bluuebunny/crossref_metadata_2025_split huggingface dataset:
10065- ET-6 MRNA-ENCAPSULATED LIPID NANOPARTICLES FOR MALIGNANT GLIOMA
Authors: Hiu Takeshi , Matsuo Ayaka , Kamiya Mariko , Matsumoto Makoto , Yoshida Michiharu , Nakamura Hikaru , Baba Shiro , Kawakami Shigeru , Matsuo Takayuki 
Published: November 2024

Abstract
Nucleic acid therapeutics hold promise for cancer treatment but have yet to be effectively applied to malignant glioma due to challenges in stability and delivery. We explored the intracerebral delivery of lipid nanoparticles (LNPs) encapsulating siRNA as a drug delivery carrier. Our goal was to develop an siRNA therapy selectively targeting malignant glioma cells by combining LNPs with Fc-domain-binding peptide lipids (FcBPs), a modification system that allows antibody orientation control. Intracerebral Delivery of mRNA-Encapsulated Lipid Nanoparticles: We aimed to deliver mRNA-encapsulated LNPs to the brain using focused ultrasound (FUS) and microbubbles (MB). Following the administration of microbubbles and mRNA-encapsulated LNPs in normal mice, FUS irradiation was performed on the brain. The introduction of firefly luciferase mRNA resulted in gene expression that was 20 times higher in the FUS-irradiated brain compared to the non-irradiated side. Gene expression was observed in vascular endothelial cells throughout the brain and in parenchymal cells outside the brain blood vessels at the FUS-irradiated site. Development of siRNA Medicines: We prepared FcBP-modified siRNA-LNPs targeting integrin αvβ3, highly expressed in malignant gliomas, using siRNA-Luc2. The modifications with FcBP or anti-integrin αvβ3 antibody did not alter the physicochemical properties or polydispersity index (PDI). In vitro, anti-integrin αvβ3-FcBP-modified siRNA-LNPs inhibited the binding of integrin to U87-MG-Luc2 cells, demonstrating high binding affinity and knockdown effects via αvβ3.Discussion:Our findings suggest that the delivery of mRNA-encapsulated LNPs into the brain is feasible using FUS and MB. Additionally, we successfully developed siRNA-LNPs modified with anti-integrin αvβ3 antibody FcBP. Future work will evaluate the cell binding and antitumor effects of siRNA-VEGF encapsulated in these LNPs, aiming to develop new treatments for malignant glioma by enhancing blood-brain barrier penetration and targeting malignant glioma.
10162- TB-6 VALIDATION OF BORON NEUTRON CAPTURE THERAPY WITH EXISTING BORON COMPOUNDS IN A RAT MALIGNANT GLIOMA MODEL
Authors: Kashiwagi Hideki , Kawabata Shinji , Eza Kenichiro , Kambara Akihiro , Yoshimura Kohei , Fujikawa Yoshiki , Futamura Gen , Hiramatsu Ryo , Nonoguchi Naosuke , Furuse Motomasa , Hu Naonori , Takata Takushi , Tanaka Hiroki , Watanabe Tsubasa , Suzuki Minoru , Miyatake Shin-Ichi , Wanibuchi Masahiko 
Published: November 2024

Abstract

BACKGROUND
Boron neutron capture therapy (BNCT) is a biologically targeted particle therapy that utilizes the capture reaction between boron and neutrons. Theoretically, tumor cell-selective boron uptake allows for tumor-selective therapy. Recently, BNCT using an accelerator neutron source has been initiated in the area of head and neck cancers and is expected to expand its application to brain tumors. In addition to boronophenylalanine (BPA), which is used in clinical practice, clinical trials for malignant gliomas have been conducted in the past using sodium borocaptate (BSH) in combination. However, to date, surprisingly few reports have accurately evaluated the validation of BNCT with BPA and BNCT with BPA/BSH in animal models. In the present study, we performed a basic research-based validation of BPA/BSH combined BNCT that has been performed in clinical trials in the past.

METHODS
Brain tumor models of F98 rat malignant glioma brain tumors were prepared. BPA and BSH were administered intravenously 2.5 hours and 12 hours before BNCT were performed, respectively. Each F98 rat malignant glioma brain tumor model was neutron irradiated and evaluated using Kaplan-Meier survival curves.

RESULTS
No significant difference in survival was observed in the BSH alone group compared to the untreated group. A significant difference in survival was observed in the BPA alone group compared to the untreated group. The BPA/BSH combination group had the longest median survival and a significant difference in survival compared to the untreated group. A significant difference in survival was observed between the BPA/BSH combination group and the BSH alone group.

CONCLUSION
The combination of BPA and BSH improved BNCT efficacy and prolonged survival. The combination of BPA and BSH, existing boron compounds, is a pioneering method of boron neutron capture therapy using two and more boron compounds, and its use is presumed to have been highly rational.
10253- ACT-16 OUTCOMES OF MAINTENANCE THERAPY USING TUMOR TREATING FIELDS (TTF) FOR GLIOBLASTOMA AND CHARACTERISTICS FOR CONTINUATION OF TTF MAINTENANCE THERAPY
Authors: Shimizu Kazuhide , Tamura Kaoru , Tanaka Yoji , Takahashi Shota , Shiraishi Midori , Osuga Hiroko 
Published: November 2024

Abstract

BACKGROUND
Tumor Treating Fields (TTF) is a novel therapy that inhibits tumor cell division and has been reported to be safe and effective in real-world settings for newly diagnosed glioblastoma in Japan since its insurance coverage in December 2017. This study evaluates the outcomes and characteristics for the continuation of TTF treatment at the Department of Neurosurgery, Tokyo Medical and Dental University.

METHODS
We retrospectively analyzed adult patients with newly diagnosed supratentorial glioblastoma who completed initial surgery and chemoradiotherapy and began outpatient maintenance therapy between December 2018 and August 2024. Patients were divided into TTF treatment (T group) and non-TTF treatment (N group). The primary endpoints were overall survival (OS) and progression-free survival (PFS), with additional evaluations of patient characteristics and TTF array adherence.

RESULTS
The study included 49 patients (T group: 14, N group: 35) with a mean age of 66 years (range 25-86). All cases were pathologically diagnosed as glioblastoma (WHO 2016 and 2021). The mean duration of TTF treatment was 282 days (21-1155 days), with a median of 124 days. OS was 837 days (27.9 months) in the T group and 536 days (17.9 months) in the N group (p=0.17), while PFS was 961 days (32.0 months) in the T group and 196 days (6.5 months) in the N group (p=0.012). Long-term TTF users (&gt;=12 months) showed a trend towards extended OS and PFS compared to shorter-term users, with a significantly lower adherence rate at 3 months in early discontinuation cases (p=0.014).

CONCLUSION
TTF is an effective maintenance therapy for glioblastoma patients, with early high adherence being crucial for its success. Comprehensive patient support, including social aspects, is essential for the continuation of TTF treatment.
10305- ACT-17 EFFECTIVENESS OF DABRAFENIB AND TRAMETINIB IN PATIENTS WITH GLIOMA WITH MUTATION OF BRAF V600E: A SINGLE CENTER ANALYSIS.
Authors: Yanagisawa Shunsuke , Oono Makoto , Kawauchi Daisuke , Omura Takaki , Aoki Takuma , Kawanishi Akiya , Narita Yoshitaka 
Published: November 2024

Abstract

BACKGROUND
In tumor cells, Dabrafenib (DB) acts on the mutated BRAF itself, and Trametinib (TR) acts on MEK and suppresses cell proliferation, and the combination of the two drugs is used for melanoma with BRAF mutations, non-small cell lung cancer, and advanced or recurrent solid tumors (excluding colon and rectal cancer) that are difficult to treat as standard. It has been approved in Japan by November 2023. In this study, we analyzed a case of using DB+TR for glioma at our center.

METHODS
DB+TR was applied to gliomas treated at our center from January 2018 to December 2023.

RESULTS
There were 10 patients, aged 32.7 years, and 3 males and 7 females. Pathological diagnoses was GBM 2, epithelioid GBM 2, anaplastic PXA 2, and anaplastic astrocytoma, glioneural tumor, gliosarcoma, and neuroepithelial tumor 1 respectively. IDH gene wild type and BRAF V600E mutation were observed in all cases. TERT mutations were observed in three C228T mutations and one C250T mutation. In 7 patients, temozolomide + radiotherapy 60Gy/30fraction was given as initial treatment. There were 9 cases in which DB+TR was used at the time of recurrence, and 1 case in which DB+TR was used in the initial treatment. As an adverse event (AE), DB+TR administration was discontinued in 1 case of intratumoral hemorrhage and 2 cases of skin rash. Skin rash was observed in other cases, but DB+TR administration could be continued with symptomatic treatment. The best effects were CR 5, PR 1 and SD 4. The median time from DB+TR use to recurrence was 21.3 (5 to 78.9) months. There were four deaths, and the median survival after discontinuation of DB+TR was 7.2 months (1.27 to 12.8).

DISCUSSION/CONCLUSION
For recurrent gliomas with BRAF V600E mutations, DB+TR showed good outcomes, although administration was discontinued due to AEs in three cases.
10311- ACT-19 A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMA WITH AN IDH1/2 MUTATION (INDIGO): UPDATED EFFICACY RESULTS
Authors: Van Den Bent Martin J , Mellinghoff Ingo K , Touat Mehdi , Blumenthal Deborah T , Peters Katherine B , Ellingson Benjamin M , Mendez Joe , Yust-Katz Shlomit , Mason Warren P , Hottinger Andreas F , Arakawa Yoshiki , Sepulveda Juan M , Wick Wolfgang , Tron Adriana E , Zhao Dan , Pandya Shuchi S , Steelman Lori , Hassan Islam , Wen Patrick Y , Cloughesy Timothy F 
Published: November 2024

Abstract

INTRODUCTION
The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral,brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint of time to next intervention (TTNI), were met in the positive, preplanned second interim analysis (IA2). The study was unblinded in March 2023 following independent data monitoring committee recommendation. Herein, we present results after an additional 6 months of follow-up between the database lock for IA2 (September 6, 2022) and study unblinding (March 7, 2023).

METHODS
Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (aged ≥12 years; Karnofsky Performance Status, ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles.

RESULTS
Overall, 331 patients were randomized (median age, 40.0 years; oligodendroglioma, 172; astrocytoma, 159). As of March 7, 2023, 123/168 (73%) patients remained on vorasidenib and 72/163 (44%) remained on placebo. PFS per BIRC remained in favor of vorasidenib (HR, 0.35; 95% CI, 0.25–0.49) and was consistent with PFS per investigator assessment (HR, 0.34; 95% CI, 0.23–0.50). Median PFS per BIRC: vorasidenib, not estimable (NE; 95% CI, 22.1–NE); placebo, 11.4 months (95% CI, 11.1–13.9). TTNI also remained in favor of vorasidenib (HR, 0.25; 95% CI, 0.16–0.40). Median TTNI: vorasidenib, NE (95% CI, NE–NE); placebo, 20.1 months (95% CI, 17.5–27.1). No new safety signals emerged.

CONCLUSIONS
Vorasidenib is a targeted therapy for patients with predominantly non-enhancing mIDH1/2 diffuse glioma following surgical intervention, as shown in the INDIGO population. These additional 6 months of follow-up confirm the previously reported statistically significant and clinically meaningful improvements in PFS and TTNI with vorasidenib.
10189- STMO-12 INTRAOPERATIVE NEUROMONITORING FOR THE LOWER-EXTREMITY REGION USING MOTOR-EVOKED POTENTIAL WITH DIRECT CORTICAL STIMULATION IN BRAIN TUMOR SURGERIES
Authors: Matsujda Ryosuke , Takatani Tsunenori , Hayashi Hironobu , Maeoka Ryosuke , Morisaki Yudai , Yokoyama Shohei , Takeshima Yasuhiro , Kawaguchi Masahiko , Nakagawa Ichiro 
Published: November 2024

Abstract

PURPOSE
To evaluate the motor function of the lower extremity (LE), we used direct cortical stimulation motor-evoked potential (D-MEP) monitoring with a single six-contact subdural strip electrode placed in the interhemispheric fissure.

METHODS
Intraoperative neuromonitoring using D-MEPs in the LE was performed in 18 cases (16 patients) for brain tumor surgery with a follow-up period of at least 3 months from December 2018 to April 2023. After dural opening, a single six-contact subdural strip electrode was placed inside the interhemispheric fissure. To identify the central sulcus, phase reversal was recorded using SSEPs. Next, direct cortical stimulation was applied to the PMC. The baseline waveform was defined as a reproducible waveform of 30 μV or higher, and a significant decrease of &gt;50% in the amplitude resulted in a warning during surgery.

RESULTS
The success rate of central sulcus identification in the LE was 66.7% (12/18 cases). D-MEP monitoring could record stable contralateral MEPs of the tibialis anterior, gastrocnemius, and abductor hallucis in 16 of 18 cases (88.9%). The mean intensity of stimulation for D-MEPs was 20.5 ± 9.9 mA, and the 16 cases showed no significant reduction in amplitude. Seventeen cases showed no deterioration of motor function of the LE at 1 and 3 months postoperatively. In the remaining case with unsuccessful D-MEP, paralysis of the LE worsened at 1 and 3months postoperatively.

CONCLUSION
The placement of electrodes in the interhemispheric fissure on the PMC of the LE enabled motor-function monitoring in the LE with D-MEPs, suggesting that D-MEP-based monitoring may be a reliable approach.
10261- STMO-22 RADICAL SURGICAL RESECTION FOR THALAMIC TUMORS USING OCCIPITAL TRANSTENTORIAL APPROACH WITH INTRAOPERATIVE MRI
Authors: Hanihara Mitsuto , Kazama Hirofumi , Saito Ryu , Yoshioka Hideyuki , Kinouchi Hiroyuki 
Published: November 2024

Abstract

BACKGROUND
Thalamic tumor has been one of the most challenging part to operate in neurosurgery due to its risks associated with surgical procedures. Occipital transtentorial approach (OTA) is adaptable not only pineal lesion but also thalamic tumor located at pulvinar part. Intraoperative MRI (iMRI) has proven to be highly useful in these procedures, providing real-time imaging that enhances the precision of tumor resection and minimizes the risk of damage to surrounding critical structures.

OBJECTIVE
To examine our surgical outcome and usefulness of OTA for thalamic gliomas. We present a retrospective review of our surgical experience with 4 patients presenting symptomatic thalamic gliomas.

METHODS
OTA was used by prone position with an ipsilateral entry. Following tent incision and dissecting arachnoid membranes around deep vein complex, resection of tumor was performed with making cleavage between tumor and normal brain. Neuronavigation and transcranial motor evoked potentials and intraoperative magnetic resonance imaging (iMRI) were used in all cases.

RESULTS
Four patients with intrinsic gliomas located at the thalamus and midbrain were operated on. One case with midbrain infiltration resulted in subtotal resection, while total resection was achieved in the remaining three cases. Pathological diagnoses are diffuse astrocytoma, pilocytic astrocytoma, pilomyxoid astrocytoma, and anaplastic pilocytic astrocytoma. Postoperative radiochemotherapy was added in one case of anaplastic pilocytic astrocytoma, respectively. The average follow-up period was 54.9 months, during which all cases maintained independent ADL without tumor recurrence.

CONCLUSION
OTA for thalamic gliomas who has main mass located at pulvinar part is a safe and reliable approach with the application of high resolution iMRI.
10002- MPC-1 HISTOLOGICAL GRADE AND TP53 MUTATIONS STRATIFY PROGNOSIS IN MOLECULAR GLIOBLASTOMA
Authors: Makino Ryutaro , Higa Nayuta , Akahane Toshiaki , Yonezawa Hajime , Uchida Hiroyuki , Takajo Tomoko , Kirishima Mari , Yokoyama Seiya , Otsuji Ryosuke , Fujioka Yutaka , Kuga Daisuke , Yamahata Hitoshi , Horie Nobutaka , Kurosaki Masamichi , Yamamoto Junkoh , Yoshimoto Koji , Tanimoto Akihide , Hanaya Ryosuke 
Published: November 2024

Abstract

BACKGROUND
In the 2021 WHO Central Nervous System tumor classification, the Glioblastoma, IDH-wildtype diagnosis has changed markedly. We compared the clinical backgrounds and prognoses of molecular glioblastoma (mGBM) and conventional glioblastoma (histological glioblastoma, hGBM) in a Japanese cohort.

METHODS
We included 274 patients with glioblastoma who were treated at five institutions from 2011 to 2023. Driver gene analysis was performed using a brain tumor-specific custom gene panel to verify the association between molecular and clinical information.

RESULTS
Patients with mGBM had a better preoperative KPS, lower Ki-67, and lower removal rates than did those who had hGBM. Overall survival was longer in patients with mGBM than in those with hGBM (1207 vs 598 days, p = 0.032). TP53 mutation (hazard ratio: 5.33, 95% confidence interval: 0.26 - 108.7, p = 0.012) and histological grade 3 (p = 0.045) were significant poor prognostic factors in mGBM.

CONCLUSION
Patients with mGBM had better preoperative KPS, worse removal rates, lower Ki-67 labeling index, and better overall survival than did those with hGBM. Additionally, histological grade of mGBM is potentially useful for estimating prognosis. Glioblastoma in the WHO CNS5 2021 remains a heterogeneous population, and prognostic stratification based on the patient’s clinical background and molecular information is desirable.
10182- NI-15 ANALYSIS OF THE HIGH UPTAKE PATTERN ON 11C-METHIONINE-PET IN ADULT NON-ENHANCED GLIOMAS
Authors: Yasuda Shoji , Imai Naoya , Ikegame Yuka , Ikuta Soko , Maruyama Takashi , Kumagai Morio , Muragaki Yoshihiro , Shinoda Jun , Yano Hirohito 
Published: November 2024

Abstract
The uptake pattern of adult non-enhanced gliomas on 11C-methionine (MET) positron emission tomography (PET) was detected in each type of tumor. This study included 52 cases of astrocytoma (A group), 34 cases of oligodendroglioma (O group), and 21 cases of glioblastoma (G group). Region of interest (ROI) was defined based on T2-weighted imaging high intensity lesions, encompassing each tumor volume. Maximum or mean standardized uptake value (SUV) and tumor/normal frontal cortex SUV ratio (TNR) were calculated from PET data. ROIs were layered internally by 5mm intervals from the tumor edge to assess the MET distribution. A high uptake pattern, meaning a TNR of 2.0 or higher, was classified by three observers. TNR, maximum, and mean SUV of the tumor were significantly lower in the A group than in the O and G groups. Although total tumor volume did not differ among groups, there were very strong correlations between increasing TNR and volume with TNR of 1.3 or higher and 2.0 or higher in the A and the O group (r=0.73-0.93); relatively poor relation in the G group (r=0.53-0.70). Maximum SUV was predominantly observed at the outermost layers across all groups, with the O group frequently exhibiting it at the layers of 5-10mm from the tumor edge (40.6%). Among 28 cases with a TNR of 2.0 or higher, the extent of high uptake area was classified into whole patterns in 5 cases and partial or spot patterns in 23 cases. The high MET distributions of the cases with partial or spot patterns were all identified as central or surface/outside patterns, and there were no cases with surface/inside pattern. The characteristic uptake patterns for each tumor subtype may help plan the surgical strategy for gliomas.
IL-4 IMMUNOTHERAPY TARGETING THE UNIQUE EXTRACELLULAR MATRIX IN RECURRENT GLIOBLASTOMA
Authors: Osuka Satoru 
Published: November 2024

Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor characterized by high treatment resistance and an extremely high rate of recurrence. To understand the mechanisms of treatment resistance and develop novel therapeutic approaches, we prepared 11 patient-derived human GBM cells and 5 mouse GBM cells from genetically engineered mouse models. We performed repeated irradiation for them to analyze the mechanisms of acquired resistance. During repeated irradiation, GBM cells enhanced radio- and chemo-resistance, increased invasiveness, and elevated ability to establish an immunosuppressive microenvironment. We identified upregulation of Collagen type I and III (COL I & III) as crucial for this adaptive resistance. COL I & III, rarely expressed in normal brain tissue but highly expressed in resistant GBM, emerged as potential markers for targeting therapy-resistant GBM tumors. To apply these findings to treatment, we focused on von Willebrand factor (vWF), which selectively binds to expose COL I & III in abnormal tissues. We developed CBD-IL-12 by conjugating vWF’s collagen-binding domain (CBD) into the immunostimulatory cytokine IL-12. In mouse models of therapy-resistant GBM, intravenously administered CBD-IL-12 accumulated specifically in tumor sites, without accumulating in normal brain tissue or other healthy organs. CBD-IL-12 enhanced dendritic cell recruitment, increased CD8+ T cell infiltration, and improved the immunosuppressive tumor environment, resulting in tumor suppression and significantly prolonged survival. Our findings suggest that extracellular matrix proteins have tumor-specific and abundant presence in the tumor microenvironment, indicating their potential application in targeted therapy. We demonstrated that therapy-resistant GBM cells exhibited upregulated expression of COL I & III, and CBD can be utilized to selectively deliver cytokines to tumor sites. This CBD-based immunotherapy approach shows promise in transforming the treatment landscape for recurrent GBM, offering a novel strategy to combat this challenging malignancy.
Lithospheric strike-slip faulting in central Tibet since 35–32 Ma and implications for the incipient Asian extrusional tectonics
Authors: Lu Haijian , Li Haibing , Xiang Zhongjin , Malusà Marco G , Li Chunrui , Zhang Zhiyong , Wu Lin , Ma Xuxuan , Pan Jiawei 
Published: November 2024

ABSTRACT
The onset age and depth of the central Tibet strike-slip faults are two still unresolved fundamental issues with regard to the Cenozoic tectonic evolution of central Tibet. Here we present a comprehensive dataset of geochronological, geochemical and structural data on recently discovered en-echelon dykes representing the incipient development of strike-slip faulting from the Lunpola basin in central Tibet. Our results provide evidence for mantle-derived, bimodal magmatism linked to lithospheric-scale strike-slip faulting at 35–32 Ma, and demonstrate that the central Tibet strike-slip faults are at least 20 Ma older than previously estimated (15–8 Ma). We suggest that these faults were originally connected with the lithospheric-scale Jiali and Ailao Shan-Red River shear zones exposed farther east, forming part of a straight, 2500–3000 km-long lithospheric shear zone that favored mantle upwelling and magmatic intrusion coeval with substantial uplift (1.5–2 km) of the central Tibet valley in the early Oligocene.