大場 茂生

Neuronal activity is known to promote glioma growth, yet whether inhibitory circuits can oppose this effect has remained unclear. Here, we show that adult gliomas receive functional γ-aminobutyric acid (GABAergic) synaptic input from local inhibitory interneurons and that this input acts as a tumor-suppressive circuit signal. Enhancing inhibitory tone, genetically or pharmacologically, restrains tumor proliferation and prolongs survival, whereas disrupting inhibitory synaptic output accelerates tumor growth. Mechanistically, inhibitory circuit activation suppresses tumor calcium dynamics, and calcium gain- and loss-of-function experiments establish these dynamics as causal regulators of proliferation and survival. Yes-associated protein 1 (YAP1) and mechanistic target of rapamycin (mTOR) emerge as calcium-coupled oncogenic programs attenuated by inhibitory activation. Thus, adult glioma progression is governed not simply by neuronal activity but by a balance between growth-promoting and growth-restraining circuit influences. These findings define inhibitory input as a suppressive component of the glioma ecosystem and suggest that strengthening inhibitory tone may offer a therapeutic strategy.

Medulloblastoma (MB) is a biologically and clinically heterogeneous pediatric brain tumor. However, large-scale molecular subgrouping studies have mainly been conducted in Western populations, and comprehensive data from Asia are limited. To address this gap, we analyzed 242 MB cases collected from 39 institutions through the Japan Pediatric Molecular Neuro-Oncology Group, performing centralized molecular classification using NanoString-based gene expression profiling, DNA methylation arrays, and multiplex ligation-dependent probe amplification (MLPA)-based copy number profiling, supplemented by targeted sequencing. The subgroup distribution was 16.1% WNT, 24.8% SHH, 17.4% Group 3, and 41.7% Group 4. CTNNB1 mutations and monosomy 6 characterized all WNT cases, whereas MYCN amplification and TP53 mutations were independent adverse markers in SHH MB. Group 3 showed the worst survival, with MYC amplification and metastasis as poor prognostic factors. In Group 4, large cell/anaplastic histology predicted poor outcomes, whereas chromosome 11 loss was correlated with a favorable prognosis. Whole chromosomal aberration-defined favorable-risk patterns consistently indicate improved outcomes in non-WNT/non-SHH MBs. We also developed a simplified MLPA-based classifier targeting six loci on chromosomes 7, 8, and 11 (SEE-6-CNA), which enabled robust and clinically feasible prognostic stratification. Overall, our findings confirm that the molecular subgroup-specific features of Japanese MBs are largely concordant with global observations and that SEE-6-CNA provides a cost-effective tool to support individualized treatment planning, particularly in resource-limited settings.

PURPOSE: This study aimed to establish and evaluate two evidence-based reconstruction protocols for [18F]fluciclovine PET on a high-resolution dedicated head PET system: a time-efficient protocol for routine clinical use, and a high-quality protocol designed to maximize small-lesion detectability. METHODS: A brain-tumor phantom (target-to-background ratio, 5:1) was scanned on a dedicated head PET scanner (BresTome, Shimadzu). Using a 60-min list-mode acquisition, parameters were optimized for two visually defined pathways (10-min clinical-efficiency; 30-min high-quality). The optimization sequence involved optimizing the relaxation factor (β) using mean percent contrast (%contrastmean), followed by a comparison of post-reconstruction filters (non-local means [NLM] and Gaussian) by maximizing a local contrast-to-noise ratio (CNR), guided by the Rose criterion. The final protocols were evaluated against Japanese brain-tumor phantom criteria for key performance metrics, including maximum percent contrast (%contrastmax), relative recovery coefficient (RC), quantitative accuracy (SUVTOT), and uniformity (SDΔSUVmean). RESULTS: Two distinct protocols were established. The 10-min clinical-efficiency protocol was optimized with β = 60 and an NLM filter (intensity 1.5), which provided the best CNR for the 7.5-mm sphere. The 30-min high-quality protocol was optimized with β = 70 and an NLM filter (intensity 1.0), which yielded the highest CNR for the 5-mm sphere. The 30-min protocol was required for enhanced visibility of the 5-mm sphere. Both protocols met the Japanese criteria for %contrastmax, relative RC, and SUVTOT, whereas SDΔSUVmean did not meet the criterion. Supplementary reconstructions of the full 60-min dataset met the SDΔSUVmean criterion. In two representative clinical cases, application of the optimized protocols yielded clinically interpretable images with clear visualization of tumor uptake. CONCLUSION: This study establishes a dual-pathway framework for [18F]fluciclovine PET. We recommend the 30-min high-quality protocol (β = 70, NLM intensity = 1.0) as the preferred option when feasible to maximize small-lesion detectability. The 10-min clinical-efficiency protocol (β = 60, NLM intensity = 1.5) serves as a practical, time-saving alternative for patients with limited tolerance. This approach provides a foundation for personalizing clinical protocols based on specific imaging needs and highlights the importance of standardizing uniformity assessment using an appropriate longer-duration reference acquisition for modern high-resolution PET systems.

Research on foundation models is actively progressing. The segment anything model (SAM) and MedSAM are representative foundation models for image segmentation. Recently, low-rank adaptation (LoRA) has been developed, allowing parameter updates without retraining the entire model, thus solving the problem with large data and time required for task-specific fine-tuning. Although many studies have used public databases, few have focused on local data. Moreover, to our knowledge, no studies have fine-tuned MedSAM using LoRA. We aimed to evaluate SAM, MedSAM, and their LoRA-tuned variants (SAM-LoRA and MedSAM-LoRA) using brain magnetic resonance images of gliomas from five centers in Japan and to compare their performance. We used 2D-based fluid-attenuated inversion recovery axial images and conducted parameter optimization based on four-fold cross-validation (189 cases) and external test evaluation (75 cases) using cases collected retrospectively. Dice coefficients, intersection over union (IoU), and the 95% Hausdorff distance (HD95) were used to evaluate the performance of SAM, MedSAM, SAM-LoRA, and MedSAM-LoRA. Additionally, subgroup evaluations were performed according to scanner manufacturer, glioma location, and calcification status. In the external test at the case level using SAM-LoRA and MedSAM-LoRA, the Dice coefficients/IoU/HD95 were 0.9166/0.8506/1.3517 and 0.9051/0.8342/1.8061, respectively. Both SAM-LoRA and MedSAM-LoRA demonstrated significantly higher Dice coefficients and IoU, as well as significantly lower HD95 values, compared with SAM and MedSAM. Subgroup evaluations also showed highly accurate extraction across different scanner manufacturers, glioma locations, and calcification statuses. SAM-LoRA and MedSAM-LoRA achieved high accuracy on an externally evaluated dataset, suggesting potential utility.

Ependymoma-like tumor with mesenchymal differentiation (ELTMD) is a recently proposed, but not yet formally defined, entity that is not recognized in the 2021 World Health Organization (WHO) classification of central nervous system tumors. Although it shares molecular features, such as ZFTA fusion, with ependymomas, it exhibits distinct histopathological and epigenetic profiles. Herein, we report the case of a 5-year-old girl with a supratentorial tumor harboring the ZFTA::NCOA2 fusion. Histopathology revealed atypical features including mesenchymal and undifferentiated components, which overlapped with those of ependymomas. DNA methylation profiling using two independent classifiers (DKFZ and NIH) yielded no matches, indicating that the tumor did not belong to any recognized CNS class. The failure of subclass assignment by both classifiers suggests that ELTMD represents a potentially epigenetically distinct subgroup. Despite being unclassifiable by the current WHO criteria, the tumor shared features with previously reported ELTMDs, supporting its recognition as an emerging tumor. This highlights the need for additional cases to refine the diagnosis, classification, and future therapeutic strategies.

Abstract <p> Coding variations do not significantly contribute to tumor aggressiveness in meningiomas except for rare alterations in CDKN2A and TERT . The aim of this study was to investigate specific molecular pathways as potential therapeutic targets. A discovery cohort of 35 meningiomas, including 26 high-grade tumors, was investigated for genetic alterations and gene expression profiling, and analyzed by unsupervised hierarchical clustering, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). The results were validated by OncoPrint analyses in a larger dataset published previously. The efficacy of an EZH2 inhibitor was evaluated in multiple meningioma cell lines. Tumors in the discovery cohort were classified into three clusters (Cluster M: Low, Mid, High) using hierarchical clustering based on genes differentially expressed across CNS WHO grades. These clusters correlated with overall survival and WHO grade. GSEA between the subgroups of Cluster M demonstrated that meningiomas gain aggressiveness through the downregulation of gene sets associated with the immune response (Low→Mid), and subsequently by the upregulation of those associated with cell cycle and cell proliferation (Mid→High). These results were corroborated by GSVA based on the enrichment score of the Hallmark gene sets as well as hierarchical clustering based on copy number losses, with enrichment of the E2F target and MYC target gene sets in high-grade clusters. OncoPrint analyses in the published dataset showed that the most aggressive type of meningiomas is characterized by upregulation of EZH2 as well as E2F1, but not MYC, in combination with NF2 alterations. Meningioma cell growth was suppressed by an EZH2 inhibitor with possible correlation with EZH2 expression. Meningiomas with NF2 alterations exhibit distinct biological behaviors depending on the expression of EZH2 and E2F1, and aggressive meningiomas are characterized by the upregulation of these pathways in combination with NF2 alterations. EZH2 is a pivotal therapeutic target for high-grade meningiomas. </p>

Objective: To quantitatively compare cerebral blood volume (CBV) in contrast-enhancing tumor areas and nonenhancing peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintense regions between glioblastoma and central nervous system lymphoma (CNSL), and to assess the incremental diagnostic value of peritumoral CBV beyond enhancing tumor CBV. Methods: The study included 34 patients with histopathologically confirmed glioblastoma (n=22) or CNSL (n=12) who underwent pretreatment magnetic resonance imaging, including FLAIR, dynamic susceptibility contrast perfusion imaging, and contrast-enhanced T1-weighted imaging. Automated regions of interest (ROIs) were defined for enhancement areas (EAs) and nonenhancing peritumoral FLAIR abnormalities (PFAs). Quantitative indices included the median CBV within EAs (CBV _EA ) and the 95th percentile CBV within PFAs (CBV _PFA ). Intergroup differences were assessed, and diagnostic performance was evaluated using univariate and multivariate logistic regression models incorporating CBV _EA and CBV _PFA , receiver operating characteristic (ROC) analysis, and likelihood ratio testing (LRT). Results: Both CBV _EA and CBV _PFA were significantly higher in the glioblastoma group than in the CNSL group [CBV _EA : 4.90 (4.14-5.58) vs. 2.84 (2.04-3.21) mL/100 g, P &lt;0.0001, CBV _PFA : 5.67 (3.75-8.08) vs. 4.10 (3.00-5.23) mL/100 g; P =0.029]. CBV _EA showed the highest discriminatory performance in univariate analysis, whereas CBV _PFA demonstrated a more modest association with tumor type. Although the AUC of the combined model was not significantly different from that of the CBV _EA model alone [CBV _EA : 0.913 (0.816-1.000) vs. combined model: 0.932 (0.848-1.000), P =0.602], the combined model showed a significant improvement in model fit according to LRT (χ ² =4.1, P =0.043). Conclusions: Automated ROI-based analysis demonstrated significant differences in peritumoral CBV between glioblastoma and CNSL, and adding peritumoral CBV to the logistic regression model significantly improved overall model fit for differentiating between these entities beyond enhancing tumor CBV alone.

BRAF p.V600E-mutant gliomas and glioneuronal tumors comprise a wide clinicopathological spectrum, yet the relationship between genomic alteration burden and histological grade remains incompletely defined. We analyzed 15 BRAF p.V600E-mutant gliomas and glioneuronal tumors across histological grades using the PleSSision Rapid sequencing platform. Single-nucleotide variants (SNVs) and copy-number alterations were assessed in parallel to characterize genomic alteration profiles. Low-grade tumors generally exhibited limited genomic alterations; however, a subset of low-grade tumors showed increased numbers of SNVs. High-grade tumors demonstrated more extensive genomic alterations, characterized predominantly by copy-number gains. A trend toward increased copy-number gains with higher WHO grade was observed. Homozygous deletion of CDKN2A was observed in pleomorphic xanthoastrocytoma, including both CNS WHO grade 2 and grade 3 tumors, and epithelioid glioblastoma. These findings indicate substantial genomic heterogeneity among BRAF p.V600E-mutant gliomas and glioneuronal tumors. While low-grade tumors are generally genomically quiet, a subset shows increased alterations, and high-grade tumors tend to acquire copy-number changes, highlighting the limitations of genomic event counts alone as a surrogate for malignant potential.

OBJECTIVE: Central nervous system (CNS) solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms with a high propensity for local recurrence and extracranial metastasis. Although surgery and radiotherapy are the mainstays of treatment, systemic therapeutic options for recurrent disease remain limited. Pazopanib, a multitargeted tyrosine kinase inhibitor, has demonstrated clinical activity in extracranial SFTs; however, evidence in CNS SFTs is scarce. METHODS: We conducted a retrospective, single-institution study of patients with recurrent CNS SFTs treated with pazopanib. Clinical data, including prior treatments, imaging responses, treatment duration, and adverse events, were collected from medical records. Exploratory next-generation sequencing-based cancer panel testing was performed in two patients. RESULTS: Four patients with recurrent CNS SFTs were included. All had undergone prior surgical resection and radiotherapy. Pazopanib achieved partial response in one patient and stable disease in three patients, with treatment durations ranging from 7 months to over 2 years. One patient experienced disease progression after an initial period of response. Adverse events, including fatigue, gastrointestinal symptoms, and hypertension, were observed in all patients but were generally manageable with supportive care or dose adjustment. Exploratory molecular profiling identified various genomic alterations in two patients. CONCLUSIONS: In this single-institution retrospective series, pazopanib provided durable disease control with acceptable tolerability in selected patients with recurrent CNS SFTs. These findings support considering pazopanib as a systemic treatment option when further local therapies are not feasible, while highlighting the need for larger multicenter studies.

BACKGROUND: We conducted a multicenter study to investigate the utility of postoperative antiseizure medication (ASM) in the occurrence of late seizure in glioblastoma. In addition, we analyzed whether postoperative ASM affects survival. METHODS: 1132 consecutive patients with newly diagnosed glioblastoma at 39 centers were enrolled. In patients treated with postoperative ASM (levetiracetam [LEV], lacosamide [LCM], or perampanel [PER]), as well as in those who received no medication, the cumulative incidence of late seizure, adverse events, and survival outcomes were analyzed. RESULTS: In total, 1099 patients (female: 482, male: 617, mean age: 67.2 years) were included, among whom, 287 developed postoperative late seizure. The mean onset time of late seizure was 193.6 days after surgery. Postoperative ASMs were administered in 628 cases, LEV in 344, LCM in 124, and PER in 160. The cumulative incidence of late seizure at 12 months was as follows: no medication in 30.9%, LEV in 17.8%, LCM in 28.8%, and PER in 16.2%. Multivariable analysis disclosed that LEV and PER displayed significantly lower cumulative incidences of postoperative late seizure compared with no medication and LCM. By contrast, median progression-free survival/overall survival did not significantly differ among ASMs. However, during the 12-24 month interval, the PER group demonstrated a more favorable prognosis than the other groups. CONCLUSIONS: LEV and PER after glioblastoma surgery were associated with a reduced risk of late seizure compared with LCM or no medication. LEV or PER may be considered as postoperative ASMs to optimize seizure control and potentially help preserve patients' QOL.

Some patients with cerebral amyloid angiopathy (CAA), which is characterized by amyloid β fibril deposition in cortical and leptomeningeal vessels, develop an inflammatory response, leading to CAA-related inflammation (CAA-RI). In such cases, histopathologically confirmed vasculitis is defined as amyloid β-related angiitis (ABRA). Here, we report the rare case of an 80-year-old woman who presented with anomic aphasia and mild right upper limb weakness. Magnetic resonance imaging revealed restricted diffusion in the subarachnoid space along the cerebral sulci and dura mater, mainly within the left parietal lobe. Additional imaging findings included lobar microbleeds, edematous white matter changes, and leptomeningeal and dural enhancement. Brain biopsy revealed vasculitis with amyloid β deposition, consistent with ABRA. Marked lymphoplasmacytic infiltration, which was present in the leptomeninges and the dural surface, was considered the cause of the subarachnoid diffusion restriction. Immunosuppressive treatment led to clinical and radiological improvement. As illustrated in this case, CAA-RI may present with atypical findings of subarachnoid diffusion restriction and dural involvement, and the recognition of these features, which can mimic rheumatoid meningitis and other inflammatory conditions, is important for differential diagnosis.

Abstract Differentiating pseudoprogression (PsP) from recurrence in cases of glioblastoma (GBM) after chemoradiotherapy is challenging, with neuroimaging as the only non-invasive method. In this study, we aimed to identify a blood biomarker for precise disease monitoring and investigated the role of Ataxin-2 (ATXN2). Blood samples (n = 45) from patients with suspected recurrence, including eight with PSP, were analyzed. In addition, tumor tissue samples (n = 22), including those from seven patients who also provided blood samples, were examined. Protein levels were assessed using quantitative proteomics and ELISA. ATXN2 levels were measured via western blotting, and localization was determined through immunohistochemistry and immunocytochemistry. ATXN2 knockdown was performed in glioma cell lines to assess its effects on proliferation, migration, and invasion. Proteomics identified ATXN2 as a potential biomarker. ELISA showed significantly higher serum ATXN2 levels in recurrence than in PsP (p = 0.028). ATXN2 ≥ 11.0 ng/mL and ≥ 8 months post-chemoradiotherapy distinguished recurrence from PsP (AUC = 0.82, sensitivity = 67.6%, specificity = 87.5%). ATXN2 was highly expressed in GBM tissues, localized in neurons and glioma cells, and its knockdown enhanced proliferation, migration, and invasion via ERK phosphorylation. ATXN2, highly expressed in GBM, may serve as a potential blood biomarker for distinguishing PsP from recurrence.

Compared to oligodendrogliomas, astrocytomas may have a relatively higher frequency of intracranial remote recurrence, despite generally favorable prognoses. Previous studies identified 8q gain, particularly in the terminal region, as a poor prognostic factor. This study evaluated MYC expression and its relationship with copy number gain at 8q24.21, in relation to recurrence patterns in astrocytomas, with a particular focus on intracranial remote recurrence. A retrospective analysis was conducted on 27 patients treated between 2006 and 2019. MYC expression was assessed by immunohistochemistry (IHC), and copy number status by metaphase comparative genomic hybridization and next-generation sequencing. Recurrence patterns were categorized as local or remote.Among 43 specimens analyzed by IHC, MYC expression was observed in 72%, with higher positivity in recurrent (80%) than initial (61%) specimens, though the difference was not statistically significant (p = 0.30). Copy number analysis showed a significant increase in 8q24.21 copy number in specimens from cases with remote recurrence compared to those with local recurrence (p = 0.033). However, no significant correlation was found between MYC copy number and protein expression (p = 0.055). These findings suggest that MYC is frequently expressed in astrocytomas, but its expression does not significantly reflect 8q gain or recurrence pattern.

Karnofsky Performance Status (KPS) is a widely used scale to assess performance status. KPS ≥ 50% implies that patients can live at home. Therefore, maintaining KPS ≥ 50% is important to improve the quality of life of patients with glioblastoma, whose median survival is less than 2 years. This study aimed to identify the factors associated with survival time with maintenance of KPS ≥ 50% (survival with KPS ≥ 50%) in patients with glioblastoma, IDH-wildtype. Ninety-eight patients with glioblastomas, IDH-wildtype, who were treated with concomitant radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ therapy, and whose KPS at the start of RT was ≥ 50%, were included. The median survival with KPS ≥ 50% was 13.3 months. In univariate analysis, preoperative KPS (≥ 80%), KPS at the start of RT (≥ 80%), residual tumor size (< 2 cm3), methylated MGMT promotor, and implantation of BCNU wafer were associated with survival with KPS ≥ 50%. In multivariate analysis, KPS at the start of RT (≥ 80%), methylated MGMT promotor, and residual tumor size (< 2 cm3) were significantly associated with increased survival with KPS ≥ 50%. A strategy of maximum possible tumor resection without compromising KPS is desirable to prolong the survival time with KPS ≥ 50%.

AbstractAbstract Background Tumor treating fields (TTFields) therapy is an important treatment for glioblastoma. However, there have been few reports showing the effectiveness thereof in clinical settings worldwide. The aim of this study was to examine the efficacy of TTFields therapy by comparing patients with compliance rates above 75% with those below 75% during the first 3 months of treatment. Methods Data were retrospectively collected from electronic medical records for consecutive patients with newly diagnosed World Health Organization grade 4 gliomas who received TTFields therapy at 12 institutes in Japan from January 2018 to December 2023. Results In total, 157 patients received TTFields therapy. We analyzed 116 patients who used TTFields for at least the first 3 months. The median age was 57 years; 67 patients were male; and the median KPS before the start of adjuvant temozolomide was 90. The average compliance rate was 78.3%. The median progression-free survival (PFS) and overall survival (OS) were 11.9 months and 23.7 months, respectively. A high compliance rate of TTFields ≥75% for the first 3 months was achieved in 67 patients and was a significant prognostic factor on PFS (P = .04). The median PFS for patients with high and low compliance rates was 12.6 and 9.0 months, respectively; the median OS was 25.3 and 21.3 months, respectively (P = .15). Conclusions TTFields use rate ≥75% in the first 3 months was significantly associated with improved PFS. There was a tendency for OS to be extended. Further analysis with a larger number of cases is required.

Posterior Quadrant Disconnection is a surgical technique designed to suppress seizure propagation while preserving motor and sensory functions in patients with drug-resistant epilepsy. Although seizure outcomes following this procedure have been reported, detailed evaluations of its impact on higher cognitive functions remain limited. This study aimed to assess the long-term seizure and cognitive outcomes following PQD in the non-dominant hemisphere, thereby evaluating the efficacy and safety of the procedure. In this case, the patient with drug-resistant epilepsy underwent preoperative evaluation using stereo electroencephalography (SEEG) to identify seizure onset zones and functional mapping related to visuospatial cognition. Following this assessment, PQD was performed. Postoperative outcomes were monitored over a 2-years period, focusing on seizure control and higher cognitive function. The patient achieved Engel class I status postoperatively, indicating complete seizure cessation. While transient hemispatial neglect was observed immediately after surgery, gradual improvement was noted over time. Furthermore, visual memory and cognitive functions showed a tendency to improve, and there were no significant declines in facial recognition or scene recognition abilities. These findings suggest that PQD can effectively improve seizure outcomes while minimizing long-term impacts on cognitive functions. This case highlights the potential of PQD to offer substantial seizure control with limited permanent effects on higher cognitive functions. By providing valuable insights into the safety and efficacy of PQD in the non-dominant hemisphere, this study underscores its viability as a treatment option for selected cases of drug-resistant epilepsy.

BACKGROUND: To improve the outcome in newly diagnosed glioblastoma patients with maximal resection, we aimed to evaluate the efficacy and safety of implantation of carmustine wafers (CWs), radiation concomitant with temozolomide and bevacizumab, and maintenance chemotherapy with six cycles of temozolomide and bevacizumab. METHOD: This prospective phase II study enrolled glioblastoma patients considered candidates for complete resection (> 90%) of a contrast-enhanced lesion. The CWs were intraoperatively implanted into the resection cavity after achieving maximal resection. Patients without a measurable contrast-enhanced lesion on magnetic resonance imaging within 48 h after resection received concomitant radiotherapy and chemotherapy with temozolomide and bevacizumab, followed by maintenance treatment with up to six cycles of temozolomide and bevacizumab. The primary endpoint was the 2-year overall survival rate in glioblastoma patients with protocol treatment. RESULTS: From October 2015 to April 2018, we obtained consent for the first registration from 70 patients across 17 institutions in Japan, and 49 patients were treated according to the protocol. We evaluated the safety in 49 patients who were part of the second registration and the efficacy in 45 glioblastoma patients treated according to the protocol. The profile of hematological and most of the non-hematological adverse effects was similar to that in previous studies, but stroke occurred in 12% of cases (6/49 patients). The estimated 2-year overall survival rate was 51.3%. CONCLUSION: Implantation of CWs, followed by concomitant radiation, temozolomide, and bevacizumab, and six cycles of temozolomide and bevacizumab may offer some benefit to survival in Japanese glioblastoma patients with maximal resection. TRIAL ID: jRCTs021180007.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

Fence-post catheter techniques are used to use tumor margins when resecting gliomas. In the present study, deep electrodes instead of catheters were used as fence-posts. The case of a 25-year-old female patient whose magnetic resonance images (MRI) revealed a tumor in the left cingulate gyrus is presented in this study. She underwent daily seizures without loss of consciousness under the administration of anti-seizure medications. Despite video electroencephalography (EEG) monitoring, the scalp inter-ictal EEG did not show obvious epileptiform discharges. We were consequently uncertain whether such frequent seizures were epileptic seizures or not. As a result, deep electrodes were used as fence-posts: three deep electrodes were inserted into the tumor’s anterior, lateral, and posterior margins using a navigation-guided method. The highest epileptic discharge was detected from the anterior deep electrode. As a result, ahead of the tumor was extendedly resected, and epileptic discharges were eliminated using EEG. The postoperative MRI revealed that the tumor was resected. The patient has never experienced seizures after the surgery. In conclusion, when supratentorial gliomas complicated by frequent seizures are resected, intraoperative EEG monitoring using deep electrodes as fence-posts is useful for estimating epileptogenic areas.

OBJECTIVE: Although a qualitative diagnosis of plaque causing carotid stenosis has been attempted with carotid computed tomography angiography (CaCTA), no clear findings have been reported. We examined the correlation between the plaque CT values and plaque images obtained by magnetic resonance imaging to derive a qualitative diagnosis of the plaque using CaCTA. METHODS: Preoperative CaCTA images acquired from patients stented for carotid stenosis were retrospectively analyzed with respect to magnetization-prepared rapid acquisition with gradient echo and time-of-flight magnetic resonance angiography data. Carotid plaques in the stenosed region were quantified in terms of CT density and the plaque/muscle ratio (magnetization-prepared rapid acquisition with gradient echo), and correlations between these 2 features were determined. Plaques were classified as stable or unstable based on the plaque/muscle ratio, with the smallest plaque/muscle ratio observed among plaques positive for intraplaque hemorrhage set as the cutoff value (1.76). RESULTS: A total of 165 patients (179 plaques) were included. Perioperative complications included minor stroke (n = 3), major stroke (n = 1, fatal), and hyperperfusion (n = 2). The correlation between CT density and the plaque/muscle ratio was nonlinear (P = 0.0139) and negative (P < 0.0001). The cutoff point (1.76) corresponded to a CT density of 83 HU, supporting this value as a standard reference for plaque stability. CONCLUSIONS: Computed tomography density exhibits a nonlinear (P = 0.0139) and highly negative correlation (P < 0.0001) with the plaque/muscle ratio. Our results demonstrate that plaque characteristics can be meaningfully diagnosed based on CaCTA image data.

OBJECTIVE: Although amide proton transfer-weighted (APTw) imaging is reported by 2-dimensional (2D) spin-echo-based sequencing, 3-dimensional (3D) APTw imaging can be obtained by gradient-echo-based sequencing. The purpose of this study was to compare the efficacy of APTw imaging between 2D and 3D imaging in patients with various brain tumors. METHODS: A total of 49 patients who had undergone 53 examinations [5 low-grade gliomas (LGG), 16 high-grade gliomas (HGG), 6 malignant lymphomas, 4 metastases, and 22 meningiomas] underwent APTw imaging using 2D and 3D sequences. The magnetization transfer ratio asymmetry (MTRasym) was assessed by means of region of interest measurements. Pearson correlation was performed to determine the relationship between MTRasym for the 2 methods, and Student's t test to compare MTRasym for LGG and HGG. The diagnostic accuracy to differentiate HGG from LGG of the 2 methods was compared by means of the McNemar test. RESULTS: Three-dimensional APTw imaging showed a significant correlation with 2D APTw imaging (r = 0.79, P < 0.0001). The limits of agreement between the 2 methods were -0.021 ± 1.42%. The MTRasym of HGG (2D: 1.97 ± 0.96, 3D: 2.11 ± 0.95) was significantly higher than those of LGG (2D: 0.46 ± 0.89%, P < 0.01; 3D: 0.15 ± 1.09%, P < 0.001). The diagnostic performance of the 2 methods to differentiate HGG from LGG was not significantly different (P = 1). CONCLUSIONS: The potential capability of 3D APTw imaging is equal to or greater than that of 2D APTw imaging and is considered at least as valuable in patients with brain tumors.

Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1–100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width1–100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses.

Abstract Background In glioma surgery, both of functional preservation and maximal safe resection are critical, however, neoadjuvant strategy has never been used because of difficulty of tissue sampling without craniotomy. Method In Keio University Hospital, oligodendrogliomas, i.e., diffuse gliomas with IDH mutation and 1p/19q codeletion, with incomplete initial resection have been treated by upfront chemotherapy and subsequent resection after tumor volume decrease (second look resection, SLR) since 2006 (J Neurooncol 124:127-35, 2015). At first, initial radiotherapy was prescribed immediately after chemotherapy or SLR only for the cases with aggressive clinical course or subarachnoid infiltration, however, cases with residual FLAIR abnormality after upfront chemotherapy or SLR were also subjected to initial radiotherapy since 2018. Cases 1) with IDH mutation and 1p/19q codeletion, and 2) without history of either chemotherapy or radiotherapy, and 3) treated with upfront chemotherapy and subsequent resection strategy, were included. Results Thirty nine cases of oligodendroglioma have been treated with the above strategy since 2006. Tumor volume decrease following upfront chemotherapy was 30-35% (median), and 19 tumors underwent SLR. Among the total 39 cases, PFS and OS after initiation of upfront chemotherapy were 81 months and not reached, respectively, and were 64 months and not reached, respectively, among the 32 cases with deferred radiotherapy. Importantly, the majority of tumor recurrence occurred at the residual FLAIR abnormality following upfront chemotherapy. Conclusions Treatment of oligodendrogliomas utilizing neoadjuvant strategy enables 1) decrease of resection volume as compared with initial maximal safe resection, 2) more precise resection, 3) confirmation of the necessity of initial radiotherapy based on the observed efficacy of chemotherapy. Moreover, the study also suggested that 4) invasion front of oligodendroglioma likely withdraw by alkylating agents, and 5) cases with residual FLAIR abnormality following chemotherapy may be appropriate subjects for initial radiotherapy.

Abstract Introduction The utility of intraoperative real-time fluorescent navigation of indocyanine green (ICG) for cerebrospinal tumors has been demonstrated in gliomas, schwannomas, and meningiomas. We reported the usefulness of the existing Second window ICG (SWIG) for metastatic brain tumors, in which 5 mg/kg is administered 24 hours before the day before surgery. Subsequently, we developed a Delayed window ICG (DWIG) administered 1 hour before observation intraoperatively and report our experience. Methods The subjects were 28 patients from August 2019 to March 2022, with an average age of 67 years, diagnosed with metastatic brain tumors. Eighteen patients were in the SWIG group and 10 in the DWIG group. Iridium (Visionsense) and KINEVO (Carl Zeiss) were used for near-infrared irradiation and observation. Results Near-infrared light was irradiated during surgery, and in all cases, fluorescence from the tumor was confirmed. Fluorescence emission could be confirmed as far as 10 mm from the brain surface. The Signal Background Ratio (SBR) of tumor to brain parenchyma was 3.4 in SWIG and 4.2 in DWIG. There is no significant difference between them.(P=0.15) All patients had contrast areas on preoperative contrast MRI, and the ratio of contrast area to brain parenchyma (T1BR) was 2.5. After intraoperative resection, all resected patients showed no contrast lesions on immediate postoperative MRI. No perioperative complications due to I CG administration were noted. Conclusions Metastatic tumors may be difficult to distinguish from the normal brain visually due to the inaccuracy of the navigation system caused by intraoperative brainshift and blurring of the boundaries under an optical microscope. Intraoperative fluorescence angiography is useful in such cases because it allows tumor localization and removal in real time. DWIG is useful for metastatic brain tumors because it is simple and easy to use, with no significant difference compared to existing SWIG.

Most osteomalacia-inducing tumors (OITs) are phosphaturic mesenchymal tumors (PMTs) that secrete fibroblast growth factor 23 (FGF23). These tumors usually occur in the bone and soft tissues, and intracranial OITs are rare. Therefore, intracranial OIT is difficult to diagnose and treat. This paper presents a case of intracranial OIT and shows a review of previous cases. A 45-year-old man underwent nasal cavity biopsy and treatment with active vitamin D3 and neutral phosphate for hypophosphatemia. Amplification of FGF23 mRNA level within the tumor was detected. Subsequently, the surgical specimen was diagnosed with a PMT and was considered the cause of the patient's osteomalacia. The patient was referred to a neurosurgery department for the excision of the intracranial tumor extending to the nasal cavity. After tumor removal, the serum levels of FGF23 and phosphorus were normalized as compared to preoperative those. The patient remains disease-free, without additional treatment, approximately 10 years after surgery, with no tumor recurrence. As per the literature, intracranial OITs usually occur in patients aged 8-69 years. Bone and muscle pain are major complaints. Approximately 60% of the patients reported previously had symptoms because of intracranial tumors. In some cases, it took several years to diagnose OIT after the onset of the osteomalacia symptoms. Laboratory data in such cases show hypophosphatemia and elevated FGF23 levels. Because FGF23 levels are associated with the severity of osteomalacia symptoms, total tumor resection is recommended. PMT and hemangiopericytoma (HPC) are histologically similar, but on immunochemistry, PMT is negative for signal transducer and activator of transcription 6 (STAT6), whereas HPC is positive. FGF23 amplification is seen in PMTs but not in HPCs. Therefore, the analysis of FGF23 and STAT6 was helpful in distinguishing PMTs from HPCs. In cases of hypophosphatemia and osteomalacia without a history of metabolic, renal, or malabsorptive diseases, the possibility of oncogenic osteomalacia should be considered.

Cyst formation in the third ventricle and the histopathological findings were rarely reported. We report a similar case of late-onset aqueductal membranous occlusion (LAMO) caused by a thin gliotic cyst and a review of related literature. A 28-year-old woman with enlarged lateral ventricles was referred to our hospital with complaints of headache and dizziness. In our hospital, the obvious cause of the hydrocephalus was unknown on any examination and we decided performing endoscopic third ventriculostomy for hydrocephalus. A thin cyst covering the entrance of the aqueduct was identified and we perforated it. Histopathological finding of the cyst wall was gliosis and our case was similar to LAMO, although not typical. The postoperative symptoms and ventricle size improved for 4 years. When suspecting cases similar to definition of LAMO, neuroendoscopic surgery would be the first-choice treatment and might detect causes undetectable on preoperative imaging such as our thin membrane.

<sec> <title>BACKGROUND</title> A common surgical approach for dominant insular lesions is to make a surgical corridor in asymptomatic cortices based on functional mapping. However, the surgical approach is difficult for posterior insular lesions in a dominant hemisphere because the posterior parts of the perisylvian cortices usually have verbal functions. </sec> <sec> <title>OBSERVATIONS</title> We present the case of a 40-year-old male whose magnetic resonance images revealed the presence of contrast-enhancing lesions in the left posterior insula. Our surgical approach was to split the sylvian fissure as widely as possible, and partially resect Heschl’s gyrus if the cortical mapping was negative for language tests. Because Heschl’s gyrus did not have verbal functions, the gyrus was used as a surgical corridor. It was wide enough for the removal of the lesion; however, because intraoperative pathological diagnosis eliminated the possibility of brain tumors, further resection was discontinued. The tissues were histologically diagnosed as tuberculomas. Antituberculosis drugs were administered, and the residual lesions finally disappeared. According to the neurophysiological tests, the patient showed temporary impairment of auditory detection, but the low scores of these tests improved. </sec> <sec> <title>LESSONS</title> The transsylvian and trans-Heschl’s gyrus approach can be a novel surgical option for excising dominant posterior insular lesions. </sec>

PKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover, PKM2 knock-down decreased Cdk1 activity while introducing a constitutively active Cdk1 reversed the effects of PKM2 knock-down on cell cycle progression. The means by which PKM2 increases Cdk1 activity have not been described. Transient interaction of T14/Y15-phosphorylated Cdk1 with cyclin B allows Cdk7-mediated pT161 Cdk1 phosphorylation followed by cdc25C-mediated removal of pT14/Y15 and activation of Cdk1 in cycling cells. In the present course of investigation, PKM2 modulation did not influence Cdk7 activity, but phosphotyrosine binding forms of PKM2 co-immunoprecipitated with pY15-containing Cdk1-cyclinB and enhanced formation of active pT161 Cdk1-cyclin B complexes. Moreover, exogenous expression of phosphotyrosine binding forms of PKM2 reversed the effects of PKM2 knock-down on G2-M arrest. We here show that PKM2 binds and stabilize otherwise transient pY15-containing Cdk1-cyclinB complexes that in turn facilitate Cdk1-cyclin B activation and entry of cells into mitosis. These results, therefore, establish metabolic enzyme PKM2 as a direct interactor and activator of Cdk1-cyclin B complex and thereby directly controls mitotic progression and the growth of brain tumor cells.

BACKGROUND: We investigated the ability of magnetic resonance imaging (MRI) to distinguish primary central nervous system vasculitis (PCNSV) from glioblastoma to facilitate the development of an appropriate treatment for PCNSV. METHODS: We enrolled patients who were treated for PCNSV or glioblastoma at our center between January 2007 and August 2018. We compared the diagnoses of the 2 conditions by retrospectively reviewing patients' data for contrast-enhanced MRI, perfusion MRI, flow-sensitive black-blood (FSBB) imaging, and 1H-magnetic resonance spectroscopy (MRS). RESULTS: We evaluated 108 patients (6 PCNSV; 102 glioblastoma). We found a statistically significant correlation between diagnosis and the contrast pattern on MRI. Perivascular enhancement was observed in all cases of PCNSV as follows: ring-like, homogeneous, and irregular patterns were observed in 53 (60%), 18 (20%), and 17 (19%) cases of glioblastoma, respectively. We identified a statistically significant correlation between diagnosis and cerebral blood volume (CBV) in 3 patients with PCNSV who underwent perfusion MRI; and all had low CBVs. Among the 55 patients with glioblastoma who underwent perfusion MRI, low and high CBVs were detected in 3 and 52 patients, respectively. There was no significant correlation between diagnosis and FSBB findings. Evaluation of 1H-MRS data showed statistically significant differences between PCNSV and glioblastoma as functions of neuronal amino acid levels on long echo time MRS, with a slightly different amino acid profile, including glutamine + glutamate on short echo time MRS. CONCLUSIONS: Contrast-enhanced MRI, perfusion MRI, and quantitative analysis of 1H-MRS are valuable techniques for distinguishing PCNSV from glioblastoma before surgery.

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.

Digital subtraction angiography (DSA) assesses the necessity of preoperative embolization in meningioma cases but entails complication risks. Previous studies evaluating meningiomas' angiographic vascularity using perfusion-weighted imaging (PWI) have performed subjective visual assessments, not managing to assess the need for preoperative embolization. We objectively assessed the angiographic stain of meningiomas and examined the usefulness of two parameters of dynamic susceptibility contrast (DSC)-PWI, normalized cerebral blood volume (nCBV) and cerebral blood flow (nCBF), in predicting vascularity and the necessity of preoperative embolization. We retrospectively examined 52 patients who underwent surgery for primary meningioma and preoperative DSA and DSC-PWI. We calculated the normalized luminance (nLum) of the tumor stain in DSA. In 29 meningioma cases with a single feeding artery, we determined the DSC-PWI parameter that correlated with meningioma angiographic vascularity and predicted the necessity of preoperative embolization. We also compared vascularity between meningiomas with single and multiple feeding arteries and between convexity and skull-base meningiomas. nCBF (cut off: 3.66, P = 0.03, area under the curve [AUC] = 0.80) alone could predict the necessity of preoperative embolization and was more significantly correlated with the nLum than nCBV (P = 0.08, AUC = 0.73). Vascularity did not differ between meningiomas with single and multiple feeding arteries; skull-base meningiomas were more vascularized than convexity meningiomas (P = 0.0027). Our objective, quantitative assessments revealed nCBF as the most suitable parameter for evaluating meningioma vascularity. Tumor vascularity assessment using nCBF values and CBF images may aid predicting the necessity of preoperative DSA.

Isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic tumors tend to be pathologically diagnosed as glioblastomas (GBMs). We previously reported that myoinositol to total choline (Ins/Cho) ratio in GBMs on magnetic resonance (MR) spectroscopy was significantly lower than that in IDH-mutant gliomas. We then hypothesized that a low Ins/Cho ratio is a poor prognosis factor in patients with GBMs, IDH-wild-type. In the present study, we calculated the Ins/Cho ratios of patients with GBMs and investigated their progression-free survival (PFS) and overall survival (OS) to determine their utility as prognostic marker. We classified patients with GBMs harboring wild-type IDH (n = 27) into two groups based on the Ins/Cho ratio, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations between the high and low Ins/Cho groups. Patients with GBMs in the low Ins/Cho ratio group indicated shorter PFS (P = 0.021) and OS (P = 0.048) than those in the high Ins/Cho group. Multivariate analysis demonstrated that the Ins/Cho ratio was significantly correlated with PFS (hazard ratio 0.24, P = 0.028). In conclusion, the preoperative Ins/Cho ratio can be used as a novel potential prognostic factor for GBM, IDH-wild-type.

Resistance to temozolomide and intratumoral heterogeneity contribute to the poor prognosis of glioma. The mechanisms of temozolomide resistance can vary within a heterogeneous tumor. Temozolomide adds a methyl group to DNA. The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to a futile DNA mismatch repair cycle, formation of double-strand breaks, and eventual cell death when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The study aim was to elucidate temozolomide resistance mechanisms and identify methods to overcome temozolomide resistance in glioma. Several temozolomide-resistant clones were analyzed. Increased homologous recombination and mismatch repair system deficiencies contributed to temozolomide resistance. Inhibition of homologous recombination resensitized resistant cells with high homologous recombination efficiency. For the mismatch repair-deficient cells, inhibition of BER by PARP inhibitor potentiated temozolomide-induced cytotoxicity. Dianhydrogalactiol is a bifunctional DNA-targeting agent that forms N7-alkylguanine and inter-strand DNA crosslinks. Dianhydrogalactiol reduced the proliferation of cells independent of MGMT and mismatch repair, inducing DNA double-strand breaks and apoptosis in temozolomide-resistant cells. Further, inhibition of chk1 or homologous recombination enhanced dianhydrogalactiol-induced cytotoxicity in the cells. Selecting treatments most appropriate to the types of resistance mechanisms can potentially improve the prognosis of glioma.

Tumor cells using the ALT mechanism to maintain telomeres are uniquely sensitive to PARP inhibitor–induced lethal chromosomal fusion.

Advances in genetic and epigenetic analyses and immunohistochemical studies involving the development of mutation-specific or histone-methylated antibodies have provided many significant findings about gliomas. Based on these findings, the WHO developed and published the classification of tumors of the central nervous system in 2016. In the classification system, molecular information was combined with pathological findings. After its publication, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO(cIMAPCT-NOW)was published to evaluate and recommend changes to future central nervous system tumor classifications. This review describes the genetic and epigenetic features of gliomas, mainly those associated with the WHO classification and cIMPACT-NOW.

Seizures are common in patients with gliomas; however, the mechanisms of epileptogenesis in gliomas have not been fully understood. This study hypothesized that analyzing quantified metabolites using magnetic resonance spectroscopy (MRS) might provide novel insights to better understand the epileptogenesis in gliomas, and specific metabolites might be indicators of preoperative seizures in gliomas. We retrospectively investigated patient information (gender, age at diagnosis of tumor, their survival time) and tumor information (location, histology, genetic features, and metabolites according to MRS) in patients with gliomas. The data were correlated with the incidence of seizure and analyzed statistically. Of 146 adult supratentorial gliomas, isocitrate dehydrogenase (IDH) mutant tumors significantly indicated higher incidence of preoperative seizures than IDH wild-type gliomas. However, MRS study indicated that glutamate concentration in IDH wild-type gliomas was higher than that in IDH mutant gliomas. Glutamate was not associated with high frequency of preoperative seizures in patients with gliomas. Instead, increased total N-acetyl-L-aspartate (tNAA) was significantly associated with them. Moreover, multivariable analysis indicated that increased level of tNAA was an independent predictor of preoperative seizures. According to MRS analysis, tNAA, rather than glutamate, might be a useful to detect preoperative seizures in patient with supratentorial gliomas.

Abstract Background: Although high dose-methotrexate therapy has been performed for primary central nervous system malignant lymphoma (PCNSL), R-MPV (rituximab, methotrexate (MTX), procarbazine and vincristine) therapy is currently the first line therapy for (PCNSL) in our hospital. This study examines the results of R-MPV therapy comparing with past treatment. Method/Subjects: Thirty-seven patients treated at our hospital from 2009 to 2020 were included. Overall survival time, progression free survival time, and toxicities were evaluated. Results: The average age of patients was 65.7 years. Patients included 21 males and 16 females. Thirty-six patients were diagnosed DLBCL by resected brain tumor tissues, and one was diagnosed DLBCL by vitreous biopsy. As initial treatment, rituximab±HD-MTX therapy (R±MTX group) was performed in 20 cases, HD-MTX therapy plus radiation (R±MTX+RT group) was performed in 12 cases, and RMPV therapy was performed in 5 cases (R-MPV group). Median OS of all cases was 69 months and median PFS was 38 months. Median OS was 69 months in R±MTX group and could not be calculated in R±MTX+RT, and R-MPV groups. Median PFS was 16 months and 56 months in R±MTX group and R±MTX+RT, respectively, and could not be calculated in the R-MPV group. Although the R-MPV group had a short follow-up period, the results were considered to be comparable to those of the R±MTX+RT group. On the other hand, grade 3/4 adverse events occurred in 50%, 25%, and 100%, respectively. Conclusion: R-MPV therapy may delay the timing of radiation and reduce the amount of radiation. On the other hand, the frequency of adverse events is high, and more strict management of treatment is required.

BACKGROUND: The extent of resection has been reported to be associated with overall survival in gliomas. The use of 5-aminolevulinic acid (5-ALA) has been recognized to increase the extent of tumor resection. OBJECTIVE: To evaluate what factors affect the intraoperative fluorescence after administration of 5-ALA in gliomas. METHODS: Correlation of intraoperative fluorescence and several clinical, radiographic, molecular biologic, and histopathologic characters was retrospectively evaluated in 104 patients (53 males and 51 females; mean age 54.2 yr) with gliomas at our institution. To clarify the mechanisms that mutant isocitrate dehydrogenase (IDH) affect the intraoperative fluorescence, in Vitro experiments using genetically engineered glioma cells harboring mutant IDH1 were performed. RESULTS: Intraoperative fluorescence was observed in 82 patients (78.8%). In addition to age, magnetic resonance imaging enhancement, World Health Organization grades, and MIB-1 index, the status of IDH was revealed to be correlated with intraoperative fluorescence. In Vitro assay revealed that mutant IDH indirectly reduced the amount of exogenous 5-ALA-derived protoporphyrinogen IX in glioma cells by increasing activity of ferrochelatase and heme oxygenase 1. CONCLUSION: Mutant IDH1/2-induced metabolite changes of exogenous 5-ALA were suggested to contribute to the lesser intraoperative fluorescence in gliomas with mutant IDH1/2 than in those without.

The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is overexpressed in several types of cancer, suggesting an additional function beyond its established role in the glycolytic pathway. We here report that PGAM1 is overexpressed in gliomas where it increases the efficiency of the DNA damage response (DDR) pathway by cytoplasmic binding of WIP1 phosphatase, thereby preventing WIP1 nuclear translocation and subsequent dephosphorylation of the ATM signaling pathway. Silencing of PGAM1 expression in glioma cells consequently decreases formation of γ-H2AX foci, increases apoptosis, and decreases clonogenicity following irradiation (IR) and temozolomide (TMZ) treatment. Furthermore, mice intracranially implanted with PGAM1-knockdown cells have significantly improved survival after treatment with IR and TMZ. These effects are counteracted by exogenous expression of two kinase-dead PGAM1 mutants, H186R and Y92F, indicating an important non-enzymatic function of PGAM1. Our findings identify PGAM1 as a potential therapeutic target in gliomas.

According to the 2016 World Health Organization (WHO) classification of central nervous system tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). IDH-mutant astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma often have wild-type p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing telomerase activation. This study analyzed IDH, ATRX, and TERT promoter mutations, and the correlation between them. Immortalized cells overcome the telomere-related crisis by activating telomerase or ALT. In glioma, telomerase is mainly activated by TERT promoter mutation, while ALT is usually associated with ATRX mutation. Although the mechanism of how ATRX mutation induces ALT remains unclear, ATRX loss alone is believed to be insufficient to induce ALT. Treatments targeting telomere maintenance are promising.

BACKGROUND/AIM: Temozolomide (TMZ) induces prolonged arrest of human glioma cells in the G2/M phase and inhibition of the G2 checkpoint intensifies the effect of TMZ. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. MATERIALS AND METHODS: To clarify the mechanism of TMZ resistance, we established TMZ-resistant (TR) clones by serial treatment of U87MG cells with TMZ. We evaluated TMZ-induced cell cycle arrest and the effect of various G2 checkpoint inhibitors. RESULTS: We observed that longer exposure (over 6 months) to TMZ enriched the proportion of TR clones that underwent only minimal G2 arrest following TMZ treatment compared to short exposure (4 months) to TMZ. Expression of MSH6 was reduced in these clones. None of the G2 checkpoint inhibitors could resensitize TR clones to TMZ. CONCLUSION: Longer drug treatment may induce resistance of cells to DNA damaging agent(s) by means of mismatch repair modification.

PURPOSE: Glioblastoma is an aggressive central nervous system tumor with a 5-year survival rate of < 10%. The standard therapy for glioblastoma is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide. New approaches to treatment of glioblastoma, such as targeting metabolism, have been studied. The object of this study is to evaluate whether asparagine could be a new target for treatment of glioblastoma. METHODS: We investigated a potential treatment for glioblastoma that targets the amino acid metabolism. U251, U87, and SF767 glioblastoma cells were treated with L-asparaginase and/or 6-diazo-5-oxo-L-norleucine (DON). L-asparaginase hydrolyzes asparagine into aspartate and depletes asparagine. L-asparaginase has been used for the treatment of acute lymphoblastic leukemia. DON is a glutamine analog that inhibits several glutamine-utilizing enzymes, including asparagine synthetase. RESULTS: Cell viability was measured after 72 h of treatment. MTS assay showed that L-asparaginase suppressed the proliferation of U251, U87, and SF767 cells in a dose-dependent manner. DON also inhibited the proliferation of these cell lines in a dose-dependent manner. Combined treatment with these drugs had a synergistic antiproliferative effect in these cell lines. Exogenous asparagine rescued the effect of inhibition of proliferation by L-asparaginase and DON. The expression of asparagine synthetase mRNA was increased in cells treated with a combination of L-asparaginase and DON. This combined treatment also induced greater apoptosis and autophagy than did single-drug treatment. CONCLUSION: The results suggest that the combination of L-asparaginase and DON could be a new therapeutic option for patients with glioblastoma.