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Introduction: Natural killer cells (NKCs) are immune cells that can attack cancer cells through the direct recognition of ligands without prior sensitization. Cord blood-derived NKCs (CBNKCs) represent a promising tool for allogenic NKC-based cancer immunotherapy. Efficient NKC expansion and decreased T cell inclusion are crucial for the success of allogeneic NKC-based immunotherapy without inducing graft-versus-host reactions. We previously established an efficient ex vivo expansion system consisting of highly purified-NKCs derived from human peripheral blood. Herein, we evaluated the performance of the NKC expansion system using CB and characterized the expanded populations. Methods: Frozen CB mononuclear cells (CBMCs), with T cells removed, were cultured with recombinant human interleukin (rhIL)-18 and rhIL-2 under conditions where anti-NKp46 and anti-CD16 antibodies were immobilized. Following 7, 14, and 21 days of expansion, the purity, fold-expansion rates of NKCs, and the expression levels of NK activating and inhibitory receptors were assessed. The ability of these NKCs to inhibit the growth of T98G, a glioblastoma (GBM) cell line sensitive to NK activity, was also examined. Results: All expanded T cell-depleted CBMCs were included in over 80%, 98%, and 99% of CD3−CD56+ NKCs at 7, 14, and 21 days of expansion, respectively. The NK activating receptors LFA-1, NKG2D, DNAM-1, NKp30, NKp44, NKp46, FcγRIII and NK inhibitory receptors TIM-3, TIGIT, TACTILE, NKG2A were expressed on the expanded-CBNKCs. Two out of three of the expanded-CBNKCs weakly expressed PD-1, yet gradually expressed PD-1 according to expansion period. One of the three expanded CBNKCs almost lacked PD-1 expression during the expansion period. LAG-3 expression was variable among donors, and no consistent changes were identified during the expansion period. All of the expanded CBNKCs elicited distinct cytotoxicity-mediated growth inhibition on T98G cells. The level of cytotoxicity was gradually decreased based on the prolonged expansion period. Conclusions: Our established feeder-free expansion system yielded large scale highly purified and cytotoxic NKCs derived from human CB. The system provides a stable supply of clinical grade off-the-shelf NKCs and may be feasible for allogeneic NKC-based immunotherapy for cancers, including GBM.

Cognitive impairment in adult patients with moyamoya disease (MMD) is sometimes overlooked and can occur in patients with no ischemic or hemorrhagic lesions. Better profiling and reliable diagnostic methods that characterize the group and associate the impairments and pathology of MMD are required in order to deliver appropriate treatments and support. The potential of 123I-iomazenil single-photon emission computed tomography (SPECT) for this issue has been reported in some studies, but the universality of this method remains unclear. A multicenter study of adult patients (aged 18-60 years) with MMD who experienced difficulties in social lives despite normal activities of daily living was implemented to delineate the common characteristics of this group of patients. In this study, iomazenil SPECT, besides patient characteristics, cognitive functions, and conventional imaging, was acquired to examine whether this method is suitable as a universal diagnostic tool. A total of 36 patients from 12 institutes in Japan were included in this study. Domain scores of world health organization quality of life 26 indicated low self-rating in physical health and psychological domains. The percentages of patients who had

Chronic subdural hematoma (CSDH) is a common pathology that typically affects the elderly in Japan, an aging society. Burr-hole irrigation is the standard treatment, but middle meningeal artery (MMA) embolization is a minimally invasive alternative. MMA embolization for CSDH has frequently been reported in recent years, and many technical innovations to improve clinical outcomes have been described. Embolic materials reaching more distally are found to avoid recurrences after MMA embolization. As a result, various studies have described the superiority of embolizing the anterior and posterior branches of the MMA, the advantages of embolic materials reaching beyond the midline, and a high degree of distal penetration using a “sugar rush technique” in which 5% soluble glucose is injected through an intermediate catheter during MMA embolization. Radiographically, reports have described the importance of a “bright falx” sign obtained by infiltrating embolic material beyond the midline and post-embolization enhancement of the dura, capsular membrane, septations, and subdural hematoma fluid as indicators of the spread of embolic materials. This review provides an overview of the current status and future challenges in MMA embolization for CSDH, focusing on technical aspects to improve clinical outcomes.

Abstract Background Glioblastoma (GBM) is the most common malignant brain tumor and has “immunologically cold” features. Changing GBM to an “immunologically hot” tumor requires a strong trigger that induces initial immune responses in GBM. Allogeneic natural killer cells (NKCs) have gained considerable attention as promising immunotherapeutic tools against cancer, where gene-edited NKCs would result in effective anti-cancer treatment. The present study focused on the immune checkpoint molecule cytokine-inducible SH2-containing protein (CISH, or CIS) as a critical negative regulator in NKCs. Methods The GBM tumor environment featured with immunological aspect was analyzed with Cancer immunogram and GlioVis. We generated human primary CIS-deleted NKCs (NK dCIS) using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) with single guide RNA targeting genome sites on CIS coding exons. The genome-edited NKCs underwent microarray with differential expression analysis and gene set enrichment analysis (GSEA). The anti-GBM activity of the genome-edited NKCs was evaluated by apoptosis induction effects against allogeneic GBM cells and spheroids. We further detected in vivo antitumor effects using xenograft brain tumor mice. Results We successfully induced human CIS-deleted NKCs (NK dCIS) by combining our specific human NKC expansion method available for clinical application and genome editing technology. CIS gene-specific guide RNA/Cas9 protein complex suppressed CIS expression in the expanded NKCs with high expansion efficacy. Comprehensive gene expression analysis demonstrated increased expression of 265 genes and decreased expression of 86 genes in the NK dCIS. Gene set enrichment analysis revealed that the enriched genes were involved in NKC effector functions. Functional analysis revealed that the NK dCIS had increased interferon (IFN)ɤ and tumor necrosis factor (TNF) production. CIS deletion enhanced NKC-mediated apoptosis induction against allogeneic GBM cells and spheroids. Intracranial administration of the allogeneic NKCs prolonged the overall survival of xenograft brain tumor mice. Furthermore, the NK dCIS extended the overall survival of the mice. Conclusion The findings demonstrated the successful induction of human primary NK dCIS with CRISPR/Cas9 with efficient expansion. CIS deletion enhanced the NKC-mediated anti-tumor effects in allogeneic GBM and could be a promising immunotherapeutic alternative for patients with GBM.

A vagus nerve stimulation (VNS) device delivers electrical pulses to the vagus nerve at a rhythm defined by the duty cycle. The standard therapeutic range is advocated for an output current of 1.5-2.25 mA and a duty cycle of 10%. As the optimal settings vary from patient to patient, some patients may benefit from additional seizure reduction when stimulated beyond the standard range. A total of 74 patients (15 children aged

Objectives: Pravastatin sodium is reported to have multiple beneficial effects in cerebral atherosclerosis and neuronal injury; however, the preventive effects on cerebral venous ischemia are still unknown. Herein, we aimed to examine the neuroprotective effects of transoral prior administration of pravastatin sodium against cerebral cortical venous ischemia with suppression of apoptosis. Methods: Thirty 8-week-old male Wistar rats were divided equally into two study groups (n = 15 vs. n = 15); the pravastatin group was fed 1% pravastatin sodium with their usual diet for 2 weeks, while the control group only received the usual diet. Two-vein occlusion (2VO) model was applied for this study, and two adjacent cortical veins in each animal were permanently occluded photochemically with rose bengal dye. During photo-thrombosis, regional changes of the cerebral blood flow (CBF) in area of the venous ischemia were recorded. At 48-h after 2VO, animals were euthanized using perfusion fixation, and we histologically measured ratios of infarcted area to contralateral hemisphere, and counted Bax- and Bcl-2-positive cells in the penumbra to investigate the implications for apoptosis. Results: The ratio of infarcted area was significantly decreased in the pravastatin group compared to the control group (P

Neurogenesis in the subventricular zone (SVZ), subgranular zone (SGZ), and cerebral cortex is now a familiar event to confirm by cerebral arterial ischemia in rat models. However, it remains unclear whether cerebral venous ischemia (CVI) alone causes neurogenesis, and where that neurogenesis occurs. After creating CVI rat models via a two-vein occlusion (2-VO) method, neurogenesis was immunohistochemically evaluated by double-labeling 5-bromo-2′-deoxyuridine (BrdU)-positive cells with neuronal nuclei (NeuN) or doublecortin (DCX) antibody. Fifty Wistar rats were divided into two major groups (BrdU-NeuN and BrdU-DCX) and then separated into two subgroups (2-VO or sham). The total number of double-positive cells expressed inside a predefined region of interest (ROI) covering the ischemic area was compared between the two subgroups. Then, we divided the ROI into six sections to evaluate and compare the distribution of double-positive cells generated in each section between the two subgroups. The 2-VO subgroup presented more double-positive cells than the sham group in both BrdU-NeuN and BrdU-DCX groups, while the BrdU-DCX+2-VO group showed a characteristic distribution of double-positive cells in ROI 2 and ROI 3, suggesting areas of the ischemic core and penumbra, with a significant difference compared to the BrdU-DCX+sham group. This study demonstrates that CVI has the potential to induce endogenous neurogenesis, with significant numbers of both newly generated neurons and precursors observed in the ischemic area. The distribution of these cells suggests that the cortex could be the main origin of neurogenesis after cortical CVI.

Objective Facet articular irregularity is associated with rapidly progressive degenerative cervical myelopathy (DCM). However, its significance compared with other known risk factors remains unknown. Therefore, this retrospective study aimed to clarify the potential impact of facet articular irregularity as a risk factor for rapid DCM progression. Methods This study included 141 consecutive patients with DCM who underwent surgical treatment at our institution. Clinical variables and radiological findings related to DCM progression were collected. Imaging findings were analyzed at the segmental level of myelopathy in each case. The patients were divided into 2 groups based on the presence or absence of rapid DCM progression, and independent risk factors were determined using logistic regression analyses. Results Overall, 131 patients with a mean age of 63.9±12.6 years were analyzed; 27 patients (20.6%) were classified into the rapid DCM progression group. The mean age was significantly higher in the rapid progression group than in the slow progression group (72.4±9.6 vs. 61.7±12.4, p

Introduction: Cell-based immunotherapy is categorized as a regenerative therapy under the Regenerative Medicine Safety Act in Japan. Natural killer (NK) cell-based immunotherapy is considered a promising strategy for treating cancer, including glioblastoma (GBM). We previously reported an expansion method for highly purified human peripheral blood-derived NK cells using a cytokine cocktail. Here, we aimed to establish a more efficient NK cell expansion method as compared to our previously reported method. Methods: T cell-depleted human peripheral blood mononuclear cells (PBMCs) were isolated from three healthy volunteers. The depleted PBMCs were cultured in the presence of recombinant human interleukin (rhIL)-18 and high-dose rhIL-2 in anti-NKp46 and/or anti-CD16 antibody immobilization settings. After 14 days of expansion, the purity and expansion ratio of CD3-CD56+ NK cells were determined. The cytotoxicity-mediated growth inhibition of T98G cells (an NK activity-sensitive GBM cell line) was evaluated using a non-labeling, impedance-based real-time cell analyzer. Results: Anti-NKp46 stimulation increased the NK cell purity and expansion ratio as compared to the non-antibody-stimulated population. Anti-CD16 stimulation weakly enhanced the NK cell expansion ratio of the non-antibody-stimulated population and enhanced the NK cell purity and expansion ratio of anti-NKp46-stimulated populations. All NK cell-containing populations tested distinctly inhibited T98G cell growth. These effects tended to be enhanced in an NK cell purity-dependent manner. In some cases, anti-CD16 stimulation decreased growth inhibition of T98G cell compared to other conditions despite the comparable NK cell purity. Conclusions: We established a robust large-scale feeder-free expansion system for highly purified human NK cells using a defined cytokine cocktail and anti-NK cell activating receptor antibodies. The expansion system could be feasible for autologous or allogeneic NK cell-based immunotherapy of GBM. Moreover, it is easily controlled under Japanese law on regenerative medicine.

Anterior cervical disc replacement (ACDR) using cervical artificial disc (CAD) has the advantage of maintaining the range of motion (ROM) at the surgical level, subsequently reducing the postoperative risk of adjacent disc disease. Following the approval for the clinical use in Japan, a post-marketing surveillance (PMS) study was conducted for two different types of CAD, namely, Mobi-C (metal-on-plastic design) and Prestige LP (metal-on-metal design). The objective of this prospective observational multicenter study was to analyze the first 2-year surgical results of the PMS study of 1-level ACDR in Japan. A total of 54 patients were registered (Mobi-C, n = 24, MC group; Prestige LP, n = 30, PLP group). Preoperative neurological assessment revealed radiculopathy in 31 patients (57.4%) and myelopathy in 15 patients (27.8%). Preoperative radiological assessment classified the disease category as disc herniation in 15 patients (27.8%), osteophyte in 6 patients (11.1%), and both in 33 patients (61.1%). The postoperative follow-up rates at 6 weeks, 6 months, 1 year, and 2 years after ACDR were 92.6%, 87.0%, 83.3%, and 79.6%, respectively. In both groups, patients' neurological condition improved significantly after surgery. Radiographic assessment revealed loss of mobility at the surgical level in 9.5% of patients in the MC group and in 9.1% of patients in the PLP group. No secondary surgeries at the initial surgical level and no serious adverse events were observed in either group. The present results suggest that 1-level ACDR is safe, although medium- to long-term follow-up is mandatory to further verify the validity of ACDR for Japanese patients.

The preoperative assessment of cerebral veins is important to avoid unexpected cerebral venous infarction in the neurosurgical setting. However, information is particularly limited regarding deep Sylvian veins, which occasionally disturb surgical procedures for cerebral anterior circulation aneurysms. The predictability of detecting deep Sylvian veins and their tributaries using a modern multimodal fusion image was aimed to be evaluated. Moreover, 51 patients who underwent microsurgery for unruptured cerebral aneurysms with Sylvian fissure dissection were retrospectively reviewed. The visualization of the four components of the deep Sylvian veins in conventional computed tomography (CT) venography and multimodal fusion images was evaluated. To compare the detection accuracy among these radiological images, the sensitivity and specificity for the detection of each of the four venous structures were calculated in comparison with those of intraoperative inspections. The kappa coefficients were also measured and the inter-rater agreement for each venous structure in each radiological image was examined. In all veins, the multimodal fusion image exhibited a high detection rate without statistical difference from intraoperative inspections (P = 1.0). However, CT venography exhibited a low detection rate with a significant difference from intraoperative inspections in the common vertical trunk (P = 0.006) and attached vein (P = 0.008). The kappa coefficients of the fusion image ranged from 0.73 to 0.91 and were superior to those of CT venography for all venous structures. This is the first report to indicate the usefulness of a multimodal fusion image in evaluating deep Sylvian veins, especially for the detection of nontypical, relatively small veins with large individual variability.

BackgroundStent apposition to the vessel wall and in-stent neointimal formation after stent-assisted coil embolization for intracranial aneurysm are important factors associated with postoperative thromboembolic complications. No assessment methods have been established to depict 3-dimensional (3D) all-round in-stent neointimal formation.ObjectiveTo demonstrate the superiority of Dyna-3D imaging assessment as a modality for all-round ISNF in comparison with conventional two-dimensional digital subtraction angiography (2D-DSA).MethodsConsecutive patients who underwent braided stent-assisted coil embolization for unruptured aneurysm between November 2016 and September 2021 were enrolled. Radiological assessments for stent apposition to the parent vessel after stent deployment and in-stent neointimal formation after 3 months were obtained. Dyna-3D was reconstructed by overlapping a plain image showing stent struts with a rotational DSA image showing the vessel lumen. Reconstructed Dyna-3D images can be rotated to any angle on the screen to evaluate to stent apposition around the vessel and in-stent neointimal formation in 3D, for comparison with 2D-DSA evaluations.ResultsAmong the 73 patients enrolled, 70 patients (96%) showed complete stent wall apposition on Dyna-3D. Higher intra-rater agreement was confirmed on assessment of in-stent neointimal formation with Dyna-3D (Cohen’s κ = 0.811) than with conventional 2D-DSA (Cohen’s κ = 0.517). in-stent neointimal formation could not be confirmed on conventional imaging in 9 cases (16%) and on Dyna-3D in 2 cases (3%). The number of in-stent neointimal formations rated as stent wire completely outside the endothelial line was significantly higher with Dyna-3D than with 2D-DSA (p = 0.0001).ConclusionAll-round 3D evaluation by Dyna-3D imaging appears useful for confirming in-stent neointimal formation after braided stent deployment in patients after stent-assisted coil embolization.

ObjectiveA case of giant pituitary neuroendocrine tumor presented along with acute visual loss due to pituitary apoplexy after receiving a COVID-19 vaccination is reported.Case presentationA 45-year-old man was referred for a giant pituitary tumor with bitemporal hemianopsia. A surgical procedure was planned and then delayed due to the COVID-19 outbreak in Japan, with a Pfizer/BioNTech vaccine administered while awaiting surgery. Three days after the second COVID-19 vaccination the patient noted a progressively worsening headache that caused pituitary apoplexy and then a decrease in vision. Emergency surgery was thus performed.ConclusionPituitary apoplexy is a rare and life-threatening complication that may occur after undergoing a COVID-19 vaccination.

Background: this study aimed to evaluate the prognostic factors associated with long-term survival after linear accelerator (linac)-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for brain metastasis (BM). Methods: This single-center retrospective study included 226 consecutive patients with BM who were treated with linac-based SRS or fSRT with a micro-multileaf collimator between January 2011 and December 2018. Long-term survival (LTS) was defined as survival for more than 2 years after SRS/fSRT. Results: The tumors originated from the lung (n = 189, 83.6%), breast (n = 11, 4.9%), colon (n = 9, 4.0%), stomach (n = 4, 1.8%), kidney (n = 3, 1.3%), esophagus (n = 3, 1.3%), and other regions (n = 7, 3.1%). The median pretreatment Karnofsky performance scale (KPS) score was 90 (range: 40–100). The median follow-up time was 13 (range: 0–120) months. Out of the 226 patients, 72 (31.8%) were categorized in the LTS group. The median survival time was 43 months and 13 months in the LTS group and in the entire cohort, respectively. The 3-year, 4-year, and 5-year survival rate in the LTS group was 59.1%, 49.6%, and 40.7%, respectively. Multivariate regression logistic analysis showed that female sex, a pre-treatment KPS score ≥ 80, and the absence of extracranial metastasis were associated with long-term survival. Conclusions: female sex, a favorable pre-treatment KPS score, and the absence of extracranial metastasis were associated with long-term survival in the current cohort of patients with BM.

Objective To evaluate cervical facet joint degeneration using a newly developed classification, investigate its prevalence and relationship with cervical degenerative spondylolisthesis, and clarify its clinical significance in patients with degenerative cervical myelopathy (DCM). Methods This study included 145 consecutive patients with DCM who underwent surgical treatment. Clinical variables and radiological findings were analyzed. A new 6-grade computed tomography (CT) classification for cervical facet joint degeneration was adapted, and its prevalence was evaluated by categorizing the joints into those at responsible and those at nonresponsible spinal segmental levels. We evaluated the association between rapidly progressive myelopathy and the presence of significant facet joint degeneration or spondylolisthesis at the responsible segmental level. Results Finally, 140 patients with a mean age of 64.1 ± 12.8 years were analyzed. The prevalence of grade 1, 2, 3, 4, 5A, and 5B classification in all facet joints was 72.0%, 9.5%, 10.9%, 4.3%, 2.9%, and 0.4%, respectively. There was a statistically significant difference in the distribution of CT grades between the joints at the responsible and nonresponsible segmental levels (p < 0.001), with a high prevalence of grade 4 or 5B degeneration at the responsible segmental level, reflecting articular irregularity. There was also a statistically significant relationship between rapidly progressive myelopathy and grade 4 or 5B degeneration at the responsible segmental level (p < 0.001), but not between rapidly progressive myelopathy and spondylolisthesis (p = 0.255). Conclusion This novel CT classification for facet joints deserves additional evaluation in patients with DCM. Abnormal findings on the articular surfaces might be related to the progression of myelopathy.

Objectives To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.Design Retrospective study.Setting Six hundred and thirty-one primary care institutions in Japan.Participants Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.Primary and secondary outcome measures Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).Results In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.Conclusions The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

Cerebral hyperperfusion syndrome (CHS) after carotid endarterectomy (CEA) is devastating, and postoperative monitoring of cerebral perfusion is essential to prevent CHS. We report two cases of successful measurement of ocular blood flow using laser speckle flowgraphy (LSFG) for bedside assessment of the changes in cerebral perfusion after CEA. An 18.7% (case 1) and 47.7% (case 2) increase in ocular blood flow were measured postoperatively using LSFG compared with the baseline. LSFG might be applicable to evaluate cerebral perfusion after CEA.

Fenestration of the middle cerebral artery (MCA) is a rare anatomic variant, and lenticulostriate arteries (LSAs) often arise from the superior limb of the fenestrated segment. A case of acute occlusion of the superior limb of a fenestrated MCA that successfully underwent mechanical thrombectomy is presented. Digital subtraction angiography performed for a 73-year-old man with acute left hemiparesis showed poor visualization of the upper half of the right M1 segment with maintenance of antegrade peripheral circulation of the MCA territory, and mechanical thrombectomy was successfully performed using a stent retriever with intravenous thrombolysis. After restoration of the MCA, the vascular variant of a fenestrated MCA was found. Clinicians must consider the possibility of acute occlusion of a fenestrated MCA before endovascular thrombectomy. Restoration of acute occlusion of the upper limb of a fenestrated MCA can avoid LSA territory infarction.

Background: This study aimed to assess the clinical outcomes of salvage surgical resection (SSR) after stereotactic radiosurgery and fractionated stereotactic radiotherapy (SRS/fSRT) for newly diagnosed brain metastasis. Methods: Between November 2009 and May 2020, 318 consecutive patients with 1114 brain metastases were treated with SRS/fSRT for newly diagnosed brain metastasis at our hospital. During this study period, 21 of 318 patients (6.6%) and 21 of 1114 brain metastases (1.9%) went on to receive SSR after SRS/fSRT. Three patients underwent multiple surgical resections. Twenty-one consecutive patients underwent twenty-four SSRs. Results: The median time from initial SRS/fSRT to SSR was 14 months (range: 2–96 months). The median follow-up after SSR was 17 months (range: 2–78 months). The range of tumor volume at initial SRS/fSRT was 0.12–21.46 cm3 (median: 1.02 cm3). Histopathological diagnosis after SSR was recurrence in 15 cases, and radiation necrosis (RN) or cyst formation in 6 cases. The time from SRS/fSRT to SSR was shorter in the recurrence than in the RNs and cyst formation, but these differences did not reach statistical significance (p = 0.067). The median survival time from SSR and from initial SRS/fSRT was 17 and 74 months, respectively. The cases with recurrence had a shorter survival time from initial SRS/fSRT than those without recurrence (p = 0.061). Conclusions: The patients treated with SRS/fSRT for brain metastasis need long-term follow-up. SSR is a safe and effective treatment for the recurrence, RN, and cyst formation after SRS/fSRT for brain metastasis.

Background: As vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue worldwide, increased rates of venous thrombotic events, mainly as cerebral venous sinus thrombosis (CVST), have been reported following adenovirus vector-based SARS-CoV-2 vaccination. However, few reports have described the occurrence of venous thrombosis after messenger RNA (mRNA)-based vaccination. Here, we describe a case of CVST after a first dose of mRNA-based vaccination that was treated with emergent endovascular mechanical thrombectomy and systemic heparinization.Case Description.A 43-year-old, previously healthy man suffered severe headache and partial seizures affecting the left arm 4 days after receiving the first dose of an mRNA-based SARS-CoV-2 vaccination (FC3661; Pfizer/BioNTech). Computed tomography showed intraparenchymal hemorrhage. Seven days after vaccination, symptoms worsened and he was transferred to our tertiary hospital. Magnetic resonance venography revealed CVST with occlusion of the superior sagittal sinus (SSS) and right transverse sinus (TS). Since no findings suggested thrombosis with thrombocytopenia syndrome, the patient underwent systemic heparinization and emergent mechanical thrombectomy with balloon transluminal angioplasty, a stent retriever and an aspiration catheter. Complete SSS and right TS recanalization were achieved and the patient was discharged without neurological deficits. Conclusion: Clinicians should be aware that apparently healthy individuals with no risk factors can develop CVST after receiving an mRNA-based vaccine and appropriate treatment including EMT need to be performed immediately.(228 words)

Background: Surgical site infection (SSI) is common following cranioplasty after decompressive craniectomy (DC). The aim of this study was to assess the risk of SSI following cranioplasty in terms of the preservation method of autogenous bone graft (ABG), comparing preservation in 80% ethanol versus the standard method of subcutaneous ABG preservation. Material and methods: The patients who underwent cranioplasty using ABGs after DC between 2008 and 2019 were retrospectively reviewed. SSIs were compared between patients whose ABG was preserved in 80% ethanol (group A) and those whose ABG was preserved subcutaneously (group B) using inverse probability of treatment weighting (IPTW) based on propensity scores to balance measurable confounders including elderly age, sex, expanded polytetrafluoroethylene, stroke, interval to cranioplasty, and diabetes mellitus. Results: Total number of 127 patients consisted of 56 in group A and 71 in group B. SSI after cranioplasty occurred in five patients each in groups A and B (8.9% vs. 7%, p = 0.748). IPTW analysis demonstrated that preservation in 80% ethanol was associated with a lower risk of SSI (odds ratio: 0.239, 95％ confidence interval: 0.0615–0.927, p = 0.039). Conclusion: The simple and less-invasive method of preserving ABGs in 80% ethanol for cranioplasty after DC might be potentially safe from an SSI perspective.

The coronavirus disease 2019 (COVID-19) pandemic has forced restrictions on social activities in some areas. There has also been a decrease in the number of trauma patients in the United States during the COVID-19 pandemic. Chronic subdural hematoma (CSDH) is a traumatic disorder that often develops following head injury. We therefore investigated the impact of the COVID-19 pandemic on CSDH. In this retrospective single-center descriptive study from April 2018 through September 2021, there were 5,282 head trauma patients and 196 patients with CSDH in the pre-pandemic group compared to 4,459 head trauma patients and 140 patients with CSDH in the intra-pandemic group. Significant decreases in the incidence rate (IR) of head trauma (951/100,000 vs. 795/100,000 person-years; IR ratio (IRR): 0.836, 95% confidence interval (CI): 0.803–0.870, p < 0.001) and also in the IR of CSDH (35.0/100,000 vs. 24.8/100,000 person-years, IRR: 0.708, 95% CI: 0.570–0.879, p = 0.002) were seen in the intra-pandemic group compared to the pre-pandemic group. In this study, the COVID-19 pandemic was associated with significant decreases in the IRs of head trauma and CSDH due to forced restrictions on social activities. Besides, the IR of mild cases of CSDH was significantly lower in the intra-pandemic group than in the pre-pandemic group (IRR: 0.68, 95% CI: 0.51–0.89, p = 0.006). Fewer people being out in communities should result in fewer chances for head trauma and CSDH. On the other hand, forced restrictions on social activities due to the COVID-19 pandemic should aggravate CSDH.

IntroductionThe present study aimed to determine the incidence of intraprocedural visual-evoked potential (VEP) changes and to identify correlations with intraprocedural ischemic complications during endovascular treatment in patients with intracranial aneurysm related to visual function.MethodsThis study analyzed data from 104 consecutive patients who underwent endovascular coil embolization to treat intracranial aneurysms related to visual function under VEP and transcranial motor evoked potential (MEP) monitoring. We analyzed associations between significant changes in MEP and VEP, defined as a >50% decrease in amplitude, and both intraprocedural complications and postoperative neurological deficits. Factors associated with postoperative neurological deficits were also assessed.ResultsTreated aneurysms were predominantly located in the internal carotid artery (95%). Five (5%) were located in the posterior cerebral artery (PCA). Significant decreases in intraprocedural VEP occurred in four patients (4%), although one of those four patients did not show concomitant MEP decreases during procedures. Immediate salvage procedures avoided postoperative visual disturbances. All VEP decreases were transient and not associated with postoperative visual impairment. One of three cases who underwent intraoperative balloon occlusion test showed tolerance to balloon occlusion of the proximal PCA under VEP assessment; parent artery occlusion was performed without postoperative visual disturbance in that case.ConclusionAlthough significant VEP decreases occurred 4% during neuro-endovascular aneurysm treatment related to visual function, intraprocedural VEP monitoring identifies ischemic changes associated with visual pathways and facilitates prompt initiation of salvage procedures.

Background: Endovascular trans-arterial obliteration of a traumatic carotid-cavernous fistula (CCF) is often problematic because large fistulae can cause coils to protrude into the internal carotid artery (ICA) and disturb tight packing at the fistulous point. This technical note describes trans-arterial stent-assisted coil embolization to treat CCF. Case presentation: A 45-year-old woman presented with left chemosis at two months after sustaining head trauma. Digital subtraction angiography (DSA) showed direct CCF with a fistula in the cavernous segment of the left ICA communicating with the left cavernous sinus. We therefore planned trans-arterial stent-assisted coil embolization. An 8-Fr balloon guiding catheter was navigated into the left ICA and microcatheters were advanced into the cavernous sinus (CS) porch. A braided stent was deployed in the ICA over the fistular portion and coil embolization proceeded under balloon inflation and the CCF was immediately obliterated. Conclusion: Stent-assisted fistulous embolization is a safe and effective technical strategy for treating CCF. Braided stents might promote fistular obliteration by flow alterations and facilitate endothelialization of a lacerated arterial segment.

Mass gatherings are events characterized by “the concentration of people at a specific location for a specific purpose over a set period of time that have the potential to strain the planning and response resources of the host country or community.” Previous reports showed that, as a result of the concentration of people in the limited area, injury and illness occurred due to several factors. The response plan should aim to provide timely medical care to the patients and to reduce the burden on emergency hospitals, and to maintain a daily emergency medical services system for residents of the local area. Although a mass gathering event will place a significant burden on the local health‐care system, it can provide the opportunity for long‐term benefits of public health‐care and improvement of daily medical service systems after the end of the event. The next Olympic and Paralympic Games will be held in Tokyo, during which mass gatherings will occur on a daily basis in the context of the coronavirus disease (COVID‐19) epidemic. The Academic Consortium on Emergency Medical Services and Disaster Medical Response Plan during the Tokyo Olympic and Paralympic Games in 2020 (AC2020) was launched 2016, consisting of 28 academic societies in Japan, it has released statements based on assessments of medical risk and publishing guidelines and manuals on its website. This paper outlines the issues and countermeasures for emergency and disaster medical care related to the holding of this big event, focusing on the activities of the academic consortium.

Giant posterior cerebral artery (PCA) aneurysms often require parent artery occlusion (PAO) because of the difficulty of direct treatment. Recently, reproducible and stable visual evoked potential (VEP) monitoring has been used for the evaluation of visual function, however, there are no reports of VEP monitoring in endovascular treatment of cerebral aneurysms. This case highlights a novel VEP monitoring during balloon occlusion test (BOT) and endovascular PAO for an enlarged giant PCA aneurysm in a pregnant woman. A 17-year-old pregnant girl at 32 weeks of gestation suffered from headache. MRI of the head depicted a giant partially thrombosed aneurysm on the left PCA (P2 segment). After cesarean section at 35 weeks of gestation, endovascular PAO was performed under VEP monitoring. Before PAO, BOT under general anesthesia and no VEP waveform changes were seen during BOT and PAO procedure. Headache completely disappeared after PAO and the patient was discharged without visual deficits. Three-months after PAO, MRI showed marked shrinkage of the aneurysm. This is the first report of giant PCA thrombosed aneurysm successfully treated by PAO under VEP monitoring.

Background: Late-onset skull base cerebrospinal fluid (CSF) leakage after stereotactic radiotherapy (SRT) is a very rare complication. Case Description: A 54-year-old woman came to our department for convulsions and was admitted. Brain magnetic resonance imaging revealed a giant tumor in the skull base region, including the sphenoid sinus, pituitary fossa, right cavernous sinus, right middle fossa, and right basal ganglia. Mild left hemiparesis was noted. An ophthalmologic examination revealed left side homonymous hemianopsia. Using an endonasal endoscopic surgical approach, tumor removal was performed, with the residual tumor removed with a transcranial approach. Residual tumor tissue remained around the right cavernous sinus; therefore, SRT was performed 1 month after the second procedure, which resulted in good control of growth. Four years later, spontaneous CSF leakage occurred, for which endoscopic endonasal surgery was performed. One month later, CSF leakage recurred, and the same procedure was again used. A third episode of recurrent CSF leakage occurred 5 days later. A transcranial approach was finally used for repair, and the patient showed complete recovery. Conclusions: Late-onset CSF leakage after SRT for a pituitary adenoma can be intractable, and several aggressive repair procedures may be needed, including a combination of endonasal and transcranial approaches. Key words: Endoscopic endonasal surgery, Late-onset cerebrospinal fluid leakage, Nonfunctioning pituitary adenoma, Stereotactic radiotherapy, Transcranial approach

Objective: There are several material options for duraplasty in surgery for foramen magnum decompression (FMD). We retrospectively analyzed surgical results and the impact of sequential alteration of posterior fossa (PF) size in patients with Chiari malformation type 1 after duraplasty using local fascia. Methods: The patients with Chiari malformation type 1 who underwent FMD with duraplasty using local fascia at our institution between 2004 and 2015 were included in the study. Some pediatric patients who underwent FMD without duraplasty and patients with insufficient follow-up data were excluded. Improvement of clinical signs, regression of syrinx, and temporal alteration of PF size were analyzed with perioperative magnetic resonance imaging. Postoperative clinical outcomes were evaluated at the final follow-up using the Chicago Chiari Outcome Scale. Correlations between the PF size alteration and size of dural patch or Chicago Chiari Outcome Scale were statistically analyzed. Results: Twelve patients were included in this study. The mean age of the patients was 31.9 (range, 18–48) years. Syrinx was incorporated in 11 patients and regressed postoperatively in all patients. The PF was significantly enlarged sequentially over time (P < 0.05). The degree of enlargement was positively correlated with size of the fascial patch (r = 0.540). Postoperative clinical outcomes at final follow-up were positively correlated with the degree of PF enlargement (r = 0.678). Conclusions: The PF was enlarged sequentially over time after duraplasty using local fascia. The degree of enlargement was positively correlated with the size of the fascial patch and the likelihood of a favorable postoperative outcome. Key words: Chiari malformation, Duraplasty, Foramen magnum decompression, Local fascia, Posterior fossa

A mild ischemic load applied after a lethal ischemic insult reduces the subsequent ischemia-reperfusion injury, and is called ischemic postconditioning (PostC). We studied the effect of ischemic PostC on synaptic glutamate release using a whole-cell patch-clamp technique. We recorded spontaneous excitatory post-synaptic currents (sEPSCs) from CA1 pyramidal cells in mouse hippocampal slices. The ischemic load was perfusion of artificial cerebrospinal fluid (ACSF) equilibrated with mixed gas (95% N2 and 5% CO2). The ischemic load was applied for 7.5 min, followed by ischemic PostC 30 s later, consisting of three cycles of 15 s of reperfusion and 15 s of re-ischemia. We found that a surging increase in sEPSCs frequency occurred during the immediate-early reperfusion period after the ischemic insult. We found a significant positive correlation between cumulative sEPSCs and the number of dead CA1 neurons (r = 0.70; p = 0.02). Ischemic PostC significantly suppressed this surge of sEPSCs. The mitochondrial KATP (mito-KATP) channel opener, diazoxide, also suppressed the surge of sEPSCs when applied for 15 min immediately after the ischemic load. The mito-KATP channel blocker, 5-hydroxydecanoate (5-HD), significantly attenuated the suppressive effect of both ischemic PostC and diazoxide application on the surge of sEPSCs. These results suggest that the opening of mito-KATP channels is involved in the suppressive effect of ischemic PostC on synaptic glutamate release and protection against neuronal death. We hypothesize that activation of mito-KATP channels prevents mitochondrial malfunction and breaks mutual facilitatory coupling between glutamate release and Ca2+ entry at presynaptic sites.

Glioblastoma is the leading malignant glioma with a poor prognosis. This study aimed to investigate the antitumor effects of natural killer cells in combination with temozolomide as the standard chemotherapeutic agent for glioblastoma. Using a simple, feeder-less, and chemically defined culture method, we expanded human peripheral blood mononuclear cells and assessed the receptor expression, natural killer cell activity, and regulatory T cell frequency in expanded cells. Next, using the standard human glioblastoma cell lines (temozolomide-sensitive U87MG, temozolomide-resistant T98G, and LN-18), we assessed the ligand expressions of receptors on natural killer cells. Furthermore, the antitumor effects of the combination of the expanded natural killer cells and temozolomide were assessed using growth inhibition assays, apoptosis detection assays, and senescence-associated β-galactosidase activity assays in the glioblastoma cell lines. Novel culture systems were sufficient to attain highly purified (>98%), expanded (>440-fold) CD3-/CD56+ peripheral blood-derived natural killer cells. We designated the expanded population as genuine induced natural killer cells. Genuine induced natural killer cells exhibited a high natural killer activity and low regulatory T cell frequency compared with lymphokine-activated killer cells. Growth inhibition assays revealed that genuine induced natural killer cells inhibited the glioblastoma cell line growth but enhanced temozolomide-induced inhibition effects in U87MG. Apoptosis detection assays revealed that genuine induced natural killer cells induced apoptosis in the glioblastoma cell lines. Furthermore, senescence-associated β-galactosidase activity assays revealed that temozolomide induced senescence in U87MG. Genuine induced natural killer cells induce apoptosis in temozolomide-sensitive and temozolomide-resistant glioblastoma cells and enhances temozolomide-induced antitumor effects in different mechanisms. Hence, the combination of genuine induced natural killer cells and temozolomide may prove to be a promising immunochemotherapeutic approach in patients with glioblastoma if the antitumor effects in vivo can be demonstrated.

Glioblastoma (GBM), which is the most common malignant brain tumor, is resistant to standard treatments. Immunotherapy might be a promising alternative for the treatment of this cancer. Chimeric antigen receptor (CAR) is an artificially modified fusion protein that can be engineered to direct the specificity and function of T cells against tumor antigens. However, the antitumor effects of EGFRvIII-targeting CAR-T (EvCAR-T) cells in GBM are limited. The inhibitory effect is induced by the interaction between programmed cell death protein 1 (PD-1) on activated EvCAR-T cells and its ligands on GBM cells. In the present study, PD-1-disrupted EvCAR-T cells were established using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The sgRNA/Cas9 expression vectors designed precisely disrupted the target region of PD-1 and inhibited the expression of PD-1 in EvCAR-T cells. The PD-1-disrupted EvCAR-T cells had an in vitro growth inhibitory effect on EGFRvIII-expressing GBM cells without altering the T-cell phenotype and the expression of other checkpoint receptors. In the future, the in vivo antitumor effect of this vector should be evaluated in order to determine if it could be applied clinically for improving the efficacy of EvCAR-T cell-based adoptive immunotherapy for GBM.

Cerebral hyperperfusion syndrome (HPS) is a potentially life-threatening complication following carotid artery stenting (CAS) and carotid endoarterectomy (CEA). Early prediction and treatment of patients at risk for HPS are required in patients undergoing CAS because HPS occurs significantly earlier after CAS than CEA. Near-infrared spectroscopy (NIRS) is often used for monitoring, and indocyanine green (ICG) kinetics by NIRS (ICG-NIRS) can detect reductions in cerebral perfusion in patients with acute stroke. However, whether ICG-NIRS can predict postoperative hyperperfusion phenomenon (HP) after carotid revascularization is unclear.Here, we evaluated whether the blood flow index (BFI) ratio calculated from a time-intensity curve from ICG-NIRS monitoring can predict HPS after CAS.The BFI ratio was prospectively monitored using ICG-NIRS in 135 patients undergoing CAS. Preoperative cerebrovascular reactivity (CVR) and the postoperative asymmetry index (AI) were also assessed with single-photon emission computed tomography before and after CAS, and the correlation was evaluated. In addition, patients were divided into two groups, a non-HP group (n = 113) and an HP group (n = 22), and we evaluated the correlation with hemodynamic impairment in the ipsilateral hemisphere and clinical results.Twenty-two cases (16%) showed HP, and four (3%) showed HPS after CAS. The BFI ratio calculated from ICG-NIRS showed a significant linear correlation with preoperative CVR and postoperative AI (r = -0.568, 0.538, P < 0.001,

Embryonic stem (ES) cells are a potential source for treatment of spinal cord injury (SCI). Although one of the main problems of ES cell-based cell therapy is tumor formation, there is no ideal method to suppress tumor development. In this study, we examined whether transplantation with bone marrow stromal cells (BMSCs) prevented tumor formation in SCI model mice that received ES cell-derived grafts containing both undifferentiated ES cells and neural stem cells. Embryoid bodies (EBs) formed in 4-day hanging drop cultures were treated with retinoic acid (RA) at a low concentration of 5 × 10 –9 M for 4 days, in order to allow some of the ES cells to remain in an undifferentiated state. RA-treated EBs were enzymatically digested into single cells and used as ES cell-derived graft cells. Mice transplanted with ES cell-derived graft cells alone developed tumors at the grafted site and behavioral improvement ceased after day 21. In contrast, no tumor development was observed in mice cotransplanted with BMSCs, which also showed sustained behavioral improvement. In vitro results demonstrated the disappearance of SSEA-1 expression in cytochemical examinations, as well as attenuated mRNA expressions of the undifferentiated markers Oct3/4, Utf1, Nanog, Sox2, and ERas by RT-PCR in RA-treated EBs cocultured with BMSCs. In addition, MAP2-immunopositive cells appeared in the EBs cocultured with BMSCs. Furthermore, the synthesis of NGF, GDNF, and BDNF was confirmed in cultured BMSCs, while immunohistochemical examinations demonstrated the survival of BMSCs and their maintained ability of neurotrophic factor production at the grafted site for up to 5 weeks after transplantation. These results suggest that BMSCs induce undifferentiated ES cells to differentiate into a neuronal lineage by neurotrophic factor production, resulting in suppression of tumor formation. Cotransplantation of BMSCs with ES cell-derived graft cells may be useful for preventing the development of ES cell-derived tumors.

Background Periprocedural lipid core plaque (LCP) has been detected in carotid arteries assessed by catheterbased near-infrared spectroscopy (NIRS). High LCP is associated with cerebral embolism after carotid artery stenting (CAS) using a first-generation stent. We aimed to evaluate whether dual-layered stents reduce embolic infarcts in patients with high LCP and change of lipid signal as assessed by NIRS during CAS. Methods Participants comprised 210 consecutive patients undergoing CAS. The study was divided into two distinct periods, with first-generation closed-cell stents used in the earlier period and dual-layered stents used in the later period. NIRS was performed at baseline, after stent implantation, and after balloon post-dilatation to analyze maximal lipid core burden index at minimal luminal area (max-LCBIMLA). Results The ipsilateral cerebral embolism rate was significantly lower with dual-layered stents (9%) than with first-generation stents (33%, p<0.001), particularly with highly lipidic lesions (12% vs 60%, p<0.001). On multivariate logistic regression analysis, high LCP and first-generation stent usage were factors related to ipsilateral cerebral embolism (both p<0.001; OR 8.28 (95% CI 3.49 to 19.64) and OR 8.07 (95% CI 2.33 to 27.93), respectively). Max-LCBIMLA decreased significantly after stenting in both groups (both p<0.01) and max-LCBIMLA after balloon post-dilatation was significantly lower with dual-layered stents (22.4±65.6) than with first-generation stents (124.2±208.2; p=0.006). Conclusions Dual-layered stents reduce embolic infarcts in patients with highly lipidic plaque lesions as assessed by NIRS who undergo CAS. Dual-layered stents significantly reduced NIRS-derived lipid signals after stenting. [ABSTRACT FROM AUTHOR]

A 45-year-old man suffered multiple cerebral infarctions in the vertebrobasilar artery territory, followed by second stroke against conservative treatment. Radiological examinations revealed intra-arterial defect in left persistent 1st intersegmental artery (PFIA) at CI level, suggesting mural thrombus, and mechanical compression of left PFIA at the level with head rotation to the right clearly revealed by reconstructed 3-dimensional radiological images, but no findings of atlantoaxial instability. One month after the second stroke, posterior fixation was performed. Postoperative course was uneventful without subsequent stroke for 24 months. This unique case demonstrated that PFIA might associate with cerebral stroke as a clinical condition of bow hunter's stroke even in middle age. Reconstructed 3-dimensional radiological images might be useful for clear demonstration of the pathophysiology in this complex clinical entity. [ABSTRACT FROM AUTHOR]