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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.

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.

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.

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

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

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

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.

Background and Purpose: Early hematoma expansion (HE) is seen in about 30% of intracerebral hemorrhage (ICH) patients, but detecting those patients with high risk of HE is challenging. The NAG scale was previously published as the simple predictive scale for HE in acute ICH patients. Multi-institutional validation for utility of the scale was the aim of this study. Methods: We retrospectively reviewed consecutive primary ICH patients, who were admitted between September 2016 and December 2018 to Jikei University Hospital or Kashiwa Hospital, Japan. NAG scale is consist of 3 factors based on examination on admission; NIHSS ≥10, Anticoagulant agents use, Glucose ≥133 mg/dl, with 1 point assigned for each parameter. Patients received an initial non-contrast computed tomography (CT) scan within 24 hours from symptom onset, and underwent follow-up CT scans at 6 hours, 24 hours, and 7 days after admission. The HE was defined as an increment in hemorrhage volume >33% or an absolute increase >6 mL on follow-up CT scans. Poor prognosis was defined as modified Rankin Scale 4-6 at discharge. We performed logistic regression analysis and receiver operating characteristic curves to determine discrimination ability of the score. Results: A total of 142 patients (96 men; median age 64 years; median NIHSS 11) were included in our study, and HE was observed in 38 patients (27%). Higher NAG sores were related to HE (P 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 the NAG scale was the independent factor for HE (Odds ratio, 2.95; 95% CI, 1.57-5.52; P = 0.001). Conclusion: Multi-institutional validation of the NAG scale showed good discrimination.

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.

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.

Objective Various risk factors for recanalization after coil embolization have been reported, but the indications for retreatment of recanalized aneurysms have not been determined. The aim of this study was to identify risk factors indicating the need for retreating recanalization during long-term follow-up (approximately 1 year). Methods A total of 172 unruptured saccular aneurysms in 155 patients treated by initial coil embolization between February 2012 and July 2019 were retrospectively analyzed. Intraluminal thrombosed aneurysms, aneurysms treated with stent assistance, and aneurysms followed without digital subtraction angiography (DSA) were excluded. Recanalization was identified in 31 aneurysms. Recanalized aneurysms (Meyer grade ≥2) were defined as major recanalization (MA); those that worsened to Meyer grade 1 were defined as minor recanalization (MI). Age, sex, aneurysm location, shape, five morphological variables (neck, height, width, dome-to-neck ratio, aspect ratio), aneurysm volume, endovascular technique, immediate Meyer grade, and volume embolization ratio (VER) were compared between MI (n = 18) and MA (n = 13). Predictors of MA were determined using logistic regression and receiver operating characteristic (ROC) curve analyses. Results On multivariate logistic regression analysis, spherical shape (odds ratio (OR) 11.9; 95% confidence interval (CI) 1.28–111) and VER (OR 1.92; 95% CI 1.13–3.28) were independent predictors of MA. On ROC curve analysis, the optimal cut-off value for the VER was 20.8% (sensitivity, 76.9%; specificity, 77.8%). Conclusions Lower VER and non-spherical shape appear to be independent risk factors for progression to MA in recanalized aneurysms, and packing with a VER >20.8% is expected to prevent progression to MA.

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.

We report the case of a patient with a spinal extradural arteriovenous fistula (AVF) associated with Cowden syndrome (CS) that was successfully treated by endovascular surgery. CS is an autosomal dominant disorder associated with diverse symptoms caused by a deleterious mutation in the phosphatase and tensin homolog (PTEN) gene. A 67-year-old woman was diagnosed with CS based on her medical history of multiple cancers for which she underwent abdominal surgery, macrocephaly, Lhermitte-Duclos disease, and facial papules. Her genetic testing demonstrated a PTEN mutation. She presented with progressive paraparesis and her MRI of the thoracolumbar spine showed the spinal cord edema along with flow voids. A spinal angiogram demonstrated a spinal extradural AVF with the perimedullary drainage. The AVF was successfully treated by endovascular surgery. The PTEN mutation can accelerate angiogenesis; thus, vascular anomalies are one of the diagnostic criteria of CS. However, only two cases of vascular anomalies involving the spinal cord in patients with CS have been reported previously. As the present case, both cases had a history of abdominal or retroperitoneal cancer. The PTEN mutation accompanied with abdominal surgery might have caused this vascular anomaly as the consequences of venous congestion around the thoracolumbar spine. A spinal extradural AVF should be considered in patients with CS who present with myelopathy, especially when the patient has a history of abdominal or retroperitoneal surgery. Regarding the treatment strategy, endovascular surgery should be considered because surgical insult could prompt secondary vascular anomalies resulting from neovascularization due to the PTEN mutation.

BACKGROUND In our previous study, bevacizumab (Bev), a humanized anti- vascular endothelial growth factor monoclonal antibody, downregulated the expression of programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immune checkpoint molecules, suppressed the infiltration of immunosuppressing cells such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and induces cytotoxic T lymphocytes (CTL) infiltration. To explore the possibility that inhibition of immunosuppressive cell infiltration and induction of CTL were attributed to not only Bev alone but also radiation (RT) or temozolomide (TMZ), we re-evaluated those alterations in the tumor tissue obtained from patients before and after the treatment using Stupp regimen (RT concomitant with TMZ) without Bev therapy. MATERIALS & METHODS We analyzed 10 tumor tissues from 5 patients with GBMs, which were paired samples of pre- and post- standard chemoradiotherapy (Stupp regimen: RT plus concomitant and adjuvant TMZ). Immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissue of 10 tumors. The sections were stained with anti-Ki-67, anti-VEGF-A, anti-VEGFR1, anti-VEGFR2, anti-CD34, anti-HIF1 alpha, anti-CA9, anti-nestin, anti-PD-1, anti-PD-L1, anti-CD4, anti-CD8, anti-Foxp3, and anti-CD163 antibodies. All expressions were assessed by authors with blinded clinical information. RESULTS Immunohistochemical analyses demonstrated that the expression levels of immune regulatory molecules such as Foxp3, CD163, PD-1, PD-L1, CD4, and CD8 were not significantly changed after the treatment using the Stupp regimen, compared with combinational usage of Bev. In addition, expressions of VEGF/VEGFR, hypoxic markers, and stem cell marker were not altered before and after Stupp regimen, either. Bev persistently inhibited immune suppressive cells and immune checkpoint molecules via down-regulation of VEGF pathway. In contrast, Stupp regimen did not affect immune regulations and tumor microenvironment. CONCLUSION These results suggested that immunosupportive effect was caused by Bev administration, leading to the novel combinational treatment strategies, in addition to Stupp regimen.

The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological “cold tumors” into the “hot tumors”. Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.

Background: Radiation-induced aneurysms have been previously reported; however, multiple and repeated de novo aneurysm formation chronologically and anatomically during long-term follow-up have not yet been observed. The pathogenesis of persistent radiation-induced vasculopathy is not fully understood. Case Description: A 31-year-old woman presented with intraventricular hemorrhage due to rupture of a right internal carotid artery (ICA) aneurysm that developed 17 years after surgical resection of a low-grade glioma in the right frontal lobe and postoperative radiotherapy (focal, 50 Gy/25 fractions). During glioma follow-up, salvage surgery with adjuvant gamma knife therapy and chemotherapy (ranimustine, vincristine, temozolomide) were performed for recurrence of the glioma. The aneurysm was treated with endovascular coil embolization. However, she experienced repeated intraventricular hemorrhages, and angiography revealed a de novo ICA aneurysm. The de novo aneurysms were treated with endovascular surgery using coil embolization and stenting. At 2 years after the third hemorrhage, the surgical wound became dehiscent, probably due to wound infection, thus epicranial soft tissue reconstruction using vascularized skin flap was performed. Despite multistaged endovascular surgery for the ICA aneurysm, she experienced repeated subarachnoid and intraventricular hemorrhages. Angiography revealed a de novo aneurysm of the right posterior cerebral artery and basilar trunk. She underwent coil embolization and stenting. Despite active management with endovascular surgery and close follow-up, she died after an eighth consecutive intraventricular and intracerebral hemorrhage caused by a de novo large aneurysm of the posterior cerebral artery. Conclusions: To the best of our knowledge, the present study is the first to report on of refractory and recurring de novo aneurysms treated by multistaged endovascular surgery during a long-term follow-up after radiotherapy and multistaged craniotomy for glioma. Key words: De novo aneurysm, Low-grade glioma, Multistaged craniotomy, Occult wound infection, Radiation-induced aneurysm

This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient’s PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays. FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays. The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.

// Ryota Tamura 1 , Toshihide Tanaka 2 , Keisuke Miyake 3 , Yusuke Tabei 4 , Kentaro Ohara 5 , Oltea Sampetrean 6 , Maya Kono 1 , Katsuhiro Mizutani 1 , Yohei Yamamoto 2 , Yuichi Murayama 7 , Takashi Tamiya 3 , Kazunari Yoshida 1 and Hikaru Sasaki 1 1 Department of Neurosurgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan 2 Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwashita, Kashiwa-shi, Chiba, Japan 3 Department of Neurosurgery, Kagawa University Hospital, Ikedo, Mituki-cho, Kita-gun, Kagawa, Japan 4 Department of Neurosurgery, Japan Red Cross Medical Center, Hiroo, Shibuya-ku, Tokyo, Japan 5 Division of Diagnostic Pathology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan 6 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan 7 Department of Neurosurgery, Jikei University Hospital, Nishishinbashi, Minato-ku, Tokyo, Japan Correspondence to: Hikaru Sasaki, email: // Keywords : bevacizumab; neoadjuvant; vascular normalization; hypoxia; glioma stem cell Received : February 08, 2016 Accepted : May 09, 2016 Published : May 17, 2016 Abstract To date, no clinical observations have been reported for histopathological changes in human gliomas under antiangiogenic treatment. We collected six glioblastomas resected under bevacizumab treatment. Histopathological investigation was performed by hematoxilyn-eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1α, CA9, and nestin as compared to eleven control glioblastomas to assess the differences in histological features, microvessel density, expression of VEGF and its receptors, tumor oxygenation, and status of glioma stem-like cells. In the six tumors resected under bevacizumab, microvascular proliferation was absent, and microvessel density had significantly decreased compared with that of the controls. The expressions of VEGF and its receptors were downregulated in two cases of partial response. HIF-1α or CA9 expression was decreased in five of the six tumors, whereas the decreased expression of these markers was noted in only one of the 11 control glioblastomas. The expression of nestin significantly decreased in the six tumors compared with that of the controls, with the remaining nestin-positive cells being relatively concentrated around vessels. We provide the first clinicopathological evidence that antiangiogenic therapy induces the apparent normalization of vascular structure, decrease of microvessel density, and improvement of tumor oxygenation in glioblastomas. These in situ observations will help to optimize therapy.

BACKGROUND: 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. CASE DESCRIPTION: An 83-year-old woman presented initially with dizziness and a gait deviation to the right. Magnetic resonance imaging (MRI) demonstrated a homogeneously enhanced mass in the right cerebellar hemisphere, and the tumor was subtotally removed by right suboccipital craniotomy. Histological 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 was less than 1%. The patient did not receive postoperative adjuvant radiation and chemotherapy. Two months after surgery, MRI showed growth of the residual tumor adjacent to the fourth ventricle, causing obstructive hydrocephalus. She underwent surgery again, and the tumor was totally removed. Histological 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. CONCLUSION: 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.

Introduction: Malignant glioma is the most common and aggressive primary brain tumor and requires multimodality treatment. Regarding surgical treatment, it is desirable to achieve maximum resection while considering function preservation. There is consensus that the survival prognosis is prolonged in gross or subtotal resection. However, there are cases in which biopsy or partial resection is performed due to the spread of lesions at the time of onset, underlying diseases, and social background. The purpose of this study was to retrospectively analyze the cases of malignant glioma at our university and to find out the factors related to the prognosis of cases in which removal was insufficient. Target: 55 cases of malignant glioma treated at our university since 2013 who underwent biopsy or partial resection. Method: Overall/progression-free survival period is the end point, and parameters are age, bevacizumab use, pathological diagnosis, photodynamic diagnosis use at operation, immunotherapy, ventricular invasion, contralateral invasion, sex, preoperative Performance Status (PS), postoperative PS, left or right, navigation use, steroid use, anticonvulsant drug type, radiation, IDH mutation, 1p19q co-deletion, MGMT methylation, TERT mutation, p53 mutation, biopsy or partial resection. After narrowing down the evaluation items by univariate analysis(Logrank test), multivariate analysis(Cox proportional hazard model)was performed. Result: The univariate analysis was significant in 5 items including bevacizumab use, radiation therapy, levetiracetam use, postoperative PS70 or higher, and partial resection instead of biopsy. Multivariate analysis detected two statistically significant differences, bevacizumab use and post-operative PS70 and above. There was no difference in the timing of bevacizumab use. Consideration: In poorly resection cases, the weight of postoperative treatment is high, so continuity of treatment and selection of postoperative treatment are important, and maintenance of ADL and use of bevacizumab are significant among them.

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

PURPOSE Vessel co-option and vascular mimicry are important resistant factors with ant-angiogenic treatment for glioblastoma, but those precise evaluation is not clear. We had three types of glioblastoma surgically removed specimens treated with / without bevacizumab (Bev). Using these samples, pathogenesis of co-option and mimicry was morphometrically clarified. MATERIALS / METHODS Three types of glioblastoma specimens were analyzed; 1) Bev naive (N group, n 14), 2) Bev effective that was treated preoperative neoadjuvant Bev (E group, n 5), 3) Bev refractory that recurred with continuous Bev treatment for paired E group (R group, n 5). Vascular density was defined as a number of type IV collagen covered lumen. Vascular mimicry was measured as a ratio of CD34 negative / type IV collagen positive lumen. Vessel co-option was graded to 3 degrees (-), (+), (++) at tumor margin. RESULTS (1)Vascular density was significantly lower with E group (p DISCUSSION/CONCLUSION The effect of Bev for glioblastoma was investigated on three points (vascular density, vascular mimicry and vessel co-option) and two pathogeneses were clarified. In Bev refractory case, density was decreased, but mimicry and co-option were increased compared to Bev naive case. In Bev effective case, density was decreased, but mimicry and co-option were unchanged. Anti-angiogenic treatment for initial and Bev refractory glioblastoma should consider targeting co-option and mimicry in addition to Bev.

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

Vascular endothelial growth factor (VEGF) is an attractive target of antiangiogenic therapy in glioblastomas. Bevacizumab (Bev), a humanized anti-VEGF antibody, is associated with the improvement of progression-free survival and performance status in patients with glioblastoma. However, randomized trials uniformly suggest that these favorable clinical effects of Bev do not translate into an overall survival benefit. The mechanisms of action of Bev appear to include the inhibition of tumor angiogenesis, as well as indirect effects such as the depletion of niches for glioma stem cells and stimulation of antitumor immunity. Although several molecules/pathways have been reported to mediate adaptation and resistance to Bev, including the activation of alternative pro-angiogenic pathways, the resistance mechanisms have not been fully elucidated; for example, the mechanism that reinduces tumor hypoxia remains unclarified. The identification of imaging characteristics or biomarkers predicting the response to Bev, as well as the better understanding of the mechanisms of action and resistance, is crucial to improve the overall clinical outcome and optimize individual therapy. In this article, the authors review the results of important clinical trials/studies, the current understanding of the mechanisms of action and resistance, and the knowledge of imaging characteristics and biomarkers predicting the response to Bev.

Unpredicted sudden death arising from hemangiopericytoma with massive intracranial hemorrhage is quite rare. We encountered a patient with recurrent infratentorial hemangiopericytoma presenting as life-threatening massive intracerebral hemorrhage. A 43-year-old man who had undergone craniotomy for total resection of an infratentorial hemangiopericytoma 17 months earlier presented with morning headache and generalized convulsions. Computed tomography revealed a massive hematoma in the right infratentorial region causing tonsillar herniation and emergency surgery was performed to evacuate the hematoma. Histological findings revealed hemangiopericytoma with hemorrhage. Neurological status remained unimproved and brain death was confirmed postoperatively. Hemangiopericytoma presenting as massive hemorrhage is quite rare. Since the risk of life-threatening massive hemorrhage should be considered, careful postoperative long-term follow-up is very important to identify tumor recurrences, particularly in the posterior cranial fossa, even if the tumor is completely removed.

A 52-year-old man with a history of malignant lymphoma of the cecum presented with lancinating facial pain in the left. Magnetic resonance imaging (MRI) revealed a tumor in the Meckel's cave extending along the trigeminal nerve. The tumor was partially removed via left retrosigmoid lateral suboccipital craniotomy. Histological examination showed findings consistent with diffuse large B cell lymphoma, which was later confirmed to be metastatic lesion from the cecal lesion. Postoperative chemotherapy with cyclophosphamide, high dose, cytarabine, steroid (dexamethasone), etoposide, and rituximab (CHASER) followed by whole brain irradiation (30 Gy) resulted in complete remission. Although facial pain persisted, the patient's general condition remained favorable and he did not experience recurrence over the 51-month follow-up period. Histological confirmation and awareness of malignant lymphoma are very important to determine the therapeutic strategy and to avoid misdiagnosis or delayed diagnosis. Long-term survival of patients with metastatic malignant lymphoma in the Meckel's cave extending along the trigeminal nerve was very rare. In addition, metastatic malignant lymphoma in the extra-axial and peripheral nervous tissue might be different from primary central nervous system lymphoma in the white matter, since the efficacy of chemotherapeutic agents against malignant lymphomas in the extra-axial regions is not attenuated by the blood brain barrier.

This report describes a rare case of a patient with growth hormone (GH)-secreting pituitary adenoma with malignant transformation resulting in multiple metastases to the dura mater of the cerebral convexity and high cervical spine. The patient was a 60-year-old man with a previous history of pituitary adenoma with suprasellar extension who had undergone transsphenoidal surgery, craniotomy for a convexity tumor, and suboccipital craniotomy for a cerebellar tumor. Thirteen years after the initial surgery, suboccipital craniotomy for a cervicomedullary junction tumor and cervicospinal surgery for a metastatic tumor was performed. Histologic findings of resected specimens demonstrated that the primary pituitary tumor was typical adenoma (similar to specimens from the initial surgery) but that the cerebellar and the dural tumor from the high cervical spine had a high incidence of mitotic figures, and cellular anaplasia with nuclear polymorphism and necrosis. In addition, the serum levels of GH were noted to have decreased with recurrence of the tumor. It was concluded that patients with pituitary adenoma, even when benign, must be carefully followed for signs of malignant transformation, and spinal or distant metastases.

The report describes a rare case of a patient with a calcified cerebellar metastasis arising from a primary ovarian cancer. The patient was a 33-year-old woman with a long history of stage IIIc ovarian cancer who had undergone transabdominal hysterectomy and bilateral oophorectomy followed by chemotherapy with gemcitabine hydrochloride. Incidentally, computed tomography (CT) revealed a cerebellar tumor with calcification. The size of the tumor gradually increased, and lateral suboccipital craniotomy was performed for gross total removal of the tumor. The histological diagnosis was ovarian mucinous adenocarcinoma. The patient's postoperative course was uneventful, and she was discharged two days after surgery. Brain metastases from ovarian cancer are rare. In the review of metastatic brain tumors arising from a primary ovarian cancer in the Department of Obstetrics and Gynecology at our institution, this phenomenon was noted in only 10 cases (0.24%) of 4,158 patients with ovarian cancer seen at our center over a period of 8 years. Moreover, only three cases of calcified metastatic brain tumor have been reported previously. In conclusion, complete tumor resection may be an acceptable approach for patients with calcified metastatic tumors both for therapeutic considerations and to obtain tissue for confirmation of histopathological diagnosis. Metastatic brain tumors can be calcified, and should be considered within the differential diagnosis of calcified intracranial lesions to avoid any delay in diagnosis or treatment.

A 63-year-old woman presented with a metastatic focus of papillary thyroid carcinoma in the cerebellopontine angle manifesting as lateral gazing nystagmus and slurred speech. Computed tomography demonstrated massive hemorrhage in the left cerebellar hemisphere. She was treated conservatively. Her symptoms resolved completely, but she experienced progressive deterioration in auditory acuity and ataxia over the next 6 months. Magnetic resonance imaging with gadolinium demonstrated an enhanced mass in the left cerebellopontine angle, and she was scheduled for elective resection of the tumor. Left retrosigmoid craniotomy was performed, and the tumor was subtotally removed except for a small amount at the junction of the trigeminal nerve and the pons. Histological examination confirmed a diagnosis of metastatic papillary thyroid carcinoma. The patient then underwent adjuvant gamma knife radiosurgery. Her clinical course was unremarkable, and her hypoacusis and ataxia resolved completely. Postoperative gallium scintigraphy revealed no residual tumor and no other systemic metastases. Hemorrhagic cerebellar metastasis from papillary thyroid carcinoma is extremely rare, but early recognition of metastatic cerebellar tumor should prompt immediate treatment to avoid the development of hearing loss, ataxia, and tonsillar herniation.

A 40-year-old man complaining of progressive body weight loss was diagnosed to have acquired immunodeficiency syndrome. Within 2 weeks after the initiation of combination antiretroviral therapy, he developed fever, massive cervical lymphadenopathy and a protruding subcutaneous abscess. A lymph node biopsy and abscess drainage revealed non-caseous granuloma and mycobacterium. The mycobacterium belonged to Runyon II group, but it showed no matches to any previously reported species. According to sequence analyses, the strain was identified as Mycobacterium shigaense. After six months of antimycobacterial treatment, the lesions were all successfully cured. This is the third case report of the novel mycobacterium, M. shigaense, presenting in associatioin with immune reconstitution syndrome.

Intracranial metastases from gastrointestinal stromal tumors (GISTs) are extremely rare. According to previous studies, only 15 cases have been reported to date. The interval between diagnosis of primary lesions and diagnosis of intracranial metastasis is long in most cases, so patients with intracranial metastatic GISTs survive for a long period of time. However, once an intracranial metastasis is diagnosed, the prognosis is dismal. Surgical treatment is considered to be the first option. However, surgical treatment alone is inadequate, and subsequent adjuvant therapy is required. In general, GISTs are considered radiation-resistant tumors, although radiotherapy could be applicable in patients prior to development of chemoresistance, and may occasionally provide pain control as palliative care. Chemotherapy is a standard therapy for GISTs. Constitutively active mutations in KIT and platelet-derived growth factor receptor (PDGFRA) play a crucial role in the biology of GISTs. GISTs show gain-of-function mutations in these kinases. Imatinib mesylate, a tyrosine kinase inhibitor with activity against KIT and PDGFRA, was the first drug approved for the treatment of metastatic or unresectable GISTs. Nonetheless, the vast majority of patients with advanced GISTs who benefit from imatinib will eventually develop progressive disease. In addition, a disadvantage of imatinib therapy for metastatic intracranial GISTs is that the drug cannot pass through the blood–brain-barrier (BBB). To address these problems, sunitinib has been approved as the second-line treatment for GISTs following imatinib failure. Sunitinib is thought to penetrate the BBB, thus expanding treatment options in imatinib-resistant disease. To improve clinical outcomes, multimodal combination therapy including rational molecular targeting agents needs to be developed.

Chronic encapsulated intracerebral hematoma is a unique type of intracerebral hematoma accompanied by a capsule that is abundant in fragile microvasculature occasionally causing delayed regrowth. A 37-year-old man who had undergone radiosurgery for an arteriovenous malformation (AVM) causing intracerebral hematoma in the left parietal lobe presented with headache, vomiting, and progressive truncal ataxia due to a cystic lesion that had been noted in the left thalamus, leading to progressive obstructive hydrocephalus. He underwent left frontal craniotomy via a transsylvian fissure approach, and the serous hematoma was aspirated. The hematoma capsule was easy to drain and was partially removed. Pathological findings demonstrated angiomatous fibroblastic granulation tissue with extensive macrophage invasion. The concentration of vascular endothelial growth factor (VEGF) was high in the hematoma (12012 pg/mL). The etiology and pathogenesis of encapsulated hematoma are unclear, but the gross appearance and pathological findings are similar to those of chronic subdural hematoma. Based on the high concentration of VEGF in the hematoma, expansion of the encapsulated hematoma might have been caused by the promotion of vascular permeability of newly formed microvasculature in the capsule.

Pediatric supratentorial ependymoma is very rare. In pediatric patients with supratentorial ependymoma, surgery alone may be an acceptable treatment when postoperative imaging confirms a gross total resection. Surgical resection is the standard and the most important treatment for ependymoma. The role of radiation therapy and/or chemotherapy following a gross total resection of supratentorial ependymoma has been uncertain. We report 2 cases of pediatric supratentorial ependymomas treated by gross total resection without postoperative adjuvant therapy. The first patient was a 7-year-old girl who presented with motor weakness and a hemiconvulsion of the right leg. Magnetic resonance imaging (MRI) revealed a large heterogeneously enhanced tumor in the left frontal lobe. The second patient was an 8-year-old girl who presented with headache. MRI revealed a huge heterogeneously enhanced tumor in the left frontal lobe. Gross total resection was achieved in both patients. Postoperative radiotherapy and chemotherapy were avoided following gross total resection. Histologically, the lesions demonstrated grade II ependymoma and anaplastic ependymoma, respectively. After follow-up of 120 months, neither patient had recurrence or dissemination. These results suggest that patients with pediatric supratentorial ependymoma treated by gross total resection alone have a favorable outcome, and postoperative radiotherapy and chemotherapy may be avoided.

Apart from generating T-helper (Th) effector responses, dendritic cells (DCs) are capable of initiating tolerance against the inciting antigens. Therefore, successful DC-based immunotherapy against malignant tumors requires an additional strategy to activate antigen-processing DCs. We studied the antitumor immune responses conferred by fusions of DCs and glioma cells in vitro. Fusion cells (FCs) were stimulated with polyriboinosinic polyribocytidylic acid [Poly(I:C)] and/or small interference RNA (siRNA) of IL-10 (IL-10-siRNA). Increased IFN-β expression induced by Poly(I:C) transfection was accompanied by enhanced production of IL-10 and IL-12p70 in the FCs. We also found that the ability of Poly(I:C)-transfected FCs to produce IL-12p70, but not IFN-β, was preserved when endogenous IL-10 was suppressed by IL-10-siRNA. To analyze the antigen-presenting function further, DCs, glioma cells, and peripheral lymphocytes were established from patients newly diagnosed with glioma. In this experiment, peripheral lymphocytes were stimulated with autologous FCs and restimulated with autologous glioma cells. CD4T cells isolated from the stimulated lymphocytes were subjected to the ELISPOT and WST-1 assays, which revealed that the IL-10-siRNA/Poly(I:C)-cotransfected FCs elicit an efficient tumor-specific Th1 response. These findings support the relevance of using Poly(I:C) and IL-10-siRNA in clinical immunotherapy protocols with an FC-based vaccine for patients with malignant glioma as a means of promoting Th1-induced tumor antigen presentation.

A 34-year-old male presented with a rare case of Rathke's cleft cyst (RCC) with calcification manifesting as persistent high fever and impaired consciousness. Physical findings revealed panhypopituitarism and bitemporal hemianopsia. Computed tomography showed mass lesions with marked calcification within the sella turcica and the suprasellar region. Magnetic resonance imaging showed solid and cystic components compressing the optic nerve. The preoperative diagnosis was craniopharyngioma. Initial endonasal transsphenoidal surgery (TSS) was performed with a surgical microscope, but the mass was extremely hard, so only partial removal was possible. Second endonasal extended TSS was performed with a neuroendoscope. The solid components were totally removed, but calcifications adhering to the optic nerve could not be removed completely. The histological diagnosis was RCC with marked granulation reaction. RCC with calcification is rare and difficult to differentiate from craniopharyngioma on neuroimages. Extremely thick calcification of the sella turcica enclosing granulation tissue and the cyst similar to armor, here called "armor-like calcification," is a characteristic imaging finding of RCC with calcification. The most important aspect is choosing a surgical approach to carefully and effectively relieve pressure upon the optic nerve. Endonasal extended TSS with an endoscope was effective in the present case.

A 67-year-old right-handed woman presented with a case of hemangiopericytoma in the lateral ventricle manifesting as digit number memory disturbance, sensory aphasia, and right quadrantanopsia. Magnetic resonance imaging demonstrated a 6-cm homogeneously enhanced mass in the trigone of the left lateral ventricle. The tumor was totally removed via the left inferior temporal gyrus. The histological findings were consistent with hemangiopericytoma. Differential diagnosis of hemangiopericytoma from meningioma and solitary fibrous tumors is very important because the clinical behavior of hemangiopericytoma is very aggressive, including local recurrence or distant metastases in the central nervous system and periphery. Histological confirmation is required to make a definitive diagnosis. The present patient did not receive radiation therapy, but developed no local recurrence or metastases. Complete surgical resection and awareness of hemangiopericytoma in the lateral ventricle are very important for good clinical outcome.

A 70-year-old man presented with a rare case of paranasal osteoma with secondary mucocele extending intracranially, manifesting as a generalized convulsion. Computed tomography showed a large calcified tumor adjacent to the cystic mass in the left frontal lobe. He underwent left frontal craniotomy, and the cystic lesion was totally removed. Histological examination confirmed the diagnosis of osteoma and mucocele. The giant paranasal sinus osteoma prevented growth of the mucocele into orbital recess and extension into the orbital space and paranasal sinus. The mucocele disrupted the dura in the anterior cranial fossa, resulting in a giant cystic intracranial lesion. Frontal osteoplastic craniotomy was effective for exposing both lesions and plastic repair of the dural perforation to prevent cerebrospinal fluid leakage and secondary infection.

A 50-year-old man presented with a dissecting aneurysm arising from the extracranial portion of the right posterior inferior cerebellar artery (PICA) causing subarachnoid hemorrhage (SAH) and manifesting as sudden onset of disturbed consciousness. Computed tomography showed SAH with ventricular reflux predominantly in the posterior fossa. Angiography revealed a fusiform aneurysm of the right PICA originating extracranially from the right vertebral artery. The aneurysm was isolated and excised. Histological examination showed dissection of the aneurysm wall. Dissecting aneurysm arising from the extracranial portion of the PICA is extremely rare.

Carotid plaque with hemorrhage leads to cerebral embolism and ischemic stroke. Plaque angiogenesis and angiogenetic factors such as vascular endothelial growth factor (VEGF) are critical in the progression of atherosclerotic carotid plaque and intraplaque hemorrhage. The correlation between plaque angiogenesis and presence of clinical symptoms was studied in 41 specimens obtained during carotid endarterectomy from 20 symptomatic and 21 asymptomatic patients treated for carotid artery stenosis. Histological findings using hematoxylin-eosin and immunohistochemical staining against von Willebrand factor and VEGF were examined. Intraplaque hemorrhage, calcification, necrosis, and invasion of foam cells were frequently observed in the carotid plaques from symptomatic patients compared with asymptomatic patients. Higher microvessel density was found in the carotid plaques with necrosis and invasion of foam cells compared with plaques without necrosis and/or foam cell invasion, and higher expression of VEGF was found from symptomatic patients compared with asymptomatic patents. These results suggest that plaque angiogenesis and higher level of VEGF expression may enhance the progression of ischemic symptoms in patients with carotid artery stenosis. Invasive macrophages in the plaque of symptomatic patients increase levels of VEGF and might enhance plaque angiogenesis and atherosclerosis progression.