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Glioblastoma (GB) is one of the most common and malignant tumours that originates in the brain. It has a high likelihood of recurrence and a poor survival rate. Professor Toshihide Tanaka, Chief Medical Officer, Jikei University School of Medicine, conducts translational research based on clinical samples of glioblastoma tumours obtained from brain tumour surgery procedures as well as animal studies. He heads up a multidisciplinary team focused on the design and selection of personalised treatments for hypervascular malignant gliomas. In their current project, the researchers are investigating the use of Bevacizumab (Bev), a monoclonal antibody that targets vascular endothelial growth factor (VEGF). VEGF enhances tumour growth by changing the surrounding environment to one more favourable for tumour growth. The effect of Bev on cancers is transient and the mechanisms of resistance to Bev are yet to be investigated in detail. The researchers are therefore seeking to discover predictive biomarkers of microenvironment-targeted therapy for GB. In order to investigate the effect and prediction factors of Bev on immunoregulation in GB, Tanaka and the team perform in situ observations using histological techniques including immunohistochemistry using tumour tissues from patients who have undergone surgical resection. The researchers have been able to demonstrate a decrease in microvascular density and an improvement in the tumour microenvironment after treatment with Bev.

In coil embolization of cerebral aneurysms, inadequate packing is known to increase the probability of recanalization. Even tightly embolized aneurysms may be recanalized, but predictive factors for recanalization have not been fully investigated. This retrospective study aimed to identify risk factors for recanalization of treated aneurysms with a volume embolization ratio (VER) ≥ 25%. A total of 301 unruptured aneurysms in 248 patients who underwent coil embolization between March 2012 and January 2021 were analyzed. Cases involving dissecting aneurysm, intraluminal thrombosis, parent artery occlusion, intraoperative rupture, re-treatment, rupture the day after surgery, postoperative coil migration, and postoperative parent artery occlusion were excluded due to the inaccuracy of VER. A total of 105 aneurysms (34.9%) treated with VER ≥ 25% were extracted. Clinical features (age, sex, medical history, family history), anatomical features (shape, location, aneurysm size, inflow angle, and volume), procedural features (stent-assisted, Raymond-Roy occlusion classification [RROC] immediately after treatment, re-treatment rate), and follow-up period were compared between Recanalization and Non-recanalization groups. Predictors of recanalization were determined using logistic regression and receiver operating characteristic (ROC) curve analyses. Eleven aneurysms were recanalized. In multivariate analysis, RROC class 3 (odds ratio [OR] 11.0; 95% confidence interval [CI] 2.03-59.4) and aneurysm volume (OR 1.005; 95%CI 1.001-1.008) were independent predictors of recanalization. ROC curve analysis showed optimal cutoff values for aneurysm volume of 69.5 mm

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.

BACKGROUND Transradial access (TRA) has a lower risk of access-site complications than transfemoral access but can cause major puncture-site complications, including acute compartment syndrome (ACS). OBSERVATIONS The authors report a case of ACS associated with radial artery avulsion after coil embolization via TRA for an unruptured intracranial aneurysm. An 83-year-old woman underwent embolization via TRA for an unruptured basilar tip aneurysm. Following embolization, strong resistance was felt during removal of the guiding sheath due to vasospasm of the radial artery. One hour after neurointervention via TRA, the patient complained of severe pain in the right forearm, with motor and sensory disturbance of the first 3 fingers. The patient was diagnosed with ACS causing diffuse swelling and tenderness over the entire right forearm due to elevated intracompartmental pressure. The patient was successfully treated by decompressive fasciotomy of the forearm and carpal tunnel release for neurolysis of the median nerve. LESSONS TRA operators should be aware that radial artery spasm and the brachioradial artery pose a risk of vascular avulsion and resultant ACS and warrant precautionary measures. Prompt diagnosis and treatment are essential because ACS can be treated without the sequelae of motor or sensory disturbance if properly addressed.

Purpose The transradial approach (TRA) in neuroendovascular treatment is known to have a lower risk of complications than the transfemoral approach (TFA). However, little research has focused on assessments of efficacy and risk of complications in the treatment of intracranial aneurysms. This study aimed to compare the efficacy and complications of TRA and TFA in coil embolization of unruptured intracranial aneurysms (UIAs) at our institution. Methods Consecutive patients who underwent endovascular surgery via TRA or TFA at a single institution from 1 April 2019, to 28 February 2022, were retrospectively analyzed. Patients were classified into TRA and TFA groups and assessed using propensity-adjusted analysis for outcomes including fluoroscopy time, volume embolization ratio (VER), and complications. Results A total of 163 consecutive UIAs were treated with coil embolization during the 35-months study period. The incidence of minor access site complications (ASCs) was significantly higher with TFA (20%, 25/126) than with TRA (2.7%, 1/37; p = 0.01). Propensity-adjusted analysis (matched for age, sex, aneurysm volume, embolization technique, and sheath size) revealed that TRA was associated with a lower risk of minor ASCs (odds ratio, 0.085; 95% confidence interval 0.0094–0.78; p = 0.029). However, TRA did not differ significantly from TFA with respect to fluoroscopy time, VER, major ASCs, and non-ASCs. Conclusions Coil embolization for UIAs via TRA can reduce risk of minor ASCs without increasing the risk of non-ASCs compared with conventional TFA, and can achieve comparable results in term of efficacy and fluoroscopy time.

When I was a medical student, I happened to see the typical histopathology of glioblatoma (GBM) containing expanding necrosis surrounded by enormous glomerulous microvasculature with endothelial proliferation resembling glomeruli in the kidney. It looks like tumor cells starving out due to lack of blood supply with accelerating growth. Since then, I have been fascinated by tumor angiogenesis that might be an attractive therapeutic target.In 1989, vascular endothelial growth factor (VEGF) and vascular permeability factor (VPF) turned out to be identical. In 1992, VEGF expression was distributed surrounding necrosis area in GBM. In 1993, anti-tumor effect of monoclonal antibody for VEGF via inhibition of angiogenesis on various tumor models including glioma was verified in vivo. In 1996, VEGF was found to inhibit the functional maturation of dendritic cells, suggesting that therapeutic blockade of VEGF may improve prospect for immunotherapy as well as inhibition of angiogenesis. Those findings made me excited with visionary idea that combination therapy of anti-VEGF therapy and dendritic cell-based immunotherapy might be a potential therapeutic approach for GBM. Currently, I am dedicated in clinical study of dendritic cell-based immunotherapy and bevacizumab for GBM.Since graduating from medical school and discovery of VEGF in the same era, my clinic and research have been supported by serendipity of a vast of experiences and many people. I would give take-home message to next generation that originality and creativity were cultivated in real-world, and that serendipity and integration were precious for development of basic and clinical research.

Introduction Among metastatic brain tumors, especially in cases where the primary tumor and metastatic brain tumor are found at the same time, it is necessary to consider the priority of treatment for intracranial lesions and the means to obtain a definitive diagnosis. In this study, we performed a statistical analysis on the factors affecting mean survival (mOS) in patients with concurrent primary and metastatic brain tumors. Subjects and Methods A total of 252 patients with metastatic brain tumors treated at our hospital since 2014 were divided into two groups: simul-meta (58 patients) and non-simul-meta (194 patients). Age, sex, primary tumor, number of tumors, presence or absence of metastasis to other organs, localization of intracranial lesions, presence or absence of carcinomatous meningitis, performance status (PS), details of therapeutic intervention (radiation therapy, chemotherapy, surgery). The background factors between the two groups were analyzed using the chi-square test. Factors affecting mOS were evaluated by univariate analysis with log-rank test and multivariate analysis with Cox proportional hazards test. Results In simul-meta and non-simul-meta, mOS was 328 and 295 days, respectively (p=0.864). As a background, lung cancer (76%: 59%; p = 0.02) and surgical intervention group (28%: 11%; p Discussion In patients with concurrent disease, it is important to complete treatment for intracranial lesions, including surgical treatment, and maintain a general condition that allows chemotherapy to be administered. In addition, considering the frequent occurrence of lung cancer, it is necessary to develop a treatment plan with molecular target therapy in mind.

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

A thrombosed giant aneurysm of the V1 and V2 segments of the vertebral artery (VA) is rare. Therefore, there is controversy regarding its optimal treatment. A case of a symptomatic giant VA aneurysm located in the V1 to V2 segments on the left treated successfully by endovascular trapping of the VA is reported. A 68-year-old woman presented with swelling in the left anterior neck. Computed tomography angiography (CTA) showed a giant aneurysm measuring 47 × 58 × 47 mm3 in the left neck. Ten days after her first visit, she presented with sudden onset of left anterior neck pain. Repeated CTA showed a partial thrombus in the aneurysm. Angiography showed two thrombosed giant aneurysms located in the V1 to V2 segments of the left VA. After endovascular trapping for the aneurysms, the anterior neck pain resolved and the aneurysm gradually shrank. This case demonstrates that endovascular surgery is better than open surgery because it is less invasive. When performing endovascular treatment, trapping will be an alternative strategy for a symptomatic giant thrombotic aneurysm of the V1 and V2 segments of the VA if the patient can tolerate ischemia.

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.

Background We have reported an extremely rare case of a frontal convexity tumor diagnosed as IgG4-related disease (IgG4-RD) with unique neuroradiological images. Case Description A 64-year-old man with a history of monoclonal gammopathy of undetermined significance and conservative treatment had presented with a left facial spasm. Computed tomography showed a high-density round tumor with perifocal edema in the right frontal convexity. Magnetic resonance imaging demonstrated unique findings, including low signal intensity on T1- and T2-weighted, fluid-attenuated inversion recovery, and diffusion-weighted images, with slight gadolinium enhancement. The tumor was totally removed via right frontal craniotomy. It had been located in the subdural space, was not adherent to the dura, and was less vascular than meningiomas. Histological investigation demonstrated plasma cells that were strongly positive for IgG4 and contained κ and λ light chains at a ratio of 1.5:1. The serum IgG4 level was elevated. The tumor met the diagnostic criteria for IgG4-RD. The patient was followed up for 3 years during postoperative adjuvant steroid therapy. The steroid therapy was discontinued, and during the next 4 years, neither tumor recurrence nor symptoms were observed. Conclusion Intracranial IgG4-RD with smoldering monoclonal gammopathy of undetermined significance is extremely rare. We reviewed the differential diagnosis of plasma cell granuloma and plasmacytoma, therapeutic implications, and clinical outcomes. Complete resection of a conspicuous and solitary IgG4-RD lesion in the frontal convexity is simple and could provide a cure with less-aggressive adjuvant therapy.

Methods for assessing platelet function in patients with neurovascular disease remain controversial and poorly studied. This study aimed to assess associations between thromboelastography 6s (TEG6s) measurements and postoperative ischemic complications in patients with unruptured intracranial aneurysms (UIAs) treated by coil embolization.Eighty-four patients with UIAs taking a combined aspirin and clopidogrel protocol were retrospectively reviewed from January 2021 to May 2022. Blood samples were obtained for TEG6s to assess platelet function on the day of coil embolization. To identify acute ischemic complications, diffusion-weighted imaging (DWI) was performed within 24 h after coil embolization. Multivariate logistic regression analysis was conducted to identify potential risk factors for postoperative positive DWI (DWI (+)) lesions.Forty-three of the 84 patients (51%) with DWI (+) lesions were identified. Compared with patients without DWI (+) lesions, Adenosine diphosphate (ADP)-induced platelet-fibrin clot strength (MAMA

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.

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.

Patient: Male, 42-year-old Final Diagnosis: Traumatic posterior cerebral artery aneurysm Symptoms: Deterioration of mental status and disorientation Medication: — Clinical Procedure: Parent artery occlusion by endovascular approach Specialty: Neurosurgery Objective: Unusual clinical course Background: Subdural hematoma (SDH) caused by traumatic intracranial aneurysm (TICA) is rare. TICAs are known to rupture easily, resulting in a high morbidity and mortality rate. Therefore, accurate diagnosis and treatment are crucial for preserving life. We describe a case of delayed SDH in the setting of posterior cerebral artery (PCA) aneurysm. Case Report: A 42-year-old man presented with sustained head injury from a traffic accident, and was being followed-up conservatively for traumatic SDH and subarachnoid hemorrhage. Three weeks after the head trauma, the patient developed a sudden deterioration of mental status and disorientation. Computed tomography revealed de novo SDH at the cerebellar tentorium. Computed tomography angiography and magnetic resonance imaging demonstrated TICA in the PCA. The patient was diagnosed with SDH due to a ruptured PCA aneurysm at the quadrigeminal segment. To avoid SDH growth due to re-rupture of the aneurysm, parent artery occlusion was subsequently performed with no complications. The patient was discharged home 2 months after endovascular treatment, with moderate disability. Follow-up angiography 2 years after the operation showed no recanalization, and the patient had returned to work. Conclusions: TICA in the PCA can cause tentorial SDH with or without the presence of subarachnoid hemorrhage. Routine cerebrovascular assessment is crucial for head trauma with hematoma adjacent to the cerebellar tentorium. Parent artery occlusion via an endovascular procedure is an alternative treatment for TICA in the PCA that is less invasive than other approaches.

Neurointervention via transradial access (TRA) is challenging when the radial artery is narrow. We performed aneurysm embolization via TRA using a novel 3-Fr guiding sheath (GS) (Axcelguide; Medikit, Tokyo, Japan) with an outer diameter of only 1.76 mm for patients with a radial artery of inner diameter less than 2 mm, and described the whole procedure and pitfalls as a technical note. Here, we present two patients with radial arteries less than 2 mm. One patient had a narrow neck intracranial aneurysm at the bifurcation of the left vertebral artery and posterior inferior cerebellar artery, which was embolized with the primary coiling technique. The other was a patient with a wide-necked extracranial aneurysm in the cavernous portion of the right internal carotid artery, which was embolized with the transcell technique with stent. We utilized a 3-Fr GS, distal access catheter, and a 0.0165-inch microcatheter for coil embolization. All aneurysms were completely occluded, without neurological or puncture site-related complications including subcutaneous hematoma, radial artery occlusion, and vasospasm. This report provides the first description of neurointervention using a 3-Fr GS. The 3-Fr GS contributed to successful completion of TRA aneurysm embolization without neurological or puncture site-related complications in patients with radial arteries narrower than 2 mm. The 3-Fr GS may be useful to accomplish aneurysmal embolization via TRA even in patients with a small radial artery.

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.

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.

DuraGensup®/sup, an absorbable, engineered collagen-based artificial graft was introduced in Japan in September 2019 for cranial, transsphenoidal, and spinal surgeries. In addition to its efficacy and safety profile, owing to sutureless dural repair, DuraGensup®/supis widely accepted by neurosurgeons. Direct tenting with DuraGensup®/supis occasionally required in patients with large dural defects, particularly in cases of tumors adherent to the dura. To overcome this limitation, we introduced a surgical technique for epidural tenting using DuraGensup®/sup. A 78-year-old man with a history of alexia underwent craniotomy for resection of a left temporal lobe metastatic tumor. We completely removed the recurrent tumor, which was strongly adherent to the dura in the middle cranial fossa. A layer of DuraGensup®/supwas used as a subdural underlay beneath the autologous dura to close the wide dural defect. To avoid postoperative epidural fluid collection, we retracted the DuraGensup®/supfrom the epidural aspect and interposed several pieces of muscle, which were sutured on the subdural aspect to ensure that the muscle pieces securely plugged the dural defect. We placed an additional overlay of DuraGensup®/supalong the autologous dura. The patient's postoperative course was uneventful without cerebrospinal fluid leakage, tension pneumocephalus, or wound infection. Reoperations for tumor resection, particularly surgical procedures for refractory meningiomas and malignant tumors cause increasing fragility and wide defects of the dura. DuraGensup®/supplacement enables sutureless closure and is less time-consuming. Our technique of epidural direct tenting with DuraGensup®/supusing muscle pieces sutured on the subdural aspect could be useful in patients with significantly large dural defects and can prevent postoperative epidural fluid collection to ensure complete dural sealing.

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 vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of programmed cell death‐1 (PD‐1)/PD ligand‐1 (PD‐L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P

Macrophages are significant in immune responses, assuming a defensive role. In contrast, macrophages often cause undesirable changes. These reactions are processes by which macrophages express different functional programs in response to microenvironmental signals, defined as M1/M2 polarization. Tumor immunity has been acknowledged for contributing to the elucidation of the mechanism and clinical application in cancer therapy. One of the mechanisms for the refractoriness to cancer immunotherapy is the production of inhibitory cytokines by tumor cells or macrophages. Therefore, therapeutic strategy targeting macrophage or macrophage-derived cytokines may be effective and attractive. This review aims to investigate macrophage-associated pathophysiology and biological behavior in cancers, especially related to microenvironment, such as hypoxia, and current topics regarding some therapies involving macrophages.

Background Surgical treatment of vertebral artery (VA)-thrombosed giant aneurysms requires achieving both obliteration of the parent artery to prevent bleeding and dome thrombectomy to relieve the brain stem from mass effect. To secure both proximal and distal control of complex VA aneurysms, the contralateral approach to the aneurysm might be a useful alternative, as previously described. We successfully treated a case of VA-thrombosed giant aneurysm in a new, original way by combining craniotomy (ipsilateral and contralateral) and the endovascular technique. Case Description A 48-year-old man presented with a thrombosed giant aneurysm of the right VA compressing the brain stem. Treatment consisted of endovascular proximal ligation of the VA followed by 2-staged craniotomy for complete trapping of the aneurysm and intra-aneurysmal thrombectomy. The VA distal to the aneurysm was obliterated via contralateral craniotomy as only that provided adequate working space. Finally, intra-aneurysmal partial thrombectomy was performed through an ipsilateral craniotomy, which also made possible the obliteration of the eventually dangerous remaining vasa vasorum and additional proximal ligation of the VA. Conclusions Based on pathologic and surgical anatomical characteristics, a combination of an endovascular procedure with 2-staged craniotomy for complete trapping, thrombectomy, and vasa vasorum obliteration could be considered a feasible way to treat VA-thrombosed giant aneurysms located ventral to the brain stem and have their distal neck portions/patent vessel beyond the midline toward the contralateral side.

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.

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.

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.

Anti-angiogenic therapy induces the apparent normalization of vascular structure, decreases microvessel density (MVD), and improves tumor oxygenation in glioblastomas (GBMs). Six initial and recurrent tumor pairs after bevacizumab (Bev) treatment were compared with GBMs from nine patients resected under neoadjuvant Bev treatment with regard to histological characteristics; MVD; MIB-1 index; and expression of vascular endothelial growth factor (VEGF) and its receptors, hypoxia markers (hypoxia-inducible factor 1 alpha, carbonic anhydrase 9), and nestin as a marker of glioma stem-like cells. In recurrent tumors post-Bev treatment, while the MVD remained low compared with the paired initial tumors (pre-Bev tumors), the expression of hypoxic markers were increased and were even higher in expression compared with the paired pre-Bev tumors in three of the six cases. MIB-1 indices were similar among the initial GBMs, neoadjuvant group, and recurrent tumors post-Bev treatment. The nestin-positive cell ratio of the post-Bev recurrent tumors was as high as that of the pre-Bev tumors. The expression of VEGF and VEGFR1 was increased in the post-Bev recurrent tumors in three and four cases, respectively, compared with the paired pre-Bev tumors. In the majority of Bev-refractory GBMs, tumor hypoxia was present with a paradoxical decrease in MVD. These findings suggest that re-activation of tumor angiogenesis is not initially involved in the acquisition of resistance to Bev.

Early hematoma expansion (HE) is seen in approximately 30% of patients with intracerebral hemorrhage (ICH), but detecting patients with a high HE risk is challenging.The NAG scale is a simple predictive scale for HE in acute ICH patients. Multi-institutional validation of the usefulness of this scale was the aim of this study.We retrospectively reviewed 142 consecutive primary ICH patients admitted to our hospital between September 2016 and December 2018. The NAG scale consists of three factors: National Institutes of Health Stroke Scale (NIHSS) score ≥ 10, anticoagulant use, and glucose ≥133 mg/dl (1 point each). Patients underwent non-contrast computed tomography (CT) within 24 h of symptom onset and follow-up CT 6 h, 24 h, and 7 days after admission. We defined HE as increased hemorrhage volume 33% or an absolute increase of6 mL on follow-up CT. Poor prognosis was defined as a modified Rankin scale score of 4-6 at discharge. We performed logistic regression analysis and created receiver operating characteristic curves to determine the discrimination ability of the NAG score.Patients constituted 96 men and 46 women (median age: 64 years; median NIHSS: 11), and HE was observed in 38/142 patients (27%). Higher NAG sores were associated with HE (P .001), poor prognosis (P .001), and in-hospital death (P .001). The C statistic was 0.72 (95% confidence interval [CI]: 0.63-0.82) for HE, 0.67 (95% CI: 0.58-0.76) for poor prognosis, and 0.85 (95% CI: 0.74-0.95) for in-hospital death. Multivariate logistic regression analysis with known risk factors showed that NAG scale score was an independent risk factor for HE (odds ratio: 2.95; 95% CI: 1.57-5.52; P = .001).The NAG scale showed good discrimination in our multi-institutional validation.