bluuebunny/crossref_metadata_2025_split huggingface dataset:
10051-CBMS-4 CURCUMIN ANALOG COMPOUND A INHIBITS THE GROWTH OF GLIOBLASTOMA BY INDUCING G2/M PHASE ARREST AND APOPTOSIS AT A LOWER CONCENTRATION THAN CURCUMIN
Authors: Ito Ryo , Hamabe Toshihide , Ono Masaya , Iwashimizu Sonoka , Inai Kyoko , Sunagawa Yoichi , Katanasaka Yasufumi , Arakawa Yoshiki , Hasegawa Koji , Morimoto Tatsuya 
Published: December 2023

Abstract

PURPOSE
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Over 15,000 patients are diagnosed with GBM yearly, with a median survival expectancy of&lt;15 months and&lt;10% survival rate beyond five years, despite applying conventional multimodal treatment containing surgical resection, chemotherapy, and radiation therapy. The efficiency of conventional therapies is limited due to the lack of specificity and the accuracy of eradicating aggressive diffusing GBM cells. Developing new therapeutic agents against GBM is strongly recommended. The purpose of this study was to investigate whether the curcumin (Cur) analogs Compound A (ComA) possess anti-tumor activity against GBM.

METHODS AND RESULTS
To evaluate the anti-tumor activity of ComA against GBM, we performed an MTT assay. The human GBM cell lines U87-MG and U251 were pre-treated with Cur or ComA, cell viability was examined using a cell counting kit, and then IC50 values were evaluated. The IC50 values for U87-MG were: Cur, 9.78 μM; ComA, 2.42 μM. Those for U251 were: Cur, 9.50 μM; ComA, 2.27 μM. To examine the effects of ComA on normal cells, the same MTT assay was performed on primary cultured astrocytes from neonatal rats. ComA did not significantly reduce the cell viability in astrocytes at concentrations that had an anti-tumor effect on GBM cells (ComA, 3 μM). Next, a cell cycle analysis was performed with PI staining and an apoptosis assay with Annexin V/PI staining using flowcytometry. ComA, at lower concentrations than Cur, induced G2/M phase arrest and apoptosis. qPCR showed that ComA decreases CDK1 and CyclinB1 mRNA levels, the cell cycle-related proteins, at a lower concentration than Cur.

DISCUSSION
These results indicate that ComA has an anti-tumor effect by inducing cell cycle arrest and apoptosis against GBM at lower concentrations than Cur.
10064-GGE-6 A MULTI-OMIC LANDSCAPE OF GLIOBLASTOMA, IDH-WILD TYPE
Authors: Nakashima Takuma , Funakoshi Yusuke , Yamamoto Ryo , Sugihara Yuriko , Nambu Shohei , Arakawa Yoshiki , Tanaka Shota , Ishida Joji , Saito Ryuta , Hanaya Ryosuke , Yoshimoto Koji , Narita Yoshitaka , Suzuki Hiromichi 
Published: December 2023

Abstract
Glioblastoma (GBM) is the most common and highly resistant malignant brain tumor. Although the previous large-scale genomic analyses identified numerous driver genes, limited progress has been achieved in the development of novel treatments. To obtain further insights into the molecular mechanisms underlying the development of GBM, an integrated analysis including epigenetic and transcriptomic analyses, known to regulate malignant tumor progression, is imperative. We analyzed 289 whole-genome sequencing (WGS) including 159 unpublished deep WGS (≥ ×120 coverage) along with RNA-seq, DNA methylation array, whole-genome bisulfite sequencing, and assay for transposase-accessible chromatin with sequencing (ATAC-seq).Mutational analysis identified known driver alterations exhibiting inter-tumoral heterogeneity. Deep WGS enables us to delineate a fine view of clonal architecture demonstrating distinct mutational signatures between clonal and subclonal mutations, suggesting different mutational processes contribute to GBM pathogenesis depending on the developmental stage. Genetic alterations are strongly associated with gene expression subtypes and DNA methylation patterns. Transcriptional deconvolution analysis reveals the heterogeneous proportion of differentiated and stem-like cell states among cases. Tumors predominantly comprised of differentiated cells display genetic and epigenetic profiles that align with the classical subtype, whereas tumors predominantly composed of stem-like cells exhibit profiles consistent with the proneural subtype. Genome-wide chromatin accessibility patterns are well associated with expression subtypes of GBM. Motif enrichment analysis of open chromatin sites identified specific transcription factor binding sites, such as the SOX10 motif in the proneural subtype, known to regulate cell states, and the CREB motif in the mesenchymal and classical subtypes, which promote cell proliferation and angiogenesis through TGF-beta regulation. These findings support a model in which the difference in chromatin structure also regulates the progression of GBM.Our analysis encompassing multilayer molecular mechanisms reveals that GBM evolves through harboring genetic alterations and epigenetic modifications depending on the tumor initiation stage and cellular differentiation status.
10082-RT-1 LONG-TERM RESULTS OF A BNCT PHASE II CLINICAL TRIAL USING AN ACCELERATOR-BASED NEUTRON SOURCE FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Kawabata Shinji , Furuse Motomasa , Kashiwagi Hideki , Kosaka Takuya , Fukuo Yusuke , Hiramatsu Ryo , Nonoguchi Naosuke , Goto Hiromi , Narita Yoshitaka , Miyatake Shin-Ichi , Wanibuchi Masahiko 
Published: December 2023

Abstract

PURPOSE
Accelerator-based neutron sources have received regulatory approval and boron neutron capture therapy (BNCT) for head and neck cancer has been introduced into clinical treatment in earnest. BNCT is a radiotherapy with cell-selective characteristics, and its application to highly invasive malignant gliomas (MG) is the origin of its development. This study reports the long-term results of a phase II study of accelerator-based BNCT (AB-BNCT) using a cyclotron-based neutron source (BNCT30) and a boronophenylalanine product (SPM-011) in patients with recurrent MG.

METHODS
A phase 2 clinical trial (JG002) in 27 patients with recurrent malignant glioma (MG) (24 with glioblastoma (GB)) was conducted using SPM-011 and BNCT30. Eligibility criteria were radiation re-irradiation with MG not previously treated with bevacizumab and patients relapsing after standard of care (radiotherapy and chemotherapy with temozolomide). The primary endpoint was one-year survival from BNCT treatment, and secondary endpoints included median overall survival (mOS) and median progression-free survival (mPFS). The 1-year survival and mOS of patients with relapsed GB in JG002 were 79.2% (95% CI: 57.0-90.8) and 18.7 months, respectively. The current long-term observation resulted in an mOS of 19.2 months (95% CI: 13.1-24.8) and survival rates of 33.3 and 20.8% at 2 and 3 years from treatment, respectively. The adverse event was cerebral edema, and 21 of the 27 patients received bevacizumab treatment after decision of disease progression (PD) on imaging.

CONCLUSION
AB-BNCT showed an acceptable safety and survival benefit in relapsed MG, predominantly GB. Following BNCT treatment, the tumor may have shown a contrast enhancement in the irradiated field, with associated brain edema. BNCT showed a survival benefit in patients with recurrent malignant gliomas, even in the long term.
10087-GGE-7 THE IMMUNE PROGNOSTIC MODEL FOR GLIOBLASTOMA BASED ON SSGSEA ENRICHMENT SCORE
Authors: Okamoto Takanari , Muraoka Daisuke , Okamura Ayako , Mizuta Ryo , Nohira Shota , Takahashi Yoshinobu , Taniyama Ichita , Ogawa Takahiro , Hashimoto Naoya , Matsushita Hirokazu 
Published: December 2023

Abstract

BACKGROUND
A deep understanding of Tumor Microenvironment (TME) holds the potential to develop effective therapeutic strategies for glioblastoma. However, there have been few reports on the comprehensive evaluation of the interaction between cancer cells and the immune system within TME. This study aimed to construct an immune prognostic model for glioblastoma based on the gene expression profiles in the tumor.

METHODS
Using The Cancer Genome Atlas (TCGA) RNA-seq data (141 cases of glioblastoma), we performed comprehensive single-sample gene set enrichment analysis (ssGSEA) on gene sets from the Molecular Signatures Database (including Hallmark, Curated, and Gene Ontology). After evaluating gene sets associated with prognosis through univariate Cox regression, we extracted gene sets related to the biological process and tumor immunity of gliomas. Finally, we employed Lasso regression to refine the gene sets and constructed a multivariate Cox regression model (nomogram). This immune prognostic model was validated using the Chinese Glioma Genome Atlas (CGGA) dataset (183 cases).

RESULTS
The immune prognostic model consisted of three gene sets related to biological processes (sphingolipids, steroid hormones, and intermediate filaments) and one related to tumor immunity (chemokine mediated signaling pathway involved in suppressed immune system). Kaplan-Meier curves for the training cohort (TCGA) and the validation cohort (CGGA) demonstrated that the high-risk group had significantly worse overall survival compared to the low-risk group (p&lt;0.01 and p=0.04, respectively). Additionally, in silico cytometry using CIBERSORTx to assess the immune cell infiltration profiles revealed a significant increase in the fraction of M2 macrophages, an immunosuppressive cell type, in the high-risk group (p&lt;0.01) in both cohorts.

CONCLUSION
Comprehensive TME assessment using ssGSEA and constructing an immune prognostic model could potentially provide valuable insights into the prognosis and immune profiles of glioblastoma patients, guiding treatment strategies.
10091-COT-12 ELUCIDATING THE PATHOPHYSIOLOGY OF POST-OPERATIVE VENOUS THROMBOEMBOLISM IN IDH-WILDTYPE MALIGNANT GLIOMAS
Authors: Natsumeda Manabu , Ando Kazuhiro , Watanabe Jun , Takahashi Haruhiko , Tsukamoto Yoshihiro , Okada Masayasu , Fujii Yukihiko , Oishi Makoto 
Published: December 2023

Abstract

BACKGROUND
We have previously reported elevated expression of podoplanin and high incidence of post-operative venous thromboembolism (VTE) in IDH-wildtype gliomas (Watanabe et al., World Neurosurgery, 2019). Podoplanin binds to C-type lectin-like receptor-2 (CLEC-2) on the surface of platelets and induces platelet aggregation, potentially leading to the development of VTE. In the present report, we monitor serum podoplanin and CLEC-2 after surgery in malignant glioma patients to directly determine if this is the cause of post-operative VTE.

METHODS
Fourty-four malignant glioma patients undergoing surgery at the Department of Neurosurgery, Niigata University Hospital between April, 2018 and August, 2020 were assessed. Platelet counts as well as serum D-dimer, podoplanin, soluble CLEC-2, and C2PAC index (soluble CLEC-2 divided by platelet count) were measured within 10 days after surgery. Serum podoplanin and soluble CLEC-2 were assessed by enzyme-linked immunosorbent assay (ELISA). Values for IDH-wildtype glioma patients and IDH-mutant glioma patients were compared to patients undergoing microvascular decompression (MVD) and healthy volunteers (HV).

RESULTS
Post-operative VTE was observed in 8 out of 35 (23%) IDH-wildtype glioma patients, compared to 1 out of 9 (11%) IDH-mutant glioma patients. Serum soluble CLEC-2 levels (p = 0.0004) and C2PAC index (p = 0.0002) were significantly elevated in IDH-wildtype glioma patients compared to IDH-mutant glioma, MVD and HV groups. A C2PAC index threshold of 3.7 provide an 87.5% sensitivity and 51.9% specificity to predict post-operative VTE in IDH-wildtype gliomas. We serially monitored podoplanin and soluble CLEC-2 in select patients, and found that podoplanin is transiently elevated, followed by soluble CLEC-2 after surgery.

CONCLUSION
Platelet aggregation due to the activation of podoplanin-CLEC2 axis leads to post-operative VTE in IDH-wildtype malignant glioma patients. The C2PAC index is a potential biomarker for the early detection of VTE after surgery in these patients.
10097-ACT-6 PHASE 1/2, PROSPECTIVE, INTERNATIONAL MULTI-CENTER STUDY TO ESTABLISH THE SAFETY AND FEASIBILITY OF BLOOD-BRAIN-BARRIER DISRUPTION COMBINED WITH CARBOPLATIN FOR RECURRENT GLIOBLASTOMA; FIRST CLINICAL EXPERIENCE IN JAPAN
Authors: Kijima Noriyuki , Oshino Satoru , Kanemoto Manabu , Okita Yoshiko , Tani Naoki , Hosomi Koichi , Hirayama Ryuichi , Emura Takuto , Matsuhashi Takahiro , Tachi Tetsuro , Kuroda Hideki , Utsuki Reina , Murakami Koki , Kagawa Naoki , Kinoshita Manabu , Kishima Haruhiko 
Published: December 2023

Abstract
The prognosis for glioblastoma is still very poor despite intensive treatment by surgery, radiation, and chemotherapy. One of the reasons for poor prognosis of glioblastoma is blood-brain-barrier (BBB), which limits the delivery of chemotherapeutic agents to the brain. Focused ultrasound (FUS) therapy is approved for essential tremor and Parkinson disease in Japan and preclinical studies suggest low-intensity focused ultrasound (LIFU) administered with microbubbles (MB) can disrupt BBB and can improve the delivery of chemotherapeutic agents. Our institutions (Osaka University Hospital and Saito Yukoukai Hospital) are the first in Japan to join the international multicenter study to examine the safety and feasibility of BBB disruption by FUS and MB combined with intravenous carboplatin for the treatment of recurrent glioblastoma. We enrolled one patient with recurrent glioblastoma located at left frontal lobe. The patient underwent 4 cycles of treatment during which the disease remained stable by contrast enhanced MRI. After the 4 cycles of treatment, the patient presented with worsening of right hemiparesis and aphasia and terminated protocol treatment because of progressive disease. The progression free survival was 111 days even though the tumor located eloquent area, left frontal lobe. In conclusion, BBB disruption strategies using FUS and MB for the treatment of neuro-oncological disease has potentials to improve the outcome of patients with glioblastoma and many clinical trials will be performed in future.
10098-MPC-10 HOW SHOULD WE RESPOND TO REPEATED WHO REVISIONS? IN-HOUSE MOLECULAR DIAGNOSIS SYSTEM BY ADVANCED MEDICAL SYSTEM
Authors: Hata Nobuhiro , Fujioka Yutaka , Otsuji Ryosuke , Kuga Daisuke , Hatae Ryusuke , Sangatsuda Yuhei , Amemiya Takeo , Noguchi Naoki , Sako Aki , Fujiki Minoru , Mizoguchi Masahiro , Yoshimoto Koji 
Published: December 2023

Abstract

BACKGROUND
Since the WHO2016 revision, required molecular markers has been increasing, placing a burden on clinical practice of diffuse gliomas. We established an in-house molecular diagnostic platform by Senshin-Iryo (meaning advanced medical care system) and have since been partially modifying the analysis method in accordance with the WHO2021 revision. We review our achievements in total 5 years.

METHODS
Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity on 1p19q and chromosomes 10 and 17, and MGMT methylation were combined into a set and submitted as a Senshin-Iryo "Drug resistance gene testing for anticancer chemotherapy" and approved in August 2018. Subsequently, in October 2021, Sanger sequencing for TERT promotor mutation was added to the set and the LOH analysis was replaced to MLPA, in order to analyze 1p19q codeletion and newly required genetic markers; EGFR, PTEN, CDKN2A, etc. in WHO2021.

RESULTS
The cumulative number of cases has reached over 200. Among them, 54 cases were analyzed after WHO2021 revision. The laboratory has maintained the diagnostic platform in which molecular diagnoses are steadily confirmed generally within two weeks. The initial expenditure was exceeded the income obtained from the patient co-payment, however, it has gradually been reduced to running costs alone, then is approaching profitability. After WHO2021 revision, diagnoses could be confirmed by molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16, only 4 (7.4%) cases remained diagnosed as diffuse glioma, NEC, exclusionary after 12 cases in which glioblastoma was confirmed by histopathological diagnosis.

CONCLUSIONS
Our Senshin-Iryo trial has functioned as a salvage system to overcome the current transition period in which the continuing revision of WHO classification causing a clinical dilemma of healthcare system.
10100-MNG-4 RISK FACTORS FOR POSTOPRATIVE RECURRENCE IN PATIENTS WITH CONVEXITY, PARASAGITTAL AND FALX MENINGIOMAS
Authors: Uzuka Takeo , Sumi Takuma , Matsuda Hadzuki , Akutsu Hiroyoshi 
Published: December 2023

Abstract

OBJECT
Meningioma has cases of repeated recurrence. Regarding convexity, parasagittal, and falx, which are representative sites of occurrence, the treatment results and prognostic factors were investigated.

METHOD
The group consisted of patients with meningioma who underwent surgical treatment at our department from January 2009 to June 2022. Tumor sites, tumor size, Simpson grades at the time of surgery, pathological findings, WHO grades, and MIB-1 labeling index (LI) were reviewed to investigate their association with the period from the first surgery to recurrence (PFS).

RESULT
The subjects were 98 cases (62 women and 36 men) aged from 21 to 87 (median age of 60.0). Convexity: 49 cases (50.5%), parasagittal: 29 cases (29.9%), falx: 20 cases (20.4%). The WHO grades were G1: 52 cases (53.6%), G2: 41 cases (41.8%), and G3: 5 cases (5.2%). Recurrence was observed in 19 of 98 cases (19.4%). Upon conducting a univariate analysis, prognostic factors significantly correlated with PFS were found to include parasagittal occurrence (P &lt;0.001), WHO grade 2/3 (P &lt;0.001), MIB-1 LI &gt;10.0 (P &lt;0.001), no psammoma bodies (P=0.013), and tumor size &gt; 40 mm (P &lt;0.001). Recurrence was observed in 12 of 29 cases (41.4%) occurring in the parasagittal region, with a rate of recurrence (P &lt;0.001) that was significantly high in comparison with that of 7 of 63 cases (11.1%) of convexity and falx meningiomas. Two or more recurrences were observed in 10 cases (10.2%), with 7 cases occurring in the parasagittal region. 6 cases (6.1%) died of tumor progression (parasagittal: 3 cases, convexity: 2 cases, falx: 1 case).

CONSIDERATION
The recurrence rate of parasagittal meningioma is significantly higher than that of convexity or falx meningioma. It is necessary to consider adjuvant therapy while taking into consideration classic risk factors such as WHO grades, MIB-1 LI, and tumor size.
10115-STMO-4 SURGICAL OUTCOMES OF AWAKE SURGERY FOR GLIOBLASTOMA
Authors: Osawa Sho , Fujita Shohei , Tsuchiya Takahiro , Yanagisawa Shunsuke , Ohno Makoto , Takahashi Masamichi , Narita Yoshitaka 
Published: December 2023

Abstract

OBJECTIVE
Awake surgery contributes to maximal resection of brain tumors and preservation of brain function. In this study, we investigated the surgical outcomes, efficacy and safety of awake surgery for glioblastoma (GBM) at our institution.

METHOD
All GBM patients who underwent awake surgery at our institution from March 2010 to February 2023 were included. We retrospectively analyzed the clinical characteristics, response to awake mapping, extent of resection, and postoperative complications.

RESULTS
Seventy-five patients, 92 surgeries were included in the study. Median age at surgery was 47 years, 51 cases (55.4%) were males, and 41 cases (44.6%) were females. Thirty-one cases (33.7%) were primary diseases, 59 cases (64.1%) were recurrent, and 2 cases (2.2%) were residual diseases. Positive responses for awake mapping were observed in 49 cases (53.3%). The resections were discontinued in 38 cases (41.3%) based on the mapping findings. Gross total resection was achieved in 48 cases (52.2%), subtotal resection in 26 cases (28.3%), partial resection in 14 cases (15.2%), and biopsy in 4 cases (4.2%). Twenty-two cases (23.9%) showed neurological deterioration in the acute postoperative period, whereas 5 cases (5.4%) showed deficit 3 months after surgery. Among patients whose excision was discontinued based on mapping findings, one case (1.1%) developed right hemiparesis due to late-onset cerebral infarction, whereas no neurological deficits were observed in the other cases 3 months after surgery.

CONCLUSION
Complications of awake surgery for glioblastoma were rare. Half of the cases showed positive response to awake mapping. Awake mapping is necessary to resect glioblastoma located in eloquent areas while preserving brain function.
10119-ACT-9 LONG-TERM USAGE OF TUMOR-TREATING FIELDS THERAPY FOR TREATMENT OF MALIGNANT GLIOMA
Authors: Takido Yuhei , Ohka Fumiharu , Motomura Kazuya , Yamaguchi Junya , Maeda Sachi , Nishikawa Tomohide , Kibe Yuji , Shimizu Hiroki , Saito Ryuta 
Published: December 2023

Abstract

OBJECTIVE
Tumor-Treating Fields therapy has been the standard therapy for newly diagnosed glioblastoma since 2018 in Japan. The patients are recommended to use the system for 18 or more hours per day. In practice, some patients could not use it long-term and dropped out from this therapy. We examined factors related to interruption of NovoTTF use.

METHODS
We reviewed the clinical course of NovoTTF-100A system (NovoTTF) in cases at our hospital from April 2018 to May 2023. We compared the group that continued to use NovoTTF or used it until the disease progressed (Group A) with the group that discontinued it for their own reasons (Group B).

RESULTS
There were 22 patients, 14 in group A and 8 in group B. The mean preoperative tumor volume was 25.3 cm3 in group A and 38.7 cm3 in group B (p=0.27). The mean number of days of NovoTTF use was 437 in Group A and 27 in Group B (p&lt;0.05). The mean usage rate was 70% in group A and 22% in group B (p&lt;0.05). Tumors were located in 6 frontal lobes, 3 temporal lobes, 3 parietal lobes, 1 basal ganglia, and 1 thalamus in group A, while 1 frontal lobe, 6 temporal lobes, and 1 parietal lobe in group B. Among six temporal lobe cases in group B, five revealed temporal lesions in the dominant hemisphere, causing moderate or severe aphasia before surgery.

CONCLUSION
The group that continued NovoTTF maintained its usage rate as well as the number of days of use, while the group of cases that discontinued for their own reasons had a low use rate. Five of the eight discontinued cases had temporal lobe lesions in the dominant hemisphere and had aphasia symptoms. Difficulties in understanding the need for NovoTTF may have contributed to the discontinuation.
10125-GGE-10 EVALUATION OF MGMT PROMOTER METHYLATION STATUS OF GBM CELL LINE CLONAL POPULATION.
Authors: Anan Mitsuhiro , Del Maestro Rolando , Hata Nobihiro , Fujiki Minoru 
Published: December 2023

Abstract
In this study, the epigenetic heterogeneity of GBM was investigated by evaluating the methylation status of the O6-methylguanine methyltransferase (MGMT) promoter in individual clones of a single cell derived from GBM cell lines. Cell lines, U251 and U373, were used for the experiments from the Brain Tumour Research Centre of the Montreal Neurological Institute. To evaluate the methylation status of the MGMT promoter, pyrosequencing and methylation-specific PCR (MSP) were used. A total of 12 U251 and 12 U373 clones were isolated. The methylation status of 83 of 97 CpG sites in the MGMT promoter were evaluated by pyrosequencing, and 11 methylated CpG sites and 13 unmethylated CpG sites were evaluated by MSP. The results demonstrate tumor heterogeneity among individual clones derived from a single GBM cell.