Language：English   Publisher：The Japan Neurosurgical Society  

<p>We aimed to retrospectively determine the resection rate of fluid-attenuated inversion recovery (FLAIR) lesions to evaluate the clinical effects of supramaximal resection (SMR) on the survival of patients with glioblastoma (GBM). Thirty-three adults with newly diagnosed GBM who underwent gross total tumor resection were enrolled. The tumors were classified into cortical and deep-seated groups according to their contact with the cortical gray matter. Pre- and postoperative FLAIR and gadolinium-enhanced T1-weighted imaging tumor volumes were measured using a three-dimensional imaging volume analyzer, and the resection rate was calculated. To evaluate the association between SMR rate and outcome, we subdivided patients whose tumors were totally resected into the SMR and non-SMR groups by moving the threshold value of SMR in 10% increments from 0% and compared their overall survival (OS) change. An improvement in OS was observed when the threshold value of SMR was 30% or more. In the cortical group (n = 23), SMR (n = 8) tended to prolong OS compared with gross total resection (GTR) (n = 15), with the median OS of 69.6 and 22.1 months, respectively (p = 0.0945). Contrastingly, in the deep-seated group (n = 10), SMR (n = 4) significantly shortened OS compared with GTR (n = 6), with median OS of 10.2 and 27.9 months, respectively (p = 0.0221). SMR could help prolong OS in patients with cortical GBM when 30% or more volume reduction is achieved in FLAIR lesions, although the impact of SMR for deep-seated GBM must be validated in larger cohorts.</p>

DOI： 10.2176/jns-nmc.2022-0351

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CiNii Research

Language：English   Publisher：(一社)日本脳神経外科学会  

膠芽腫患者を対象とした後ろ向き研究を実施し、FLAIR病変切除率を評価することで、supramaximal resection(SMR)の臨床効果について検討した。2006年12月～2018年8月に神経膠腫と診断された成人患者のうち、肉眼的全切除(GTR)が施行された成人33例(年齢中央値64歳、男性19例)を対象とした。評価項目は腫瘍切除率(手術前後のFLAIRおよびガドリニウム強調T1強調画像の腫瘍体積を3D画像体積分析装置により測定)、SMR率(0%から10%刻み)などとした。腫瘍を皮質灰白質との接触により、皮質群23例(SMR 8例、GTR 15例)、深在性群10例(SMR 4例、全切除6例)に分けて検討した。その結果、SMR閾値が30%以上の場合に全生存期間の改善が観察された。皮質群ではGTRと比較してSMRで全生存期間が延長する傾向が認められた(69.6ヵ月対22.1ヵ月)。一方、深在群ではGTRと比較してSMRで全生存期間が有意に短縮していた(10.2ヵ月対27.9ヵ月、p=0.0221)。以上から、FLAIR病変のsupramaximal resectionは神経膠腫患者の生存期間を延長可能であることが示された。

Language：English   Publisher：Neuroradiology  

Purpose: Isocitrate dehydrogenase (IDH)-wildtype diffuse astrocytic glioma with telomerase reverse transcriptase (TERT) promoter mutation is defined as glioblastoma by the WHO 2021 criteria, revealing that TERT promotor mutation is highly associated with tumor aggressiveness. The aim of this study was to identify features from MR spectroscopy (MRS) and multi-exponential models of DWI distinguishing wild-type TERT (TERTw) from TERT promoter mutation (TERTm) in IDH-wildtype diffuse astrocytic glioma. Methods: Participants comprised 25 adult patients with IDH-wildtype diffuse astrocytic glioma. Participants were classified into TERTw and TERTm groups. Point-resolved spectroscopy sequences were used for MRS data acquisition. DWI was performed with 13 different b-factors. Peak height ratios of NAA/Cr and Cho/Cr were calculated from MRS data. Mean apparent diffusion coefficient (ADC), perfusion fraction (f), diffusion coefficient (D), pseudo-diffusion coefficient (D*), distributed diffusion coefficient (DDC), and heterogeneity index (α) were obtained using multi-exponential models from DWI data. Each parameter was compared between TERTw and TERTm using the Mann–Whitney U test. Correlations between parameters derived from MRS and DWI were also evaluated. Results: NAA/Cr and Cho/Cr were both higher for TERTw than for TERTm. The α of TERTw was smaller than that of TERTm, while the f of TERTw was higher than that of TERTm. NAA/Cr correlated negatively with α, but not with other DWI parameters. Cho/Cr did not show significant correlations with any DWI parameters. Conclusion: The combination of NAA/Cr and α may have merit in clinical situation to predict the TERT mutation status of IDH-wildtype diffuse astrocytic glioma without intense enhancement.

DOI： 10.1007/s00234-023-03177-y

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Language：English   Publisher：Science Translational Medicine  

Despite the success of cancer immunotherapies such as programmed cell death-1 (PD-1) and PD-1 ligand 1 (PDL1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

DOI： 10.1126/scitranslmed.abq0021

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

高齢患者の内側側頭葉に発症した、BRAF変異を伴わずH3 K27M変異を伴った、グレード3神経節膠腫の稀少例を報告した。症例は56歳男性で、一過性の視野欠損を主訴に、他院に来院した。MRI所見では左側頭葉に腫瘍を認め、生検により、びまん性星細胞腫と病理診断されたが、18ヵ月の経過観察の間に病変が徐々に増大し、生検から36ヵ月後に施行したT1強調画像でガドリウム増強が認められたため、九州大学病院脳神経外科に紹介された。治療では腫瘍切除術が行われ、切除試料の組織学的検査から、グレード3の神経節膠腫と診断され、テモゾロミドによる同時化学放射線治療が施行された。治療サイクル2サイクル後に病状進行による悪化はみられたが、腫瘍切除術後23ヵ月以上の生存転帰が得られた。なお、Sanger法によるシーケンス解析と高感度融解曲線解析をIDH1遺伝子、IDH2遺伝子、BRAF遺伝子、H3F3A遺伝子の各遺伝子について行ったところ、IDH1/2やBRAF V600E遺伝子変異は検出されなかったが、H3 K27M遺伝子変異が検出された。

Language：English   Publisher：Neuropathology  

The mutation p.K27M in H3F3A (H3 K27M mutation) is mainly detected in diffuse midline glioma. However, recent studies have demonstrated that H3 K27M mutation could also be observed in a subset of gangliogliomas. Importantly, most H3 K27-mutated ganglioglioma cases also harbor BRAF V600E mutation. Herein, we report a rare case of H3 K27M-mutated ganglioglioma grade 3 without BRAF mutation arising in the medial temporal lobe in an elderly man. A small biopsy specimen was sampled. The pathological diagnosis was diffuse astrocytoma. The tumor progressed gradually during an 18-month follow-up period. Gadolinium enhancement on magnetic resonance imaging was noted 36 months after the biopsy. The patient was referred to a hospital for tumor resection. Histological analysis of resected specimens led to a diagnosis of ganglioglioma grade 3 with H3 K27M mutation. The patient underwent concurrent temozolomide chemotherapy with radiotherapy. Although the patient's condition deteriorated after chemotherapy due to disease progression, he survived for more than 23 months after tumor resection. We present this rare case and discuss the involvement of H3 K27M mutation in ganglioglioma grade 3.

DOI： 10.1111/neup.12793

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Language：English   Publisher：World Neurosurgery  

Background: Controversies exist regarding the aggressive recurrence of glioblastoma after bevacizumab treatment. We analyzed the clinical impact of bevacizumab approval in Japan by evaluating the clinical course and relapse pattern in patients with glioblastoma. Methods: We included 100 patients with IDH-wild-type glioblastoma from September 2006 to February 2018 in our institution. The patients were classified into the pre-bevacizumab (n = 51) and post-bevacizumab (n = 49) groups. Overall, progression-free, deterioration-free, and postprogression survivals were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were evaluated. Results: Significant improvement in progression-free (pre-bevacizumab, 7.5 months; post-bevacizumab, 9.9 months; P = 0.0153) and deterioration-free (pre-bevacizumab, 8.5 months; post-bevacizumab, 13.8 months; P = 0.0046) survivals was seen. These survival prolongations were strongly correlated (r: 0.91, P < 0.0001). The nonenhancing tumor pattern was novel in the post-bevacizumab era (5 of 33). The presence of a nonenhancing tumor did not indicate poor postprogression survival (hazard ratio: 0.82 [0.26–2.62], P = 0.7377). The rate of early focal recurrence was significantly lower (P = 0.0155) in the post-bevacizumab (4 of 33) than in the pre-bevacizumab (18 of 39) era. There was a significant decrease in early focal recurrence after approval of bevacizumab in patients with unresectable tumors (P = 0.0110). The treatment era was significantly correlated with a decreased rate of early focal recurrence (P = 0.0021, univariate analysis; P = 0.0144, multivariate analysis). Conclusions: Approval of first-line bevacizumab in Japan for unresectable tumors may prevent early progression and clinical deterioration of glioblastoma without worsening the clinical course after relapse.

DOI： 10.1016/j.wneu.2021.12.075

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Language：English   Publisher：Surgical Neurology International  

Background: Angiolipomas are benign mesenchymal tumors comprising mature adipocytes and abnormal blood vessels, commonly found in the subcutaneous tissue of the trunk and rarely in the skull. Furthermore, sporadic cases of angiolipoma with arteriovenous fistula (AVF) have been reported. Case Description: We reported the case of a 72-year-old woman who presented with head swelling, seizures, and cognitive dysfunction. Computed tomography and magnetic resonance imaging revealed a right frontal bone tumor exceeding a sagittal suture of up to 10.7 cm. Angiography revealed AVF and varices formation. Endovascular embolization was performed to treat the AVF and reduce blood loss during surgical resection. Two days after the embolization, a craniotomy was performed; however, uncontrollable bleeding was observed at the time of tumor resection. Postoperatively, the patient was symptom-free and has been stable for 2 years without recurrence. Conclusion: Despite careful preoperative evaluation and treatment planning, the patient in this case report was difficult to treat. Such cases require adequate preparation.

DOI： 10.25259/SNI_422_2022

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PubMed

Language：English   Publisher：British Journal of Radiology  

Objective: To determine whether the γ distribution (GD) model of diffusion MRI is useful in the evaluation of the isocitrate dehydrogenase (IDH) mutation status of glioblastomas. Methods: 12 patients with IDH-mutant glioblastomas and 54 patients with IDH-wildtype glioblastomas were imaged with diffusion-weighted imaging using 13 b-values from 0 to 1000 s/mm2. The shape parameter (κ) and scale parameter (θ) were obtained with the GD model. Fractions of three different areas under the probability density function curve (f1, f2, f3) were defined as follows: f1, diffusion coefficient (D) < 1.0×10−3 mm2/s; f2, D > 1.0×10−3 and <3.0×10−3 mm2/s; f3, D > 3.0 × 10−3 mm2/s. The GD model-derived parameters measured in gadolinium-enhancing lesions were compared between the IDH-mutant and IDH-wildtype groups. Receiver operating curve analyses were performed to assess the parameters' diagnostic performances. Results: The IDH-mutant group’s f1 (0.474 ± 0.143) was significantly larger than the IDH-wildtype group’s (0.347 ± 0.122, p = 0.0024). The IDH-mutant group’s f2 (0.417 ± 0.131) was significantly smaller than the IDH-wildtype group’s (0.504 ± 0.126, p = 0.036). The IDH-mutant group’s f3 (0.109 ± 0.060) was significantly smaller than the IDH-wildtype group’s (0.149 ± 0.063, p = 0.0466). The f1 showed the best diagnostic performance among the GD model-derived parameters with the area under the curve value of 0.753. Conclusion: The GD model could well describe the pathological features of IDH-mutant and IDH-wildtype glioblastomas, and was useful in the differentiation of these tumors. Advances in knowledge: Diffusion MRI based on the γ distribution model could well describe the pathological features of IDH-mutant and IDH-wildtype glioblastomas, and its use enabled the significant differentiation of these tumors. The γ distribution model may contribute to the non-invasive identification of the IDH mutation status based on histological viewpoint.

DOI： 10.1259/bjr.20210392

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Language：English   Publishing type：Research paper (scientific journal)  

Introduction: First-line bevacizumab (BEV) is now available as a treatment option for glioblastoma patients with severe clinical conditions in Japan. However, the survival benefits remain controversial. To elucidate these potential survival benefits, we retrospectively analyzed survival in glioblastoma patients receiving BEV. Methods: We analyzed survival in 120 patients with IDH-wild type glioblastoma treated from 2002 to 2018. Overall survival (OS) was assessed in three treatment era subgroups [pre-temozolomide (TMZ), TMZ, and TMZ–BEV], and the correlations of prognostic factors with survival were evaluated. Results: An improvement in survival was observed after BEV approval (median OS in the pre-TMZ, TMZ, and TMZ–BEV eras: 14.6, 14.9, and 22.1 months, respectively). A Cox proportional hazards model identified extent of resection and MGMT methylation status as significant prognostic factors in the TMZ era; however, these factors were not significant in the TMZ–BEV era. In subgroup analyses, patients with MGMT methylation had improved OS after TMZ introduction (pre-TMZ vs. TMZ, 18.5 vs. 28.1 months; P = 0.13), and those without MGMT methylation had significantly increased OS after BEV approval (TMZ vs. TMZ–BEV, 12.2 vs. 16.7 months; P = 0.04). Conclusions: Our findings imply that optional first-line administration of BEV can overcome the impact of conventional risk factors and prolong survival complementary to TMZ. The patient subgroups benefitting from TMZ and BEV did not seem to overlap, and stratification based on risk factors, including MGMT methylation status, might be effective for selecting patients in whom BEV should be preferentially used as a first-line therapy.

DOI： 10.1007/s11060-019-03339-0

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND. Current clinical biomarkers for the programmed cell death 1 (PD-1) blockade therapy are insufficient because they rely only on the tumor properties, such as programmed cell death ligand 1 expression frequency and tumor mutation burden. Identifying reliable, responsive biomarkers based on the host immunity is necessary to improve the predictive values. METHODS. We investigated levels of plasma metabolites and T cell properties, including energy metabolism markers, in the blood of patients with non-small cell lung cancer before and after treatment with nivolumab (n = 55). Predictive values of combination markers statistically selected were evaluated by cross-validation and linear discriminant analysis on discovery and validation cohorts, respectively. Correlation between plasma metabolites and T cell markers was investigated. RESULTS. The 4 metabolites derived from the microbiome (hippuric acid), fatty acid oxidation (butyrylcarnitine), and redox (cystine and glutathione disulfide) provided high response probability (AUC = 0.91). Similarly, a combination of 4 T cell markers, those related to mitochondrial activation (PPARγ coactivator 1 expression and ROS), and the frequencies of CD8+PD-1^hi and CD4+ T cells demonstrated even higher prediction value (AUC = 0.96). Among the pool of selected markers, the 4 T cell markers were exclusively selected as the highest predictive combination, probably because of their linkage to the abovementioned metabolite markers. In a prospective validation set (n = 24), these 4 cellular markers showed a high accuracy rate for clinical responses of patients (AUC = 0.92). CONCLUSION. Combination of biomarkers reflecting host immune activity is quite valuable for responder prediction.

DOI： 10.1172/jci.insight.133501

Language：English   Publishing type：Research paper (scientific journal)  

Current clinically approved biomarkers for the PD-1 blockade cancer immunotherapy are based entirely on the properties of tumour cells. With increasing awareness of clinical responses, more precise biomarkers for the efficacy are required based on immune properties. In particular, expression levels of immune checkpoint-associated molecules such as PD-1, PD-L1, and CTLA-4 would be critical to evaluate the immune state of individuals. Although quantification of their soluble form leased from the membrane will provide quick evaluation of patients’ immune status, available methods such as enzyme-linked immunosorbent assays to measure these soluble factors have limitations in sensitivity and reproducibility for clinical use. To overcome these problems, we developed a rapid and sensitive immunoassay system based on chemiluminescent magnetic technology. The system is fully automated, providing high reproducibility. Application of this system to plasma of patients with several types of tumours demonstrated that soluble PD-1, PD-L1, and CTLA-4 levels were increased compared to those of healthy controls and varied among tumour types. The sensitivity and detection range were sufficient for evaluating plasma concentrations before and after the surgical ablation of cancers. Therefore, our newly developed system shows potential for accurate detection of soluble PD-1, PD-L1, and CTLA-4 levels in the clinical practice.

DOI： 10.1038/s41598-019-46548-3

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: The significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients. Patients and methods: We evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS. Results: A total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as “molecular GBM.” IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings. Conclusion: GdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting “molecular GBM” by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients.

DOI： 10.1016/j.clineuro.2019.105556

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.inat.2019.100498

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: The purpose of this study was to identify magnetic resonance imaging (MRI) features that are associated with telomerase reverse transcriptase promoter mutation (TERTm) in glioblastoma. Materials and methods: A total of 112 patients with glioblastoma who had MRI at 1.5- or 3.0-T were retrospectively included. There were 43 patients with glioblastoma with wild-type TERT (TERTw) (22 men, 21 women; mean age, 47 ± 25 [SD] years; age range: 3–84 years) and 69 patients with glioblastoma with TERTm (34 men, 35 women; mean age 64 ± 11 [SD] years; age range, 41-–85 years). The feature vectors consist of 11 input units for two clinical parameters (age and gender) and nine MRI characteristics (tumor location, subventricular extension, cortical extension, multiplicity, enhancing volume, necrosis volume, the percentage of necrosis volume, minimum apparent diffusion coefficient [ADC] and normalized ADC). First, the diagnostic performance using univariate and multivariate logistic regression analyses was evaluated. Second, the cross-validation of the support vector machine (SVM) was performed by using leave-one-out method with 43 TERTw and 69 TERTm to evaluate the diagnostic performance. In addition, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for the differentiation between TERTw and TERTm were compared between logistic regression analysis and SVM. Results: With multivariate analysis, the percentage of necrosis volume and age were significantly greater in TERTm glioblastoma than in TERTw glioblastoma. SVM allowed discriminating between TERTw glioblastoma and TERTm glioblastoma with sensitivity, specificity, PPV, NPV, and accuracy of 85.7% [60/70; 95% confidence interval (CI): 75.3–92.9%], 54.8% (23/42; 95% CI: 38.7–70.2%), 75.9% (60/79; 95% CI: 69.1–81.7%), 69.7% (23/33; 95% CI: 54.9–81.3%) and 74.1% (83/112; 95% CI: 65.0–81.9%), respectively. Conclusion: The percentage of necrosis volume and age may surrogate for predicting TERT mutation status in glioblastoma.

DOI： 10.1016/j.diii.2019.02.010

Language：English   Publishing type：Research paper (scientific journal)  

Background: We previously reported a favorable outcome in a case series of patients with oligodendrogliomas treated with upfront chemotherapy; however, their progression-free survival (PFS) was relatively short considering their long-term overall survival (OS). This suggests that salvage treatments after progression were effective. However, the clinical impact of salvage treatments on outcomes of patients with recurrent oligodendrogliomas has not been precisely investigated. Methods: Our case series included 28 patients with newly diagnosed isocitrate dehydrogenase–mutant and 1p/19q-codeleted oligodendroglial tumors treated with upfront procarbazine, nimustine, and vincristine. Clinical outcomes and patterns of recurrence were reviewed retrospectively. Results: The median follow-up period of enrolled patients was 90.2 months. Disease progression occurred in 15 patients (53.6%), whereas the cancer appeared as local relapse alone in 14 (93.3%) patients. Salvage treatments were performed for all local relapses; thereafter, most of the subsequent progressions also appeared as resectable local relapses. The 5-year PFS and OS rates from the first progression were 30.3% and 92.9%, respectively. These relatively short PFS and favorable OS indicated the effectiveness of salvage treatment even after multiple progression. Thus far, 9 (60%) of 15 patients are deterioration-free with locally controlled lesions or complete remission; however, clinical deterioration was observed in 6 patients, and 4 of them experienced dissemination. Conclusions: In isocitrate dehydrogenase–mutant and 1p/19q-codeleted oligodendrogliomas, most of the tumors that demonstrated early progression appeared as local, nonlethal lesions, which have been well-controlled by salvage treatments. A precise diagnosis of oligodendrogliomas using molecular parameters is crucial to receive the best benefit from salvage treatment.

DOI： 10.1016/j.wneu.2018.03.069

Language：English   Publishing type：Research paper (scientific journal)  

In this study, we reclassified 400 consecutive glioma cases including pediatric cases, using the revised 2016 WHO classification with samples collected from the Kyushu University Brain Tumor Bank. The IDH1/2, H3F3A, key genetic markers in the 2016 classification, were analyzed using high-resolution melting, with DNA extracted from frozen tissues. The 1p/19q codeletions were evaluated using a microsatellite-based loss of heterozygosity analysis, with 18 markers, to detect loss of the entire chromosome arm. In the integrated diagnosis, 29 oligodendroglioma cases and 28 anaplastic oligodendroglioma cases were diagnosed as “IDH-mutant and 1p/19q-codeleted,” while 2 oligodendroglioma cases and 5 anaplastic oligodendroglioma cases were diagnosed as not otherwise specified (NOS). These “NOS” cases were either IDH-mutants or 1p/19q-codeleted, although characteristic oligodendroglial features were evident histologically. Better overall survival of patients with oligodendroglioma correlated with the molecular characteristic of “IDH-mutant and 1p/19q-codeleted,” rather than the WHO grade. Eleven “glioblastoma, IDH-wild-type” cases were classified as “1p/19q-codeleted”, however, chromosome 10 loss was also detected in 10 out of 11 cases. The 2016 WHO criteria for glioma classification leads to better diagnosis of patients. However, there are technical pitfalls and problems to be solved in the molecular analysis of routine diagnostics.

DOI： 10.1007/s10014-018-0313-4

Language：English   Publishing type：Research paper (scientific journal)  

Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent β-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia.

DOI： 10.1111/neup.12408

Language：English   Publishing type：Research paper (scientific journal)  

A recurrent glycine-to-arginine/valine alteration at codon 34 (G34R/V) within H3F3A, a gene that encodes the replication-independent histone variant H3.3, reportedly occurs exclusively in pediatric glioblastomas. However, the clinicopathological and biological significances of this mutation have not been completely elucidated; especially, no such data exist for tumor samples from Japanese patients. We analyzed 411 consecutive glioma cases representing patients of all ages. Our results demonstrated that 14 patients (3.4%) harbored H3F3A mutations, of which four had G34R mutations and 10 had K27M mutations. G34R-mutant tumors were located in the parietal region in two patients and the basal ganglia in one patient. One patient showed multi-lobular extension similar to the pattern observed in gliomatosis cerebri. Regarding neuroradiological features, intratumoral calcification was evident in two cases and all cases showed no or scarce contrast enhancement on MRI. Histopathologically, the four G34R-mutant cases included three glioblastomas and one astroblastoma. We have also investigated alterations in histone methylation including H3K27me3, H3K9me3, and H3K4me3 in G34R-mutant samples by immunohistochemistry. These results indicate that G34R-mutant tumors are likely to show extensive infiltration and alterations in global histone trimethylation might also play an important role in G34R mutant tumors.

DOI： 10.1007/s10014-017-0287-7

Language：English   Publishing type：Research paper (scientific journal)  

Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH-wildtype (IDH-wt) pGBMs. IDH-mutant (IDH-mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH-mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH-wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long-surviving case, but genetic alterations in the astrocyte-sGBM pathway were generally prevalent in IDH-mut pGBMs. Our results present a unique phenotype of IDH-mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs.

DOI： 10.1111/neup.12362

Language：English   Publishing type：Research paper (scientific journal)  

Brain tumors harbor various BRAF alterations, the vast majority of which are the BRAF kinase-activating V600E mutation. BRAF mutations are most frequently detected in certain subtypes of low-grade glioma, such as pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT). However, it is unclear whether gliomas harboring BRAF mutations can be invariably regarded as these glioma subtypes or their derivatives. To address this question, we analyzed 274 gliomas in our institutional case series. We performed high-resolution melting analyses and subsequent direct Sanger sequencing on DNA isolated from snap-frozen tumor tissues. As expected, BRAF mutations were detected in the aforementioned low-grade gliomas: in 4/27 PAs, 2/3 PXAs, 4/8 GGs, and 1/6 DNTs. In addition to these gliomas, 1/2 astroblastomas (ABs) and 2/122 glioblastomas (GBs) harbored BRAF mutations. Pathological investigation of the two GBs revealed that one was a GB displaying epithelial features that presumably arose from a precedent GG, whereas the other GB, which harbored a rare G596 A mutation, showed marked epithelial features, including astroblastic rosettes. Our results indicate that in addition to being present in established BRAF-associated gliomas, BRAF mutations might be associated with epithelial features in high-grade gliomas, including sheet-like arrangement of polygonal tumor cells with a plump cytoplasm and astroblastic rosettes, and thus could potentially serve as a genetic marker for these features.

DOI： 10.1111/neup.12347

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: The AVAglio trial established the beneficial effect of add-on bevacizumab (BEV) for the treatment of newly diagnosed glioblastomas (nd-GBMs) that led to the approval of BEV for the treatment of these patients in Japan. However, the rationality of using BEV as a first-line treatment for nd-GBMs remains controversial. The purpose of this study was to analyze the outcomes of a case series of nd-GBM patients. Patients and methods: The outcomes of 69 nd-GBM patients treated after 2006 were retrospectively analyzed. Clinical and genetic analyses were performed, and estimates of progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Since add-on BEV therapy was only used for partially resected GBMs (pr-GBMs) after its approval in 2013, the patients were subdivided into 3 treatment groups: Type I, partial removal with temozolomide (TMZ)/BEV and concurrent radiotherapy (CCRT); Type II, partial removal with TMZ and CCRT; and Type III, gross total removal with TMZ and CCRT. Results: The PFS rate of Type I patients was significantly higher than that of Type II patients (P=0.014), but comparable to that of Type III patients. Differences in OS rates between Type I and Type II patients were less apparent (P=0.075), although the median OS of Type I patients was ∼8 months higher than that of Type II patients (17.4 vs 9.8 months, respectively). The clinical deterioration rate during initial treatment was significantly (P=0.024) lower in Type I than in Type II patients (7.7% vs 47.4%, respectively). Differences in OS rates between Type I and Type II patients with a poor performance status (PS) were significant (P=0.017). Conclusion: Our findings suggest that add-on BEV can prevent early clinical deterioration of pr-GBM patients and contribute to a prolonged survival, especially for those with a poor PS.

DOI： 10.2147/OTT.S125587

Language：English   Publishing type：Research paper (scientific journal)  

Recently updated phase III trials revealed the favorable effect of add-on procarbazine-lomustine-vincristine chemotherapy (CT) to radiotherapy (RT) in treating anaplastic oligodendrogliomas with 1p19q codeletion (codel). However, the underlying rationality of deferring RT and upfront CT administration for these tumors is yet to be elucidated. Here, we retrospectively analyzed the long-term outcome of our case series with oligodendroglial tumors treated with deferred RT and upfront procarbazine+nimustine+vincristine (PAV) in the introduction administration. We enrolled 36 patients with newly diagnosed oligodendroglial tumors (17, grade II and 19, grade III) treated during 1999-2012 and followed up for a median period of 69.0 months. Their clinical and genetic prognostic factors were analyzed, and progression-free survival, overall survival (OS), and deterioration-free survival (DFS) were evaluated. Regardless of the WHO grade, the 25 patients with 1p19q codel tumors never received RT initially, and of these 25, 23 received PAV treatment upfront. The 75% OS of patients with 1p19q codel tumor was 135.3 months (did not reach the median OS), indicating a favorable outcome. Multivariate analysis revealed that IDH mutation and 1p19q, not WHO grade, are independent prognostic factors; furthermore, IDH and 1p19q status stratified the cohort into 3 groups with significantly different OS. The DFS explained the prolonged survival without declining performance in patients with both grade II and III 1p19q codel tumors. Deferred RT and upfront PAV treatment for 1p19q codel oligodendrogliomas were associated with favorable outcomes without compromising performance status, regardless of WHO grade.

DOI： 10.2147/OTT.S115911

Language：English   Publishing type：Research paper (scientific journal)  

High resolution melting (HRM) is a simple and rapid method for screening mutations. It offers various advantages for clinical diagnostic applications. Conventional HRM analysis often yields equivocal results, especially for surgically obtained tissues. We attempted to improve HRM analyses for more effective applications to clinical diagnostics. HRM analyses were performed for IDH1^R132 and IDH2^R172 mutations in 192 clinical glioma samples in duplicate and these results were compared with sequencing results. BRAF^V600E mutations were analyzed in 52 additional brain tumor samples. The melting profiles were used for differential calculus analyses. Negative second derivative plots revealed additional peaks derived from heteroduplexes in PCR products that contained mutations; this enabled unequivocal visual discrimination of the mutations. We further developed a numerical expression, the HRM-mutation index (MI), to quantify the heteroduplex-derived peak of the mutational curves. Using this expression, all IDH1 mutation statuses matched those ascertained by sequencing, with the exception of three samples. These discordant results were all derived from the misinterpretation of sequencing data. The effectiveness of our approach was further validated by analyses of IDH2^R172 and BRAF^V600E mutations. The present analytical method enabled an unequivocal and objective HRM analysis and is suitable for reliable mutation scanning in surgically obtained glioma tissues. This approach could facilitate molecular diagnostics in clinical environments.

DOI： 10.1371/journal.pone.0160489

Language：English   Publishing type：Research paper (scientific journal)  

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

DOI： 10.1186/s40478-016-0351-2

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND PURPOSE: Glioblastoma multiforme is highly aggressive and the most common type of primary malignant brain tumor in adults. Imaging biomarkers may provide prognostic information for patients with this condition. Patients with glioma with isocitrate dehydrogenase 1 (IDH1) mutations have a better clinical outcome than those without such mutations. Our purpose was to investigate whether the IDH1 mutation status in glioblastoma multiforme can be predicted by using MR imaging. MATERIALS AND METHODS: We retrospectively studied 55 patients with glioblastoma multiforme with wild type IDH1 and 11 patients with mutant IDH1. Absolute tumor blood flow and relative tumor blood flow within the enhancing portion of each tumor were measured by using arterial spin-labeling data. In addition, the maximum necrosis area, the percentage of cross-sectional necrosis area inside the enhancing lesions, and the minimum and mean apparent diffusion coefficients were obtained from contrast-enhanced T1-weighted images and diffusion-weighted imaging data. Each of the 6 parameters was compared between patients with wild type IDH1 and mutant IDH1 by using the Mann-Whitney U test. The performance in discriminating between the 2 entities was evaluated by using receiver operating characteristic analysis. RESULTS: Absolute tumor blood flow, relative tumor blood flow, necrosis area, and percentage of cross-sectional necrosis area inside the enhancing lesion were significantly higher in patients with wild type IDH1 than in those with mutant IDH1 (P < .05 each). In contrast, no significant difference was found in the ADC_minimum and ADC_mean. The area under the curve for absolute tumor blood flow, relative tumor blood flow, percentage of cross-sectional necrosis area inside the enhancing lesion, and necrosis area were 0.850, 0.873, 0.739, and 0.772, respectively. CONCLUSIONS: Tumor blood flow and necrosis area calculated from MR imaging are useful for predicting the IDH1 mutation status.

DOI： 10.3174/ajnr.A4491

Language：English   Publishing type：Research paper (scientific journal)  

We conducted this study to clarify the current trends and healthcare resource usage in the treatment of inpatients with primary malignant brain tumors. The Diagnostic Procedure Combination (DPC) data of all inpatients treated between 2013 and 2014 in the 370 core and branch hospitals enrolled in the Japanese Neurosurgical Society training program were collected. DPC is a discharge abstract and administrative claims database of inpatients. We assessed 6,142 primary, malignant brain tumor patients. Patient information, diagnostic information, treatment procedure, and healthcare resource usage were analyzed. Chemotherapy was the most frequent treatment (27% of cases), followed by surgery (13%) and surgery + chemo-radiotherapy (11%). Temozolomide (TMZ), the most frequently used chemotherapeutic drug, was administered to 1,236 patients. Concomitant TMZ and radiotherapy was administered to 816 patients, and was performed according to the Stupp regimen in many cases. The mean length of hospital stay (LOS) was 16 days, and the mean medical cost was 1,077,690 yen. The average medical cost of TMZ-only treatment was 1,138,620 yen whilst it was 4,424,300 yen in concomitant TMZ patients. The LOS was significantly shorter in high-volume than in low-volume hospitals, and the medical cost was higher in hospitals treating 21–50 patients compared to those treating 1–10 patients. However, the direct medical cost of TMZ treatment was the same across different volume hospitals. This is the first report of current trends and healthcare resource usage in the treatment of primary malignant brain tumor inpatients in the TMZ era in Japan.

DOI： 10.2176/nmc.oa.2016-0172

Language：English   Publishing type：Research paper (scientific journal)  

To investigate patient background and current trends in the treatment of brain tumor patients, we analyzed a patient dataset using the Diagnosis Procedure Combination(DPC) database. The DPC data of all inpatients treated between April 2013 and March 2014 in the 327 core and branch hospitals enrolled in the Japan Neurosurgical Society training program were collected. Using ICD-10 code, we could extract 6,142 primary malignant brain tumor patients, 2,538 secondary malignant brain tumor patients, 2,043 pituitary tumor patients, 3,854 meningioma patients, and 5,666 other benign brain tumor patients from amongst a total of 501,609 patients. In this study, we focused on the primary and secondary malignant brain tumor patients. Using a K-code, we could extract 1,564 primary malignant brain tumor patients and 1,072 secondary malignant brain tumor patients who underwent surgery. Treatment modalities were analyzed for these patients. This study provides a general picture of the current trend of treatment for malignant brain tumors in Japan. But further study is needed to validate this patient dataset.

DOI： 10.7887/jcns.24.693

Language：English   Publishing type：Research paper (scientific journal)  

Proneural and mesenchymal are two subtypes of glioblastoma identified by gene expression profiling. In this study, the primary aim was to detect markers to develop a clinically applicable method for distinguishing proneural and mesenchymal glioblastoma. The secondary aims were to investigate the temporospatial dynamics of these markers and to explore the association between these markers and the expression of chromatin-modifying genes. One hundred thirty-three glioma samples (grade II: 14 samples, grade III: 18, grade IV: 101) were analyzed. We quantified the expression of 6 signature genes associated with proneural and mesenchymal glioblastoma by quantitative reverse transcription-polymerase chain reaction. We assigned proneural (PN) and mesenchymal (MES) scores based on the average of the 6 markers and calculated a predominant metagene (P-M) score by subtracting the MES from the PN score. We used these scores to analyze correlations with malignant transformation, tumor recurrence, tumor heterogeneity, chromatin-modifying gene expression, and HDAC7 expression. The MES score positively correlated with tumor grade, whereas the PN score did not. The P-M score was able to distinguish the proneural and mesenchymal subtypes. It was decreased in cases of tumor recurrence and malignant transformation and showed variability within a tumor, suggesting intratumoral heterogeneity. The PN score correlated with the expression of multiple histone-modifying genes, whereas the MES score was associated only with HDAC7 expression. Thus, we demonstrated a simple and straightforward method of quantifying proneural/mesenchymal markers in glioblastoma. Of note, HDAC7 expression might be a novel therapeutic target in glioblastoma treatment.

DOI： 10.1007/s11060-015-1886-y

Language：English  

Immune checkpoint inhibitors, especially anti-programmed cell death-1 (PD-1) antibodies, have revolutionized cancer therapy. A PD-1 antibody, nivolumab, was the first of these agents to be approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, as a new cancer drug for melanoma, in July 2014. While PD-1 mAb therapy has so far been approved only for untreated malignant melanomas and non-small cell lung cancer, many clinical studies on various types of cancer have been conducted worldwide. Immune checkpoint inhibitors target lymphocytes rather than cancer cells, and evoke an anti-tumor immune reaction. Since the activated lymphocytes recognize various tumor-associated antigens including a mutated antigen, immune checkpoint inhibitors exhibit continuous long-term effectiveness, despite the generation of genetic mutations in cancer cells. As compared with previous cancer treatments, immune checkpoint inhibitors show superior efficacy against tumors with fewer side effects. Therefore, these novel immune checkpoint inhibitor agents are anticipated to become a 4th cancer treatment option following surgery, chemotherapy, and radiation therapy. Herein, we review the main clinical results of PD-1 mAb cancer immunotherapy obtained to date and discuss issues relevant to administering this form of treatment.

Language：English  

The most recent definition of glioblastoma with oligodendroglioma component (GBMO) assigned clinical significance to the observation of oligodendroglial foci within glioblastomas. However, the pathological mechanism of its histogenesis has not yet been determined. We report the genetic analysis of a GBMO case that evolved from an astrocyte lineage. A 37-year-old male underwent a third craniotomy for the removal of recurrent lesions of a secondary glioblastoma originating from a previous diffuse astrocytoma. The lesion in the right frontal lobe contained oligodendroglial foci within a glioblastoma background, while the remaining lesions showed only classic glioblastoma histology. Genetic analyses revealed distal 10q loss of heterozygosity (LOH) occurring de novo in the oligodendroglial tissue, as well as 10p, 17p LOH, and isocitrate dehydrogenase-1 gene (IDH1) mutations inherited from the previous lesions. The final recurrent glioblastoma underwent LOH on almost the entire of chromosome 10. Based on these results, the importance of an oligodendroglial component in glioblastomas may be limited.

DOI： 10.1007/s12253-014-9850-2

Language：English  

A 23-year-old woman was injured in a rear-end collision. She had general malaise and posterior neck pain, which were more severe when she was in an upright position. Magnetic resonance imaging (MRI) revealed the presence of cerebellar tonsil descensus and syringomyelia in the spinal cord. Radioisotope (RI) cisternography showed signs of an early accumulation of RI in the bladder, and a delayed accumulation of RI in the cerebral fornix. We considered the possibilities of cerebrospinal fluid (CSF) hypovolemia and congenital Chiari type-1 malformation as being responsible for her headache. To obtain a definitive diagnosis, we performed gadolinium (Gd)-enhanced MR cisternography and found evidence of CSF leakage. We performed an epidural blood patch (EBP), and her symptoms resolved. In 2 years since the episode, her symptoms have not recurred, and additional treatment has not been required. In addition, MRI performed 2 years after the EBP did not reveal any changes. There seems no previous report which described successful differentiation of pre-existing congenital Chiari type-1 malformation from the acquired one caused by symptomatic CSF hypovolemia. Because treatment protocols differ between these two conditions, the establishment of a correct diagnosis is important.

DOI： 10.2176/nmc.cr.2013-0100

Language：English  

The accessory anterior cerebral artery (AccACA) is an anomalous vessel arising from the anterior communicating artery. Although AccACA is not particularly rare, aneurysms arising from the AccACA is extremely rare. Here, we report two cases of unruptured AccACA aneurysms. Patient 1 was a 58-year-old woman with an unruptured distal AccACA aneurysm. Magnetic resonance imaging and three-dimensional computed tomography angiography (3D-CTA) demonstrated a left middle cerebral artery aneurysm that was subsequently clipped successfully by direct surgery. No aneurysm was detected in the distal anterior cerebral artery (ACA) due to the narrow imaging range at that time. Postoperatively, an aneurysm of the distal ACA was incidentally identified on 3D-CTA. This AccACA aneurysm was also clipped by direct surgery about 5 months later, and the patient was discharged without any neurological deficits. Patient 2 was a 46-year-old woman with an aneurysm at the proximal portion of the AccACA. Since the aneurysm was small and patient was asymptomatic, the observation-approach was selected. In introducing these cases, we discuss AccACA aneurysms and the process of diagnosis. Aneurysm can arise over the entire length of the ACA, from the anterior communicating artery to the peripheral portion, particularly the supracallosal portion, so observation and imaging of the peripheral region is important in cases where an AccACA is present.

Language：English  

A 73-year-old female visited her local doctor after repeatedly experiencing temporary weakness in her left upper and lower extremities. The patient underwent a cervical magnetic resonance imaging (MRI) scan and was diagnosed with right internal carotid artery stenosis. Despite administration of antiplatelet drugs, her symptoms continued, and she was referred to our department for medical treatment. Her medical history revealed hypertension, hyperlipidemia, and cholesteatoma. We diagnosed symptomatic internal carotid artery stenosis and performed carotid endarterectomy (CEA). However, tight adhesions between the carotid artery and surrounding tissue made separation difficult, and surgery had to be discontinued. Some of the extracted adherent tissue consisted of hyalinized fibrous tissue that had the appearance of soft tissue which had organized because of inflammation. Although there have been no reports of cholesteatoma directly causing adhesion around the internal carotid artery, it has been reported to have led to abscess formation in the parapharyngeal space adjacent to the carotid space. Because the boundaries of the parapharyngeal space and carotid space are anatomically incomplete, inflammation often affects the area between them. As far as we know, this report, which also includes a discussion of the literature, is the first to indicate that cholesteatoma causes strong adhesions around the carotid artery.