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

Background: In endoscopic endonasal surgery of pituitary tumors, the intraoperative judgment and tissue identification depend largely on surgeons’ surgical experience. Objective: To assess whether the delayed-window indocyanine green (ICG) (DWIG) technique can visualize and distinguish the normal pituitary gland and tumor under the endoscope in real-time during surgery. Methods: Eight patients with pituitary adenoma who received 12.5 mg ICG were observed by near-infrared (NIR) fluorescence during the surgery to identify the pituitary gland and tumors. Results: The normal pituitary gland and pituitary adenoma were visualized by NIR fluorescence in all 8 patients. The relative ratio of the fluorescence emission of the normal gland to that of the tumor (signal-to-background ratio [SBR] normal gland/tumor) increased after 15 min, peaking at 5.8±4.9 at 90 min. It suggested that pituitary gland was more clearly visualized during that period. The tumor/blood (SBR tumor) and normal gland/ blood (SBR gland) NIR fluorescence was significantly positively correlated with each Ktrans on dynamic contrast-enhanced MRI, indicating blood–brain barrier (BBB) permeability. Conclusions: This study showed the utility of the DWIG technique for identifying a normal pituitary gland from a tumor in endoscopic endonasal surgery from 15 to 90 min following ICG administration, “negative tumor staining”. Permeability can contribute to gadolinium enhancement on MRI and to ICG retention and NIR fluorescence in a normal pituitary gland and tumor.

Under healthy condition, more than one urethra-closing reflex, including both bladder afferent-independent and -dependent actions function during momentary elevation of intravesical (bladder) pressure to prevent urinary incontinence. In the current study, the effects of a novel selective 5-hydroxytryptamine type 2C (5-HT2C) receptor agonist, TAK-233, on evoked momentary urethra-closing functions were investigated in female rats and humans to elucidate 5-HT2C receptor functions. In anesthetized female rats, TAK-233 dose-dependently and significantly increased the urethral resistance during sneezing in rats with distended vaginas and bilaterally transected pelvic nerves. The drug also dose-dependently and significantly increased urethral resistance during momentary intravesical pressure elevation by electrical stimulation of abdominal muscles in rats with a transected spinal cord at the T8-9 level and intact pelvic nerves. The increased effects observed during electrical stimulation were abolished by either an intravenously administered selective 5-HT2C receptor antagonist, SB 242084, or bilateral transection of the pelvic nerves or somatic nerves innervating the external urethral sphincter and pelvic floor muscles. In the spinal cord-transected and pelvic nerve-intact rats, TAK-233 enlarged the urethra-closing responses induced by both passive and abrupt intravesical pressure elevation measured by a micro-tip transducer located in the middle urethra. Additionally, the effects of TAK-233 on the stimulus threshold of urethral contractile responses induced by transcranial magnetic stimulation were investigated in healthy female volunteers. The drug dose-dependently and significantly lowered this stimulus threshold, indicating an increased sensitivity of the response. These results demonstrate that 5-HT2C receptor stimulation enhances the evoked momentary urethra-closing functions in both female rats and humans. Significance Statement 5-hydroxytryptamine (serotonin) type 2C (5-HT2C) receptor stimulation by TAK-233 enhanced urethral resistance in rats during an evoked momentary event in which the bladder afferent-independent or -dependent reflex functions via striated muscle-mediated mechanisms. The increases in sensitivity of transcranial magnetic stimulation-evoked urethral contractile responses in healthy female subjects indicates that this mechanism also functions in humans. The evoked momentary conditions activating these reflexes provide a suitable model to demonstrate the exerting effects of 5-HT2C receptor stimulation.

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

Pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) is a promising technique allowing the rapid characterization of the polymer structure and additives of microgram-scale plastics. However, the Py-GC/MS analysis of polymers with urethane bonds is challenging because they produce highly reactive pyrolyzates such as amines and isocyanates polymerizing in the GC column, which limits the efforts to elucidate the pyrolysis mechanism and plastic characterization by online GC analysis. Herein, a novel pyrolysis-gas-phase derivatization-GC/MS (Py-GPD-GC/MS) technique was developed, allowing the pyrolysis of polymers and the subsequent direct gas-phase derivatization of pyrolyzates, employing a modified tandem μ-reactor-GC/MS system. This work conducted the gas-phase trifluoroacetylation of 4,4'-methylenedianiline (MDA), which is one of the major polyurethane (PU) pyrolyzates, using

Meningiomas are a common pathology in the central nervous system requiring complete surgical resection. However, in cases of recurrence and post-irradiation, accurate identification of tumor remnants and a dural tail under bright light remains challenging. We aimed to perform real-time intraoperative visualization of the meningioma and dural tail using a delayed-window indocyanine green (ICG) technique with microscopy. Fifteen patients with intracranial meningioma received 0.5 mg/kg ICG a few hours before observation during the surgery. We used near-infrared (NIR) fluorescence to identify the tumor location. NIR fluorescence could visualize meningiomas in 12 out of 15 cases. Near-infrared visualization during the surgery ranged from 1 to 4 h after the administration of ICG. The mean signal-to-background ratio (SBR) of the intracranial meningioma in delayed-window ICG (DWIG) was 3.3 ± 2.6. The ratio of gadolinium-enhanced T1 tumor signal to the brain (T1BR) (2.5 ± 0.9) was significantly correlated with the tumor SBR (

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

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

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) and meningioma exhibit similar radiographic features; however, they differ in their prognoses. Preoperative differentiation between them is important for determining the treatment and follow-up plan. The aim of this study was to determine the factors that can be used to differentiate SFT/HPC from meningioma and World Health Organization (WHO) grade I from grade II meningioma.The analysis included 84 cases: 5 of SFT/HPC, 72 of WHO grade I meningioma, and 7 of WHO grade II meningioma. Clinical characteristics and conventional magnetic resonance imaging, perfusion magnetic resonance imaging, and magnetic resonance spectroscopy (MRS) LCModel parameters were evaluated via multivariate logistic regression analysis to identify the factors that distinguish SFT/HPC from meningioma.Patients with SFT/HPC were mostly men and were younger than those with meningioma. The percentage of T2-weighted images in meningioma was greater than that in SFT/HPC. There were significant differences between SFT/HPC and meningioma in levels of glutamate, phosphocholine, myo-inositol, or glycerophosphocholine + phosphocholine derived from long echo-time MRS, and myo-inositol derived from short echo-time MRS. Stepwise logistic regression analysis revealed that the age of45 years and myo-inositol in short echo-time MRS of ≧6.347 were associated with a diagnosis of SFT/HPC with high sensitivity and specificity. However, no factors were found that differentiated WHO grade I meningioma from WHO grade II meningioma.Age and myo-inositol level calculated from MRS are useful factors for distinguishing SFT/HPC from meningioma preoperatively.

Background Azilsartan is an angiotensin II receptor blocker indicated for the treatment of adult hypertension. A previous single-dose study suggested that azilsartan may also be a promising agent for paediatric hypertension. However, the long-term safety and efficacy of azilsartan in children have not been established. Methods We conducted a phase 3, single-arm, open-label, prospective study to evaluate the safety and efficacy of azilsartan in pediatric patients with hypertension. Twenty-seven patients aged 6–15 years were treated with once-daily azilsartan for 52 weeks. The starting dose was 2.5 mg for patients weighing N = 22) and 5 mg for patients weighing ≥ 50 kg (N = 5), with doses titrated up to a maximum of 20 and 40 mg, respectively. Results Azilsartan showed acceptable tolerability at doses up to 20 mg in patients weighing Conclusions Our study suggests that azilsartan has an acceptable safety profile in hypertensive patients aged 6–15 years. Azilsartan may be a promising agent for treating paediatric hypertension.

Background: Cerebral amyloid angiopathy-related inflammation (CAA-I) presents with slowly progressive nonspecific neurological symptoms, such as headache, cognitive function disorder, and seizures. Pathologically, the deposition of amyloid-β proteins at the cortical vascular wall is a characteristic and definitive finding. Differential diagnoses include infectious encephalitis, neurosarcoidosis, primary central nervous system lymphoma, and glioma. Here, we report a case of CAA-I showing acute progression, suggesting a glioma without enhancement, in which a radiological diagnosis was difficult using standard magnetic resonance imaging. Case Description: An 80-year-old woman was admitted due to transient abnormal behavior. Her initial imaging findings were similar to those of a glioma. She presented with rapid progression of the left hemiplegia and disturbance of consciousness for 6 days after admission and underwent emergent biopsy with a targeted small craniotomy under general anesthesia despite her old age. Intraoperative macroscopic findings followed by a pathological study revealed CAA-I as the definitive diagnosis. Steroid pulse therapy with methylprednisolone followed by oral prednisolone markedly improved both the clinical symptoms and imaging findings. Conclusion: Differential diagnosis between CAA-I and nonenhancing gliomas may be difficult using standard imaging studies in cases presenting with acute progression. A pathological diagnosis under minimally invasive small craniotomy may be an option, even for elderly patients.

Recent advance in molecular characterization of gliomas showed that patient prognosis and/or tumor chemosensitivity correlate with certain molecular signatures; however, this information is available only after tumor resection. If molecular information is available by routine radiological examinations, surgical strategy as well as overall treatment strategy could be designed preoperatively.With the aim to establish an imaging scoring system for preoperative diagnosis of molecular status in lower-grade gliomas (WHO grade 2 or 3, LrGGs), we investigated 8 imaging features available on routine CT and MRI in 45 LGGs (discovery cohort) and compared them with the status of 1p/19q codeletion, IDH mutations, and MGMT promoter methylation. The scoring systems were established based on the imaging features significantly associated with each molecular signature, and were tested in the another 52 LrGGs (validation cohort).For prediction of 1p/19q codeletion, the scoring system is composed of calcification, indistinct tumor border on T1, paramagnetic susceptibility effect on T1, and cystic component on FLAIR. For prediction of MGMT promoter methylation, the scoring system is composed of indistinct tumor border, surface localization (FLAIR), and cystic component. The scoring system for prediction of IDH status was not established. The 1p/19q score ≥ 3 showed PPV of 96.2% and specificity of 98.1%, and the MGMT methylation score ≥ 2 showed PPV of 77.4% and specificity of 67.6% in the entire cohort.These scoring systems based on widely available imaging information may help to preoperatively design personalized treatment in patients with LrGG.

Objective The efficacy and safety of triple therapy with azilsartan (AZI), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) compared with dual therapy with AZI/AML or HCTZ monotherapy were evaluated in Japanese essential hypertensive patients in a double-blinded manner. Patients and methods A total of 353 patients with office blood pressure (BP) of at least 150/95 mmHg were randomized to a 10-week treatment with AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, AZI/AML 20/5 mg, HCTZ 12.5 mg, or HCTZ 6.25 mg. Results The mean change from baseline in office diastolic/systolic BPs at week 10 was -25.9/-41.4, -24.9/-38.6, and -22.4/-34.5 mmHg in the AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, and AZI/AML 20/5 mg groups, respectively. AZI/AML/HCTZ 20/5/12.5 mg led to a significantly greater reduction in diastolic and systolic BP than the dual therapy. In addition, the change in home diastolic BP measured with telemetry devices showed a significant difference between the two triple therapy groups. The incidences of adverse events except dizziness postural were similar among the treatment groups in the triple therapy groups. Conclusion Triple therapy with AZI/AML/HCTZ 20/5/12.5 mg shows a greater antihypertensive effect than the dual therapy and has acceptable safety profiles for Japanese essential hypertensive patients. It was also observed that home BP measurement by automated telemetry could detect changes in BP that were not detected in office BP measurement, although further investigation is needed.

Brainstem glioma is impossible to resect completely, and patients with this type of glioma show a poor prognosis. Therefore, a more effective adjuvant therapy is required to prolong survival. Bevacizumab is an endothelial growth factor monoclonal antibody with strong anti-vascular effects, which may suppress tumor progression. We performed a retrospective study of data from 6 patients with brainstem glioma showing malignant features who were treated with bevacizumab. Tumor-associated lesions, as evaluated by T2 weighted or fluid-attenuated inversion-recovery magnetic resonance imaging, were reduced in all patients, although the timing of the start of bevacizumab administration and pretreatment were not uniform. Clinical symptoms improved in 4 patients and progression was inhibited in 2 patients. The Karnofsky performance status improved from 56.7 to 71.7 on average. The median reduction ratio of tumor-associated lesions was 76.3%, but tumor suppression did not last in any of the cases. Furthermore, 5 patients died of tumor progression, and 1 patient died of a complication of necrotizing colitis. The median progression-free survival after bevacizumab administration was 7 months. The median overall survival after diagnosis was 16.5 months. Bevacizumab might be a potential therapeutic option for progressive brainstem gliomas with malignant features.

Purpose We evaluated the diagnostic performance of histogram analysis of data from a combination of dynamic susceptibility contrast (DSC)-MRI and dynamic contrast-enhanced (DCE)-MRI for quantitative differentiation between central nervous system lymphoma (CNSL) and high-grade glioma (HGG), with the aim of identifying useful perfusion parameters as objective radiological markers for differentiating between them. Methods Eight lesions with CNSLs and 15 with HGGs who underwent MRI examination, including DCE and DSC-MRI, were enrolled in our retrospective study. DSC-MRI provides a corrected cerebral blood volume (cCBV), and DCE-MRI provides a volume transfer coefficient (Ktrans) for transfer from plasma to the extravascular extracellular space. Ktrans and cCBV were measured from a round region-of-interest in the slice of maximum size on the contrast-enhanced lesion. The differences in t values between CNSL and HGG for determining the most appropriate percentile of Ktrans and cCBV were investigated. The differences in Ktrans, cCBV, and Ktrans/cCBV between CNSL and HGG were investigated using histogram analysis. Receiver operating characteristic (ROC) analysis of Ktrans, cCBV, and Ktrans/cCBV ratio was performed. Results The 30th percentile (C30) in Ktrans and 80th percentile (C80) in cCBV were the most appropriate percentiles for distinguishing between CNSL and HGG from the differences in t values. CNSL showed significantly lower C80 cCBV, significantly higher C30 Ktrans, and significantly higher C30 Ktrans/C80 cCBV than those of HGG. In ROC analysis, C30 Ktrans/C80 cCBV had the best discriminative value for differentiating between CNSL and HGG as compared to C30 Ktrans or C80 cCBV. Conclusion The combination of Ktrans by DCE-MRI and cCBV by DSC-MRI was found to reveal the characteristics of vascularity and permeability of a lesion more precisely than either Ktrans or cCBV alone. Histogram analysis of these vascular microenvironments enabled quantitative differentiation between CNSL and HGG.

Lycopene-5,6-diol stereoisomers (1a,b) and (2a,b) and γ-carotene-5′,6′-diol stereoisomers (3a,b) and (4a,b) were synthesized by a stepwise C15 + C10 + C15 double Wittig reaction strategy. The key compounds erythro(anti)-C15-dihydroxy aldehydes 17a,b and their threo(syn)-stereoisomers 23a,b were prepared via Sharpless asymmetric epoxidation of geraniol and nerol followed by acidic hydrolysis of the epoxides in a stereospecific manner. The enantiomerically enriched anti-isomers were obtained by way of recrystallization of 2,3-epoxygeranyl 3,5-dinitrobenzoates 9a,b, whereas syn-isomers were obtained as enantiomerically pure forms via recrystallization of dihydroxyneryl 3,5-dinitrobenzoates 21a,b. In order to determine the absolute stereochemistry of natural products, HPLC separation methods for each enantiomers 1a,b–4a,b were established by using a column carrying a chiral stationary phase.

Objective To investigate the characteristics of materials used as prostheses for microvascular decompression surgery (MVDs) in Japan and their possible adverse events (AEs) to determine preferable materials for MVDs. Methods A questionnaire was sent to all members of the Japanese Society for MVDs, and answers were obtained from 59 institutions. Results Among a total of 2789 MVDs, 1088 operations for trigeminal neuralgia, 1670 for hemifacial spasm, and 31 others, including 117 reoperations, were performed between April 2011 and March 2014. Nonabsorbable material was used in 96.5% of MVDs, including polytetrafluoroethylene (PTFE) (80.5%), polyurethane (11.9%), expanded PTFE (2.1%), and silk thread (1.47%). The use of absorbable materials, including fibrin glue (87.5%), cellulose (13.5%), gelatin (4,77%), and collagen (1.76%), was reported. The major combinations were PTFE with fibrin glue (58.7%) followed by PTFE alone (7.60%). Eighty-eight AEs in 85 (3.2%) cases were reported among 2672 first operations. AEs included 51 central nervous system dysfunctions, 15 wound infections/dehiscence, and 10 others, which were presumed to be related to the intraoperative procedure. Among relatively high-, moderate-, and low-volume centers, there were no significant differences in the frequency of AEs (P = 0.077). Tissue-prosthesis adhesion and/or granuloma formation were reported in 13 cases of 117 reoperations. The incidence of adhesion-related recurrence was 11.1% of all reoperations. Conclusions The number of AEs was quite low in this survey, and intradural use of any prosthesis reported in this paper might be justified; however, further development of easily handled and less-adhesive prosthesis materials is awaited.

This randomized, double‐blind, phase III study evaluated the efficacy and safety of once‐daily treatment with alogliptin (25 mg once daily), alone or with metformin hydrochloride (500 mg once daily or 250 mg twice daily), in Japanese patients with type 2 diabetes. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to the end of treatment (week 24). The least squares (LS) mean (standard error) change in HbA1c from baseline to the end of treatment (week 24) was 0.16 (0.072)% in alogliptin alone, −0.49 (0.049)% in alogliptin/metformin once daily, and −0.60 (0.049)% in alogliptin/metformin twice daily. The LS mean difference in HbA1c change from baseline between alogliptin/metformin once daily and alogliptin alone (alogliptin/metformin once daily minus alogliptin alone) was −0.65% (95% confidence interval [CI] −0.821, −0.480) and between alogliptin/metformin once daily and twice daily (once daily minus twice daily) was 0.11% (95% CI −0.026, 0.247). The overall frequency of adverse events was similar among the groups. This study showed that the efficacy of alogliptin/metformin once daily was superior to alogliptin alone and non‐inferior to alogliptin/metformin twice daily, and that alogliptin/metformin once daily was safe and well tolerated in Japanese patients with type 2 diabetes.

Recent progress in neuro-oncology has validated the significance of genetic diagnosis in gliomas. We previously investigated IDH1/2 and TP53 mutations via Sanger sequencing for adult supratentorial gliomas and reported that PCR-based sequence analysis classified gliomas into three genetic subgroups that have a strong association with patient prognosis: IDH mutant gliomas without TP53 mutations, IDH and TP53 mutant gliomas, and IDH wild-type gliomas. Furthermore, this analysis had a strong association with patient prognosis. To predict genetic subgroups prior to initial surgery, we retrospectively investigated preoperative radiological data using CT and MRI, including MR spectroscopy (MRS), and evaluated positive 5-aminolevulinic acid (5-ALA) fluorescence as an intraoperative factor. We subsequently compared these factors to differentiate each genetic subgroup. Multiple factors such as age at diagnosis, tumor location, gadolinium enhancement, 5-ALA fluorescence, and several tumor metabolites according to MRS, such as myo-inositol (myo-inositol/total choline) or lipid20, were statistically significant factors for differentiating IDH mutant and wild-type, suggesting that these two subtypes have totally distinct characteristics. In contrast, only calcification, laterality, and lipid13 (lipid13/total Choline) were statistically significant parameters for differentiating TP53 wild-type and mutant in IDH mutant gliomas. In this study, we detected several pre- and intraoperative factors that enabled us to predict genetic subgroups for adult supratentorial gliomas and clarified that lipid13 quantified by MRS is the key tumor metabolite that differentiates TP53 wild-type and mutant in IDH mutant gliomas. These results suggested that each genetic subtype in gliomas selects the distinct lipid synthesis pathways in the process of tumorigenesis.

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

Gliomas are the most common primary brain tumors.There are no serum markers for the diagnosis of gliomas,and histopathological examination of surgically resected tissue is essential.Some recent studies have suggested that radiological examination may help to identify molecular signature of gliomas preoperatively.We intended to establish an imaging scoring system for preoperative diagnosis of molecular status in gliomas. We reviewed WHO grade 2 - 3 gliomas surgically treated at Keio University Hospital between April 2006 and March 2015.We analyzed an association between several radiological characteristics and genetic features of gliomas. The imaging findings were evaluated by two neurosurgeons and two radiologists independently, and the final judgement was made by consensus of more than 3 people. Calfication (CT),indistinct tumor border (T1),paramagnetic susceptibility effect (T1),inhomogenous tumor contents (FLAIR) and non temporal location were found to be more common in tumors with a -1p/19q codeletion.No imaging findings were associated with IDH mutation.Indistinct tumor border,surface localization (FLAIR),inhomogenous tumor contents were also found to be associated with promoter methylation of the MGMT gene. Based on these findings, an imaging scoring system for prediction of molecular status was designed,which was now under validation with another patient cohort.

The pyrolysis behaviors of seven kinds of polyurethane elastomers (PUEs) with different ratios between the hard segment (HS) and soft segment (SS) were investigated for both fast pyrolysis (300, 350, 450, 850 °C) and slow pyrolysis at the heating rate of 10 °C min–1 by thermogravimetric analysis (TG), pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), and evolved gas analysis-mass spectrometry (EGA-MS). These PUEs were synthesized from 4,4′-diphenylmethane diisocyanate (MDI), 1,4-butane diol (BD), and poly(oxytetramethylene glycol) (PTMG). Atomic force microscopy measurements found that the HS domains were formed in PUEs containing HS, and these domains were aggregated at extremely high HS ratio. The main pyrolysate derived from HS was MDI under all conditions. In fast pyrolysis tests, the decomposition of SS proceeded sufficiently at 450 °C, and a lot of low molecular weight compounds were produced at 850 °C. In slow pyrolysis tests, three-step degradation was observed, and this degradation behavior was influenced by the HS domain and SS matrix structures. The first step is the HS pyrolysis inside the HS domain, then the HS surrounded by SS is pyrolyzed. Finally, the SS matrix is pyrolyzed. The HS pyrolysates changed from isocyanate to amine with increasing temperature. We believe that the newly found pyrolysis behavior of PUEs with different ratios between the HS and SS will promote future studies on the characterization of PUE materials and the pyrolytic recovery of chemical feedstock from PUE wastes.

Management of gliomas depends on histological diagnosis; there are, however, limitations to the systems presently used. Tumors in the same entity can have different clinical courses, especially when they are diagnosed as WHO grade II-III. Previous studies revealed that genetic subgrouping of gliomas provides useful information that could help establishment of treatment procedures on the basis of the genetic background of the tumors. Recently, the authors analyzed the chromosomal copy number aberrations (CNAs) of adult supratentorial gliomas by comparative genomic hybridization using microdissected tissue sections. The tumors were classified into subgroups according to chromosomal CNAs. WHO grade II-III gliomas contained a variety of genetic subgroups that correlated well with the clinical course. Of these, long progression-free survival was observed for tumors with +7q and those with -1p/19q, low-grade tumors of 2 major lineages, and, in our preliminary data, both were closely correlated with mutation of IDH1. Furthermore, in contrast with +7q tumors, the great majority of +7 or +7/-10q groups had wildtype IDH1. Genetic studies suggest that cytogenetic characterization may provide an additional classification system for gliomas, and new criteria could help to establish rational and objective means for analysis of treatment procedures.

Stereotactic biopsy has been validated for tissue sampling of deep-seated lesions that cannot be easily resected via open craniotomy. However, some inherent problems including the inability to directly observe the lesion and difficulty in confirming hemostasis limit its usefulness. To overcome these issues, we used the endoscope in brain tumor biopsy, for not only intraventricular tumors but also intraparenchymal tumors. The rigid scope was used in association with a surgical navigation system for intraparenchymal lesions via a transcortical route. There were no useful anatomical landmarks when the trajectory to the lesions was decided; therefore, surgical navigation system was required for the transcortical procedures. The endoscopic procedure described here was attempted in 21 cases of intraparenchymal lesions between January 2007 and February 2012. A definitive diagnosis was obtained in all cases, and genetic analysis was performed when required. Serious postsurgical hemorrhage or neurological deficits were not observed in any cases. Endoscopic surgery provides a clear view of the target and makes it easier to differentiate tumor tissue from normal brain tissue. Moreover, the endoscope helped to confirm hemostasis during the procedure. Thus, endoscopic biopsy has the potential to contribute toward safe and reliable diagnosis of brain tumors.

Diets high in saturated fatty acids activate chronic inflammation. We previously reported that, in even acute inflammation caused by lipopolysaccharide (LPS), liver injury was exacerbated in rats fed a lard-rich diet. Peroxisome proliferator-activated receptors (PPARs) are related to inflammation and are also key regulators of lipid metabolism. In this study, we examined effects of high-fat diet on liver injury and hepatic lipid metabolism during endotoxemia, measuring hepatic PPARs and other markers.Male Wistar rats were fed a high-fat diet (HFD, 60 kcal% fat) or control diet (CD, 10 kcal% fat) for 4 or 12 wk, injected with LPS and sacrificed at 0, 1.5, or 6 h. Analyses included plasma aspartate transaminase (AST) and alanine transaminase (ALT) levels, messenger RNA (mRNA) and protein levels of hepatic PPARα and PPARγ, and mRNA levels of enzymes related to fatty acid oxidation and synthesis.Endotoxemic rats on HFD for 12 wk, but not 4 wk, had higher mRNA and protein levels for hepatic PPARs, than did those on CD (P 0.01-0.05). Similarly, these rats had increased mRNA expression of hepatic fatty acid oxidation- and synthesis-related enzymes (P 0.01-0.05). Rats injected with LPS had more severe liver injury, indicated by plasma AST/ALT, if on the HFD for 12 wk, compared with for 4 wk.Consumption of a lard-rich diet for 12 wk worsened liver injury and increased hepatic PPARα and PPARγ expression in endotoxemic rats.

The histological diagnosis of gliomas is defined by the tumor cell type and their malignant features including mitosis, nuclear atypism, necrosis, and vascular proliferation.1, 2 However, the systems presently used to define these tumors have limitations because interpreting cellularity, anaplasia, or even cell type is not purely objective. Furthermore, the clinical outcome of the tumor varies widely within the same histologic grade, which is partly due to interobserver discrepancies in diagnosis.3, 4, 5, 6 Progress in the genetic analysis of gliomas has validated the genetic subgrouping of these tumors. Better understanding of glioma development may help identify groups that are at risk for early progression, and specific genetic aberrations may serve as reliable predictors of the clinical outcome.7, 8, 9 Since Cairncross et al.10 reported that allelic loss of chromosome 1p is a statistically significant marker of prognosis for anaplastic oligodendrogliomas, many studies on DNA copy number aberrations (CNAs) in gliomas have reported the utility of CNAs in tumor classification.11, 12, 13, 14, 15, 16, 17, 18, 19 The results from these studies indicated the following: 1p/19q codeletion (1p/19q codel) marks a subset of oligodendroglial tumors,12, 15 the gain of whole chromosome 7 is the most frequent aberration in high‐grade astrocytomas,13 the gliomas with losses on chromosomal arms 9p and 10q and gain on chromosome 7 show trends toward short survival,14 the gain on chromosomal arm 7q appears to be a key early event in a subgroup of astrocytomas,16 and +7q and 1p/19q codel are mutually exclusive in low‐grade gliomas.16 Many of the cytogenetic analyses were carried out for glioblastomas, but we have also previously shown that grade II–III adult supratentorial gliomas could be classified into clinically relevant subgroups based on the CNAs.20 The astrocytomas of these grades contained a wide variety of genetic subgroups in contrast to oligodendrogliomas and glioblastomas, which are characterized with 1p/19q codel and +7/−10q, respectively. Our data showed that tumors with +7 had a worse outcome than tumors with 7q, although it was not confirmed that the former could develop from the latter; that is, it is not clear that a stepwise DNA copy number gain on chromosome 7, beginning as partial gain of 7q, develops along with glioma progression. As astrocytomas are generally refractory to adjuvant therapy compared to oligodendrogliomas and the treatment strategy for astrocytomas should be established according to their biological/genetic nature, further characterization of these astrocytic tumors with gain of chromosome 7 is warranted. Application of information provided by genetic analysis to the treatment of cancers has been a major challenge in medical oncology as well as neuro‐oncology. If genetic subtypes predict outcome and therapeutic responses, these criteria could help establish rational and objective means for analyzing treatment protocols and a diagnostic system for predicting prognosis in grade II–III gliomas. Recently, many studies focusing on genetic prognostic markers for gliomas have highlighted the clinical significance of the mutational status of the gene coding isocitrate dehydrogenase 1 (IDH1).21 Mutations in IDH1 are associated with improved prognosis in glioblastoma and are considered to develop during the early stages of tumorigenesis of astrocytoma and oligodendroglioma,22, 23, 24 which usually progress to a higher‐grade tumor. Although mutant IDH1 is not a predictive marker for radiation or chemotherapy, this information could help in deciding the adjuvant therapy for gliomas, and thus might serve as a critical factor for genetic subgrouping of the tumors. Therefore, we wished to determine how the IDH1 status fits in our CNA‐based genetic subgrouping of gliomas and investigated the IDH1 status in 174 adult supratentorial astrocytic and oligodendroglial gliomas. We evaluated the correlation of the IDH1 status and the genetic subgrouping in order to create an accurate tumor classification system.

Genetic subgrouping of gliomas has been emphasized recently, particularly after the finding of isocitrate dehydrogenase 1 (IDH1) mutations. In a previous study, we investigated whole-chromosome copy number aberrations (CNAs) of gliomas and have described genetic subgrouping based on CNAs and IDH1 mutations. Subsequently, we classified gliomas using simple polymerase chain reaction (PCR)-based methods to improve the availability of genetic subgrouping. We selected IDH1/2 and TP53 as markers and analyzed 237 adult supratentorial gliomas using Sanger sequencing. Using these markers, we classified gliomas into three subgroups that were strongly associated with patient prognoses. These included IDH mutant gliomas without TP53 mutations, IDH mutant gliomas with TP53 mutations, and IDH wild-type gliomas. IDH mutant gliomas without TP53 mutations, which mostly corresponded to gliomas carrying 1p19q co-deletions, showed lower recurrence rates than the other 2 groups. In the other high-recurrence groups, the median progression-free survival (PFS) and overall survival (OS) of patients with IDH mutant gliomas with TP53 mutations were significantly longer than those of patients with IDH wild-type gliomas. Notably, most IDH mutant gliomas with TP53 mutations had at least one of the CNAs +7q, +8q, −9p, and −11p. Moreover, IDH mutant gliomas with at least one of these CNAs had a significantly worse prognosis than did other IDH mutant gliomas. PCR-based mutation analyses of IDH and TP53 were sufficient for simple genetic diagnosis of glioma that were strongly associated with prognosis of patients and enabled us to detect negative CNAs in IDH mutant gliomas.

Object The supraorbital eyebrow approach is a minimally invasive technique that offers wide access to the anterior skull base region and parasellar area through asubfrontal corridor. The use of neuroendoscopy allows one to extend the approach further to the pituitary fossa, the anterior third ventricle, the interpeduncular cistern, the anterior and medial temporal lobe, and the middle fossa. The supraorbital approach involves a limited skin incision, with minimal soft-tissue dissection and a small craniotomy, thus carrying relatively low approach-related morbidity. Methods All consecutive patients who underwent the endoscopic supraorbital eyebrow approach were retrospectively analyzed for lesion location, pathology, length of stay, complications, and cosmetic results. Results During a 56-month period, 97 patients (mean age 58.5 years) underwent an endoscopic eyebrow approach to resect extra- and intraaxial brain lesions. The most common pathologies treated were meningiomas (n = 41); craniopharyngiomas (n = 22); dermoid tumors (n = 7); metastases (n = 4); gliomas (n = 3); and other miscellaneous frontal, parasellar, and midbrain (n = 23) lesions. The median length of postoperative hospital stay was 2.7 days (range 1–8 days). In 82 patients a total removal of the lesion was performed, while in 15 patients a near-total or subtotal removal was achieved. There were no postoperative hematomas, cerebrospinal fluid leaks, or severe neurological deficits, with the exception of 2 cases of visual deterioration and 1 case each of meningitis, stroke, and third cranial nerve paresis. Other complications directly related to the approach included 2 cases of skin burn as a direct result of heat transmission from the microscope light, 1 case of right frontal palsy, 2 cases of frontal numbness, and 1 case of bone remodeling 1 year after surgery. Conclusions The endoscopic supraorbital eyebrow approach is a safe and effective minimally invasive approach to remove extra- and intraaxial anterior skull base, parasellar, and frontal lesions, promoting a rapid recovery and short hospital stay. The location of the eyebrow incision demands a meticulous cosmetic closure, but, with proper technique, cosmetic results are excellent.

Gliomas are the most common primary neoplasms of the central nervous system [1]. Histopathological examination of surgically resected tissue is essential for the diagnosis of gliomas, and it forms the basis on which decisions regarding the use of adjuvant therapies are taken. This methodology has several potential difficulties, however. These include the fact that even pathologically identical tumors may have a different prognosis, that occasionally different areas of the same tumor tissue can have different histological characteristics [2], and that there is no entirely objective way of interpreting cellularity, anaplasia, or even cell type. To address these problems, many studies have tried to distinguish tumors on the basis of genetic and protein markers with the aim of standardizing decisions regarding therapeutic strategy based on the tumor subtypes they defined [3, 4]. Of particular note are the allelic losses of chromosomes 1p and 19q (−1p/19q), which have been reported as being positive predictors of chemotherapeutic response for anaplastic oligodendroglial tumors [5, 6]. Moreover, after Parsons et al. demonstrated that some gliomas carry a mutation in the IDH1 gene, genetic investigations have become increasingly important in the study of glioma biology [7]. However, although genetic analysis does provide important information, it requires an invasive surgical procedure. In addition to information provided by genetic analysis, some recent studies have suggested an association between radiological features and tumor type. To better understand the association between the radiological and genetic features of gliomas and to establish prognostic radiological criteria, we designed a study to test whether certain radiological features could be used to predict genetic aberrations in World Health Organization (WHO) grade II–III astrocytic and oligodendroglial tumors.

Seizures occurring after clipping of unruptured cerebral aneurysms have rarely been documented in the literature. The objective of this retrospective study is to clarify whether the frequency of early seizures, i.e., seizures occurring within 14 days of surgery, is influenced by patient- or aneurysm-specific characteristics. Data on 1,000 consecutive patients who underwent clipping of unruptured anterior circulation aneurysms were reviewed. They consisted of 387 men and 613 women with mean age of 59.8 ± 9.7 years. Fifty-one patients (5.1 %) developed early seizures. Interestingly, the frequency was similar to that occurring after clipping of unruptured posterior circulation aneurysms (n = 20, 5.0 %). Multivariate regression analysis revealed that younger age was correlated with early seizures (odds ratio (OR) 0.902; 95 % confidence interval (CI) 0.891–0.989). However, other variables, including aneurysm size and operation length, were not correlated. Although patients with history of epilepsy exhibited relatively high frequency of early seizures, the difference was not statistically significant. The frequency was unaffected by location or multiplicity of aneurysms. Thirty-one patients (61 %) developed seizures within 24 h of clipping. Regarding seizure types, 34 (67 %) developed generalized seizures and the other 17 (33 %) experienced partial seizures. Patients with generalized seizures were significantly more likely to harbor an iatrogenic brain lesion than those with partial seizures (47 vs. 18 %; OR 4.148; 95 % CI 1.005–17.113). Among 40 patients with follow-up period >12 months, seizures were temporary without recurrence in 38 (95 %). Although early seizures are mostly benign, a small possibility of them becoming a permanent morbidity needs to be explained to patients undergoing elective clipping.

Chronic subdural haematoma (CSDH) is an uncommon but potentially serious complication of clipping unruptured cerebral aneurysms. We conducted a study to identify the patients who are at risk of developing postoperative CSDH. The data from 713 consecutive patients who underwent clipping of unruptured anterior circulation aneurysms were reviewed, and risk factors correlated with CSDH were identified by multivariate regression analysis of demographic variables. Fifteen patients (2.1%) developed CSDH after the surgery. Advanced age (odds ratio [OR] 1.151, 95% confidence interval [CI] 1.051-1.261) and male gender (OR 3.167, 95% CI 1.028-9.751) were correlated with CSDH. Subsequently, all 713 patients were quadrichotomized on the basis of gender and age, with 70 years as the cut-off value for age. The frequency of CSDH in men70 years of age was 1.3% and that in men ≥70 years of age was 15.1%, with risk of CSDH was significantly higher in the older men (OR 13.39; 95% CI: 3.42-52.44). The frequency of CSDH in women70 years of age was 0.6% and that in women ≥70 years of age was 3.7%. As in men, the risk of CSDH was significantly higher in the older women (OR 6.69, 95% CI 1.10-40.73). The interval between the aneurysm clipping and CSDH development was 0.5-6 months, suggesting that clinical observation should be continued up to 6 months after surgery. Although prognosis for patients with a postoperative CSDH complication is generally favourable, the risk of CSDH should be taken into account when considering elective clipping of unruptured aneurysms in patients ≥70 years of age.

Although brain metastases are one of the most frequently diagnosed sequelae of systemic malignancy, their optimal management still is not well defined. In that respect, the different diagnostic and therapeutic approaches of BMs patients is an issue for serious discussions. The treatment options include surgical excision, WBRT, radiosurgery, chemotherapy, immunotherapy, etc. Nowadays, the aforementioned treatment modalities are usually combined in different treatment schemes. More than one option is used for the same patient and combining these treatment modalities gives better results than when separately use them. The value of surgical excision of progressing brain metastases treated with gamma knife surgery (GKS) is not well investigated.With the present study, we aim to investigate the value of surgical excision of symptomatic brain lesions that have been previously treated with GKS.