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Liner and nonlinear-optical properties of oligothiophenes self-assembled monolayers (SAM) are studied by optical second harmonic interference technique. Linear polarizability and first hyperpolarizability as functions of the number of thiophene rings are calculated using a self-consistent approach for linear and nonlinear optical properties. Both of these dependencies can be described by a power law; a nonzero first hyperpolarizability points to the asymmetry of delocalized electron system that might be due to an adsorption of thiophene molecules on a metal substrate. The influence of a dipole-dipole interaction of molecules arranged in the SAM is discussed. [ABSTRACT FROM AUTHOR]

A study was conducted to examine the synchronization modes of coupled relaxation electrochemical oscillators. The result reveals that networks of coupled relaxation electrochemical oscillators can perform some primitive information manipulation tasks.

A procedure to alter the connections from excitatory to inhibitory in networks of identical discrete electrochemical oscillators, without changing the architecture of the network is investigated. It is concluded that, it can be stated that when a network of identical discrete electrochemical oscillators is controlled potentiostatically with respect to a point reference electrode, under bistable or periodic oscillatory conditions.

Background: Isocitrate dehydrogenase-mutant astrocytoma without cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion typically follows a slow clinical course. However, some cases show early progression on magnetic resonance imaging, and these characteristics remain under-reported. This study aimed to elucidate the characteristics of isocitrate dehydrogenase-mutant astrocytoma showing early progression on magnetic resonance imaging., Methods: This retrospective study included 52 cases of primary astrocytoma, isocitrate dehydrogenase-mutant, Central Nervous System (CNS) 5 World Health Organization grade 2-3 according to the World Health Organization 2021 classification. Patients underwent surgery followed by radiation therapy and/or chemotherapy at our institution from 2006 to 2019. Progression-free survival and overall survival were analyzed., Results: There were 24 and 28 grade 2 and grade 3 astrocytomas, respectively. The median patient age was 38 years. Forty-three patients underwent radiotherapy. Progression was diagnosed by magnetic resonance imaging in 22 patients with initial radiotherapy. Thirteen of the 22 patients underwent surgery, and seven of the 13 patients received surgery within 24 months of the initial radiotherapy. Histopathologically, radiation necrosis was confirmed in four of these seven patients (57.1%). The true progression-free survival rate, excluding radiation necrosis, at 2 years after surgery was 91.3% for grade 2 astrocytoma and 88.5% for grade 3 astrocytoma. The 5-year overall survival rate was 85.7% for grade 2 tumours and 76.4% for grade 3 tumours., Conclusions: Radiation necrosis should be considered in cases showing early progression of isocitrate dehydrogenase-mutant astrocytoma, and a second surgery should be performed to confirm true recurrence or radiation necrosis. Astrocytomas with telomerase reverse-transcriptase promoter mutations may relapse relatively early and should be followed up with caution., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Isocitrate dehydrogenase ( IDH ) wild-type glioblastoma (GBM) is a highly aggressive brain tumor with a high recurrence rate despite adjuvant treatment. This study aimed to evaluate the risk factors for non-local recurrence of GBM. In the present study, we analyzed 104 GBMs with a single lesion (non-multifocal or multicentric). Univariate analysis revealed that subventricular zone (SVZ) involvement was significantly associated with non-local recurrence (hazard ratio [HR]: 2.09 [1.08-4.05]). Tumors in contact with the trigone of the lateral ventricle tended to develop subependymal dissemination ( p = 0.008). Ventricular opening via surgery did not increase the risk of non-local recurrence in patients with SVZ involvement ( p = 0.190). A systematic review was performed to investigate the risk of non-local recurrence, and 21 studies were identified. A meta-analysis of previous studies confirmed SVZ involvement (odds ratio [OR]: 1.30 [1.01-1.67]) and O -6-methylguanine DNA methyltransferase promoter methylation (OR: 1.55 [1.09-2.20]) as significant risk factors for local recurrence. A time-dependent meta-analysis revealed a significant association between SVZ involvement and dissemination (HR: 1.69 [1.09-2.63]), while no significant association was found for distant recurrence (HR: 1.29 [0.74-2.27]). Understanding SVZ involvement and specific tumor locations associated with non-local recurrence provides critical insights for the management of GBM.

Awake surgery contributes to the maximal safe removal of gliomas by localizing brain function. However, the efficacy and safety thereof as a treatment modality for glioblastomas (GBMs) have not yet been established. In this study, we analyzed the outcomes of awake surgery as a treatment modality for GBMs, response to awake mapping, and the factors correlated with mapping failure. Patients with GBMs who had undergone awake surgery at our hospital between March 2010 and February 2023 were included in this study. Those with recurrence were excluded from this study. The clinical characteristics, response to awake mapping, extent of resection (EOR), postoperative complications, progression-free survival (PFS), overall survival (OS), and factors correlated with mapping failure were retrospectively analyzed. Of the 32 participants included in this study, the median age was 57 years old; 17 (53%) were male. Awake mapping was successfully completed in 28 participants (88%). A positive response to mapping and limited resection were observed in 17 (53%) and 13 participants (41%), respectively. The EOR included gross total, subtotal, and partial resections and biopsies in 19 (59%), 8 (25%), 3 (9%), and 2 cases (6%), respectively. Eight (25%) and three participants (9%) presented with neurological deterioration in the acute postoperative period and at 3 months postoperatively, respectively. The median PFS and OS were 15.7 and 36.9 months, respectively. The time from anesthetic induction to extubation was statistically significantly longer in the mapping failure cohort than that in the mapping success cohort. Functional areas could be detected during awake surgery in participants with GBMs. Thus, awake mapping influences intraoperative discernment, contributes to the preservation of brain function, and improves treatment outcomes.

A combination of BRAF and MEK inhibitors is reported to be effective for gliomas with the BRAF V600E mutation; however, its efficacy in gliomas with leptomeningeal metastases (LMM) is still unknown. In this report, we describe two pediatric patients with high-grade glioma featuring the BRAF V600E mutation who were treated with dabrafenib and trametinib for LMM. Both 2 cases underwent craniotomy for primary intracranial lesions and were diagnosed as a high-grade glioma with BRAF V600E mutation; one case was consistent with anaplastic pleomorphic xanthoastorocytoma, the other was epithelioid glioblastoma. They received standard treatment for the lesions but subsequently were found to have new lesions including multiple spinal dissemination. We started administering dabrafenib and trametinib. Within a few days of starting treatment, the symptoms improved dramatically and MRI performed one month after the prescription of the two drugs demonstrated remission of both brain and spinal lesions. This report shows that dabrafenib and trametinib are effective not only for recurrent lesions but also for LMM in pediatric patients., Competing Interests: Conflict of interestNarita Y. has a grant from MBL which developed a commercially available kit detecting BRAF V600E., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: The neurological status of glioblastoma patients rapidly deteriorates. We recently demonstrated that early diagnosis and surgery within 3 weeks from the initial symptoms are associated with improved survival. While glioblastoma is a semi-urgent disease, the prehospital behaviors and clinical outcomes of glioblastoma patients are poorly understood. We aimed to disclose how prehospital patient behavior influences the clinical outcomes of glioblastoma patients., Methods: Isocitrate dehydrogenase-wildtype glioblastoma patients treated at our institution between January 2010 and December 2019 were reviewed. Patients were divided into two groups, neurosurgeon and non-neurosurgeon groups, based on the primary doctor whom patients sought for an initial evaluation. Patient demographics and prognoses were examined., Results: Of 170 patients, 109 and 61 were classified into the neurosurgeon and non-neurosurgeon groups, respectively. The median age of neurosurgeon group was significantly younger than the non-neurosurgeon group (61 vs. 69 years old, P = 0.019) and in better performance status (preoperative Karnofsky performance status scores $\ge$80: 72.5 vs. 55.7%, P = 0.027). The neurosurgeon group exhibited a significantly shorter duration from the first hospital visit to the first surgery than the non-neurosurgeon group (18 vs. 29 days, P < 0.0001). Furthermore, the overall survival of the neurosurgeon group was significantly more prolonged than that of the non-neurosurgeon group (22.9 vs. 14.0 months, P = 0.038)., Conclusion: Seeking an initial evaluation by a neurosurgeon was potentially associated with prolonged survival in glioblastoma patients. A short duration from the first hospital visit to the first surgery is essential in enhancing glioblastoma patient prognosis., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Treatment of brain metastases (BMs) from colorectal cancer (CRC) has transitioned with the expansion of indications for stereotactic radiotherapy. Our study aimed to assess changes in prognosis and prognostic factors associated with changes in treatment for BMs from CRC., Methods: We retrospectively surveyed treatments for and outcomes of BMs from CRC in 208 patients treated during 1997-2018. Patients were divided into two groups according to time of BM diagnosis, i.e., 1997-2013 ("first period") and 2014-2018 ("second period"). We compared overall survival between the periods and assessed how the transition impacted prognostic factors affecting overall survival, including the following prognostic factors such as Karnofsky performance status (KPS), volume-related factors (BM number and diameter), and BM treatment modalities as covariates., Results: Of the 208 patients, 147 were treated in the first period and 61 in the second period. Whole-brain radiotherapy use decreased from 67 to 39% in the second period, and stereotactic radiotherapy use increased from 30 to 62%. Median survival after BM diagnosis improved from 6.1 to 8.5 months (p = 0.0272). Multivariate analysis revealed KPS, control of primary tumor, stereotactic radiotherapy use, and chemotherapy history as independent prognostic factors during the entire observation period. Hazard ratios of KPS, primary tumor control, and stereotactic radiotherapy were higher in the second period, whereas prognostic impact of chemotherapy history before BM diagnosis was similar in both periods., Conclusion: Overall survival of patients with BMs from CRC improved since 2014, which can be attributed to advances in chemotherapy and the more widespread use of stereotactic radiotherapy., (© 2023. The Author(s).)

The World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5) introduced a newly defined astrocytoma, IDH-mutant grade 4, for adult diffuse glioma classification. One of the diagnostic criteria is the presence of a CDKN2A/B homozygous deletion (HD). Here, we report a robust and cost-effective quantitative polymerase chain reaction (qPCR)-based test for assessing CDKN2A HD. A TaqMan copy number assay was performed using a probe located within CDKN2A. The linear correlation between the Ct values and relative CDKN2A copy number was confirmed using a serial mixture of DNA from normal blood and U87MG cells. The qPCR assay was performed in 109 IDH-mutant astrocytomas, including 14 tumors with CDKN2A HD, verified either by multiplex ligation-dependent probe amplification (MLPA) or CytoScan HD microarray platforms. Receiver operating characteristic curve analysis indicated that a cutoff value of 0.85 yielded optimal sensitivity (100%) and specificity (99.0%) for determining CDKN2A HD. The assay applies to DNA extracted from frozen or formalin-fixed paraffin-embedded tissue samples. Survival was significantly shorter in patients with than in those without CDKN2A HD, assessed by either MLPA/CytoScan or qPCR. Thus, our qPCR method is clinically applicable for astrocytoma grading and prognostication, compatible with the WHO CNS5., (© 2023. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

Background: Bone and soft tissue sarcomas are rare tumors and extremely rarely metastasize to the brain. Previous studies have examined the characteristics and poor prognostic factors in cases of sarcoma brain metastasis (BM). Due to the rarity of cases of BM from sarcoma, limited data exist concerning the prognostic factors and treatment strategies., Methods: A retrospective single-center study was performed on sarcoma patients with BM. The clinicopathological characteristics and treatment options for BM of sarcoma were investigated to identify predictive prognostic factors., Results: Between 2006 and 2021, 32 patients treated for newly diagnosed BM at our hospital were retrieved among 3133 bone and soft tissue sarcoma patients via our database. The most common symptom was headache (34%), and the most common histological subtypes were alveolar soft part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (25%). Non-ASPS (p = 0.022), presence of lung metastasis (p = 0.046), a short duration between initial metastasis, and the diagnosis of brain metastasis (p = 0.020), and the absence of stereotactic radiosurgery for BM (p = 0.0094) were significantly correlated with a poor prognosis., Conclusions: In conclusion, the prognosis of patients with brain metastases of sarcomas is still dismal, but it is necessary to be aware of the factors associated with a relatively favorable prognosis and to select treatment options appropriately., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001., Methods: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method., Results: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples., Conclusions: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Glioblastoma (GBM) infrequently recurs in the infratentorial region. Such Infratentorial recurrence (ITR) has some clinically unique characteristics, such as presenting unspecific symptoms and providing patients a chance to receive additional radiotherapy. However, the clinical significances of ITR are not well studied., Methods: We reviewed newly diagnosed isocitrate dehydrogenase (IDH)-wildtype GBM patients treated at our institution between October 2008 and December 2018. ITR was defined as any type of recurrence in GBM, including dissemination or distant recurrence, which primarily developed in the supratentorial region and recurred in the infratentorial region., Results: Of 134 patients with newly diagnosed IDH-wildtype GBM, six (4.5%) were classified as having ITR. There was no significant difference in median duration from the first surgery to ITR development between patients with and without ITR (12.2 vs. 10.2 months, P = 0.65). The primary symptoms of ITR were gait disturbance (100%, n = 6), dizziness (50.0%, n = 3), nausea (33.3%, n = 2), and cerebellar mutism (16.7%, n = 1). In four cases (66.7%), symptoms were presented before ITR development. All patients received additional treatments for ITR. The median post-recurrence survival (PRS) of ITR patients was significantly shorter than that of general GBM patients (5.5 vs. 9.1 months, P = 0.023). However, chemoradiotherapy contributed to palliating symptoms such as nausea., Conclusions: ITR is a severe recurrence type in GBM patients. Its symptoms are neurologically unspecific and can be overlooked or misdiagnosed as side effects of treatments. Carefully checking the infratentorial region, especially around the fourth ventricle, is essential during the GBM patient follow-up., (© 2023. The Author(s).)

Background: Glioblastoma (GBM) is a rapidly growing and most life-threatening malignant brain tumor. The significance of early treatment to the clinical outcomes of patients with GBM is unclear., Objective: To determine whether early diagnosis and surgery improve the preoperative and postoperative Karnofsky performance status (KPS) and prognosis of patients with GBM., Methods: Data of isocitrate dehydrogenase-wildtype patients with GBM treated at our institution between January 2010 and December 2019 were reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. In addition, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Representative symptoms and patient prognoses were examined., Results: Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The median tumor volume was significantly smaller in the former group. The proportion of patients with preoperative KPS scores 90 was 48.6% and 29.6% in the early and late diagnosis groups ( P = .016). The early, intermediate, and late surgery groups included 43, 24, and 86 patients. The median overall survival was significantly longer in the early surgery group than in the late surgery group (28.4 vs 18.7 months, P = .006). Multivariate analysis demonstrated that significant predictors of shorter survival included extent of tumor resection (partial or biopsy), preoperative and postoperative KPS 60, and O6-methylguanine-DNA-methyltransferase promoter status (unmethylated)., Conclusion: Early diagnosis within 2 weeks and surgical interventions within 3 weeks from the symptom onset are associated with prolonged patient survival. Early GBM treatment will benefit patients with GBM., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of Congress of Neurological Surgeons.)

Purpose: Gliomas are characterized by immunosuppressive features. Programmed death-ligand 1 (PD-L1) is overexpressed and plays an important role in the immunosuppressive tumor microenvironments of gliomas. However, the radiographical and prognostic significance of PD-L1 expression remains unclear., Methods: Using tissue microarrays, we evaluated PD-L1 expression and the presence of tumor-infiltrating CD4+ and CD8+T cells and CD204+macrophages using immunohistochemical analysis. Contrast enhancement area and fluid-attenuated inversion recovery (FLAIR) hyperintensity area were evaluated by two-dimensional analysis. Kaplan-Meier analysis was performed to evaluate the overall survival time in 44 patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma., Results: We evaluated 71 patients with newly diagnosed high-grade gliomas who were treated between October 1998 and April 2012. PD-L1 expression was observed in 15 patients (21.1%). A significant association of PD-L1 expression with the CD4+ and CD8+ T cell densities, but not with CD204+ macrophage densities, was observed (p = 0.025, p = 0.0098, and p = 0.19, respectively). The FLAIR-to-enhancement ratio was significantly higher in PD-L1+ tumors than in PD-L1- tumors (p = 0.0037). PD-L1 expression did not show a significant association with the median survival time (PD-L1 + vs. PD-L1-: 19.2 vs 14.9 months; p = 0.39)., Conclusion: PD-L1 expression was associated with CD4+ and CD8+ T cell infiltration, indicating a significant interplay between PD-L1 and immune cells. The positive correlation of PD-L1 expression with an increased FLAIR-to-enhancement ratio suggested that radiographical characteristics could reflect the immunological status. Our results did not support the prognostic impact of PD-L1 in patients with IDH-wildtype glioblastomas., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Several studies have reported that gross total resection contributes to improved prognosis in patients with butterfly glioblastoma (bGBM). However, it sometimes damages the corpus callosum and cingulate gyrus, leading to severe neurological complications., Case Description: We report two cases of bGBM that was safely and maximally resected using brief and exact awake mapping after general anesthesia. Two patients had butterfly tumors in both the frontal lobes and the genu of the corpus callosum. Tumor resection was first performed on the nondominant side under general anesthesia to shorten the resection time and maintain patient concentration during awake surgery. After that, awake surgery was performed for the lesions in the dominant frontal lobe and genu of the corpus callosum. Tumor resection was performed through minimal cortical incisions in both frontal lobes. Postoperative magnetic resonance imaging showed gross total resection, and the patients had no chronic neurological sequelae, such as akinetic mutism and abulia., Conclusion: bGBM could be safely and maximally resected by a combination of asleep and brief awake resection, which enabled patients to maintain their attention to the task without fatigue, somnolence, or decreased attention. The bilateral approach from a small corticotomy can avoid extensive damage to the cingulate gyrus., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

Objective: The optimal duration of maintenance temozolomide therapy is controversial. We aimed to examine the clinical benefits of continuing temozolomide therapy beyond 12 cycles in patients with glioblastoma., Methods: We included 41 patients with isocitrate dehydrogenase 1/2-wildtype glioblastoma, who received 12 or more cycles of temozolomide therapy between June 2006 and December 2019. We evaluated the outcome between 16 patients who continued temozolomide therapy beyond 12 cycles up to 24 cycles (≥13 cycles group) and 25 patients wherein temozolomide therapy was discontinued at 12 cycles (12 cycles group)., Results: The median progression-free survival and survival time after completing 12 cycles (residual progression-free survival and residual overall survival) did not differ between the 12 cycles group and ≥13 cycles group (residual progression-free survival: 11.3 vs. 9.2 months, P = 0.61, residual overall survival: 25.7 vs. 30.2 months, P = 0.76). Multivariate analysis including temozolomide therapy beyond 12 cycles, age at 12 cycles, Karnofsky performance status at 12 cycles, residual tumor at 12 cycles, maintenance therapy regimen and O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation status revealed that extended temozolomide therapy beyond 12 cycles was not correlated with residual progression-free survival and residual overall survival (P = 0.80 and P = 0.41, respectively) but Karnofsky performance status at 12 cycles ≥80 was significantly associated with increased residual overall survival (P = 0.0012)., Conclusions: Continuing temozolomide beyond 12 cycles confers no clinical benefit over the discontinuation of temozolomide at 12 cycles. Karnofsky performance status at 12 cycles ≥80 may serve as a novel predictive factor for long-term survival., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The current World Health Organization classification of diffuse astrocytic and oligodendroglial tumors requires the examination of isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations. Conventional analysis tools, including Sanger DNA sequencing or pyrosequencing, fail in detecting these variants of low frequency owing to their limited sensitivity. Digital polymerase chain reaction (dPCR) is a recently developed, highly sensitive, and precise quantitative rare variant assay. This study aimed to establish a robust limit of quantitation of the dPCR assay to detect a small fraction of IDH1 R132H mutation. The dPCR assays with serially diluted IDH1 R132H constructs detected 0.05% or more of mutant IDH1 R132H in samples containing mutant DNA. The measured target/total value of the experiments was proportional to the dilution factors and was almost equal to the actual frequencies of the mutant alleles. Based on the average target/total values, together with a twofold standard deviation of the normal DNA, a limit of quantitation of 0.25% was set to secure a safe margin to judge the mutation status of the IDH1 R132H dPCR assay. In clinical settings, detecting IDH1 R132H using dPCR assays can validate ambiguous immunohistochemistry results even when conventional DNA sequencing cannot detect the mutation and assure diagnostic quality., (© 2022. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

The aim of the present study was to determine which individual or combined CpG sites among O 6 -methylguanine DNA methyltransferase CpG 74-89 in glioblastoma mainly affects the response to temozolomide resulting from CpG methylation using statistical analyses focused on the tumor volume ratio (TVR). We retrospectively examined 44 patients who had postoperative volumetrically measurable residual tumor tissue and received adjuvant temozolomide therapy for at least 6 months after initial chemoradiotherapy. TVR was defined as the tumor volume 6 months after the initial chemoradiotherapy divided by that before the start of chemoradiotherapy. Predictive values for TVR as a response to adjuvant therapy were compared among the averaged methylation percentages of individual or combined CpGs using the receiver operating characteristic curve. Our data revealed that combined CpG 78 and 79 showed a high area under the curve (AUC) and a positive likelihood ratio and that combined CpG 76-79 showed the highest AUC among all combinations. AUCs of consecutive CpG combinations tended to be higher for CpG 74-82 in exon 1 than for CpG 83-89 in intron 1. In conclusion, the methylation status at CpG sites in exon 1 was strongly associated with TVR reduction in glioblastoma., Competing Interests: The authors declare no conflict of interest.

Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.

Next-generation sequencing-based comprehensive genomic profiling test (CGPT) enables clinicians and patients to access promising molecularly targeted therapeutic agents. Approximately 10% of patients who undergo CGPT receive an appropriate agent. However, its coverage of glioma patients is seldom reported. The aim of this study was to reveal the comprehensive results of CGPT in glioma patients in our institution, especially the clinical actionability. We analyzed the genomic aberrations, tumor mutation burden scores, and microsatellite instability status. The Molecular Tumor Board (MTB) individually recommended a therapeutic agent and suggested further confirmation of germline mutations after considering the results. The results of 65/104 patients with glioma who underwent CGPTs were reviewed by MTB. Among them, 12 (18.5%) could access at least one therapeutic agent, and 5 (7.7%) were suspected of germline mutations. A total of 49 patients with IDH -wildtype glioblastoma showed frequent genomic aberrations in the following genes: TERT promoter (67%), CDKN2A (57%), CDKN2B (51%), MTAP (41%), TP53 (35%), EGFR (31%), PTEN (31%), NF1 (18%), BRAF (12%), PDGFRA (12%), CDK4 (10%), and PIK3CA (10%). Since glioma patients currently have very limited standard treatment options and a high recurrence rate, CGPT might be a facilitative tool for glioma patients in terms of clinical actionability and diagnostic value.

Background: We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG)., Methods: We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan's criteria for RIG in our database during 2001-2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing., Results: The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9-30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy., Conclusions: RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma., (© 2022. The Author(s).)

Purpose: Although the usefulness of O 6 -methylguanine DNA methyltransferase (MGMT) promoter methylation analysis for predicting response to chemoradiotherapy and the prognosis of patients with glioblastoma has been widely reported, there is still no consensus regarding how to define MGMT promoter methylation percentage (MGMTpm%) cutoffs by pyrosequencing method. The aim of this study was to determine the optimal cutoff value of MGMT promoter methylation status using volumetric analysis focused on the tumor volume ratio (TVR) measured by MRI., Methods: This retrospective study included newly diagnosed IDH wild-type glioblastoma patients with residual tumor after surgery, followed by local radiotherapy with temozolomide. TVR was defined as the tumor volume at 6 months after the initial chemoradiotherapy administration divided by the tumor volume before the start of therapy. The mean MGMTpm% of 16 CpG islands (74-89) was analyzed using pyrosequencing. We statistically analyzed the correlation between MGMTpm%, TVR, and change in Karnofsky performance status., Results: The study included 44 patients with residual tumors. Thirteen (92.9%) of 14 patients with MGMTpm% ≥ 23.9% showed 50% or more volumetric response, leading to prolonged survival, and 17 (70.8%) of 24 patients with MGMTpm% < 8.2% had progressive disease after initial chemoradiotherapy administration. Three (50.0%) of six patients with MGMTpm% 8.2% to < 23.9% had stable disease or partial response., Conclusion: Evaluation of MGMTpm% by pyrosequencing is important in predicting the volumetric response and prognosis of glioblastoma patients with residual tumors., (© 2022. The Author(s).)

Objective: With an increase in the number of imaging examinations and the development of imaging technology, a small number of glioblastomas (GBMs) are identified by incidental radiological images. These incidentally discovered glioblastomas (iGBMs) are rare, and their clinical features are not well understood. Here, we investigated the clinical characteristics and outcomes of iGBM., Methods: Data of newly diagnosed iGBM patients who were treated at our institution between August 2005 and October 2019 were reviewed. An iGBM was defined as a GBM without a focal sign, discovered on radiological images obtained for reasons unrelated to the tumor. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS)., Results: Of 315 patients with newly diagnosed GBM, four (1.3%) were classified as having iGBM. Health screening was the most common reason for tumor discovery (75.0%). The preoperative Karnofsky performance status score was 100 in three patients. Tumors were found on the right side in three cases. The mean volume of preoperative enhanced tumor lesion was 16.8 cm 3 . The median duration from confirmation of an enhanced lesion to surgery was 13.5 days. In all cases, either total (100%) or subtotal (95-99%) resections were achieved. The median PFS and OS were 10.5 and 20.0 months, respectively., Conclusions: The iGBMs were often small and in the right non-eloquent area, and the patients had good performance status. We found that timely therapeutic intervention provided iGBM patients with favorable outcomes. This report suggests that early detection of GBM may lead to a better prognosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Mutant isocitrate dehydrogenase ( IDH ) 1/2 gene products gain a new ability to produce D-2-hydroxyglutarate (D2HG). IDH1/2 mutations are thought to be associated with seizures owing to the structural similarity between D2HG and glutamate. However, the effects of D2HG on seizures in clinical settings are not fully understood. We sought to investigate the relationship between tissue 2-hydroxyglutarate (2HG) concentration and preoperative seizures using clinical samples., Methods: We included 104 consecutive patients with diffuse glioma who underwent surgery from August 2008 to May 2016 and whose clinical presentation and IDH1/2 status were identified. The presence of preoperative seizures, tumor location, histopathologic diagnosis, IDH1/2 status, and 1p/19q codeletion were assessed from the patient charts. Tissue 2HG concentration was measured using liquid chromatography-tandem mass spectrometry. To evaluate 2HG distribution without artefactual tissue disruption, we applied matrix-assisted laser desorption/ionization high-resolution mass spectrometry imaging (MALDI-MSI) in 12 patients' surgically resected samples. We assessed the correlation of preoperative seizures with tissue 2HG concentration, IDH1/2 status, WHO grade, and 1p/19q codeletion., Results: Tissue 2HG concentration was higher in IDH1/2 mutant tumors ( IDH -Mut, n = 42) than in IDH1/2 wild-type tumors ( IDH -WT, n = 62) (median 4,860 ng/mg vs 75 ng/mg) ( p < 0.0001). MALDI-MSI could detect 2HG signals in IDH -Mut, but not in IDH -WT. Preoperative seizures were observed in 64.3% of patients with IDH -Mut and 21.0% patients with IDH -WT ( p < 0.0001). The optimal cutoff value of tissue 2HG concentration for predicting preoperative seizures was 1,190 ng/mg, as calculated by the receiver operating characteristic curve. Increased preoperative seizure risk was only observed in tumors with 2HG concentration above the cutoff value among IDH -Mut ( IDH -Mut with above the cutoff value: 71.4% vs IDH -Mut with below the cutoff value: 28.6%; p = 0.031). Multivariate analysis, including IDH1/2 mutation status, tissue 2HG concentration, WHO grade, and 1p/19q codeletion, revealed that only increased tissue 2HG concentration was associated with preoperative seizures (odds ratio 5.86, 95% confidence interval 1.02-48.5; p = 0.048)., Discussion: We showed that high tissue 2HG concentration was associated with preoperative seizures, suggesting that excess 2HG increases risk of preoperative seizures in IDH1/2 mutant tumors., (© 2021 American Academy of Neurology.)

The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 -), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN -) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55-4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN - was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09-5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There is no standard treatment for patients with recurrent high-grade gliomas who progress after bevacizumab treatment. We evaluated the outcomes of re-irradiation combined with bevacizumab for patients refractory to bevacizumab., Methods: Between January 2015 and September 2019, patients with progression after bevacizumab treatment were treated with re-irradiation combined with bevacizumab (25 Gy in five fractions)., Results: Fourteen patients [glioblastoma, isocitrate dehydrogenase (IDH) wild type (N = 6), glioblastoma, IDH mutant (N = 4), anaplastic astrocytoma, IDH wild type (N = 1), anaplastic astrocytoma, IDH mutant (N = 1), glioblastoma, not otherwise specified (N = 1) and radiologically diagnosed brainstem glioma (N = 1)] were included in this study. The median survival and progression-free survival times after re-irradiation combined with bevacizumab were 6.1 and 3.8 months, respectively. The 6-month survival and progression-free survival rates were 54.5 and 15.7%, respectively. Patients with a Karnofsky performance status of ≥70 tended to have longer median survival time (9.3 vs. 5.4 months, respectively; P = 0.058) and had a significantly longer median progression-free survival time (4.2 vs. 3.7 months, respectively; P = 0.046) than those with a Karnofsky performance status of <70. Four patients (28.6%) achieved a complete or partial radiological response, and three patients (21.4%) had an improved Karnofsky performance status after re-irradiation combined with bevacizumab. Grade 3/4 toxicities included leukopenia in four patients (28.6%), hypertension in three (21.4%), proteinuria in one (7.1%) and gastrointestinal hemorrhage in one (7.1%)., Conclusions: Re-irradiation combined with bevacizumab for patients with recurrent high-grade gliomas who progress after bevacizumab treatment was feasible. Re-irradiation combined with bevacizumab is a potential treatment option, especially for patients with a Karnofsky performance status of ≥70., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

External auditory canal (EAC) carcinoma is a rare and unusual malignancy. The complex anatomy and relationship between the tumor and surrounding tissues in a limited space render it difficult to attain safe resection margins during surgery. A high jugular bulb (HJB) is one such anatomical variation that has important surgical implications that complicate the surgical procedure for EAC carcinoma. A 73-year-old woman presented with a 3-month history of right ear pain. Pathological findings and computed tomography (CT) revealed EAC carcinoma, which was expanding to the middle ear (ME). Although there was no cavity inside the ME, an HJB was detected. Surgical treatment using a temporal incision for temporal craniotomy achieved complete resection of the tumor and preserved facial nerve function. The patient recovered without complications and was discharged 17 days after the operation. Temporal incision and temporal craniotomy is a useful approach for EAC carcinoma with HJB., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare, (Copyright © 2020. Published by Elsevier B.V.)