland Braden 
Published: November 2024

Abstract
We recently identified immunotherapy responder and nonresponder human microbiota compositions in the murine model of glioma. In this study, we sought to understand how human microbiota in mice influence the immune landscape in glioma. To test this, we utilized our novel humanized microbiome (HuM) mouse model (human microbiota transplanted into gnotobiotic mice) to determine the effect of immunotherapy in a mouse model of glioma utilizing single-cell RNA sequencing and 16S rRNA microbiome sequencing. We focused on two HuM mouse lines in this study: HuM1 (nonresponder) and HuM2 (responder). To confirm microbiota differences,16S rRNA sequencing revealed significant differences between alpha and beta diversity between HuM1 and HuM2 groups. HuM2 responder mice also displayed a significant increase in the relative abundances of Odoribacter, Muribaculaceae, and Ruminococcus genera compared to HuM1 mice. HuM1 and HuM2 mice were then injected with GL261 glioma cells into the brains, treated with one dose of anti-PD-1 or isotype control on day 13, and all mice were euthanized on day 14 for scRNA-sequencing of CD45+ cells in the tumors. We identified 21 clusters of immune cells in the tumors. Furthermore, we found significant differences between HuM1 and HuM2 mice in isotype control conditions including higher percentages of immature B cells, neutrophils, and microglia in HuM2 mice. In anti-PD-1 treated tumors, there was a robust increase in the percentage of innate immune cells in the tumor following, specifically the monocyte/macrophage (MM1; Cxcl10+) population in both HuM1 and HuM2 mice. However, the HuM2 MM1 cluster showed an increase in gene expression of Nos2 and decrease in Arg1, indicating that the MM1 population in HuM2 mice are more inflammatory (anti-tumor) compared to HuM1. Ultimately, our data demonstrate that the gut microbiome influences the tumor-immune landscape, and harnessing positive microbial compositions remains a viable translational avenue to pursue.
IMMU-49. TARGETING ALTERNATIVE SPLICING VARIANTS TO STIMULATE ANTI-TUMOR IMMUNITY IN A NOVEL SYNGENEIC MOUSE MODEL OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Wang Anthony , Owens Geoffrey , Pan Yang , Kim Wi-Jin , Sun Matthew , Peeters Sophie , Treger Janet , Lee Alexander , Armellini Amber , Na Brian , Everson Richard , Daniels David , Nathanson David , Liau Linda , Prins Robert , Xing Yi 
Published: November 2024

Abstract
The prognosis for pediatric high-grade gliomas associated with mutations in the H3-A3 histone gene is very poor. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant (DHG), we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens (TAs). We used the RCAS/tv-A system to target the expression of H3/G34R and PDGFb, and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. To identify TAs, we implemented a new computational workflow to identify nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two DHG patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele. Splenocytes isolated from successfully treated mice were analyzed through bulk TCR sequencing, and in comparison with control mice and publicly-accessible TCR libraries, 6 highly-represented TCR clonotypes were identified only in treated mice. In summary, we demonstrate that effective TAs can be extracted from RNAseq data, and can be targeted with DC vaccination to generate a systemic anti-tumor cytotoxic T cell response to eliminate DHG in a novel immunocompetent mouse model.
IMMU-54. THERAPEUTIC TARGETING OF STING IN MENINGIOMAS
Authors: Youngblood Mark , Tripathi Shashwat , Najem Hinda , Gomez Mateo , Sadagopan Nishanth , Sears Thomas , Hurley Lisa , Wang Wenxia , Congivaram Harrshavasan , Choudhury Abrar , Steffens Alicia , Oyon Daniel , Fernandez Luis , Selner Ashley , Fares Jawad , Hagan Matthew , Palmer Aaron , Karras Constantine , Trybula Joy , Zhang Peng , Stegh Alexander , Curran Michael , Ashley David , Magill Stephen , Horbinski Craig , Chandler James , Lesniak Maciej , Miska Jason , Dunn Gavin , Raleigh David , Heimberger Amy 
Published: November 2024

Abstract
Up to one-quarter of meningiomas recur within five years of resection; however, there are currently no established adjuvant therapies for lesions that are intractable to surgery and radiation. To identify novel treatment approaches, scRNA-sequencing datasets were reanalyzed from thirteen meningiomas and nine adjacent dura samples including &gt;30,000 immune cells from varying WHO grades and molecular subtypes. In contrast to gliomas, immune-inducing STING (stimulator of interferon genes) was expressed within the meningioma tumor cells, consistent with DNA methylation profiling that showed hypomethylation of the STING promotor in 93% of cases (267 of 288 meningiomas; beta &lt; 0.2). Meningiomas in the immune-enriched subgroup additionally exhibited significant hypomethylation in the 3’ UTR of this gene (p = 1.9 x 10-9). Using sequential multiplex immune fluorescence, STING expression was confirmed in neoplastic, myeloid, and endothelial cells within all grades of meningiomas, but not in adjacent dura and brain. Downstream STING pathway activation markers such as p-IRF3 were partially expressed, suggesting that further activation of the STING pathway may offer therapeutic benefits. Ex vivo single-cell suspensions of resected human meningiomas treated with the STING agonist 8803 induced 25-45% growth inhibition in 7/8 cases within 72 hours (p &lt; 0.001; two-way ANOVA). There was no growth inhibition of the meningioma cell lines IOMM-LEE and CH157 treated with 8803, which lack immune cells and contain only clonal neoplastic cells. However, when the IOMM-LEE meningioma cells were implanted in vivo, a single dose of 8803 induced a &gt;50% reduction in tumor volume relative to the vehicle control injection at multiple time points (p &lt; 0.001; two-way ANOVA) indicating that the immune system is an essential component of STING efficacy in these tumors. Our results reveal widespread expression of STING in neoplastic and myeloid populations in meningiomas and clarify a new treatment indication for use of the STING agonist 8803.
INNV-04. SINGLE INSTITUTION RETROSPECTIVE STUDY TO DETERMINE TIME TO FIRST PROGRESSION IN MGMT METHYLATED GLIOBLASTOMA PATIENTS WHO RECEIVED STANDARD OF CARE
Authors: Thakkar Jigisha , Ng Isaac , Jani Ronak , Goyal Abhishek , Prabhu Vikram , Anderson Douglas , Wainwright Derek , Borys Ewa , Mallik Atul , Barton Kevin 
Published: November 2024

Abstract

MGMT methylated glioblastomas respond well to standard of care with temozolomide, have a longer survival as well as increased risk of pseudo-progression as compared to unmethylated patients. Shorter survival in these patients despite effective treatments is due to misdiagnosis of true progression (in cases with pseudo-progression) that leads to overtreatment or discontinuation of effective treatments. There are limited non-invasive diagnostic tools to distinguish true progression from pseudo-progression. Knowing the expected time to first true progression will aid with interpretation of MRI changes and serve as an additional tool to distinguish true from pseudo-progression.

OBJECTIVE
We sought to define the time to first progression in MGMT methylated glioblastoma patients who were treated with standard of care/Stupp protocol (this has not been previously defined).

METHODS
We conducted a retrospective analysis of an IRB-approved database at our institution from 2019 to 2022 of all MGMT methylated glioblastoma patients who completed Stupp protocol. Time to first progression (time from initial surgery to first true progression) was determined by treating multidisciplinary team based on radiographic review +/- pathology. Eligible MGMT methylated glioblastoma patients had IDH status determined by NGS and completed standard Stupp protocol after surgery.

RESULTS
Approximately 30% (27) patients with IDH wild-type glioblastoma were MGMT methylated. 10 patients met eligibility criteria. 50% of MGMT methylated GBM patients had multifocal disease at presentation. Median time to first progression in MGMT methylated GBM who received standard of care was 28 months. 20% patients have not had first progression 3 years after initial surgery.

CONCLUSION
MRI changes on surveillance scans should be carefully interpreted in the first 28 months. Knowing time to first true progression will aid with management decisions and decrease unnecessary early aggressive interventions in MGMT methylated glioblastoma patients. We will validate these findings in a larger patient population at our institution.
INNV-08. PRE-CLINICAL AND CLINICAL EVIDENCE FOR THE TREATMENT OF DMG/DIPG USING EMULATE THERAPEUTICS’ ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD SIGNAL TECHNOLOGY
Authors: Figueroa Xavier 
Published: November 2024

Abstract
EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds via a magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical studies demonstrate an effect in slowing down and inhibiting tumor growth. The results of feasibility (Phase I/II) clinical trials testing the EMTx technology for treating recurrent GBM (rGBM) were published in CNS Oncology (CNS Oncol 2023 Pages CNS102, Accession Number: 37462385 DOI: 10.2217/cns-2022-0016). Reported results suggest that the A1A signal is non-inferior to best supportive care (BSC) and when the A1A signal is combined with BSC, a 3-month increase in overall survival (OS) was observed. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured at under 12 months, with no clinical trials demonstrating a significant increase in OS in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program (Hælo® medical device) demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months, with median survival of 17 months. EMTx recently completed an orthotopic mouse model of DIPG at University of California San Francisco. The results from exposing the mice to the A1A signal demonstrated a significant survival advantage (P = 0.0163) via the slowing down of cell division. Data to be submitted for peer review publication. The animal model is encouraging and supports the observed results of our compassionate use program. EMTX will submit these results to the FDA for regulatory approval via the Humanitarian Device Exemption pathway. The company will conduct a study with DIPG patients from both the US and India. Subject to FDA protocol approval, 30-35 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best supportive care + single therapy (Hælo®) clinical trial.
INNV-11. DELIVERY OF TTFIELDS TO THE INFRATENTORIAL BRAIN USING HFE ARRAYS
Authors: Ze’evi Oshrit , Naveh Ariel , Manzur Doron , Shapira Nadav 
Published: November 2024

Abstract

INTRODUCTION
Tumor Treating Fields (TTFields) therapy is a noninvasive, locoregional treatment comprising alternating electric fields delivered to the tumor via two pairs of skin-placed transducer arrays. TTFields physically disrupt cancer cell viability through a multimodal mechanism that includes antimitotic and antitumor immune effects. TTFields therapy is FDA-approved for glioblastoma (GBM) and CE marked for WHO grade 4 glioma. While clinically approved array layouts for GBM target supratentorial tumors, TTFields distribution depends on the arrays’ locations and dedicated layouts are needed to target infratentorial tumors. To increase patient comfort, Novocure developed HFE arrays that are thinner and lighter than existing INE arrays. Here, we evaluate innovative HFE array layouts for TTFields delivery to infratentorial tumors at therapeutic intensities (~1 V/cm).

METHODS
TTFields delivery was simulated using Sim4Life v6.2 in a male computational model. 32 layouts of HFE arrays were placed on the model’s scalp, neck, and scapulae, with one placed at a standard cerebral location. Local Average Field Intensity (LAFI) and Local Minimum Power Density (LMiPD) were calculated in the cerebrum, cerebellum and brainstem.

RESULTS
Standard cerebral layout provided LAFI of 2.47 V/cm to the cerebrum, while providing 1.50 and 1.10 V/cm to the cerebellum and brainstem, respectively (LMiPD 2.22, 1.34 and 0.64 mW/cm3). Layouts comprising arrays on the scapulae (right and left) paired in cross configuration with arrays on either the temples or forehead, provided LAFI of 1.87-2.17 V/cm (LMiPD 1.05-2.20 mW/cm3) to the cerebrum, while providing 1.64-2.13 V/cm (LMiPD 1.77-2.26 mW/cm3) to the cerebellum and 1.74-1.89 V/cm (LMiPD 2.28-2.89 mW/cm3) to the brainstem.

CONCLUSION
Lower array placement provides higher levels of field intensity in the cerebellum and brainstem versus standard cerebral layout, while still providing adequate field intensity to the cerebrum. This simulation-based study suggests feasibility of delivering therapeutic TTFields intensities to infratentorial tumors using dedicated HFE array layouts.
INNV-14. OUTCOMES OF PATIENTS WITH ISOCITRATE DEHYDROGENASE-MUTANT WHO GRADE 4 ASTROCYTOMA TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY: A REAL-WORLD ANALYSIS
Authors: Connelly Jennifer M , navgeropoulos@novocure.com Nick , Conlon Patrick , Chavez Gordon , Farber Ori 
Published: November 2024

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) therapy is approved for the treatment of patients with newly diagnosed glioblastoma, based on the EF-14 study which demonstrated improvement in progression free survival and overall survival (OS). EF-14 included patients with the isocitrate dehydrogenase (IDH) mutation (IDHmut), which has since been reclassified as IDHmut WHO grade 4 astrocytoma (Astrocytoma IDHmut/G4) and confers a more favorable prognosis than IDH wild type. However, large real-world datasets are lacking. Here, we report real-world outcomes of patients with Astrocytoma IDHmut/G4 treated with TTFields in the US.

METHODS
Utilizing electronic health records from the xCures real-world data platform, patients with newly diagnosed Astrocytoma IDHmut/G4 receiving TTFields in the US from January 1 to December 31, 2019 were analyzed and IDH-mut status was confirmed. Survival was analyzed based on IDH-mut status and TTFields usage, with patients categorized into 2 usage groups (minimum 30 days treatment): high (≥50%) and low (&lt;50%) usage.

RESULTS
Among 1285 patients with known IDH status, 82 had an IDH-mut and were included. The median (range) age of patients was 40.6 (21–75) years, with the majority being men (n=58/71%) and with methylguanine-methyltransferase-promoter methylation (n=48/59%). Median TTFields therapy duration and usage were 9.4 months and 76.8%, respectively. OS at 2 and 4 years was 66% (95% CI: 56–77%) and 44% (34–57%), respectively. Patients with high TTFields usage had increased OS compared to low usage (HR: 0.53 [0.28–1.02], P=0.057, n=80). Among 22 patients with a minimum 4 years of survival, 5 were still on therapy as of the data cutoff.

CONCLUSIONS
These findings demonstrate the utility of the xCures platform in systematically assessing outcomes for a rare glioma subtype in the real-world setting, and suggests that patients with Astrocytoma IDHmut/G4 may benefit from TTFields therapy. Additional patient follow-up and correlative data will be presented.
INNV-17. SAME-DAY DISCHARGE AFTER LASER INTERSTITIAL THERMAL THERAPY: A PROSPECTIVE COHORT PILOT STUDY WITH A MATCHED CONTROL GROUP
Authors: Berke Chandler , Khalafallah Adham , Knott Maxon , Susic Nikola , Gurses Muhammet , Lu Victor , Ivan Michael , Komotar Ricardo , shah Ashish 
Published: November 2024

Abstract

BACKGROUND
Laser interstitial thermal therapy (LITT) has emerged as a minimally invasive treatment modality for intracranial pathologies, offering precision and control over tissue damage. With implementation of enhanced recovery after surgery (ERAS) protocols within neurosurgery, identifying patients amenable for same-day discharge (SDD) is an important step towards streamlining perioperative care following LITT, and correspondingly, we aim to summarize our initial experience.

METHODS
We conducted a prospective study at the University of Miami Hospital of 7 patients who underwent LITT for intracranial pathologies and were discharged on the same day of ablation (post-ablation day 0, PAD0). We then performed a retrospective case-control study against a historic matched PAD1 cohort comparing categorical and continuous variables for statistical significance.

RESULTS
The mean age of the PAD0 cohort was 55 years with 71% males. Preoperative neurological status and comorbidities did not differ significantly between the PAD0 and PAD1 cohorts for KPS (median [IQR]: 80 [80-90] vs. 90 [80-90], p=0.40), mFI-5 (median [IQR]: 1 [1.5] vs. 0 [1], p=0.54), and mFI-11 (median [IQR]: 1 [1.5] vs. 1 [1], p=0.52). PAD0 outcomes demonstrated no immediate complications, neurosurgical readmissions, or significant neurological deficits within 6 months post-procedure and were non-significantly different than PAD1 patients. No PAD0 patient experienced intracranial hemorrhage or vasogenic edema following LITT that necessitated further intervention.

CONCLUSIONS
Our study demonstrates the safety and feasibility of same-day discharge following LITT for intracranial pathologies in the appropriately selected patient. Through meticulous patient selection and optimized perioperative protocols, expedited recovery without compromising patient outcomes was achieved. This approach holds potential for substantial cost savings and resource optimization within healthcare systems. Further research and quality improvement initiatives are warranted to refine patient selection criteria and maximize the benefits of same-day discharge in LITT practice.
INNV-22. CEREBELLOPONTINE EPIDERMOID CYST TO SQUAMOUS CELL CARCINOMA: MALIGNANT TRANSFORMATION, LEPTOMENINGEAL CARCINOMATOSIS, AND MANAGEMENT
Authors: Hennawy Mirna , Fatehi Mostafa , Yip Stephen , Oh Justin , Harrison Rebecca 
Published: November 2024

Abstract

BACKGROUND
Intracranial epidermoid cysts (EDC) are rare, slow-growing, congenital tumors, that generally follow a benign course. EDCs have a rare potential for transformation to squamous cell carcinoma (SCC). We present a case of a malignant EDC transformation to SCC with leptomeningeal (LM) dissemination.

METHODS
Case report and review of literature.

CASE PRESENTATION
A 44-year-old female presented for evaluation of left-sided tinnitus and sensorineural hearing loss, which revealed a left cerebellopontine angle (CPA) tumor. She underwent a subtotal resection at age 47. One year later, she had rapid symptomatic recurrence of the cyst, as well as LM deposits of the right internal acoustic canal bundle, the left trigeminal nerve, and along the lumbar and sacral spine. She underwent repeat resection of the CPA lesion, with pathology now consistent with SCC, with CDKN2A loss. She received focal radiation therapy at the posterior fossa and the lumbar spine. SCC-directed chemotherapy with pembrolizumab and carboplatin followed by 5 cycles of pembrolizumab monotherapy was given as adjuvant therapy, prior to her developing symptomatic LM disease.

CONCLUSION
Malignant transformation of intracranial EDC is a rare occurrence in these typically benign tumours. Prognosis is especially poor when there is associated LM involvement, with median survival noted to be 10 months. Awareness of this phenomenon amongst clinicians is needed to ensure appropriate surveillance and aggressive treatment if it remains within patient wishes, though there is no consensus on recommendations for treatment. The patient presented has maintained disease stability with LM dissemination for over 10 months and ongoing, with a regimen of chemoradiotherapy informed by therapeutic approach to systemic SCC. To our knowledge, this is the first reported case of EDC to SCC transformation and LM dissemination stabilized with chemoradiotherapy using an immune-checkpoint inhibitor.
INNV-24. CONGENITAL EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES AND TREATMENT IN A NEWBORN
Authors: Casey Jessica , Raman Sarina , Lasky Joseph , Gupta Sumit 
Published: November 2024

Abstract

BACKGROUND
Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare but deadly pediatric brain tumor with no standard of care treatment. We present a unique case of congenital ETMR and treatment strategy using intrathecal topotecan and no radiation therapy. Case report: A term baby was admitted to NICU at 12 hours of life with respiratory arrest requiring intubation. CT of the brain revealed a 4.2x3.9x3.5cm left posterior fossa hyperdense hemorrhagic mass with moderate hydrocephalus. She underwent posterior fossa craniotomy for biopsy and evacuation at two days of life. Pathology was consistent with an ETMR. MRI brain after first resection was not concerning. She underwent re-resection at 3 months of age due to re-growth (2x3x3cm). She was then treated as per Head Start 4 chemotherapy regimen with vincristine, cisplatin, etoposide, cyclophosphamide, and methotrexate, followed by consolidation with three tandem auto-hemopoietic stem cell transplants (HSCT) with carboplatin and thiotepa conditioning. Maintenance treatment consisted of intrathecal topotecan every four weeks (0.2mg per dose &lt;1 year old, 0.25mg per dose when ≥1 year old) for 12 doses. She also received oral vorinostat (100mg PO QD) and isotretinoin (80mg/m2 divided BID) during maintenance for 1 year. No radiation was given. The treatment course was complicated by mucositis, febrile neutropenia, pseudomonas sepsis and an episode of respiratory arrest secondary to choking from epistaxis. The patient is currently doing well and continues to remain in remission for over seven months after end of treatment.

CONCLUSION
We present a case of congenital ETMR with a unique treatment option and strategy using Head Start 4 therapy with three tandem auto-HSCT as consolidation, followed by 12 months of maintenance therapy with intrathecal topotecan, oral vorinostat, and isotretinoin, without any radiation, leading to sustained remission.