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Background: An open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma. Methods: Patients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%. Results: Of the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27–66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4–17.7) and 1.5 (1.4–1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3–4 and 2.0% for Grade 5; most adverse events resolved and were manageable. Conclusions: The 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types. Clinical Trial Registration: JapicCTI-152967. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) is widely used in Europe and the United States. For the safe use of TMZ in the Japanese, as representative of Asians, the pharmacokinetics of TMZ was investigated in Japanese patients and compared to that in Caucasians. The pharmacokinetics and safety of TMZ following oral administration of 150 and 200 mg/m2 per day for the first 5 days of a 28-day treatment cycle were investigated in six Japanese patients with relapsed gliomas. The time-to-maximum plasma concentration (tmax) of TMZ was about 1 h and the elimination half-life of terminal excretion phase (t1/2λz) was about 2 h. A dose-dependent increase was observed in maximum plasma concentration (Cmax) and AUC, while values for t1/2λz, apparent total body clearance (CL/F), and apparent distribution volume (Vz/F) were independent of dose. After administration for 5 days, changes in pharmacokinetics and accumulation were not observed. The plasma 5-(3-methyl)1-triazen-1-yl-imidazole-4-carboxamide (MTIC) concentration changed in parallel with the TMZ plasma concentration, and the Cmax and AUC of MTIC were about 2% of those of TMZ. The pharmacokinetic parameters of TMZ and MTIC in Japanese patients in this study were comparable to those previously determined in Caucasian subjects. Adverse events occurred in all patients, but toxicities were mostly mild or moderate, and continuation of administration was possible by adjusting the dose and by delaying the start of the next treatment cycle. The pharmacokinetic and safety profile of TMZ in Japanese patients was comparable to that in Caucasians. The treatment regimen used in Europe and the United States will be suitable for Asian patients, including Japanese. [ABSTRACT FROM AUTHOR]

Background. The efficacy of temozolomide has been evaluated in phase I and phase II trials in patients with recurrent malignant gliomas in the United States and the European Union. We report a feasibility study of the palliative efficacy of temozolomide for patients with recurrent anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Methods. Sixteen patients with at least two prior chemotherapy regimens were enrolled in the study. Nine patients were confirmed to have GBM and 7 patients were confirmed to have AA at the latest pathology review, and all had a Karnofsky performance status (KPS) of over 50%. The median age was 57 years (range, 31–65 years). Results. No cumulative toxicity was observed at any dose level when temozolomide was administered on a once-daily, 5-day schedule. Myelosuppression occurred, with the nadir being mid-late in the cycle (day 14 or 21). National Cancer Institute common toxicity criteria (NCI-CTC) grade 3 or 4 hematological toxicity did not occur. In the 9 GBM patients, the overall response rate (complete response + partial response [CR + PR]) was 0%. The median time to progression (TTP) was 3.5 months, and the rates of progression-free survival (PFS) at 6 and 12 months were 40% and 0%. In the 7 AA patients, the overall response rate (CR + PR) was 29% and median TTP was 9 months, while PFS rates at 6 and 12 months were 80% and 30%. Conclusion. The favorable safety profile and the efficacy of temozolomide in Japanese patients are not incompatible with the results seen with patients in the United States and the European Union. [ABSTRACT FROM AUTHOR]

Context: There is little evidence of the effectiveness of aromatherapy massage in palliative care despite its popularity.Objectives: This study aimed to investigate the effects of a 30-minute single session of aromatherapy massage at night time on quality of sleep and fatigue in palliative care.Methods: A randomized controlled trial from January 2018 to March 2019. After being stratified by sex, participants were randomly assigned to an aromatherapy massage group and a control group. The effects of aromatherapy massage were evaluated on the massage day and the next day using the Richards-Campbell Sleep Questionnaire and the Brief Fatigue Inventory.Results: Of the 74 participants, data of 27 participants in the treatment group and 30 participants in the control group were analyzed. Analysis of covariance indicated that quality of sleep and fatigue did not improve owing to the aromatherapy massage, although usual fatigue in preceding 24 hours and enjoyment of life subscales of the Brief Fatigue Inventory showed signs of contribution (P = 0.07 and 0.09, respectively). Post hoc analyses indicated that higher age and performance status were factors with moderate correlation with better sleep (P = 0.03; r = 0.45 and P = 0.03; r = 0.40, respectively), and that older patients tended to experience greater improvement in fatigue (P = 0.02; r = -0.47).Conclusion: A single aromatherapy massage session is no more effective than not having a massage in improving sleep quality in palliative care settings. However, older patients and those in poor health conditions may benefit from aromatherapy massage. [ABSTRACT FROM AUTHOR]

Simple Summary: This was a multicenter, single-arm, phase II study comprising two protocol treatments. Patients were enrolled after craniotomy or biopsy and initiated the concurrent phase; oral daily temozolomide concomitant with radiation therapy during the first 6 weeks of treatment. Bevacizumab was intravenously administered every other week. The protocol-defined secondary therapy (i.e., BBP regimen) was given as bevacizumab monotherapy or in combination with other chemotherapeutic agents upon first progression or recurrence until further progression or unacceptable toxicity developed. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. Expression profiling using RNA sequencing identified that Cluster 2, enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab. [ABSTRACT FROM AUTHOR]

The CHADS2 and CHA2DS2-VASc scores are widely used to assess ischemic risk in the patients with atrial fibrillation (AF). However, the discrimination performance of these scores is limited. Using the data from a community-based prospective cohort study, we sought to construct a machine learning-based prediction model for cerebral infarction in patients with AF, and to compare its performance with the existing scores. All consecutive patients with AF treated at 81 study institutions from March 2011 to May 2017 were enrolled (n = 4396). The whole dataset was divided into a derivation cohort (n = 1005) and validation cohort (n = 752) after excluding the patients with valvular AF and anticoagulation therapy. Using the derivation cohort dataset, a machine learning model based on gradient boosting tree algorithm (ML) was built to predict cerebral infarction. In the validation cohort, the receiver operating characteristic area under the curve of the ML model was higher than those of the existing models according to the Hanley and McNeil method: ML, 0.72 (95%CI, 0.66–0.79); CHADS2, 0.61 (95%CI, 0.53–0.69); CHA2DS2-VASc, 0.62 (95%CI, 0.54–0.70). As a conclusion, machine learning algorithm have the potential to perform better than the CHADS2 and CHA2DS2-VASc scores for predicting cerebral infarction in patients with non-valvular AF. [ABSTRACT FROM AUTHOR]

Abstract: Background: The diagnosis of pseudo-responses after bevacizumab treatment is difficult. Because diffusion-weighted imaging (DWI) is associated with cell density, it may facilitate the differentiation between true- and pseudo-responses. Furthermore, as high b-value DWI is even more sensitive to diffusion, it has been reported to be diagnostically useful in various clinical settings. Materials and methods: Between September 2008 and May 2011, 10 patients (5 males, 5 females; age range 6–65 years) with recurrent glioma were treated with bevacizumab. All underwent pre- and post-treatment MRI including T2- or FLAIR imaging, post-gadolinium contrast T1-weighted imaging, and DWI with b-1000 and b-4000. Response rates were evaluated by MacDonald- and by response assessment in neuro-oncology working group (RANO) criteria. We also assessed the response rate by calculating the size of high intensity areas using high b-value diffusion-weighted criteria. Prognostic factors were evaluated using Kaplan–Meier survival curves (log-rank test). Results: It was easier to identify pseudo-responses with RANO- than MacDonald criteria, however the reduction of edema by bevacizumab rendered the early diagnosis of tumor progression difficult by RANO criteria. In some patients with recurrent glioma treated with bevacizumab, high b-value diffusion-weighted criteria did, while MacDonald- and RANO criteria did not identify pseudo-responses at an early point after the start of therapy. Discussion and conclusion: High b-value DWI reflects cell density more accurately than regular b-value DWI. Our findings suggest that in patients with recurrent glioma, high b-value diffusion-weighted criteria are useful for the differentiation between pseudo- and true responses to treatment with bevacizumab. [Copyright &y& Elsevier]

Demonstrates the conservation of the biochemical mechanisms of signal transduction among mammalian Notch. Role of mouse Notch1 in the development of cell fate; Use of membrane fraction of fibroblast transfectants; Observation of the cytoplasmic portion of Notch1.

Background Double origin of the posterior inferior cerebellar artery (DOPICA) has been rarely reported in the literature, with a reported incidence of 1.45%. In contrast, a high concurrence rate of DOPICA and vertebral artery dissecting aneurysm has been reported. Clinical presentation A 61-year old woman presented with vomiting and diplopia with preceding headache. Magnetic resonance imaging (MRI) showed fresh infarction of the left lateral medulla and a vertebral artery dissecting aneurysm of the left vertebral artery. The next day, she exhibited transient loss of consciousness and worsening of headache, and MRI depicted subarachnoid hemorrhage. Four-vessel digital subtraction angiography showed a posterior inferior cerebellar artery (PICA) arising both intracranially and extracranially from the left vertebral artery. Although the dissecting lesion involved the V3 and V4 portion, it did not involve an extracranially originating PICA. Internal trapping of the V3 and V4 portion was chosen as the extracranial channel was expected to supply the PICA territory. This procedure was safely performed. Conclusion Early endovascular intervention should be considered in the treatment of dissecting aneurysm of vertebral artery associated with DOPICA for patients with relatively long lesions even in unruptured cases. [ABSTRACT FROM AUTHOR]

: BackgroundThe neurenteric cyst is an uncommon congenital lesion. In most reported cases, it has been operated on via a posterior approach using a laminectomy, despite the fact that the cyst is usually located ventral to the spinal cord. Reports have shown that early postoperative results have been good with the posterior approach, but very few studies of the long-term postoperative recurrence of neurenteric cysts have been conducted. Here, we report on a case of recurrent neurenteric cyst that was operated on using an anterior approach.: Case descriptionA 42-year-old woman presented with a cervical neurenteric cyst that had recurred eight years after its partial removal via a posterior approach. The patient complained of pain on the lateral side of her upper arms, and an magnetic resonance imaging showed that the recurrent cyst was located ventral to the spinal cord and compressed the cord dorsally at the C4-6 level.The patient was operated on via an anterior approach using a vertebrotomy at the lower half of C5 and the upper half of C6. The cyst was attached to the spinal cord firmly and was subtotally removed, with the thickest portion adhering to the cord not being removed. The caudal end of the cyst was observed with the assistance of a rigid endoscope.: ConclusionA neurenteric cyst may recur after partial removal, and the patient’s condition may deteriorate during postoperative follow-up. The anterior surgical approach provides good visualization and facilitates safe removal of the lesion. [Copyright &y& Elsevier]

Abstract We have recently isolated two genes encoding proteins which have either homology or affinity to RBP-J, a transcription factor involved in Notch signaling. Kyo-T interacts with RBP-J and possibly regulates the function of RBP-J. RBP-L has a highly homologous region with RBPJ but the function of RBP-L is unknown. Fluorescence in situ hybridization analysis of human metaphase chromosomes localized Kyo-T and RBP-L to Xq26 and 20q12-13.1, respectively. [ABSTRACT FROM AUTHOR]