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Background Gadolinium-enhanced magnetic resonance imaging and T2-weighted imaging/fluid-attenuated inversion recovery imaging are used to determine the efficacy of bevacizumab (Bev) against glioblastoma (GBM). Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) reflects hypoxia in the tumor microenvironment (TME). This study compared FMISO-PET findings for alterations in tumor oxygenation in the TME of GBM during Bev treatment. Materials and Methods We retrospectively reviewed data from 7 patients with newly diagnosed IDH (isocitrate dehydrogenase)-wildtype GBM who underwent FMISO-PET during follow-up. Three patients received preoperative neoadjuvant Bev (neo-Bev) followed by radiation therapy and temozolomide, and subsequently underwent surgical resection. Re-operation was performed for recurrence. FMISO-PET was performed at each time point. Four patients who underwent tumor resection after FMISO-PET without any preoperative interventions were also included as a Control group. Surgically obtained tumor tissues were analyzed for expression of a marker of hypoxia (carbonic anhydrase; CA9), stem cell markers (nestin, FOXM1), and immunoregulatory molecules (CD163, FOXP3, PD-1, PD-L1) by immunohistochemistry (IHC). Results All 3 patients treated with preoperative chemoradiotherapy showed reduced FMISO accumulation (maximum tumor-to-blood ratio and hypoxic volume) and decreases in CA9 and FOXM1 compared with Controls. Two cases in the preoperative neo-Bev group showed recurrence with increasing FMISO accumulation. IHC showed increased CA9- and FOXM1-positive cells at recurrence in both cases. A trend toward fewer CA9-positive cells was seen in patients with low FMISO accumulation both with and without neo-Bev (r = 0.90, p = 0.006). Expressions of immunoregulatory molecules tended to be lower after neo-Bev compared with the Control group and increased at recurrence, but these differences were not significant. Conclusion FMISO-PET effectively visualized improvements in TME oxygenation after preoperative chemoradiotherapy including Bev. Increased FMISO accumulation at the time of recurrence, even under Bev treatment, suggests that FMISO-PET might be useful for monitoring the duration of Bev efficacy by reflecting tumor oxygenation.

Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy.We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features.We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis.Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.

Objective The present study aimed to establish whether our modified Nakaguchi computed tomography (CT) classification improves the interrater agreement of chronic subdural hematoma (CSDH) classification and prediction of CSDH recurrence relative to 2 other CT classifications. Methods This retrospective study considered 277 consecutive patients with CSDH and 307 hematomas treated with burr-hole surgery between January 2009 and December 2018. Two neurosurgeons blinded to patients' clinical data classified the CT scans of patients with CSDH into 4 or 5 types according to the Nomura classification (high, iso, low, mixed, and layering), Nakaguchi classification (homogenous, laminar, separated, and trabecular), and our modified Nakaguchi classification (homogenous, gradation, laminar, separated, and trabecular). The κ statistic was used to evaluate the interrater agreement of the 3 CT classifications. Univariable and multivariable logistic regression analyses were used to calculate odds ratios for CSDH recurrence. Results κ values of the modified, Nakaguchi, and Nomura classification were 0.78, 0.63, and 0.70, respectively. During the 3 months follow-up, the recurrence rate for CSDH was 11.4% (35/307 hematomas). Of the types defined by the modified classification, the gradation type was associated with the highest recurrence (mean recurrence rate, 15.9% ± 0.3%). Multivariable logistic regression analyses showed that a gradation-type hematoma, as defined with the modified classification, was an independent risk factor associated with recurrence (odds ratio, 2.36; 95% confidence interval, 1.11–4.98; P = 0.025). Conclusions The modified classification was useful for preoperative CT classification of CSDH and the prediction of recurrence, with high agreement between raters.

Background: Sporadically occurring vestibular schwannomas (VSs) are the most frequent tumors in the cerebellopontine cistern and internal meatus and are commonly associated with hearing loss. These tumors have demonstrated spontaneous shrinkage rates of 0–22%; however, the relationship between tumor shrinkage and changes in hearing remains unclear. Case Description: We report a case of a 51-year-old woman with a diagnosis of a left-sided VS and accompanying moderate hearing loss. The patient was treated with a conservative approach for 3 years, and the tumor showed a regression along with an improvement in her hearing ability during the yearly follow-ups. Conclusion: The spontaneous shrinkage of a VS along with an associated improvement in hearing is a rare phenomenon. Our case study may support that the “wait and scan” approach is an alternative option for patients with VS and moderate hearing loss. Further investigations are needed to understand spontaneous VS regression and hearing changes.

To date, few clinical observations have been reported for changes of alternative angiogenic factors (other than vascular endothelial growth factor [VEGF]) in human gliomas under bevacizumab (Bev). The elucidation of the mechanism of action and resistance is imperative to overcome resistance to Bev and develop a more effective therapy. This study aims to investigate the status and change of alternative angiogenic factors regarding Bev usage.The present study used 56 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naive Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory/autopsied Bev group). The expression of alternative angiogenic factors including basic fibroblast growth factor (bFGF), placental growth factor (PlGF), Angiopoietin1 (Ang-1), Angiopoietin2(Ang-2) and EphrinA2 were investigated via immunohistochemistry. In large tumor vasculature (diameter >15μm), the expression of PlGF was significantly higher in the effective Bev group than naive Bev group. The expression of Ang-2 was persistently suppressed in the refractory/autopsied Bev group. In microtumor vasculature (diameter

BackgroundPreviously, we reported that bevacizumab (Bev) produces histological and neuroradiographic alterations including changes in tumor oxygenation, induction of an immunosupportive tumor microenvironment, and inhibition of stemness. To confirm how those effects vary during Bev therapy, paired samples from the same patients with newly diagnosed glioblastoma (GBM) who received preoperative neoadjuvant Bev (neoBev) were investigated with immunohistochemistry before and after recurrence.MethodsEighteen samples from nine patients with newly diagnosed GBM who received preoperative neoBev followed by surgery and chemoradiotherapy and then autopsy or salvage surgery after recurrence were investigated. The expression of carbonic anhydrase 9 (CA9), hypoxia-inducible factor-1 alpha (HIF-1α), nestin, and Forkhead box M1 (FOXM1) was evaluated with immunohistochemistry.For comparison between neoBev and recurrent tumors, we divided the present cohort into two groups based on neuroradiographic response: good and poor responders (GR and PR, respectively) to Bev were defined by the tumor regression rate on T1-weighted images with gadolinium enhancement (T1Gd) and fluid-attenuated inversion recovery images. Patterns of recurrence after Bev therapy were classified as cT1 flare-up and T2-diffuse/T2-circumscribed. Furthermore, we explored the possibility of utilizing FOXM1 as a biomarker of survival in this cohort.ResultsA characteristic “pseudo-papillary”-like structure containing round-shaped tumor cells clustered adjacent to blood vessels surrounded by spindle-shaped tumor cells was seen only in recurrent tumors. Tumor cells at the outer part of the “pseudo-papillary” structure were CA9-positive (CA9+)/HIF-1α+, whereas cells at the inner part of this structure were CA9−/HIF-1α+ and nestin+/FOXM1+. CA9 and HIF-1α expression was lower in T1Gd-GR and decreased in the “T2-circumscribed/T2-diffuse” pattern compared with the “T1 flare-up” pattern, suggesting that tumor oxygenation was frequently observed in T1Gd-GR in initial tumors and in the “T2-circumscribed/T2-diffuse” pattern in recurrent tumors. FOXM1 low-expression tumors tended to have a better prognosis than that of FOXM1 high-expression tumors.ConclusionA “pseudo-papillary” structure was seen in recurrent GBM after anti-vascular endothelial growth factor therapy. Bev may contribute to tumor oxygenation, leading to inhibition of stemness and correlation with a neuroimaging response during Bev therapy. FOXM1 may play a role as a biomarker of survival during Bev therapy.

Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summarized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (

Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot-Marie-Tooth (CMT) disease in Japanese patients.We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients.In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum.Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

Malignant progression of grade I meningioma with a long latency period is rare. We experienced grade II/III meningiomas with refractoriness and recurrence from grade I meningiomas through multiple surgeries. Three patients with atypical/anaplastic meningioma experienced long-latent recurrence after initial surgery for grade I (meningothelial) meningioma without following adjuvant radiotherapy were included in the present study. Histological findings of the initial tumors in all cases (case 1, 2, and 3) revealed meningothelial meningioma with 1%, 5%, and 0.1% MIB-1 positive cells, respectively. Surprisingly, magnetic resonance imaging (MRI) detected a recurrent tumor 2, 12, and 12 years after the initial operation, respectively. Case 1 was atypical meningioma after third recurrence, and case 2 and 3 were anaplastic meningioma after second and third recurrence, respectively. The patient in case 2 received adjuvant radiotherapy. In case 2, the tumor recurred intracranial and distant metastasis to the lung with huge substantial pleural effusion was detected. To investigate the pathogenesis of malignant progression from benign to malignant meningioma, CD163/CD68 expression by immunohistochemically and FOXM1 mRNA expression by RT-PCR were compared using surgical specimens from initial and recurrent tumors in all three patients. The ratio of CD163/CD68 positivity and FOXM1 mRNA expression were increased in recurrent tumors compared with matched initial tumors. CD163 and FOXM1 expression levels were induced even in recurrent grade I meningioma, suggesting that macrophage polarization and pro-mitotic transcriptional factor might be associated with clinical behavior of meningioma and be useful as a prediction marker for malignant progression. Careful long-term follow-up is important for early diagnosis of malignant progression in meningiomas, even if grade I meningioma is completely resected. Development of a multidisciplinary approach including radiation and novel molecular targeted therapy is expected for recurrent and malignant meningiomas.

BackgroundNOTCH2NLCGGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a fewNOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations ofNOTCH2NLC-related IPNs.MethodAmong 2692 Japanese patients clinically diagnosed with IPN/Charcot–Marie–Tooth disease (CMT), we analysedNOTCH2NLCrepeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination ofNOTCH2NLCrepeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR.ResultsNOTCH2NLCrepeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8–59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7–61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear.ConclusionsThese findings of this study help us understand the clinical heterogeneity ofNOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan.We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA).We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect.This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

Background Preoperative neoadjuvant bevacizumab (neoBev) reduces enhancement and perifocal edema by inhibition of angiogenesis and vascular permeability for glioblastoma (GBM). The aim of this study was to investigate safety and efficacy of neoBev for newly diagnosed GBM through an exploratory prospective multi-center study. METHODS & PATIENTS 15 patients with newly diagnosed GBM were enrolled in the present study. Eligibility was a patient with a brain tumor representing with ring-shaped enhancement and perifocal edema on magnetic resonance imaging (MRI). Based on neuroimage of typical GBM, neoBev and temozolomide (TMZ) were administered prior to craniotomy. Two weeks after neoBev, the tumor volume on T1-weighted gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev and TMZ administration, patients underwent surgical resection. The primary endpoint was feasibility and safety, and the secondary endpoint was efficacy. Adverse events including systemic toxicity and wound healing delay during radiation (RT), TMZ, and Bev combined therapy were carefully monitored throughout clinical course including extent of resection. RESULTS Average of tumor regression rate two weeks after neoBev on T1Gd and FLAIR were 37.0% and 54.0%, respectively. Cerebral blood flow and cerebral blood volume were reduced after neoBev. Patients underwent surgical resection safely without excess blood loss due to less vascular and less degree of brain swelling. Two patients underwent awake surgery without any complications. Postoperative MRI showed that the all tumors were totally removed except one with multiple invasive tumors. Histological diagnosis of all patients was GBM, IDH-1 wild-type. Postoperative course was uneventful without neurological deficit and adverse effects except one postoperative hematoma in the resection cavity and one wound infection due to wound dehiscence. CONCLUSION Preoperative neoBev for newly diagnosed GBM might contribute to safe surgery. Clinical outcome of this therapeutics is now currently under investigation.

Background Since phase 3 randomized clinical trials failed to show the benefit of bevacizumab(Bev) from the induction therapy, Bev was widely used for the recurrence glioblastoma(GBM) cases. Given that Bev treatment for newly diagnosed GBM(nd-GBM) is permitted only in Japan, we could confirm the appropriate usage and timing of Bev for the GBM patient clinically. Here, we report the clinical benefit of Bev for nd-GBM based on the retrospective cohort study. Methods We retrospectively investigated 172 GBM patients who were treated with surgery, radiation therapy(RT) and temozolomide(TMZ) at our hospitals in 2006 to 2020. We classified with and without Bev patients for age, Karnofsky performance status(KPS) and extent of resection(EOR). Kaplan-Meier survival analysis was used to compare median overall survival(mOS) between patients who were treated with Bev simultaneously during Stupp regimen(S-Bev) and without Bev(NS-Bev). Results Bev provided prolonged mOS in the elderly(>60 years old)(p Conclusion Bev therapy commenced simultaneously with concurrent RT and TMZ might contribute to improve mOS for patients with high risk including the elderly, poor KPS and low EOR. Stratification based on risk factors including age and EOR might be effective for patients in whom Bev should be preferentially used as a first-line therapy.

Since a diffuse midline glioma (DMG) has no effective therapy, it is an urgent need to develop new therapeutic strategy. We performed immunotherapy using fusions of autologous dendritic cells (DC) with tumor cells in DMG cases in which tumor tissue was collected by surgery aimed at biopsy, and evaluate the effectiveness and examine the pros and cons of surgical intervention against DMG. Among the patients with basal ganglia or brain stem tumors received surgery at our hospital, 5 adult cases of DMG with H3K27M gene mutation were registered. All patients received radiation therapy and temozolomide chemotherapy. 4 cases received bevacizumab chemotherapy when the patients had recurrence or progression of the disease. The tumor-fused DCs (TFDC) were made by DCs induced from autologous peripheral blood mononuclear cells and tumor cells established from surgical specimens. They were injected subcutaneously into the neck 3 ~ 6 times in a 14 ~ 28 day cycle as the immunotherapy. The adverse events, PFS, and OS were evaluated. A transient complication of facial numbness was observed in one case on right after surgery. Although two patients had CR in those therapies, both of them died of disease (OS at 18 and 32 months, respectively). Since the remaining three cases were registered very recently, adverse event or treatment efficacy judgment have not been determined at the time of submission of the abstract. Serious surgical complications have not been observed in the presented cases. Surgery may be acceptable for DMG as long as the surgery is performed by sufficiently experienced surgeon in an appropriate environment. The TFDC immunotherapy, which can be performed only by collecting a small amount of tumor tissue, expects to be a novel treatment for MDG. In this presentation, the pros and cons of surgical intervention aimed at TFDC immunotherapy for DMG will be examined.

Background Gd-enhanced MRI and T2WI/FLAIR images are used to determine the efficacy of bevacizumab(Bev) in glioblastoma(GBM). FMISO-PET reflects hypoxia in tumor tissue. In this study, we hypothesized that FMISO-PET could detect a series of changes in the hypoxic environment during the Bev effect and at the time of Bev recurrence, and compared images and pathological findings after initial Bev treatment and recurrence. Subjects and Methods Seven patients with first-episode GBM, IDH-wild type were included in the study. 3 patients underwent tumor resection after completion of Bev, radiation, and temozolomide treatment, and reoperation was performed at recurrence. FMISO-PET was performed at each time point. Four patients who underwent tumor resection after FMISO-PET in the absence of treatment were also included. The explanted specimens were analyzed for expression of hypoxia (CA9) and stem cell surface marker (FOXM1) by immunohistochemistry (IHC). Results All three patients treated with preoperative chemoradiotherapy showed reduced FMISO accumulation. Two of them showed recurrence and increased FMISO accumulation, and IHC showed increased CA9 and FOXM1 positive cells at the time of reoperation. There was a trend toward fewer CA9-positive cells in patients with low FMISO accumulation, including controls. Conclusion FMISO-PET was used to visualize the improvement of oxygenation in tumor tissues after preoperative chemoradiotherapy including Bev, and the increased FMISO accumulation at the time of Bev resistance suggested that FMISO-PET may be useful for monitoring the duration of Bev treatment effect by reflecting the oxygenation of tumor tissues. The results suggest that FMISO-PET may be useful for monitoring the duration of response to Bev therapy.

Although immunotherapy has become an attractive approach to cancer treatment in patients with broad types of aggressive tumors, phase III clinical trials of immunotherapy for glioblastoma (GBM) have not achieved extended survival of patients. Dendritic cells perform an essential role in the immune system as antigen-presenting cells and tumor fused dendritic cells (TFDCs) can induce tumor-specific cytotoxic T cells as a cancer vaccine. We have previously described the safety and mechanisms of TFDCs therapy, as well as immunological and clinical responses of patients with GBM, however, there were little known about predictive and prognostic biomarkers specific to TFDCs therapy. In the present study, we investigated the whole transcriptome sequencing of tumor cells, and novel prognostic factors were identified through molecular profiling GBM treated with TFDCs immunotherapy. Fifty-three patients were eligible in this study and 28 samples from patients with newly diagnosed GBM IDH wild-type were included. Of these 28 samples, 15 high-quality RNA samples successfully extracted from tumors were analysed. The samples were divided into two groups based on the median patient's overall survival. Differential expression analyses and enrichment analysis between the two groups were carried out using CLC Genomics Workbench (QIAGEN), and Gene Ontologies (GO) were assigned. A total of 473 differentially expressed genes were detected including 327 enriched GO terms. Fifteen GO terms out of 327 GO terms represented the highest enrichment scores, revealed that five GO terms were associated with the major histocompatibility complex (MHC). The relationship among the MHC, immune-related genes, and clinical outcomes was investigated using the Cox regression model and Kaplan–Meier log-rank test. Low expression of HLA-A in the tumors turned out to be a significantly favorable prognostic impact (p = 0.01). The decreased expression of HLA-A might be a novel prognostic factor in GBM patients treated with TFDCs immunotherapy.

Objective Visual field defects occasionally occur secondary to tumors in the parietal and the occipital lobes. The aim of this study was to analyze the efficacy of improvement in hemianopsia after surgery for metastatic brain tumors involving or adjacent to the optic radiation (OR). Methods The study included 49 patients with brain metastasis in the parietal and occipital lobes in the present study. Preoperative and postoperative neurological assessments included visual field, Mini-Mental State Examination, and Karnofsky performance scale. Results Of 49 patients, 33 (67.3%) presented with preoperative homonymous hemianopsia. Of these 33 patients, the visual field was improved postoperatively in 17 patients (51.5%). In all patients regardless of preoperative hemianopsia, postoperative visual fields did not deteriorate. Tractography demonstrated that the OR was split by the tumor (n = 6) and fanning of fibers expanded along the lateral side of the tumor (n = 11). All tumors were removed via surgical access toward the medial side of the tumor. Gross total resection was achieved in most tumors in the group with visual improvement (n = 16/17; 94.1%). Improvement in the visual field was attributed to tumor location in the subcortical white matter, removal rate of the tumor, and higher postoperative Karnofsky performance scale score. Conclusions The OR tended to deviate to the lateral side of the tumor in the parieto-occipital junction. The postoperative visual field improved even in cases of an occipital tumor. Based on the present study, total resection via an appropriate surgical route should be considered to preserve the OR, leading to improvement in the postoperative visual field.

It is important to distinguish foramen magnum arachnoiditis (FMA) from Chiari malformation (CM) before surgery because the operative strategies for these diseases differ. In the current study, we compared pretreatment magnetic resonance imaging (MRI) of FMA with CM and investigated the MRI findings useful to differentiate between these diseases. We retrospectively reviewed patients with FMA or CM aged ≥ 18 years who underwent surgeries at our institution between 2007 and 2019. The morphologies of the syrinx, neural elements, and posterior cranial fossa were preoperatively evaluated with MRI. We used the receiver operating characteristic (ROC) curve for the fourth ventricle-to-syrinx distance (FVSD). Ten patients with FMAs and 179 with CMs were included. FVSD in the FMA group was significantly shorter than that in the CM group (7.5 mm [IQR, 2.8–10 mm] in FMA vs. 29.9 mm [IQR, 16.3–52.9 mm] in CM, p

The underlying mechanism of chronic subdural hematoma (CSDH) after minor head injury is complex, probably due to mechanical injury of the arachnoid membrane, hematological coagulopathy, and pathological angiogenesis in the dura caused by inflammatory cytokines including vascular endothelial growth factor (VEGF). To confirm whether VEGF might be a reliable predictive biomarker for the natural history of CSDH, including progression and recurrence, we analyzed the correlation of VEGF concentration in the subdural fluid with CT findings and clinical features, including interval from minor head injury. Based on CT classification by hematoma density, the mean concentration of VEGF in hematoma fluid was found to be highest in the trabecular group, whereas the recurrence of CSDH was most frequent in the separated group in which VEGF concentration was low. There was a significant correlation between VEGF concentration and the CT classification. Furthermore, only in the trabecular group, a significant negative correlation between the VEGF concentration and interval from minor head injury to surgery was observed. These results suggest that VEGF concentration in the hematoma alone could not be a reliable predictive biomarker for the natural history of CSDH including its recurrence. Amongst the classified groups of CSDH, the trabecular group is likely to follow a different time course of VEGF concentration in the hematoma fluid compared to the other three groups.

Background The design process of a removable partial denture (RPD) consists of rests, major connectors, minor connectors, denture base, and retainer. The abutment tooth contour determines the location of the retention portion of the clasp at the retention areas. The load capacity of the clasp depends on various factors such as type, the position of a clasp, tooth position, clasp length, and pullout location. As a general rule, the amount of retention required to dislodge the RPD from the supporting structure should always be the minimum necessary to resist reasonable dislodging forces. Excessive force from the clasps may cause many problems. Although there are many reports on the retentive force of cast clasps using large devices, it has not been possible to measure it using simple devices until now. Method The purpose of the present study is to develop a small-sized retentive force measurement device that can easily measure the retentive force of a clasp used for an RPD. It is to examine inter-rater and intra-rater reliability. A small-sized retentive force measurement device that can be easily measured in the laboratory has been developed. Using commercially available hard plaster cast, a skilled dental technician has made 10 types of cast clasps used in clinical practice using conventional techniques. Three assessors measured the retentive force of 10 types of cast clasps. To confirm the reliability, the intra-class correlation coefficients ICC (1,1) and ICC (1,3) of the 3 assessors were calculated, and the reliability within the assessor was examined. The inter-class correlation coefficients ICC (3,1) and ICC (3,3) were calculated, and the reliability of the assessors was examined. Result The intra-class correlation coefficients of 3 assessors are as follows: assessor 1 has ICC (1,1) = 0.971, ICC (1,3) = 0.990, assessor 2 has ICC (1,1) = 0.967, ICC (1,3) = 0.989, assessor 3 has ICC (1,1) = 0.962, ICC (1,3) = 0.987. The inter-class correlation coefficients of 3 assessors are as follows: ICC (3,1) = 0.993, ICC (3,3) = 0.998. From the evaluation standard of the intraclass correlation coefficients of reliability value by ICC, it was evaluated as almost perfect and high reproducibility was confirmed. Conclusion The developed small-sized retentive force measurement device has reproducibility within and between the assessors.

Rapid recurrence of a pilocytic astrocytoma with anaplastic transformation is extremely rare. The case of an elderly patient with a cerebellar pilocytic astrocytoma with anaplastic transformation during short-term follow-up is reported.An 83-year-old woman presented initially with dizziness and a gait deviation to the right. Magnetic resonance imaging demonstrated a homogeneously enhanced mass in the right cerebellar hemisphere, and the tumor was subtotally removed by right suboccipital craniotomy. Histologic examination showed that the tumor cells contained eosinophilic cytoplasm and spindle-shaped processes with Rosenthal fibers and eosinophilic granular bodies, diagnosed as a typical pilocytic astrocytoma (PA). The MIB-1 index was1%. The patient did not receive postoperative adjuvant radiation and chemotherapy. Two months after surgery, magnetic resonance imaging showed growth of the residual tumor adjacent to the fourth ventricle, causing obstructive hydrocephalus. She underwent surgery again, and the tumor was totally removed. Histologic findings showed mitotic cells and increased cellularity compared with the primary tumor, which was compatible with anaplastic transformation of PA with a MIB-1 index of 50%. Postoperatively, she was observed with best supportive care without postoperative adjuvant therapy. Nine months after the second operation, she died due to tonsillar herniation and obstructive hydrocephalus caused by a recurrent tumor. An autopsy was performed.It is extremely rare, as in the present case, that a cerebellar PA in an elderly patient recurs rapidly with anaplastic transformation, despite deferred postoperative adjuvant therapy including radiation and chemotherapy. A novel molecular-targeted therapy is needed for anaplastic PA showing aggressive biological behavior.

Background: Previously we reported that bevacizumab (Bev) produces tumor oxygenation with immunosupportive tumor microenvironment (TME) and inhibition of stemness. To confirm whether those effects might contribute prolongation of clinical outcome, in the present study paired samples from same patients with newly diagnosed GBM who received Bev during its effectiveness and refractoriness were investigated by immunohistochemistry. Methods: Eighteen samples from 9 patients with newly diagnosed GBM who received preoperative neoadjuvant Bev (neoBev) followed by surgical operation and chemoradiotherapy in addition to salvage surgery after recurrence were investigated. Expressions of FOXM1, HIF-1, and CD163 were evaluated by immunohistochemistry. Overall survial (OS) were analyzed with the present cohort divided into two groups between good and poor responder (GR and PR, respectively) of Bev defined as tumor regression rate judged by T1 gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) images. Results: In the group of good responder of T1Gd (T1Gd-GR; defined as >38% of regression rate after neoBev), OS was prolonged compared with T1Gd-PR along with inhibition of FOXM1 expression and HIF-1a. In contrast, in the group of good responder of FLAIR (FLAIR-GR; defined as >54% of regression rate after neoBev), there were no significant differences of OS and FOXM1 expression between GR and PR. HIF-1a expression tended to be elevated in T1Gd-PR of initial tumors, T1Gd-GR of recurrent tumors, and FLAIR-PR of both initial and recurrent tumors.Conclusion: T1Gd-GR after neoBev might attribute to inhibition of FOXM1 and oxygenation. Bev might provide tumor oxygenation, leading to inhibition of stemness and M2 TAM infiltration during its effectiveness. These results suggested that Bev combined with immunotherapy for newly diagnosed GBM might provide clinical benefits including inhibition of stemness and induction of immunosupportive TME, when tumor volume assessed by T1 Gd. was significantly decreased following neoBev.

Although bevacizumab was shown to improve progression-free survival and performance status of the patients with high-grade gliomas, clinical trials consistently showed lack of benefit in terms of patients’ overall survival. The recurrent tumors are inevitably more aggressive and invasive as compared with the original tumors, and the in-situ observation in actual human specimens is essential to elucidate the mechanism of resistance. In Japan, bevacizumab was approved not only for recurrent but also for newly diagnosed cases. The safety as well as efficacy of resection following neoadjuvant bevacizumab has been reported, and a phase II study is currently ongoing (UMIN-000025579). In the present study, the expression of angiogenic factors other than VEGF (basic fibroblast growth factor (bFGF), placenral growth factor (PlGF), angiopoietin1/2 and ephrinA2) was investigated by immunohistochemistry to be compared among tumors with no previous bevacizumab treatment, those resected following bevacizumab, and those refractory to bevacizumab. Fifty-nine samples from 42 patients were included; 24 of newly diagnosed glioblastomas with no previous bevacizumab (naïve group), 16 resected following neoadjuvant bevacizumab (effective group), and 6 resected after recurrence or autopsied (refractory/autopsied group). 12 were paired samples (8 naïve and refractory, 4 effective and refractory). The expression of PlGF significantly increased in the effective group as compared with the naïve group (p=0.003). In the paired specimens, there was a trend towards increased expression of PlGF in the second specimens (refractory/autopsied group) as compared with the specimens of initial surgery (p=0.083). Angiopoietin1, angiopoietin2 and ephrinA2 were characteristically expressed in the microvessels less than 15μm. The increased expression of PlGF might be associated with the recurrence after bevacizumab.

A 40-year-old man presented with a severe headache, lower back pain, and lower abdominal pain 1 month after a head injury caused by falling. Computed tomography (CT) of the head demonstrated bilateral chronic subdural hematoma (CSDH) with a significant amount in the left frontoparietal region. At the same time, magnetic resonance imaging (MRI) of the lumbar spine also revealed CSDH from L2 to S1 level. A simple drainage for the intracranial CSDH on the left side was performed. Postoperatively, the headache was improved; however, the lower back and abdominal pain persisted. Aspiration of the liquefied spinal subdural hematoma was performed by a lumbar puncture under fluoroscopic guidance. The clinical symptoms were dramatically improved postoperatively. Concomitant intracranial and spinal CSDH is considerably rare so only 23 cases including the present case have been reported in the literature so far. The etiology and therapeutic strategy were discussed with a review of the literature. Therapeutic strategy is not established for these two concomitant lesions. Conservative follow-up was chosen for 14 cases, resulting in a favorable clinical outcome. Although surgical evacuation of lumbosacral CSDH was performed in seven cases, an alteration of cerebrospinal fluid (CSF) pressure following spinal surgery should be reminded because of the intracranial lesion. Since CSDH is well liquefied in both intracranial and spinal lesion, a less invasive approach is recommended not only for an intracranial lesion but also for spinal lesion. Fluoroscopic-guided lumbar puncture for lumbosacral CSDH following burr hole surgery for intracranial CSDH could be a recommended strategy.

BACKGROUND/OBJECTIVES Relapsed or refractory brain tumors in childhood continue to have a dismal prognosis in spite of intensive multidisciplinary treatment. Cancer immunotherapy is newly developed to be expected as next promising treatment for highly aggressive pediatric cancer. This trial was designed to evaluate the safety and effectiveness of an immunotherapy with fusions of dendritic cells (DCs) and tumor cells in patients with malignant brain tumors. METHODS Patients with histopathologically confirmed malignant and recurrent/refractory brain tumor were eligible for this immunotherapy trial. Autologous cultured tumor cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region and repeated 3–10 times in each 28–84 days cycle. Treatment-related toxicity, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS Six patients were enrolled, three with high grade glioma and three with ependymoma. Median age at first course of immunotherapy was 10 years (range 8–25 years) and median follow-up time from the first course of immunotherapy was 13.5 months (range 3–33 months). All patients with immunotherapy were well tolerated to this treatment with no adverse events except local erythema in injected site. Median progression free survival and overall survival were 18 months and 18.5 months, respectively. CONCLUSIONS FC immunotherapy with autologous DCs and tumor cells for brain tumor in children and young adults were extremely well tolerated and showed encouraging responses in this series. Further phase II study of FC immunotherapy is planned to improve survival and reduce treatment related morbidity.

BACKGROUND: The immunosuppressive tumor microenvironment (TME) contributes to the tumor progression and treatment failure. Our previous study demonstrated alterations in the TME during bevacizumab (Bev) therapy in human glioblastoma (GB) specimens obtained from patients who underwent surgical resection. Continuous Bev administration downregulates the expression of programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), suppresses the infiltration of tumor associated macrophages (TAMs) and regulatory T cells (Tregs), and increases cytotoxic T lymphocytes (CTLs) infiltration. However, one may argue that these immunosupportive effects might also be induced by radiation therapy (RT) or temozolomide (TMZ), and they cannot necessarily be attributed to Bev alone. METHODS: In the present study, changes in the molecules relevant to the TME were analyzed by immunohistochemistry using paired pre- and post-treatment samples of malignant glioma specimens from 15 patients who received RT and TMZ therapy without Bev. RESULTS: The expression levels of CD34, vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (VEGFR2), HIF-1α, CA9, nestin, CD4, CD8, CD163, PD-1, and PD-L1 were not significantly changed after the treatment with RT and TMZ. However, VEGFR1 expression and the number of Foxp3-positive cells tended to be upregulated and increased after the treatment (P=0.058, P=0.082, respectively). CONCLUSIONS: This was the first study to show the alterations of TME following RT and TMZ therapy using paired pre- and post-treatment malignant glioma samples. Long-term treatment of RT and TMZ might worsen immunosuppressive TME in malignant gliomas.

A 40-year-old man presented with a series of generalized tonic-clonic seizures after febrile illness. He developed status epilepticus and required mechanical ventilation with anesthetics. Steroid pulse, intravenous immunoglobulin, and immunoadsorption therapy were administrated, and the status epilepticus improved; however, drug-resistant seizures remained. Despite the use of several antiepileptic drugs, seizures frequently occurred. Additional administration of potassium bromide resulted in significant suppression of seizures. Potassium bromide is regarded as an effective medication for pediatric refractory epilepsy after encephalitis. The present case is considered to be new-onset refractory status epilepticus (NORSE) syndrome based on clinical features, and potassium bromide could be effective in treating adult refractory epilepsy, such as NORSE syndrome.

Aneurysmal subarachnoid hemorrhage(SAH)associated with intracerebral hematoma(ICH)typically has a poor outcome. SAH with ICH tends to have a worse prognosis than SAH alone. The aim of the present study was to evaluate whether coil embolization during endovascular surgery with ventricle drainage and without ICH evacuation is an appropriate treatment.A retrospective review was conducted between March 2012 and May 2015. Thirteen patients with SAH with ICH who underwent coil embolization were retrospectively analyzed. Modified Rankin Scale(mRS)scores were compared for postoperative clinical outcomes of different hematoma locations.All ruptured aneurysms in the present series of patients were treated using endovascular surgery. Six patients underwent additional ventricle drainage. Only one patient underwent craniotomy for evacuation of the hematoma following coil embolization. Despite ten out of thirteen patients(76.9%)having a preoperative SAH clinical grade, as evaluated using the World Federation of Neurosurgical Societies grading system of IV or V, six(46.2%)patients had a favorable outcome(mRS=0-2).Coil embolization for ruptured aneurysms, especially those located in the frontal lobe, with ICH and without cerebral herniation may be a feasible alternative and less invasive treatment.

BACKGROUND Brainstem tumours account for 10–15% of brain tumors in childhood. Diffuse intrinsic pontine glioma (DIPG) accounts for 60–80% of them and are diagnosed based on clinical findings and radiologic features. All the rest of tumours excluding DIPG are very rare, heterogeneous group of tumours including low-grade glioma and malignant embryonal tumors. It is often difficult to diagnose and decide treatment strategy for their rarity. METHODS To present our experience with atypical brainstem tumours, a retrospective chart review was conducted to identify eligible cases treated over a ten-year period. All tumors involving brainstem, felt not to be DIPGs for absence of clinical/neuroimaging features were included. Demographic information, pathological findings, neuroimaging characteristics, surgical and nonsurgical management plans, and survival data were collected for analysis. RESULTS Between April 2007 and March 2017, 16 patients (14 initial and 2 recurrent) aged from 3 to 20 years were identified. 14 of them were symptomatic and 4 of them were asymptomatic at reference. Of 10 symptomatic cases, 10 were biopsied and pathological diagnosis was low-grade glioma in 8, glioblastoma in 2 cases. They had treatment depending on the pathological diagnosis. Of 4 asymptomatic cases, one with small focal tumour, with no findings suggesting malignant tumour with 11C-methioninePET or MRS, progressed to show typical clinical and image findings of DIPG in a year. For other three, they remain asymptomatic without progression with no treatment for 25months, 60months, and 65 months respectively. Malignant transformation was observed in one with biopsy-conformed oligoastrocytoma with no K27M-H3 mutations treated with chemotherapy and another with pilocytic astrocytoma treated with chemotherapy and radiotherapy. CONCLUSIONS Though molecular findings such as K27M-H3 mutations can predict clinical outcome in some cases, it still remains difficult to diagnose and find treatment strategy of atypical brainstem tumours. The need and usefulness of nationwide registry study is warranted.

BACKGROUND This trial was designed to evaluate the safety and clinical responses to an immunotherapy with fusions of dendritic and glioma cells in patients with lower grade glioma (LGG; WHO grade II-III glioma). METHOD Autologous cultured glioma cells obtained from surgical specimens were fused with autologous dendritic cells (DC) using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region of subjects. Toxicity, progression-free survival (PFS), overall survival (OS), and MRI findings were evaluated. DNA for whole exome and RNA for whole transcriptome extracted from HLA-A*24:02 positive glioma cells were analyzed by next generation sequencer. Variant peptides showing strong binding affinity to HLA-A*24:02 but not the corresponding wild type peptides were selected as candidate of neo-antigens. RESULTS The number of subjects of this trial were 24 (initially diagnosed cases: 20, recurrence cases: 4). WHO grade III cases were 20, and grade II cases were 4. Male were 15, and female were 9. Mean of follow up periods were 53.0 months (the longest follow up period: 1322 months). The number of events on PFS and OS were 8 and 6, respectively. Mean of candidate of neo-antigen peptides in HLA-A*24:02 positive patients (n=8) was 34. Among these candidates, twelve types of common neo-antigen peptide were identified. Neo-antigen peptides specifically expressed in the glioma cells from the effective group were not identified. CONCLUSIONS These results indicate that the efficacy of FC-immunotherapy may not always depend on the number of gene mutations or the expression of the specific neo-antigens. FC-immunotherapy, as a means of producing specific immunity against neo-antigens may safely induce anti-tumor effects in patients with LGG. Analysis of prognostic factor in glioma immunotherapy may be the next area of major interest.

With the rapidly spreading use of the Internet, many systems for connection to the Internet using various media and methods have appeared. One is a system using a satellite link as a unidirectional link, which is expected to provide broadband Internet service to areas in which a ground Internet environment has not yet been developed. However, most of the protocols which are regarded as standard on the Internet assume that the links composing the Internet can provide bidirectional communications. Consequently, when a unidirectional link is used as a part of the network, it is difficult to make direct use of the protocols which are considered standard on the Internet. Consequently, this paper considers the situation in which Internet connection service is provided by using a unidirectional link, and proposes and implements the required dynamic assignment of network resources and the associated management scheme. The system is also evaluated in the actual environment. It is shown that by applying the proposed method, it becomes possible to utilize a unidirectional link combined with a bidirectional link on the ground, resulting in an efficient Internet connection environment. It is also shown that the connection to the network is provided without constraints on its use. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 88(1): 82–90, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10104

This paper describes the network architecture of an Asia-wide satellite Internet that considers the situations in developing regions. The design considerations for the architecture are costs, effective use of satellite bandwidth, scalability, and routing strategy when combined with terrestrial links. The architecture includes using one-way shared satellite links to reduce costs, IP multicast to leverage the broadcast nature of satellite links, QoS, audio-video application gateway to adapt to the limited bandwidth of satellite links. This architecture is implemented in an operational network testbed connecting 13 countries and supporting a distance learning project.

Many developing countries are not gaining benefits from the Internet as the network infrastructure has not yet been built due to the economic or administrative restrictions of these regions. Asian Internet Interconnection Initiatives (AI3) has been developing a research consortium of 29 partner institutions in 13 countries utilizing an Internet infrastructure over a satellite links. The project aims to develop partnerships and human networks to foster researchers within the regions to carry out research on the satellite Internet and to develop their regions. We have successfully conducted productive research and also developed a distance-learning environment as a result of more than a decade of experiments. This paper aims to share the operational know-how and results of research from AI3's activities to construct a network and applications that would support developing regions.

This paper describes an overview of JCSAT-3, which was launched in August 1995. JCSAT-3 is located at 128 deg E longitude in geosynchronous orbit with a predicted service lifetime of 12 yr. JCSAT-3 is a multifaceted international communication satellite which covers most of Asia, Japan, India, Australia, New Zealand, and Hawaii in the Ku and C bands. Users can access and transmit with Ku to Ku, Ku to C, C to Ku, and C to C from any region. First, this paper presents the system performance for the JCSAT-3 payload subsystem and bus subsystem. Second, the ground segment for JCSAT-3 is described. (Author)