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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.

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.

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.

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.

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.

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.

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.