bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-26. CORE OUTCOME SETS FOR USE IN FUTURE MENINGIOMA CLINICAL STUDIES: RESULTS OF THE COSMIC PROJECT
Authors: Millward Christopher , Islim Abdurrahman , Keshwara Sumirat , Srikandarajah Nisaharan , Brodbelt Andrew , Marson Anthony , Williamson Paula , Jenkinson Michael
Published: November 2023

OBJECTIVE

Core Outcome Sets (COS) define the minimum outcomes that should be measured and reported in all clinical trials for a specific health condition or health area. The aim was to develop two COS for intracranial meningioma; one for clinical trials (COSMIC: Intervention) and one for observational studies (COSMIC: Observation).

METHODS

A study advisory group was formed with representation from international stakeholders of charities (IBTA, TBTC, brainstust), neurosurgery societies (SBNS, BIMS) and neuro-oncology societies (BNOS, EANO, EORTC, ICOM, RANO-PRO, SNO). Two systematic literature reviews and trial registry searches were performed to identify outcomes reported in published and ongoing 1) meningioma clinical trials, and 2) studies of incidental/untreated meningioma. Outcomes were deduplicated and categorised. Individuals were recruited from stakeholder groups (including meningioma patients and carers, healthcare professionals, researchers) to participate in 2-round, international, modified eDelphi surveys. The final core outcome sets were ratified through online consensus meetings.

RESULTS

The COSMIC: Intervention systematic review identified 660 verbatim outcomes, rationalized into 24 Delphi survey items. Following the consensus meeting, 15 outcomes were included in the final set. For COSMIC: Observation, 267 verbatim outcomes were identified and rationalized into 17 Delphi survey items. 16 outcomes were included in the final set. There were eight core outcomes common to both COSMIC: Intervention and COSMIC: Observation COS, namely tumour growth, physical, emotional, and neurocognitive functioning, overall quality of life, progression-free survival, meningioma specific mortality and overall survival. Role and social functioning were core outcomes in COSMIC Observation but not COSMIC intervention.

CONCLUSIONS

The COSMIC study has defined the core outcome sets for use in future meningioma clinical trials and studies. Role and social functioning were important to incidental meningioma patients and likely reflects the anxiety and uncertainty around clinical treatment. International stakeholder agreement should ensure widespread use and adoption.
NCOG-37. BELZUTIFAN IN ADULTS WITH VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA: A SINGLE-CENTER EXPERIENCE
Authors: Neth Bryan , Webb Mason , White Jessica , Uhm Joon , Pichurin Pavel , Sener Ugur
Published: November 2023

INTRODUCTION

Belzutifan is a selective inhibitor of hypoxia-inducible factor 2-alpha that has been FDA approved for Von Hippel–Lindau (VHL) syndrome-associated tumors. There is limited real-world evidence in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan.

METHODS

We retrospectively reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2023.

RESULTS

4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months). Therapy was well tolerated. The most common adverse effect was anemia. No patients had treatment pauses or dose adjustments due to toxicity. No patients experienced hypoxia.

DISCUSSION

We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.
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

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

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

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

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

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 (< 4 mg twice daily versus > 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 (< 4 mg twice daily), while 28 received more frequent dexamethasone dosing (> 4 mg three times daily). Patients with higher frequency dexamethasone dosing were more likely to have radiographic evidence of midline shift (p < 0.001), compression of ventricles (p < 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

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

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 >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 >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

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

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

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 < 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 < 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

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
TMET-19. TARGETING AMINO ACID METABOLIC VULNERABILITIES IN IDH-MUTANT AND IDH-WILDTYPE GLIOMAS
Authors: Ohba Shigeo , Teranishi Takao , Hirayama Akiyoshi , Hitachi Keisuke , Yamaguchi Hisateru , Natsumeda Manabu , Tateishi Kensuke , Pieper Russell , Hirose Yuichi
Published: November 2023

IDH-wildtype and IDH-mutant glioma have different genetical and metabolic background although their histological appearances are similar. The aim of the study is to reveal the difference in metabolites between IDH-wildtype glioma and IDH-mutant glioma, and to find the effective treatment according to the status of IDH in gliomas. Two artificial cell lines made from human astrocyte were used: NHAE6E7hTERTRas (IDH-wildtype) and NHAE6E7hTERTIDHmut (IDH-mutant). Capillary electrophoresis- and ion chromatography–coupled mass spectrometry revealed that the amount of asparagine was lower in NHAE6E7hTERTRas cells compared with NHAE6E7hTERTIDHmut cells. L-asparaginase, which converts asparagine into aspartate, was more effective in former cells than latter cells. L-asparaginase induced autophagy and inhibition of autophagy by 3-MA suppressed L-asparaginase-induced antitumor effect, which meant that the antitumor effect was at least partially due to the L-asparaginase-induced autophagy. Metabolic assay also showed the lower amount of glutamine, glutamate and 2-oxoglutarate in NHAE6E7hTERTIDHmut cells than NHAE6E7hTERTRas cells. Pharmacological or genetical inhibition of GLUD1 which converts glutamate to 2-oxoglutarate, suppressed proliferation of the cells by inducing ROS and apoptosis in NHAE6E7hTERTIDHmut cells. ROS inhibitor, NAC suppressed GLUD1 inhibitor-induced ROS, apoptosis, and cytotoxicity in NHAE6E7hTERTIDHmut cells, revealing that cytotoxicity by GLUD1 inhibitor was at least partially due to the inhibitor-induced ROS. Mutant IDH1 overexpressed glioma cell line showed similar sensitivity to GLUD1 inhibitor to NHAE6E7hTERTIDHmut, which suggested that the difference of sensitivity to GLUD1 inhibitor was due to the status of mutant IDH. In addition, GLUD1 inhibitor suppressed the growth of xenografted glioma cells with overexpressed mutant IDH1. In conclusion, L-asparaginase and Glud1 inhibitor will be new therapeutic option for IDH-wildtype glioma and IDH-mutant glioma, respectively.
TMIC-29. BEVACIZUMAB IS ASSOCIATED WITH INCREASED RATE OF RECURRENCE IN GLIOBLASTOMA
Authors: Mekonnen Mahlet , Vohra Sanah , Chandla Anubhav , Malkhasyan Yelena , Yang Isaac
Published: November 2023

BACKGROUND

The primary cause of Glioblastoma’s (GBM) dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. Bevacizumab has increasingly been used in the treatment of recurrent GBM. However, the data on Bevacizumab has been mixed regarding its efficacy in improving patient survival. Moreover, there is no conclusive evidence in the literature regarding Bevacizumab treatment and its association with increased incidence of distant or diffuse recurrence. Objective: To provide conclusive evidence on the recurrence rate associated with Bevacizumab treatment in GBM patients

METHODS

UCLA GBM patients were reviewed for recurrence pre-and post-Bevacizumab treatment. Patients whose Bevacizumab treatment was not flanked by surgeries and patients with only one surgery were excluded. After exclusion criteria were applied, 94 patients were included in the results. The number of recurrences preceding and following Bevacizumab was recorded.

RESULTS

In a cohort of 94 patients, the average recurrence rate pre-Bevacizumab treatment was 0.29 ± 0.88, whereas the average recurrence rate post-Bevacizumab treatment was 2.51 ± 1.64. Overall, the recurrence rate was significantly higher in GBM patients post-Bevacizumab treatment (95% CI [1.83, 2.59]; p< 0.0001).

CONCLUSION

Our results suggest that Bevacizumab treatment is associated with an increased rate of recurrence. This finding is indicative of tumor transition to a more aggressive phenotype that is associated with Bevacizumab treatment.
TMIC-31. MULTI-PLATFORM GENOMIC LANDSCAPE OF INTRA-TUMORAL HYPOXIA IN GLIOBLASTOMA
Authors: Mansouri Sheila , Patil Vikas , Liu Jeff , Gandhi Shreya , Sosa Julio , Wu Ron , Devaraja Kaviya , Singh Olivia , Ali Hafsah , Karimi Shirin , Mamatjan Yasin , Chen Sujun , Dvorkin-gheva Anna , Khan Shahbaz , He Hansen , Kislinger Thomas , Gaiti Federico , Wouters Bradley , Zadeh Gelareh
Published: November 2023

Hypoxia is a prominent characteristic of aggressive tumors, including glioblastoma (GB), and is linked to therapy resistance. Understanding the molecular mechanisms underlying hypoxia-induced changes in neoplastic and non-neoplastic cells is crucial for developing targeted therapies. In this study, we took a comprehensive approach to investigate the genomic, epigenomic, and spatial transcriptomic profiles of intra-tumoral hypoxia in GB at bulk and single-cell levels. Our objectives were to identify a GB-specific hypoxia gene signature and uncover novel mechanisms of GB's response to hypoxia. Pimonidazole (PIMO), a hypoxia marker, was administered to 77 GB patients. We utilized immune-guided laser microdissection to extract DNA and perform methylome profiling of PIMO+ (hypoxic) and PIMO- regions. Visium 10X spatial transcriptomics was employed to identify differentially expressed genes in PIMO+ tumor regions. Through single-nuclear multi-omics profiling, we examined gene expression and chromatin accessibility of the hypoxic neoplastic and non-neoplastic cells at the single-cell level. The hypoxia transcriptome in GB exhibited general commonalities, in addition to unique features, compared to other reported hypoxia signatures. Some of these alterations were accompanied by changes at the DNA methylome level. Importantly, we found a heterogenous molecular landscape across PIMO+ regions within each sample. While a general transition to a MES-like state was observed, we found a mixture of cell states across the different PIMO+ regions. We also found distinct sub-hypoxic microenvironments harboring unique immune cell populations that overlapped with specific cell type states, cell cycle states, and deregulation of specific cellular pathways. These sub-regions were associated with specific anatomic features and displayed prognostic utility in GBM patient cohorts. Our single-cell multi-omics analysis further revealed intra-tumoral copy number aberrations and changes in chromatin accessibility associated with hypoxic cells. Our findings demonstrate that the hypoxic microenvironment in GB is heterogenous with unique targetable features that could lead to novel treatment modalities.
TMIC-42. ACROLEIN PRODUCED BY GLIOMA CELLS UNDER HYPOXIA INHIBITS NEUTROPHIL AKT ACTIVITY AND SUPPRESSES ANTI-TUMORAL ACTIVITIES
Authors: Tong Zhen-Jie , Tsai Hong-Chieh , Hwang Tsong-Long , Wang Hsiang-Tsui
Published: November 2023

Glioblastoma (GBM), WHO grade 4 glioma, is the most malignant primary brain tumor. The median overall survival of GBM ranges from 12 to 16 months. The tumor microenvironment of GBM is characterized by tissue hypoxia and infiltration of immunosuppressive cells. Neutrophils have been reported to shift from an anti-inflammatory phenotype to a pro-tumoral role (N2 phenotype) during glioma progression. However, the mechanism of this transformation remains unclear. Acrolein (Acr) is a highly-reactive α,β-unsaturated aldehyde produced under hypoxic conditions via lipid peroxidation, resulting in cellular impairment through DNA or protein conjugation. In this study, we found that acrolein produced by U87MG cells under hypoxic conditions suppresses neutrophil superoxide generation, inhibits neutrophil tumor-suppressive activities, and induces N2 marker arginase 1 (Arg-1) expression. Scavenging acrolein with dimercaprol reverses these effects. Further investigation revealed that acrolein inhibits AKT enzymatic activity by forming Acr-AKT conjugates at Cys 310. In a syngeneic subcutaneous mice glioma model, dimercaprol treatment is associated with decreased tumor size, reduced acrolein conjugate expression in the tumor tissue, and restored neutrophil superoxide generation. In addition, we also found that the higher acrolein-DNA adduct expression in tumor tissues is associated with a poor prognosis of glioma patients, and the evaluated acrolein-protein conjugates in the serum of glioma patients are correlated to the functional impairment of neutrophils. These results suggest acrolein polarizes the neutrophils toward the N2 phenotype and contributes to the immunosuppressive microenvironment and glioma progression. Acrolein scavenging may be a novel strategy for glioma treatment.
TMIC-45. SEX DIFFERENCES IN YAP1-CD276 EXPRESSION AND FUNCTION IN MEDULLOBLASTOMA IMMUNE EVASION
Authors: Abdelfattah Nourhan , Natarajan Sivaraman , Madonado Jose , Borland Hannah , McMinimy Rachael , Chen Shu-hsia , Camargo Fernando , Olson James , George Joshy , Yun Kyuson
Published: November 2023

Sex differences in human diseases are well established; however, little is known about the molecules that link oncogenic events and sex as a biological variable in tumorigenesis and treatment response. Here, we report that Yap1 has a sex-specific role in SHH medulloblastoma (MB) progression and immune suppression. Through integrated genomic, transcriptomic, proteomic, and in vivo transcriptional target analyses, we show that Yap1 concurrently promotes stemness and blocks differentiation of cancer stem cells through at least two distinct but complementary molecular mechanisms. In parallel, Yap1 also promotes immune suppressive tumor microenvironment by directly regulating CD276, Csf1, Igf1, and Igfbp3 transcription and modulating the IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, while Yap1 function is critical for promoting stemness in male and female MB cells, Yap1 plays a more dominant role in promoting immune suppression and Th2 polarization in male MBs. Furthermore, we discovered that a YAP1-target gene, CD276, expression level is higher in female MBs in both mice and humans, demonstrating for the first-time sex differences in expression levels of an immune checkpoint molecule in MB. Functionally, anti-CD276 treatment is more effective in reversing T cell suppression from male MB cells compared to female MB cells, and CD276 expression level stratifies male but not female MB patient survival. Supporting the clinical relevance of our findings, we show that the sex difference in Yap1 function is evolutionarily conserved across multiple tumor types: YAP1 target gene signature predicts poor survival in males but not females in MB, glioblastoma, low-grade glioma, mesothelioma, and hepatocellular carcinoma. In summary, we provide the first evidence of sex-biased expression and function of YAP1 and CD276 in mouse and human cancers and identified the YAP1-CD276 axis as a key contributor to sex differences in immune checkpoint response.
Readministration of high-dose adeno-associated virus gene therapy vectors enabled by ImmTOR nanoparticles combined with B cell-targeted agents
Authors: Ilyinskii Petr O , Roy Christopher , Michaud Alicia , Rizzo Gina , Capela Teresa , Leung Sheldon S , Kishimoto Takashi Kei
Published: November 2023

Tolerogenic ImmTOR nanoparticles encapsulating rapamycin have been demonstrated to mitigate immunogenicity of adeno-associated virus (AAV) gene therapy vectors, enhance levels of transgene expression, and enable redosing of AAV at moderate vector doses of 2 to 5E12 vg/kg. However, recent clinical trials have often pushed AAV vector doses 10-fold to 50-fold higher, with serious adverse events observed at the upper range. Here, we assessed combination therapy of ImmTOR with B cell-targeting drugs for the ability to increase the efficiency of redosing at high vector doses. The combination of ImmTOR with a monoclonal antibody against B cell activation factor (aBAFF) exhibited strong synergy leading to more than a 5-fold to 10-fold reduction of splenic mature B cells and plasmablasts while increasing the fraction of pre-/pro-B cells. In addition, this combination dramatically reduced anti-AAV IgM and IgG antibodies, thus enabling four successive AAV administrations at doses up to 5E12 vg/kg and at least two AAV doses at 5E13 vg/kg, with the transgene expression level in the latter case being equal to that observed in control animals receiving a single vector dose of 1E14 vg/kg. Similar synergistic effects were seen with a combination of ImmTOR and a Bruton's tyrosine kinase inhibitor, ibrutinib. These results suggest that ImmTOR could be combined with B cell-targeting agents to enable repeated vector administrations as a potential strategy to avoid toxicities associated with vector doses above 1E14 vg/kg.
Real eigenvector distributions of random tensors with backgrounds and random deviations
Authors: Sasakura Naoki
Published: November 2023

As in random matrix theories, eigenvector/value distributions are important quantities of random tensors in their applications. Recently, real eigenvector/value distributions of Gaussian random tensors have been explicitly computed by expressing them as partition functions of quantum field theories with quartic interactions. This procedure to compute distributions in random tensors is general, powerful, and intuitive, because one can take advantage of well-developed techniques and knowledge of quantum field theories. In this paper we extend the procedure to the cases that random tensors have mean backgrounds and eigenvector equations have random deviations. In particular, we study in detail the case that the background is a rank-one tensor, namely, the case of a spiked tensor. We discuss the condition under which the background rank-one tensor has a visible peak in the eigenvector distribution. We obtain a threshold value, which agrees with a previous result in the literature.
Effect of Rhythmically Cued Exercise Interventions on Functions in Patients With Parkinson Disease: A Meta-Analysis
Authors: Huang Xin , Dong Ke , Gan Chu , Xu Zhiqin , Lei Di , Dong Xinghua , Liu Hanjun , Chen Xi
Published: November 2023

Objective

The purpose of this review was to investigate the efficacy of rhythmically cued exercise interventions on motor function, cognition, and mental state in patients with Parkinson disease.

Methods

PubMed, Cochrane Database, Web of Science, Embase, and CINAHL were searched June 15, 2023. Original studies investigating the efficacy of rhythmically cued exercise interventions on the functions of patients with Parkinson disease were included. The Cochrane risk-of-bias assessment tool was used to evaluate the risk of bias. The protocol was registered in PROSPERO (CRD42022371203).

Results

A total of 38 original studies involving 1486 participants were included. Rhythmically cued exercise interventions demonstrated superior effects on motor function compared to exercise therapy without rhythm (standardized mean difference [SMD] = −0.31). However, no significant improvements were observed in cognition and mental state. Overall, significant improvements were observed in motor examination (SMD = −0.61), Timed “Up & Go” Test (mean difference [MD] = −0.91), activities of daily living (SMD = −0.49), balance (SMD = 0.59), walking velocity (MD = 0.06), step length (MD = 2.65), and stride length (MD = 0.04) following rhythmically cued exercise interventions. No significant improvements were observed in freezing of gait and cadence. Assessment of publication bias showed no significant evidence of publication bias. Meta-regression analyses revealed a significant association between treatment duration and improvement in motor function. Furthermore, adverse events and dropout rates did not significantly differ between the 2 groups.

Conclusion

Rhythmically cued exercise interventions are effective in improving motor function in the early to middle stages of Parkinson disease. More than 10 weeks of intervention yielded better results. However, these interventions do not have a significant impact on cognition and mental states. Importantly, rhythmically cued exercise interventions are safe and well tolerated. Large-scale trials are needed for further confirmation.

Impact

This study contributes to the development of safe and reliable home rehabilitation programs, aiming to enhance the quality of life for patients with Parkinson disease.
A microRNA sponge, LINC02193, promotes neutrophil activation by upregulating ICAM1 and is correlated with ANCA-associated vasculitis
Authors: Liu Yun , Feng Yifan , Kong Xiufang , Wei Yuanyuan , Zhan Minglang , Wang Jinghua , Dai Xiaojuan , Wang Li , Ma Lili , Chen Huiyong , Jiang Lindi
Published: November 2023

Objective

To investigate the pathogenic role and underlying mechanisms of long noncoding RNAs (lncRNAs) in ANCA-associated vasculitis (AAV).

Methods

RNA-sequencing (RNA-seq) was applied to screen the expression profile of lncRNAs in peripheral leukocytes from five AAV patients and five healthy controls (HC). Candidate lncRNAs were preliminarily verified in peripheral leukocytes from 46 AAV patients and 35 HC by qRT-PCR. Then, the identified LINC02193 was further validated in peripheral neutrophils from 67 AAV patients, 45 HC and 64 disease controls. Correlation between LINC02193 levels and disease activity was analysed. Then, a loss-of-function study was conducted to investigate the role of LINC02193 in neutrophils activation. Furthermore, bioinformatics analysis, dual luciferase reporter and RNA immunoprecipitation assays were performed to explore the mechanism of LINC02193 regulating neutrophils activation.

Results

A total of 467 upregulated and 412 downregulated lncRNAs were identified in AAV patients. From the top five upregulated lncRNAs, an elevation of LINC02193 was validated in a larger sample of AAV patients, and positively correlated with disease activity. Knockdown of LINC02193 inhibited reactive oxygen species and nitric oxide production, neutrophil extracellular traps release and adhesion to endothelial cells of differentiated human promyelocytic leukaemia HL-60 cells, whereas overexpression of ICAM1 counteracted these effects. Mechanistic analysis demonstrated that LINC02193 acted as an miR-485-5p sponge to relieve the repressive effect of miR-485-5p on ICAM1, thus promoting ICAM1 expression.

Conclusion

LINC02193, a novel lncRNA identified in AAV, could function as competing endogenous RNAs for miR-485-5p to promote ICAM1 expression and neutrophils activation, suggesting its potential as a therapeutic target of AAV.
Reported Outcome Measures in Mohs Micrographic Surgery in Studies With Defined Techniques for Embedding and Processing of Tissue: A Systematic Review
Authors: Govas Panayiota , Ha Megan V. , Wessel Charles B. , Hurst Anne , Gordon Beth R. , Carroll Bryan T.
Published: November 2023

BACKGROUND

Mohs micrographic surgery (MMS) is a technique that combines surgical excision and histologic evaluation to achieve higher cure rates for skin cancer than traditional surgical excision. Competing performance measures have fostered numerous histologic techniques for MMS.

OBJECTIVE

To analyze differences in primary outcomes in the published literature regarding the technique of tissue processing and embedding during the MMS process.

METHODS

A systematic review was performed of the published literature in MEDLINE, PubMed, Embase, and Cochrane library that included a description of the manipulation of tissue during the grossing and embedding steps of MMS.

RESULTS

Inclusion criteria were met by 61 articles. Of these studies, the cure/recurrence rate was assessed in 1 article (1.6%), tissue conservation was assessed in 47 (77%), time-saving was assessed in 35 (57%), cost-saving was assessed in 6 (10%), and decreased artifact were assessed in 20 (33%).

CONCLUSION

There is a lack of standardization for assessing clinical outcomes in the published literature regarding MMS process techniques. Cure is a critical outcome in studies comparing MMS processing methodologies.