bluuebunny/crossref_metadata_2025 huggingface dataset:
10022-MET-2 CLINICAL FEATURES OF RENAL CELL CARCINOMA BRAIN METASTASES COMPARED WITH OTHER CARCINOMAS
Authors: Yamamoto Yohei , Tanaka Toshihide , Takei Jun , Teshigawara Akihiko , Nawate Shohei , Tomoto Kyoichi , Ishi Takuya , Hasegawa Yuzuru , Akasaki Yasuharu , Murayama Yuichi
Published: December 2023

INTRODUCTION

In recent years, the positioning of surgical treatment for metastatic brain tumors has changed. To extract conditions suitable for surgical treatment, the background factors for each primary lesion were verified by retrospective analysis of our case.

SUBJECTS AND METHODS

From 2014 to 2022, 425 patients with metastatic brain tumors diagnosed and treated at our university were included. There were 219 lung cancers, 46 breast cancers, 64 gastrointestinal cancers, 26 renal cell carcinomas, and 70 others. First, the tumor volume and edema volume were measured, and the ROC curve was drawn for the presence or absence of symptoms to determine the cutoff value. After that, statistical analysis was performed on the following items for each primary lesion. The items were tumor volume (T), edema volume (E), tumor edema ratio (E/T), age, KPS, hemorrhage, cyst formation, meningitis, metastasis to other organs, posterior fossa, simultaneous detection, and single tumor.

RESULTS

The symptomatic cutoff was 1514mm3 for tumor volume (sensitivity 0.86 specificity 0.74) and 15616 mm3 for edema volume (sensitivity 0.85 specificity 0.85). The tumor edema ratio was significantly higher in renal cell carcinoma. Factors with significant differences were older age and multiple lesions in lung cancer, younger age and posterior fossa in breast cancer, lower KPS in gastrointestinal cancer, and solitary cases and bleeding in renal cell carcinoma.

DISCUSSION/CONCLUSION

In this analysis, many cases of brain metastasis from renal cell carcinoma are solitary, and because they exhibit extensive edema that seems to be affected by VEGF, they tend to develop symptoms while they are small, and they are characterized by hemorrhage easily during the course. These findings suggest that patients with brain metastases from renal cell carcinoma should be given priority for surgical treatment.
10024-CO-1 A MULTICENTER PERFORMANCE COMPARISON STUDY OF AN IDH STATUS PREDICTION MODEL USING THE VISUAL TRANSFORMER MODEL
Authors: Takahashi Satoshi , Takahashi Masamichi , Kinoshita Manabu , Miyake Mototaka , Kobayashi Kazuma , Sese Jun , Ichimura Koichi , Narita Yoshitaka , Hamamoto Ryuji , Diagnosis Consortium Glioma Molecular
Published: December 2023

PURPOSE

To compare the performance and explainability of the visual transformer (ViT) and convolutional neural network (CNN) architectures in predicting genomic mutations from brain MRI.

METHODS

The performances of the ViT and CNN classification models in predicting the IDH mutation status of gliomas were compared. The two models were fine-tuned on the TCIA dataset. The fine-tuned models were evaluated on the TCIA dataset and an external independent dataset, namely the Japanese Cohort (JC) dataset. To evaluate their explanatory power, the gradient-weighted class activation mapping (Grad-CAM) visualization of the CNNs model and attention map visualization of the ViT model were compared.

RESULTS

The visual transformer model consistently outperforms the convolutional neural network on both the TCIA and JC datasets (p-value = 0.021, p-value < 0.001, statistically different). The attention map of the ViT model accurately highlighted the tumor, and the Grad-CAM of the CNN model sometimes highlighted non-tumor areas.

CONCLUSION

The ViT model was more robust against differences in the image domain. The ViT model's attention map had superior explainability.
10037-SPE-3 APPROACH TO SAFE AND RELIABLE BRAIN TUMOR SURGERY APPLYING INTRAOPERATIVE GAMMA OSCILLATION REGULARITY ANALYSIS
Authors: Kobayashi Yusuke , Satou Yosuke , Kawauchi Yuta , Kon Takashi , Tanioka Daisuke , Shimizu Katsuyoshi , Mizutani Tohru
Published: December 2023

In primary brain tumors, the complexity of Electroencephalogram (EEG) has been reported to be higher compared to healthy individuals. In gliomas, a significant decrease in gamma oscillation regularity in the tumor-surrounding brain cortex has been demonstrated. It is considered acceptable to remove the areas with significantly decreased gamma oscillation regularity as non-functional regions with deteriorated normal brain function. This article introduces the practical application of safe and reliable brain tumor surgery using an approach from non-functional regions through intraoperative analysis of gamma oscillation regularity. The patient had undergone a partial resection surgery for a left temporal lobe tumor at another hospital and was diagnosed with a glioblastoma. Upon transfer to our hospital, the patient exhibited mild motor aphasia but had good comprehension. Language dominance was determined to be on the left side through the WADA test. Approximately 50% of the tumor, which was enhanced near the Broca's area and Wernicke's area, remained after the first surgery. We performed a non-awake extraction surgery for the residual tumor using intraoperative analysis of gamma oscillation regularity. By depicting a non-functional field during the operation, almost all of the tumors to be contrasted were removed without exacerbation of symptoms. Since the non-functional field can be depicted intraoperatively, surgery can be performed safely even in patients who cannot tolerate awake surgery. Brain tumor surgery using intraoperative analysis of gamma oscillation regularity is considered highly beneficial.
10038-ANGI-2 NEW ANTI-ANGIOGENIC THERAPY WITH THE ANTI-DEPRESSANT TOWARD TUMOR DERIVED ENDOTHELIAL CELLS (TDECS)
Authors: Michiue Hiroyuki , Tsuboi Nobushige , Otani Yoshihiro , Uneda Atsuhito , Suruga Yasuki , Yuji Matsumoto , Joji Ishida , Fujii Kentaro , Kurozumi Kazuhiko , Date Isao
Published: December 2023

BACKGROUND

Anti-angiogenic therapy has been reported to prolong patient survival in some malignancies, but has not been shown to be effective in glioblastoma. We focused on the relationship between the differentiation of glioma stem-like cells (GSCs) into tumor-derived endothelial cells (TDECs) and resistance to anti-angiogenic therapy. In particular, we elucidated the mechanism of drug resistance of TDECs to anti-angiogenesis inhibitors, and identified and elucidated the efficacy of novel anti-angiogenesis inhibitors with potential clinical application.

METHODS

005 mouse GSCs were differentiated into TDECs under hypoxic conditions and analyzed by RNA-Seq over time. Furthermore, novel angiogenesis inhibitors for glioblastoma were evaluated by tube formation assay and existing blood-brain barrier permeable drugs. Novel angiogenesis inhibitors were administered in vitro to differentiated TDECs and in vivo to the 005 mouse brain tumor model and evaluated by RNA-Seq, immunohistochemistry, MRI imaging, and survival.

FINDINGS

In the GSCs005 brain tumor model, inhibition of the Vascular Endothelial Growth Factor (VEGF) pathway had no anti-tumor effect and conversely increased TDECs. A drug screening by Existing Drugs Redevelopment showed that the antidepressant sertraline inhibited TDEC tube formation. Sertraline decreased the expression of Lama4 and Ang2 in TDECs, which play an important role in non-VEGF-mediated angiogenesis in tumors. sertraline in combination with VEGF pathway inhibitors showed prolonged survival in the 005 model.

CONCLUSION

Diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways was shown to induce anti-angiogenic resistance. The combination of sertraline and VEGF pathway inhibitors with antidepressants was an effective anti-angiogenic therapy for glioblastoma and could be applied safely and cost-effectively.
10045-MET-4 CEREBROSPINAL FLUID DIVERSION FOLLOWED BY SYSTEMIC THERAPY FOR LEPTOMENINGEAL METASTASIS-RELATED HYDROCEPHALUS IN PATIENTS WITH SOLID CANCER: ASSESSMENT WITH CLASSIFICATION OF EANO-ESMO CLINICAL PRACTICE GUIDELINE
Authors: Mitsuya Koichi , Deguchi Shoichi , Suzuki Takahiro , Hayashi Nakamasa
Published: December 2023

BACKGROUND

Management of leptomeningeal metastasis-related hydrocephalus (LM-H) is particularly challenging to control severe symptoms by intracranial hypertension. The aim of this study is assessment the outcomes of CSF diversion followed by systemic therapy for LM-H in patients with solid cancer.

METHODS

The authors reviewed 80 patients with LM-H required CSF diversion between October 2008 and May 2023. CSF diversion followed by chemotherapy and/or radiotherapy was indicated when a patient had (1) controlled extra-CNS metastases and (2) systemic life expectancy longer than three months after control of LM. The outcomes were analyzed with Kaplan-Meier estimates.

RESULTS

The patients consisted of 49 women and 31 men with a mean age of 57 years (range 35-81) . Primary cancers were lung (NSCLC) in 47 (59%), breast (BC) in 16 (20%), gastric (GC) in 10 (13%), cholangiocarcinoma 1 and other cancer in 6. Forty patients (50%) underwent whole brain radiotherapy, 17 patients (21%) cranio-spinal irradiation, and 45 patients (56%) were administrated systemic chemotherapy after CSF diversion. CSF diversion yielded a rapid improvement of their performance status (PS) in 90%. The median OS was significantly longer in patients with maintenance chemotherapy than in those without chemotherapy (4.5 versus 2 months, p<0.001). The patients were classified with EANO-ESMO clinical practice guideline (cytology, MR findings and clinical findings). Type A (linear) in 34, B (Nodular) in 14, C (linear and nodular) in 13 ID (normal) in 19. Linear enhancement groups (IA+IC) were shorter survival than other nodular (IB) and normal findings (ID) (p=0.0038) in long survivor over 6 months. Post-surgical complications were infection in 3, peritoneal dissemination in 2, and shunt malfunction in 1.

CONCLUSION

Combination of CSF diversion and systemic therapy is a safe and effective strategy in patients with LM-H.
10049-GGE-3 CHARACTERISTICS OF CHROMOSOMAL ABERRATIONS IN GLIOMAS AND THEIR IMPACT ON RECURRENCE
Authors: Negoto Tetsuya , Yoshitake Hidenobu , Hashimoto Aya , Moritsubo Mayuko , Furuta Takuya , Sakata Kiyohiko , Nakamura Hideo , Morioka Motohiro
Published: December 2023

INTRODUCTION

Chromosome instability is the inability to evenly distribute sister chromatids during mitosis, which leads to chromosomal numerical/structural abnormalities and increases the genetic heterogeneity of the tumor. In this study, we investigated the association between chromosome aberration characteristics and recurrence in clinical specimens of gliomas using the Spectral Karyotyping.

METHODS

Chromosome karyotypes were analyzed for a total of 121 cells from 26 gliomas (Glioblastoma 14, PXA 3, Astrocytoma 5, Oligodendroglioma 3, Ependymoma 1, 18 primary cases and 8 recurrent cases) removed at our hospital. In addition, each case was quantitatively analyzed for numerical aberrations/ cell (AS: Aneuploidy score), structural abnormalities/ cell (SS: Structural abnormality score), and karyotype concordance rate between cells /case (HS: Heterogeneity Score) were quantitatively analyzed.

RESULTS

In the analysis of all cases, numerical aberrations in chromosomes X and 7 (21.5%/16.9%) and structural aberrations in chromosomes 1, 4, and 5 (>10.0%) were highly prevalent, with structural aberrations in large chromosomes and numerical aberrations in small chromosomes. On the other hand, quantitative analysis showed that the mean for the first occurrence (18 cases); AS: 2.22±0.94/ SS: 1.48±0.96/ HS: 22.2±7.41, and for the recurrence (8 cases); AS: 4.68±1.75/ SS: 7.50±1.44/ HS: 55.0±11.1, indicating that numerical and structural abnormalities were more common in the recurrent lesions The recurrent lesions showed more numerical and structural abnormalities and higher intra-tumor heterogeneity. In addition, in cases in which the primary/recurrent lesions were analyzed in pairs, the frequency of numerical and structural chromosomal abnormalities was higher in the recurrent lesions.

DISCUSSION

This study clarified the characteristics of chromosomal aberrations in each pathological classification of gliomas and suggested the involvement of chromosomal instability in the recurrence process. We look forward to further clarification of the pathogenesis of gliomas with a focus on chromosomal instability.
10050-TB-1 ADDITIONAL RAS/MAPK PATHWAY ACTIVATION ALLOWS CELLS TO DIFFERENTIATE DURING TUMORIGENESIS.
Authors: Miki Shunichiro , Koga Tomoyuki , Furnari Frank
Published: December 2023

Activation of the RAS/MAPK pathway has been introduced in most of the glioblastoma models reported to date. To examine the roles of this pathway in tumorigenesis from different cells of origin, we differentiated human induced pluripotent stem cells (hiPSCs) with CDKN2A/2B null, PTEN null, and TERT promoter mutation (TPM), which we have previously generated, into neural stem cells (NPCs) and astrocytes, and also prepared cell lines with lentiviral EGFRvIII overexpression in both. 4 cell lines were transplanted into the brains of immunodeficient mice, and differences in tumorigenesis were compared between NPCs and astrocyte states with and without MAPK/RAS pathway activity. In NPCs, overexpression of EGFRvIII significantly shortened the time required for tumorigenesis. In Astrocytes, however, tumor formation was observed only in cells with EGFRvIII overexpression. RNA sequencing revealed the primary spheres formed from the tumors with EGFRvIII overexpression clustered similarly regardless of whether they were derived from NPCs or astrocytes, suggesting that similar tumors were formed from both sources. To further clarify the effect on the RAS/MAPK pathway, we prepared CDKN2A/2B null, PTEN null, TPM, and NF1 null iPSCs. Tumor formation was also confirmed when the cell line was differentiated into astrocytes and transplanted into immunodeficient mice. Although the cell of origin of glioblastoma is still controversial, recent reports indicate that tumorigenesis itself starts from undifferentiated cells. Our results suggest that the RAS/MAPK pathway activation in glioblastoma enhances tumorigenesis, allows cells to differentiate during the process, and also enables cells to transform even after differentiation by acquiring the activation.
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

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<15 months and<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

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

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

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<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<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

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

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

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

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 <0.001), WHO grade 2/3 (P <0.001), MIB-1 LI >10.0 (P <0.001), no psammoma bodies (P=0.013), and tumor size > 40 mm (P <0.001). Recurrence was observed in 12 of 29 cases (41.4%) occurring in the parasagittal region, with a rate of recurrence (P <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

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

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<0.05). The mean usage rate was 70% in group A and 22% in group B (p<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

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.
10126-ACT-10 FACTORS AFFECTING THE PATTERN OF RECURRENCE OF IDH-WILDTYPE GLIOBLASTOMA
Authors: Tsuchiya Takahiro , Ohno Makoto , Takahashi Masamichi , Yanagisawa Shunsuke , Osawa sho , Fujita Shohei , Narita Yoshitaka
Published: December 2023

INTRODUCTION

IDH-wildtype glioblastoma is a quite poor prognosis disease with which almost all cases recur in spite of postoperative radiation and chemotherapy. Survival rates are particularly low after dissemination.

METHODS

We included 120 patients with IDH-wild type glioblastoma treated at our hospital from January 2015 to December 2019. Patient backgrounds, MGMT promotor methylation status, imaging findings, and recurrence patterns were analyzed. Subependymal, subarachnoid, and spinal dissemination, plus distant metastasis, were defined as non-local recurrence.

RESULTS

Of 105 patients with a single lesion at diagnosis, 65 had local recurrence and 15 had non-local recurrence. 36 of 65 patients had local recurrence and 12 had non-local recurrence in the second recurrence. 17 of 36 patients had local recurrence and 8 had non-local recurrence in the third recurrence. The cumulative number of non-local recurrences was 54 (45.0%). Surgical ventricular opening and tumor proximity to the ventricles were associated with non-local recurrence (p=0.006, p=0.019). The patients with tumor proximity to the ventricle had non-local recurrence at the first recurrence and those with non-proximity to the ventricle had non-local recurrence at the second or later recurrence (p=0.038). MGMT promotor methylation status and postoperative ischemia were not significantly different from non-local recurrence (p=0.122, p=0.088), but MGMT promotor unmethylation was a risk factor for early non-local recurrence, especially within 1 year (p=0.033). Frontal lobe lesions were less frequently disseminated and more frequently MGMT promotor methylated (p=0.032, p=0.024). Parietal lobe lesions had more MGMT promotor methylation (p=0.006), and temporal lobe lesions had more dissemination (p=0.023). Distant metastasis commonly occurred from the frontal lobe to the ipsilateral or contralateral, and the frontal lobe was frequently associated.

CONCLUSION

IDH-wildtype glioblastoma is characterized by repeated local recurrence and cumulative non-local recurrence. The pattern of recurrence differs depending on the tumor localization, especially adjacent to ventricle, and MGMT promotor methylation status.
10141-GMC-13 MULTIREGIONAL GENOMIC ANALYSIS: A NOVEL APPROACH FOR DETECTING PATHOGENIC DRIVER MUTATION ASSOCIATED WITH MALIGNANT PROGRESSION IN NEUROCUTANEOUS MELANOSIS
Authors: Takahashi Haruhiko , Natsumeda Manabu , Tsukamoto Yoshihiro , Okada Masayasu , Hara Norikazu , Koyama Akihide , Miyashita Akinori , Yuki Akihiko , Shimizu Hiroshi , Kakita Akiyoshi , Ikeuchi Takeshi , Oishi Makoto
Published: December 2023

Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via ventriculo-peritoneal shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three pathogenic mutations, GNAQ R183Q, S1PR3 G89S and NRAS G12V were found. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discover novel driver mutations associated with tumorigenesis and targeted therapy.
10143-COT-16 DIFFUSE BONE MARROW METASTASIS OF HIGH GRADE GLIOMA
Authors: Nitta Naoki , Fukami Tadateru , Yoshida Kazumichi
Published: December 2023

BACKGROUND

Extraneural metastasis of the high grade glioma has rarely been reported and its diffuse bone marrow metastasis is extremely rare. Case description: A 32-year-old man was referred and admitted to Shiga University of Medical Science Hospital for the treatment for three remote recurrent lesions in the brain after the treatment of the primary brain tumor in the right frontal lobe in the referring hospital. One of those lesions was subtotally resected, with histological and immunohistochemical analysis showing a grade 4 glioma, and stereotactic radiation therapy was performed at all three lesions. A lumbar spine MRI showed signal changes in the first and 4th vertebral bodies and the level of LDH was gradually increased during this hospitalization. Three months later, the patient was referred to our hospital again because of intractable lumbago with metastatic lesions in the lumbar vertebrae and the psoae major. Laboratory data showed pancytopenia and extremely elevated level of LDH-1 and LDH-2, suggesting aggressive hemolysis. Abdominopelvic CT also showed slight osteolytic changes in the ilia, sacra, and femurs. Biopsy of the psoas major and iliac bone marrow showed invasion of grade 4 glioma cells. The patient was diagnosed as having diffuse bone marrow metastasis of grade 4 glioma, and died 12 days after the second admission.

CONCLUSIONS

We have presented a rare case of diffuse bone marrow metastasis of high grade glioma. LDH elevation might mean hemolysis by bone marrow metastasis in patients with high grade glioma.
10152-PEDT-5 JAPANESE SUBGROUP ANALYSIS OF A PHASE II TRIAL OF DABRAFENIB PLUS TRAMETINIB (D+T) IN BRAF V600-MUTANT PEDIATRIC LOW-GRADE GLIOMA (PLGG) AND RELAPSED/REFRACTORY (R/R) BRAF V600-MUTANT PEDIATRIC HIGH-GRADE GLIOMA (PHGG)
Authors: Terashima Keita , Koga Yuhki , Mukaiyama Akihira , Kurihara Ryohei , Okada Keiko
Published: December 2023

BACKGROUND

pLGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. pHGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. The result of a phase II global clinical trial (NCT02684058) of D+T vs carboplatin + vincristine (C+V) in first-line BRAF V600-mutant pLGG and single arm D+T in relapsed/refractory (r/r) BRAF V600-mutant pHGG has already been described. Briefly, the primary endpoint was the independently assessed overall response rate, ORR (CR+PR) using RANO criteria. The ORR was 47% (95% CI, 35%-59%) with D+T vs 11% (95% CI, 3%-25%) with C+V (P<.001; odds ratio, 7.2 [95% CI, 2.3-22.4]) in pLGG and 56.1% (95% CI, 39.7%-71.5%) in pHGG. Safety was consistent with the established profile of D+T in other indications. We report results for the Japanese subgroup.

RESULTS

A total of 6 Japanese pts were included in pLGG (D+T; n=4, C+V; n=2). And a total of 11 Japanese pts with diverse WHO Grade III/IV gliomas were included in r/r pHGG. The best overall response assessed by independent reviewer were as followed; D+T; SD 75% (n=3), PD 25% (n=1), C+V; CR 50% (n=1), PD 50% (n=1) in pLGG and CR 9.1% (n=1), PR 27.3% (n=3), SD 9.1% (n=1), PD 36.4% (n=4) in r/r pHGG. Treatment-related grade ≧3 adverse events were D+T; 25% (n=1) and C+V; 100% (n=2) in pLGG and 27.3% (n=3) in r/r pHGG.

DISCUSSION AND CONCLUSIONS

Treatment with D+T showed encouraging efficacy in Japanese pLGG and r/r pHGG. Profile of AEs was similar or consistent which is reported in other adult cohorts. Thus, these results suggest that D+T may represent a critical treatment advance for pLGG and r/r pHGG Japanese pts with BRAF V600-mutant.
10159-STMO-7 INTRAOPERATIVE MRI SURGERY FOR POSTERIOR FOSSA LESIONS
Authors: Hanihara Mitsuto , Ogiwara Masakazu , Kazama Hirofumi , Kinouchi Hiroyuki
Published: December 2023

Background: Intraoperative MRI (iMRI) is an important modality in brain tumor surgery to identify residual tumors, however, it is problematic due to patient positional limitations. In this study, we investigated the usefulness of iMRI for posterior fossa lesions. Materials and Methods: Of 320 cases of brain tumors removed using iMRI from June 2016 to April 2023, 24 cases of posterior fossa lesions were included. Tumor type, approach method, imaging availability, tumor removal rate, and complications were examined retrospectively. Results: Tumor types included 8 gliomas, 5 epidermoid cysts, 4 meningiomas, 3 metastatic brain tumors, 1 schwannoma, and 3 others. Eleven patients underwent midline suboccipital approach in the supine position, 8 patients underwent lateral suboccipital approach, 2 patients underwent occipital transtentorial approach, and 2 patients underwent anterior transpetrosal approach in the supine position. transpetrosal approach in 2 cases and subtemporal approach in 1 case. iMRI showed residual lesion in 14 of 24 patients. More than half of the gliomas and epidermoid cysts had intraoperative residual disease, whereas only one meningioma did. Total resection was achieved except for one case of intentional residual schwannoma and two cases of glioma. Discussion: iMRI requires the upper body to fit within a gantry, and it is difficult to image in the park bench position. However, various approaches is possible by using a supine-lateral or semi-prone position. In the concorde position, where the fourth ventricle and upper cerebellum are approached, it is useful to insert a mat in the anterior thoracic and raise the upper body. For tumors in the dorsal brainstem and upper cerebellum, the occipital transtentorial approach was used. iMRI is effective in the removal of all tumors, including gliomas in intramedullary tumors and epidermoid cysts in extramedullary tumors. Conclusion: iMRI can be used in posterior cranial fossa lesions.