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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

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.

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.

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.

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.

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.

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.