bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-35. UNRAVELING THE MECHANISTIC UNDERPINNINGS OF MRNA VACCINE MEDIATED INNATE IMMUNE ACTIVATION AND LYMPHOCYTE TRAFFICKING FOR HIGH-GRADE GLIOMAS
Authors: DeVries Anna , Mendez-Gomez Hector , Chardon-Robles Jonathan , Thomas Nagheme , McGuiness James , Carrera-Justiz Sheila , Castillo Paul , Weidert Frances , Mitchell Duane , Sayour Elias 
Published: November 2023

Abstract

BACKGROUND
High-grade gliomas are an aggressive subset of CNS tumors in need of novel treatment strategies. However, tumor heterogeneity, the immunosuppressive tumor microenvironment (TME) and the lack of immunogenic tumor specific targets have limited the translational power of many immunotherapies for high-grade gliomas. The promising application of mRNA vaccines has the potential to restore immunosurveillance through peripheral and intratumoral reprograming of the TME.

METHODS
Our lab has developed a lipid particle multilamellar aggregate (RNA-LPA) vaccine that encapsulates tumor specific RNA and delivers the payload to the immune system in a highly immunogenic fashion, similar to that of a virus. We sought to assess anti-tumor activity across preclinical murine models and investigate the mechanisms for response.

RESULTS
We demonstrated the immune activation potential of RNA-LPAs encoding for glioma associated antigens (i.e., pp65 and H3K27M) in preclinical murine models. We also showed activity of personalized RNA-LPA in canine and human studies (NCT04573140) for patients with high-grade gliomas. Exogenous RNA is recognized by pathogen recognition receptors (PRRs) which trigger a type I interferon (IFN) response and proinflammatory cytokine production. While most RNA based vaccines activate an innate immune response primarily through toll-like receptor 7 (TLR7), we reveal that RNA-LPAs activate the innate immune system through retinoic acid-inducible gene 1 protein (RIG-I). As a result of PRR signaling, the type I IFN and cytokine/chemokine response (IL-6, G-CSF, TNF-alpha, CXCL9, CXCL10, CCL2, CCL4) mediates massive recruitment of activated dendritic cell and activated T cell in lymphoreticular organs where antigen presenting cells and cytolytic T cell colocalize to initiate an adaptive immune response against glioma specific antigens.

CONCLUSION
RNA-LPAs are a novel platform immunotherapy that initiate anti-tumor immunity against malignant brain tumors through noncanonical activation of intracellular PRRs and widespread recruitment of peripheral blood mononuclear cells to sites of RNA-LPA localization.
EXTH-46. SCHLAFEN11 IS A POWERFUL BIOMARKER OF CHEMOSENSITIVITY IN MEDULLOBLASTOMAS
Authors: Natsumeda Manabu , Nakata Satoshi , Murai Junko , Haruhiko Takahashi , Okada Masayasu , Watanabe Jun , Tsukamoto Yoshihiro , Tateishi Kensuke , Osuka Satoru , Raabe Eric , Pouponnot Celio , Pommier Yves , Oishi Makoto , Kakita Akiyoshi , Eberhart Charles 
Published: November 2023

Abstract
Non-biased and biased screening for prognostic factors in medulloblastomas showed that Schlafen family member 11 (SLFN11) is a powerful prognostic marker. SLFN11 is a putative DNA/RNA helicase, whose expression improves response to DNA damaging agents in some cancers, but its role in medulloblastoma has not been reported. SLFN11 protein and mRNA level were found to be expressed exclusively in WNT-activated and a proportion of SHH-activated medulloblastoma. WNT pathway activation did not acutely induce SLFN11, rather, its expression correlated with a specific hypomethylation site on the SLFN11 promoter. Genetic introduction of SLFN11 into medulloblastoma cell lines with no baseline expression dramatically increased their response to the DNA damaging agents cisplatin and SN-38 in vitro. Intracranial xenograft studies also showed markedly increased sensitivity to cisplatin after induced SLFN11 overexpression in medulloblastoma cells. In addition, CRISPR-mediated deletion of SLFN11 in a medulloblastoma cell line with high baseline expression reduced the response to chemotherapy. SLFN11 could also be upregulated pharmacologically by the histone deacetylase-inhibitor RG2833, supporting the importance of epigenetic control. Importantly, markedly increased sensitivity to cisplatin and SN-38 was seen in initially SLFN11-negative medulloblastoma cells also treated with RG2833, suggesting an approach by which more aggressive medulloblastoma subtypes might be targeted. Our findings suggest a novel mechanism for the increased chemosensitivity of some medulloblastoma subtypes linked to a specific biomarker, as well as a novel combinatorial chemotherapeutic strategy for the treatment of more aggressive medulloblastoma subtypes (Groups 3 and 4) lacking SLFN11.
EXTH-65. IDENTIFICATION OF LOMERIZINE AS A POTENTIAL ANTI-GLIOBLASTOMA DRUG
Authors: Ichinose Toshiya , Tanaka Shingo , Kinoshita Masashi , Nakada Mitsutoshi 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is one of the most malignant primary brain tumors. Despite development of surgical techniques, chemotherapy and radiotherapy, GBM prognosis is still poor. Here, we identified lomerizine, a prophylactic drug for migraine, as a potential anti-GBM drug from thousands of existing compounds. We investigated its therapeutic effects both in vitro and in vivo with the purpose of drug repositioning. Materials and method: Human patient-derived glioma stem cell line (GSC; KGS01, KGS10, KGS15), their differentiated cells, and GBM cell lines (A172, SNB19, T98, U87) were used. Proliferation assay, migration assay and invasion assay were performed with all cell lines. Sphere-forming assay was performed with GSCs. Various signaling pathways altered by lomerizine were analyzed by Western blotting. In addition, induction of apoptosis was evaluated by immunofluorescence and Annexin V assay. Anti-GBM effects of lomerizine in vivo was validated with a mouse brain tumor model. Result: Lomerizine inhibited proliferation, migration, and invasion dose-dependently in all cell lines, especially in GSCs. Sphere formation was also suppressed by lomerizine in all GSCs. STAT3, which is involved in tumorigenesis, was dephosphorylated after the treatment with lomerizine in a dose-dependent manner in all cell lines. Furthermore, apoptosis induction by lomerizine was confirmed in both immunofluorescence and Annexin V assay. In vivo experiments showed a significant tumor suppression and prolongation of overall survival in the group of mice treated with lomerizine.

CONCLUSION
This study suggests that lomerizine has anti- GBM effects.
EXTH-68. SYSTEMIC NEUTRALIZATION OF IL6 SENSITIZES IDH-WILDTYPE GLIOBLASTOMA PRECLINICAL MODELS TO IMMUNE CHECKPOINT INHIBITION
Authors: Young Jacob , Cho Nam Woo , Lucas Calixto-Hope , Mirchia Kanish , Seo Kyounghee , Chen William , Nguyen Minh , Chen Arya , Phillips Joanna , Ozawa Tomoko , Bhaduri Aparna , Aghi Manish , DeRisi Joseph , Berger Mitchel , Butowski Nicholas , Spitzer Matthew , Raleigh David 
Published: November 2023

Abstract
IDH-wildtype glioblastomas are resistant to immune checkpoint inhibition (ICI). Here we integrate spatial and single-cell approaches across paired human glioblastomas before or after ICI with functional studies in immunocompetent intracranial mouse glioblastoma models to reveal mechanisms and therapeutic vulnerabilities underlying glioblastoma resistance to ICI. Spatial proteomic and transcriptomic approaches were used to identify biochemical and gene expression programs underlying ICI response or resistance in paired human glioblastoma samples (n = 7). Intracranial SB28 glioblastoma allografts were implanted in C57BL/6J mice and treated with (1) convection enhanced delivery (CED) of AAV9 gene therapy vectors encoding cytokines that reprogram the tumor immune microenvironment (TIME) in other cancers (Il1b, Ccl4, Apoa1), (2) systemic anti-PD1, (3) local anti-IL6, (4) systemic anti-IL6, or (5) combination systemic treatment with anti-PD1 and anti-IL6. Histological, mass cytometry (CyTOF), and multiplexed cytokine assays were used to assess the glioblastoma TIME in response to treatment over time. Mice were monitored for survival and tumor growth was measured using intracranial bioluminescence. Human glioblastomas with radiographic responses to ICI had lower pre-treatment IL6 levels on spatial profiling than glioblastomas resistant to ICI. Intratumor IL6 was suppressed by all AAV9 cytokine conditions compared to AAV9-GFP in mice. Mouse survival was improved by combination systemic treatment with anti-PD1 and anti-IL6, but was not improved by either antibody alone, or by anti-IL6 CED. CyTOF revealed combination systemic therapy reprogrammed the glioblastoma TIME by increasing activated immune cell types such as MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and by decreasing immunosuppressive Tregs. In summary, systemic anti-IL6 in combination with systemic anti-PD1 reprograms the glioblastoma TIME to sensitize preclinical models to ICI. These results provide mechanistic validation of findings from human glioblastomas that respond to ICI and shed light on a therapeutic vulnerability underlying the glioblastoma TIME.
QLTI-07. DOSE-EFFECT RELATIONSHIP OF DEXAMETHASONE ON OUTCOMES OF BRAIN METASTASES
Authors: Webb Lauren , White Jessica , Neth Bryan , Sener Ugur , Mustafa Rafid 
Published: November 2023

Abstract

BACKGROUND
Dexamethasone is commonly used to manage peritumoral edema and alleviate neurologic symptoms in patients with intracranial tumors. The optimal dexamethasone dose for brain metastases is unknown and widely variable. Recent literature reports the most common regimen is 4 mg four times daily. However, the half-life of dexamethasone is 35-54 hours, suggesting that such frequent dosing may be unnecessary. We explored the dose-effect relationship of dexamethasone on brain metastases patient outcomes to improve quality of care.

METHODS
We retrospectively identified 100 patients (1/1/2016 – 12/31/2022) with brain metastases who were treated with dexamethasone and had adequate follow-up. All patients received standard oncologic care including chemotherapy, radiotherapy, and/or surgical intervention. We evaluated the association between dexamethasone dosing regimens (&lt; 4 mg twice daily versus &gt; 4 mg three times daily), clinical outcomes (performance status, clinical and radiographic response to corticosteroids, survival), and dexamethasone adverse effects during the acute presentation and at first neuro-oncologic follow-up.

RESULTS
Seventy-two patients received less frequent dexamethasone dosing (&lt; 4 mg twice daily), while 28 received more frequent dexamethasone dosing (&gt; 4 mg three times daily). Patients with higher frequency dexamethasone dosing were more likely to have radiographic evidence of midline shift (p &lt; 0.001), compression of ventricles (p &lt; 0.001), and herniation (p = 0.0020) at presentation. Those with more frequent dosing more often demonstrated radiographic response to dexamethasone (67.9% vs. 45.8%, p = 0.0323), but there were no differences in symptomatic improvement, Karnofsky Performance Status, seizure reduction, survival, or the frequency of adverse events (e.g., hyperglycemia, hypertension, infection, psychosis) between the two cohorts.

CONCLUSIONS
These results suggest that for most patients with brain metastases, less frequent dexamethasone dosing may lead to clinical outcomes that are similar to those patients who received more frequent dosing. However, higher doses of dexamethasone can be considered for those with more concerning radiologic features.
QOL-10. MULTIDISCIPLINARY MEDICAL CARE SYSTEM FOR BRAIN TUMOR SURVIVORS IN JAPAN
Authors: Saito Norihiko , Hirai Nozomi , Koyahara Yuki , Sato Sho , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Izukura Hideaki , Sakurai Takatoshi , Iwabuchi Satoshi 
Published: November 2023

Abstract
INTRODUCTION: Brain tumor patients suffer from psychological distress and various aftereffects. Although the number of "brain tumor survivors" has been increasing due to improved outcomes of brain tumor treatment, the support system for them is inadequate in Japan. Therefore, we are examining issues affecting the QOL faced by brain tumor patients and their families, with the aim of establishing a fulfilling medical care system with a multidisciplinary approach. Here, we report on the current status of the multidisciplinary medical care system. METHODS: The EORTC QLQ-C30, 14-item resilience scale, PHQ-9, and Pittsburgh Sleep Quality Index are used to assess QOL. Based on these, an optimal care plan for brain tumor patients was developed through multidisciplinary team of professionals among physicians, nurses, clinical neuropsychologists, speech-language pathologists, occupational therapists, pharmacists, and nutritionists. A brain tumor survivorship program designed to support brain tumor patients, survivors, and care givers was developed, and this program was launched in December 2021. RESULTS AND DISCUSSION: Quality of life assessment of brain tumor patients revealed their problems and unmet needs, which enabled the development of optimal care plans in collaboration with multiple disciplines. In addition, neuropsychological approaches and cognitive behavioral therapy have been utilized as interventions for cognitive dysfunction. The Brain Tumor Survivorship Program has 18 participants as of May 31, 2023. In addition to providing online resources, patient support meetings were held virtually, providing an opportunity for participants to communicate directly with each other. CONCLUSION: We believe it is essential to establish a long-term follow-up system specifically for brain tumor patients. Through the multidisciplinary medical care system, we plan to continue to scientifically investigate and develop a support system for the various survivorship issues that brain tumor patients and their families experience across the trajectory of the illness.
RBIO-01. GAMMATILE ® (GT) AS A BRACHYTHERAPY PLATFORM FOR RAPIDLY GROWING BRAIN METASTASIS
Authors: Dharnipragada Rajiv , Ferreira Clara , Reynolds Margaret , Shaw Rena , Dusenbery Kathryn , Chen Clark 
Published: November 2023

Abstract

BACKGROUND
A subset of brain metastasis (BM) shows rapid recurrence post-initial resection or aggressive tumor growth between interval scans. Here we provide a pilot experience in the treatment of these brain metastasis with GammaTile ® (GT), a collagen tile-embedded Cesium 131 (131Cs) brachytherapy platform.

METHODS
We identified ten consecutive patients (2019-2023) with brain metastasis that showed either 1) symptomatic recurrence while awaiting post-resection radiosurgery or 2) enlarged by &gt;25% of tumor volume on serial imaging and underwent surgical resection followed by GT placement. Procedural complication, 30-day readmission, local control, and overall survival were assessed.

RESULTS
For this cohort of ten BM patients, three patients suffered tumor progression while awaiting radiosurgery and seven showed &gt;25% tumor growth prior to surgery and GT placement. There were no procedural complications or 30-day mortality. All patients were discharged home, with a median hospital stay of two days (range: 1-9 days). 4/10 patients experienced symptomatic improvement while the remaining patients showed stable neurologic conditions. With a median follow-up of 186 days (6.2 mo, range: 69-452 days), no local recurrence was detected. The median overall survival (mOS) for the newly diagnosed BM was 265 days from the time of GT placement. No patients suffered from adverse radiation effects.

CONCLUSION
Our pilot experience suggests that GT offers favorable local control and safety profile in patients suffering from brain metastases that exhibit aggressive growth patterns and support the future investigation of this treatment paradigm.
SURG-10. DEVELOPMENT OF 2 COMPLEMENTARY INNOVATIVE APPROACHES FOR REAL-TIME, LABEL-FREE INTRAOPERATIVE TUMOR DETECTION TO ENHANCE EXTENT OF RESECTION OF LOW GRADE GLIOMAS
Authors: De Vleeschouwer Steven , Cuypers Eva , Van Hese Laura , Theys Tom , Heeren Ron , Vandebriel Roeland , Luthman Siri , Vunckx Kathleen , Jayapali Murali , Charle Wouter , Solie Lien , Giannantonio Tommaso , Alperovich Anna , Zhang Xiaohan 
Published: November 2023

Abstract
Brain tumor surgery aims to maximize tumor resection while avoiding neurological deficits. Accurate characterization of tissue and delineation of resection margins are essential to achieve optimal surgical outcome. Hyperspectral imaging (HSI) and Real-time Rapid Evaporative Ionization Mass Spectrometry ( REIMS) are both novel technological adjuncts able to accurately detect intraoperatively zones of low grade glioma without substantially altering the surgical work flow. For HSI, we successfully demonstrate how an HSI system can interface with a clinically approved surgical microscope making use of the microscope’s available light sources and optical ports. We integrated the HSI system into the clinical workflow during brain surgery, specifically for resections of low-grade gliomas (LGG). During the study the acquired dataset was used to train an AI algorithm to detect LGG, providing 81% accuracy on unseen data. Real-time Rapid Evaporative Ionization Mass Spectrometry (REIMS) enables in-situ tissue characterization based on the mass spectrometric analysis of electrosurgical vapors generated during dissection. We demonstrate the use of REIMS for the molecular characterization of brain tumor tissue, thereby providing quasi real-time assessment of tumor type. A classification model containing 31 sampling points in normal brain tissue and 93 in glial tumor tissue provided 89.3% sensitivity and 91.1% specificity. Both techniques, HSI and REIMS display a high intraoperative diagnostic accuracy in terms of glioma tissue detection and are complementary, real-time and label-free methods which we developed and tested up to the stage of high Technology Readiness levels (TRL) of 7 and 5 respectively.
SURG-17. COMPARABLE SAFETY PROFILE BETWEEN NEURO-ONCOLOGY PROCEDURES INVOLVING STEREOTACTIC NEEDLE BIOPSY (SNB) FOLLOWED BY LASER INTERSTITIAL THERMAL THERAPY (LITT) AND LITT ALONE PROCEDURES
Authors: Sharma Mayur , Do Truong , Palzer Elise , Huling Jared , Chen Clark 
Published: November 2023

Abstract

INTRODUCTION
Tissue diagnosis through stereotactic needle biopsy (SNB) is often needed prior to laser interstitial thermal therapy (LITT). Whether these procedures should be performed in the same surgery or in separate surgeries remain unclear. As a first step to address this question, we assess safety profile of procedures involving LITT alone versus SNB+LITT.

METHODS
Using International Classification of Disease (ICD) codes, we queried the National Readmissions Database (NRD, 2010-2018) for malignant brain tumor patients who underwent either 1) LITT alone or 2) elective LITT in combination with SNB (SNB+LITT). Survey regression methods were utilized. Additionally, the procedural outcome of LITT or SNB+LITT performed by the senior surgeon (2014-2022) were reviewed.

RESULTS
During the study period, an estimated 678 malignant brain tumor patients underwent LITT alone versus 373 patients that underwent SNB+LITT. Patients undergoing LITT and SNB+LITT exhibited statistically comparable median lengths of hospital stay (IQR; LITT = 2 day [1, 3]; SNB+LITT = 1 day [1, 3]; p = 0.405) and likelihood of routine discharge (LITT = 73.5%; SNB+LITT = 81.1%; p = 0.068). the odds of 30-day medical or neurological readmissions were comparable between LITT and SNB+LITT treated patients (all p ≥ 0.793) In the single surgeon experience of 218 procedures performed over an eight year period (2014-2022), the complications (LITT = 3.9%; SNB+LITT = 2.6%, p = 0.709), discharge within 48 hours (LITT = 84.5%; SNB+LITT = 87.8%; p = 0.556), routine discharge (LITT = 91.3%; SNB+LITT = 93.9%; p = 0.604), and unplanned 30-day readmission (LITT = 3.9%; SNB+LITT = 1.7%; p = 0.423) were similarly comparable between LITT and SNB+LITT. The most common complications were: hemorrhage (n = 3) and LITT-associated edema (n = 3) followed by hydrocephalus (n = 1). Of the 115 patients who underwent SNB+LITT, the frozen pathology diagnosis was revised on final pathology in two patients (2/115 or 1.7%).

CONCLUSION
The length of hospital stay, the likelihood of routine discharge, and 30-day readmission for malignant brain tumor patients who underwent LITT and SNB+LITT were comparable.
SURG-41. PROGNOSTIC IMPACT OF EXTENDED RESECTIONS IN IDH MUTANT LOWER-GRADE DIFFUSE GLIOMA: RESULTS FROM A VOLUMETRIC ANALYSIS
Authors: Jungk Christine , Gluszak Mara , von Deimling Andreas , Herold-Mende Christel , Trong Philip Dao , Unterberg Andreas 
Published: November 2023

Abstract
In IDH mutant (IDHmut) glioma, the prognostic impact of extended resections is still under debate. A potential outcome benefit may be influenced by the tumor’s molecular phenotype. Also, many studies lack objective quantitative assessment of residual tumor volume (RTV). Here, we analyzed the prognostic benefit of surgery in a molecularly defined cohort of patients harboring an astrocytoma or oligodendroglioma, IDHmut, WHO grade 2 and 3, for whom volumetric analysis of RTV was possible. Patient-, tumor- and treatment-related factors including pre- and post-operative MR FLAIR tumor volumes were correlated with progression-free (PFS) and overall (OS) survival. Confounders of resectability were analyzed by multiple linear regression. 206 patients treated at our institution over one decade were identified retrospectively. Mean age was 40.37 years. 105 patients suffered from IDHmut astrocytoma and 101 patients from oligodendroglioma. Resection (n = 185 patients; 89.8%) as opposed to biopsy was associated with prolonged PFS and OS in astrocytoma (p = 0.007; p = 0.038) and WHO grade 2 tumors (p = 0.012; p &lt; 0.0001). In patients undergoing resection, median pre- and post-operative tumor volumes did not differ between tumor subtypes but were significantly larger in WHO grade 3 than 2 tumors (pre-operative: 71.3 vs. 28.8 cm3; RTV: 7.78 vs. 1.98 cm3). Median RTV of the complete cohort was 4.6 cm3. There was a stepwise improvement of outcome with decreasing RTV (PFS: p = 0.0003; OS: p = 0.0004; data given for quartiles), with the strongest effect observed for patients with no RTV (median PFS: undefined vs. 58 months; p = 0.007). In multivariable analysis, RTV independently predicted OS (p = 0.001; HR 1.012) but not PFS. Resectability was only influenced by pre-operative FLAIR tumor volume (p &lt; 0.0001). In summary, a continuous association of RTV and outcome was observed, even at the highest levels of resection. This finding was more pronounced in astrocytoma. Thus, a maximal resection should be strived for whenever safely achievable.
TMET-05. LIPOPHAGY CONTROLS CHOLESTEROL HOMEOSTASIS AND BRAIN TUMOR GROWTH
Authors: Geng Feng , Zhong Yaogang , Su Huali , Lefai Etienne , Yong William , Chakravarti Arnab , Guo Deliang 
Published: November 2023

Abstract
Cholesterol is an essential structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol, but with an abundant presence of cholesteryl esters (CEs) in their lipid droplets (LDs). Mechanistically, we found that SREBP-1, a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked GBM cells became quite sensitive to cholesterol deficiency with poor growth. Our study unravels a previously unrecognized SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis, while providing a potential new therapeutic avenue for GBM