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Purpose: Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3β (GSK3β), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma.Experimental Design: The active fraction of GSK3β that is phosphorylated at the tyrosine 216 residue (pGSK3βY216) was identified in glioblastoma cell lines. GSK3β activity for phosphorylating its substrate was detected in these cells by nonradioisotopic in vitro kinase assay.Results: Higher expression levels of GSK3β and pGSK3βY216 were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3β activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells in vitro. Inhibition of GSK3β was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type p53 and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation.Conclusion: These results indicate that GSK3β exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways. Consequently, we propose that GSK3β provides a potential therapeutic target in glioblastoma.

Supplementary Data from Potential Therapeutic Effect of Glycogen Synthase Kinase 3β Inhibition against Human Glioblastoma

Supplementary Figures 1-5, Table 1 from NKX2.2 Suppresses Self-Renewal of Glioma-Initiating Cells

Glioblastoma (GBM) is the most aggressive and destructive form of brain cancer. Animal models that can unravel the mechanisms underlying its progression are needed to develop rational and effective molecular therapeutic approaches. In this study, we report the development of mouse models for spontaneous gliomas representing distinct progressive stages of disease that are governed by defined genetic alterations. Neural stem/progenitor cell (NPC)-specific constitutive Ras activation in vivo plus p53 deficiency led to development of primarily anaplastic astrocytoma (grade III), whereas combined loss of p53 plus p16Ink4a/p19Arf led to development of GBM (grade IV) at 100% penetrance within 6 weeks. These glioma models showed enhanced stem cell properties (stemness) accompanied by malignant progression. Notably, we determined that, in our models and in human specimens, downregulation of the homeodomain transcription factor NKX2.2, which is essential for oligodendroglial differentiation, was correlated with increased tumor malignancy. NKX2.2 overexpression by GBM-derived glioma-initiating cells (GIC) induced oligodendroglial differentiation and suppressed self-renewal capacity. By contrast, Nkx2.2 downregulation in mouse NPCs accelerated GBM formation. Importantly, the inhibitory effects of NXK2.2 on GIC self-renewal were conserved in human cells. Thus, our mouse models offer pathobiologically significant advantages to investigate the nature of brain tumors, with improved opportunities to develop novel mechanism-based therapeutic approaches. Cancer Res; 71(3); 1135–45. ©2010 AACR.

The Notch signal regulates both cell viability and apoptosis, and maintains stemness of various cancers including glioblastoma (GBM). Although Notch signal inhibition may be an effective strategy in treating GBM initiating cells (GICs), its applicability to the different subtypes of GBM remains unclear. Here, we analyzed the effectiveness of MRK003, a preclinical γ-secretase inhibitor, on GICs. Nine patient-derived GICs were treated by MRK003, and its efficacy on cell viability, apoptosis, sphere forming ability and Akt expression level which might be related to Notch downstream and be greatly important signals in GBM was evaluated. MRK003 suppressed viability and sphere-formation ability, and induced apoptosis in all GICs in varying doses of MRK003. Based on their sensitivities to MRK003, the nine GICs were divided into "relatively sensitive" and "relatively resistant" GICs. Sensitivity to MRK003 was associated with its inhibitory effect on Akt pathway. Transgenic expression of the myristoylated Akt vector in relatively sensitive GICs partially rescued the effect of MRK003, suggesting that the effect of MRK003 was, at least in part, mediated through inhibition of the Akt pathway. These GICs were differentiated by the expression of CD44 and CD133 with flow cytometric analysis. The relatively sensitive GICs are CD44-high and CD133-low. The IC50 of MRK003 in a set of GICs exhibited a negative correlation with CD44 and positive correlation with CD133. Collectively, MRK003 is partially mediated by the Akt pathway and has strong therapeutic potential for CD44-high and CD133-low GICs.

Hyperintense lesions around the resection cavity on magnetic resonance diffusion-weighted imaging (MR-DWI) frequently appear after brain tumor surgery due to the damage of surrounding brain. The putative connection between the lesion and the prognosis for patients with glioblastoma (GBM) was explored. This retrospective study reviewed consecutive sixty-one patients with newly diagnosed GBM. Postoperative MRI was performed within 2 weeks after the initial surgery. We classified the cases into two groups depending on whether DWI hyperintense lesions were observed or not [DWI(+) group and DWI(−) group]. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. Forty-two patients were identified. The various extents of hyperintense lesions around the resection cavity were observed in 28/42 (66.7 %) cases. In the DWI(+) and DWI(−) groups, median PFS was 10.0 [95 % confidence interval (CI) 8.4–11.5] and 6.7 (95 % CI 4.9–8.5) months, respectively (p = 0.042), and median OS was 18.0 (95 % CI 12.2–23.8) and 17.0 (95 % CI 15.7–18.3) months, respectively (p = 0.254). On multivariate analysis, the presence of DWI hyperintense lesion was more likely to be an independent predictor for 6-month PFS (p = 0.019; HR, 0.038; 95 % CI 0.002–0.582). Tumor recurrence appeared outside the former DWI hyperintense lesion. Hyperintense lesions surrounding the resected GBM on MR-DWI might be a favorable prognostic factor in patients with GBM.

Glioblastoma (GBM) is one of the most lethal malignancies in humans, and novel therapeutic strategies are urgently required for its treatment. Tyrosine kinases (TKs) play a pivotal role in intercellular signal transduction and regulate crucial processes of tumor cell biological activities in GBM. This information provides the basis for the molecular target therapies for GBMs. TK inhibitors (TKIs) are expected to be effective therapeutic strategies. However, one important limitation is that GBMs exhibit marked resistance to the TKIs currently available, yet the mechanisms underlying TKI resistance have not been fully characterized. In the current review, we will address the varieties of chemoresistance mechanisms against TKIs in GBM. The mechanisms responsible for TKI refractoriness in GBMs are divided into 2 aspects. The first includes tumor-related concerns, such as a lack of target expression, the multiplicity of targets, redundancy, the appearance of resistant cells, and tumor changes in characteristics. The second includes drug-related concerns, such as inefficient drug effects, delivery, pharmacokinetics, and intolerable side effects. A better understanding of these mechanisms is needed to develop accurate tests to predict the lack of response to TKIs and for developing novel approaches aimed at overcoming the resistance to TKIs.

Glioma, the most common primary brain tumor, is characterized by proliferative-invasive growth. However, the detailed biological characteristics of invading glioma cells remain to be elucidated. A monoclonal antibody (clone HMab-1) that specifically and sensitively recognizes the isocitrate dehydrogenase-1 (IDH1) protein carrying the R132H mutation can identify invading glioma cells by immunostaining. To investigate the degree of invasion in gliomas of distinct grades and the proliferative capacity of the invading cells, immunofluorescent staining was conducted using antibodies against IDH1-R132H and Ki-67 on 11 surgical and autopsy specimens of the tumor core and the invading area. Higher numbers of IDH1-R132H-positive cells in the invading area correlated with a higher tumor grade. Double staining for IDH1-R132H and Ki-67 demonstrated that most invading cells that expressed IDH1-R132H were not stained by the Ki-67 antibody, and the ratio of Ki-67-positive cells among IDH1-R132H-positive cells was significantly lower in the invasion area than in the tumor core in all grades of glioma. These data suggest that higher grade gliomas have a greater invasive potential and that invading cells possess low proliferative capacity.

It is well known that chronic subdural hematoma (CSDH) occasionally arises in patients harboring an arachnoid cyst (AC) located in the middle fossa. Although the pathogenesis of CSDH associated with ACs remains unknown, several possible mechanisms have been proposed. In many reported cases, the patients with ACs in the middle fossa would be symptomatic according to development of CSDH. A 9-year-old girl presenting with a headache, nausea, and diplopia was referred to our department. Magnetic resonance imaging showed an AC in the left-side middle fossa and ipsilateral CSDH with a remarkable mass effect. Irrigation of the CSDH, partial removal of the outer membrane of the AC and CSDH, and endoscopic cystocisternostomy were performed to relieve her symptoms. Postoperative clinical course was excellent. Histopathological examination of the outer membrane of the CSDH demonstrated an arachnoid cell layer and hemorrhage from the granulation inside the membrane, and collagen fibers outside the membrane. These findings strongly suggested that the membrane and the content of the CSDH were derived from the outer membrane of the AC, and the CSF including the hemorrhage within the membrane, respectively. Laceration and hemorrhage from granulation tissue within the outer membrane of the AC are considered as one of the developmental mechanisms of the CSDH associated with AC in the middle fossa.

We treated a case of recurrent glioblastoma (GBM) with bevacizumab and assessed its effect biologically. A 55-year-old man with a left frontal lobe GBM was experiencing recurrence 7 months postoperation. We administered bevacizumab concomitant with temozolomide (TMZ). Follow-up magnetic resonance imaging (MRI) showed dramatic but temporal tumor reduction; however, the patient died of re-recurrent disease 6 months after beginning bevacizumab. We obtained an autopsy and analyzed the detailed molecular change. In the autopsy specimen, the quantity of microvessels was significantly reduced. Vascular endothelial growth factor receptor (VEGFR) 1 and VEGFR2 were downregulated, most likely due to a negative feedback mechanism by blocking of VEGF signaling. Matrix metalloproteinase (MMP)-2 and membrane-type 1 MMP were upregulated, resulting in the higher activation of MMP-2 in the autopsy specimen. MIB-1 staining index and phosphorylation levels of p44/42-mitogen-activated protein kinase did not change, whereas phosphorylated protein kinase B (Akt) was decreased in the autopsy specimen, suggesting compensation and/or amplification of other proliferative signaling pathways such as suppression of apoptosis signaling. Consequently, bevacizumab might inhibit the VEGF autocrine loop, which then causes a change in molecular expression related not only to enhancement of tumor invasion but also maintenance of tumor proliferation.

Arteriovenous shunting visualized by angiography is one of the major features of glioblastomas, and the visualization is dependent on the presence of extensive shunting. Extensive arteriovenous shunting is associated with the risk of poorly controlled intraoperative bleeding. When a tumor with extensive arteriovenous shunting is located in close proximity to the eloquent regions of the brain, a meticulous surgical procedure is necessary. In the present study, the site-oriented visualization of angiographical arteriovenous shunting was evaluated from the perspective of surgical treatment, with a particular focus on the perisylvian region that is in close proximity to motor and language regions (dominant hemisphere), as well as large arteries and veins. Twenty-six consecutive patients underwent a resection of glioblastoma between February 2007 and September 2012. All patients were presurgically examined using digital subtraction angiography. The patients were subdivided into the following two groups based on the location of the tumor: 1) perisylvian glioblastoma (18 patients) and 2) non-perisylvian glioblastoma (eight patients). Angiography to detect the arteriovenous shunting was performed. In addition, the number of intratumoral vessels, tumor proliferative activity (MIB-1 labeling index), and volume of intraoperative bleeding were evaluated and compared between the two groups. Angiographical arteriovenous shunting was definitively visualized in 13 of 18 (72 %) perisylvian glioblastomas, in contrast to only one of eight (13 %) non-perisylvian glioblastomas (p = 0.007). There were no significant differences between the two groups with respect to the number of intratumoral vessels, MIB-1 labeling index, and volume of intraoperative bleeding. However, massive intraoperative bleeding of > 2,000 mL occurred in one perisylvian glioblastoma patient. Glioblastomas in the perisylvian region tend to be associated with extensive arteriovenous shunting that can be definitively visualized by performing an angiography. Because arteriovenous shunting carries the risk of intraoperative bleeding, perisylvian glioblastomas—particularly in the dominant hemisphere—should be resected with a meticulous surgical procedure and strategy.

Nonenhancing intrinsic brain tumors have been empirically treated with a strategy that has been adopted for World Health Organization (WHO) grade II gliomas (low-grade gliomas: LGGs), even though small parts of the tumors might have been diagnosed as WHO grade III gliomas after surgery. However, the best surgical strategy for nonenhancing gliomas, including LGGs, is still debatable. LGGs have the following features: slow growth, high possibility of histologically malignant transformation, and no clear border between the tumor and adjacent normal brain. We retrospectively examined 26 consecutive patients with nonenhancing gliomas who were surgically treated at Kanazawa University Hospital between January 2006 and May 2012, with special reference to functional reorganization, extent of resection (EOR), and functional mapping during awake surgery. These categories are closely related with the features of LGG, i.e. functional reorganization due to slow-growing nature, EOR with related malignant transformation, and functional mapping for delineating the unclear tumor border. Finally, we discuss surgical strategies for slow-growing gliomas that are represented by LGGs and nonenhancing gliomas. In conclusion, slow-growing gliomas tend to undergo functional reorganization, and the functional reorganization affects the presurgical evaluation for resectability based on tumor location related to eloquence. In the clinical setting, to definitely identify the reorganized functional regions, awake surgery is recommended. Therefore, awake surgery could increase the extent of the resection of the tumor without deficits, resulting in the delay of malignant transformation and increase in overall survival.

Object Disturbance of the arcuate fasciculus in the dominant hemisphere is thought to be associated with language-processing disorders, including conduction aphasia. Although the arcuate fasciculus can be visualized in vivo with diffusion tensor imaging (DTI) tractography, its involvement in functional processes associated with language has not been shown dynamically using DTI tractography. In the present study, to clarify the participation of the arcuate fasciculus in language functions, postoperative changes in the arcuate fasciculus detected by DTI tractography were evaluated chronologically in relation to postoperative changes in language function after brain tumor surgery. Methods Preoperative and postoperative arcuate fasciculus area and language function were examined in 7 right-handed patients with a brain tumor in the left hemisphere located in proximity to part of the arcuate fasciculus. The arcuate fasciculus was depicted, and its area was calculated using DTI tractography. Language functions were measured using the Western Aphasia Battery (WAB). Results After tumor resection, visualization of the arcuate fasciculus was increased in 5 of the 7 patients, and the total WAB score improved in 6 of the 7 patients. The relative ratio of postoperative visualized area of the arcuate fasciculus to preoperative visualized area of the arcuate fasciculus was increased in association with an improvement in postoperative language function (p = 0.0039). Conclusions The role of the left arcuate fasciculus in language functions can be evaluated chronologically in vivo by DTI tractography after brain tumor surgery. Because increased postoperative visualization of the fasciculus was significantly associated with postoperative improvement in language functions, the arcuate fasciculus may play an important role in language function, as previously thought. In addition, postoperative changes in the arcuate fasciculus detected by DTI tractography could represent a predicting factor for postoperative language-dependent functional outcomes in patients with brain tumor.

While complete neck clipping of ruptured cerebral aneurysms prevents rerupture, recurrent subarachnoid hem- orrhage (SAH) due to the rupture of an aneurysm at the same sites of the previous aneurysm may occur, even if no resid- ual neck was detected during and after neck clipping. We present the cases of 3 patients with recurrent SAH due to re- growth after neck clipping of aneurysms at the anterior communicating artery (AComA). Two of the recurrent AComA aneurysms, accessed via the pterional approach, arose from the arterial wall adjacent to the previous necks; the third was a de novo aneurysm. Because their growth was in a posterior or superior direction, we posit that a portion of the neck was inadvertently not clipped during the first operation, and thus, flow in the AComA and perforators to the hypothalamus was maintained. Our findings suggest that unrecognized residual necks, vascular wall fragility around the earlier aneurysm, and hemodynamic changes following neck clipping contributed to their recurrence of SAH. Therefore, we recommend follow-up angiographic study to confirm complete neck clipping, especially in patients in whom the pterional approach was used.

Object Recently, intraoperative mapping has disclosed that, in addition to the classic language centers (that is, the Broca and Wernicke centers), other cortical regions may also play an important role in language organization. In the prefrontal cortex, although the lateral superior frontal gyrus (LSFG) could have language-related functions, there are no detailed reports that demonstrate the anatomical connection between the LSFG and other well-known language cortices, such as the Broca center. To show the existence of the structural connection, white matter association fibers between the inferior frontal gyrus (IFG) and the LSFG were examined using fiber dissection (FD) and diffusion tensor (DT) imaging–based tractography. Methods Eight cadaveric cerebral hemispheres were dissected to reveal the association fibers between the IFG and LSFG. The DT imaging–based tractography studies targeting the prefrontal cortex were obtained in 53 right-handed patients who had no organic cerebral lesions. Results The association fiber tract between Brodmann area 44/45 (the Broca center in the dominant hemisphere) and LSFG were detected in all specimens by FD. In the DT imaging–based tractography studies, the tract was identified in all patients bilaterally, except for the 4 in whom the tract was detected only in the left hemisphere. This tract was spread significantly wider in the left than in the right hemisphere, and left lateralization was evident in male patients. Conclusions Based on its character, this tract was named the Broca-LSFG pathway. These findings suggest a close relationship between this pathway and language organization. The structural anatomy of the Broca-LSFG pathway may explain speech disturbances induced by LSFG stimulation that are sometimes observed during intraoperative language mapping.

【目的】左総頚動脈（CCA）狭窄症に対するステント留置術の際にガイディングシースの保持を右上腕動脈経由のGooseNeck Snareで行った症例を報告する．【症例】70歳，男性．一過性の右片麻痺で発見された症候性左CCA狭窄症に対してステント留置術を行った．狭窄病変とCCA起始部の距離が短いためガイディングシースを十分遠位まで挿入できなかった．そのため右上腕動脈経由のGooseNeck Snareでガイディングシースを保持してステント留置術を施行し得た．【結論】上腕動脈経由のGooseNeck Snareによる左CCAのガイディングシースの保持は有用であった．Objective: We report a case of left common carotid artery stenting in which the guide sheath was held in place by a GooseNeck Snare inserted from the right brachial artery. Case presentation: A 70-year-old man presented with transient right hemiparesis and symptomatic left common carotid artery stenosis. During carotid artery stenting, we were unable to insert the guide sheath into the distal site of the carotid artery because of the short distance between the origin of the carotid artery and the stenotic lesion. By holding the guide sheath in place using the GooseNeck Snare inserted from the right brachial artery, stenting was performed successfully. Conclusion: Transbrachial GooseNeck Snare was useful for stabilization of the guide sheath during left common carotid artery stenting.

Introduction At present, the risk of future hemorrhage or ischemic insult from vertebral artery (VA) dissection cannot be estimated from available imaging data. We investigated the relationship between symptoms and the angiographic patterns of the dissecting site on balloon test occlusion (BTO) to develop guidelines for clinical decision-making. Methods We retrospectively reviewed 18 patients with unilateral VA dissection who presented with subarachnoid hemorrhage (SAH) or cerebral infarction. We analyzed the angiographic findings at the dissecting site on contralateral VA angiograms during BTO of the affected VA, classified the angiographic patterns into two types, and compared the symptoms they presented. Results Patients with dissection opacified from the distal to the proximal side are more likely to present with cerebral infarction than SAH. Conversely, patients with dissection opacified from the proximal to the distal side had a significantly higher incidence of SAH. Conclusions Angiographic findings at the dissecting site on contralateral VA angiograms during BTO of the affected VA are helpful for considering the treatment and prognosis of patients with VA dissecting aneurysms.

Accumulating evidence has revealed that the tyrosine kinases play a major role in glioma proliferation and invasion. The largest family of tyrosine kinases, the Eph family, and its ligands, the ephrins, are frequently overexpressed in glioma, suggesting important roles for their bidirectional signals in glioma pathobiology. Ephs bind to cell surface-associated ephrin ligands on neighboring cells and have many biological functions during embryonic development of the central nervous system, including axon mapping, cell migration, and angiogenesis. Recent findings suggest that Eph/ephrin signaling affects glioma cell growth, migration, and invasion in vitro and in vivo. However, their roles in glioma seem complex, because both tumor growth promoter and suppressor potentials have been ascribed to Ephs and ephrins. Here, we review recent advances in research on the role of Eph/ephrin signaling in glioma and suggest that the Eph/ephrin system could be a potential target of glioma therapy.

Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.

Background and importance We report the case of a patient with multiple neuroepithelial tumors of different histological cell types. In this patient, synchronous appearance of tumors of the central nervous system, ie, cervical ependymoma and a fourth ventricle choroid plexus papilloma, was noted. Clinical presentation A 36-year-old man presented with sensory disturbance of the bilateral upper extremities. Magnetic resonance imaging revealed a heterogeneously enhanced mass with syringomyelia in the upper cervical cord and a well-enhanced mass in the fourth ventricle. The patient underwent bilateral suboccipital craniotomy and laminectomy from the level of C1 to C3 for both lesions. The lesions were grossly resected. Histological and immunohistochemical examinations revealed that the cervical tumor was an ependymoma, and the fourth ventricle tumor was a choroid plexus papilloma. Conclusion The appearance of synchronous multiple neuroepithelial tumors of different histological cell types is extremely rare, and this is the first known case of ependymoma occurring synchronously with choroid plexus papilloma, both tumors having different histological cell types. Displacement and maldifferentiation of primitive, multipotent neuroepithelial cells may be a causative factor for this unique presentation.

Choroid plexus carcinoma (CPC) is a malignant tumor with a strong tendency to spread along the cerebrospinal fluid pathway. There is no standardized chemotherapy protocol for this rare tumor. We report a 38-year-old man with CPC in the lateral ventricle with obstructive hydrocephalus. Because of the poor demarcation between thalamus and fornix, subtotal tumor resection was performed. Postoperative spine magnetic resonance (MR) image revealed whole spinal axis dissemination. After diagnosis of CPC, the patient was treated with whole ventricular and spine radiation concomitant with temozolomide chemotherapy, although the O 6-methylguanine-DNA methyltransferase (MGMT) promoter was found to be unmethylated. Although MR images revealed transient stable disease during adjuvant therapy, tumor progression was depicted after four cycles of temozolomide therapy. We discuss the ineffectiveness of adjuvant temozolomide therapy for CPC in connection with O 6-methylguanine-DNA methyltransferase promoter methylation. © 2011 The Japan Society of Brain Tumor Pathology.

Glioblastoma (GBM) is the most aggressive and destructive form of brain cancer. Animal models that can unravel the mechanisms underlying its progression are needed to develop rational and effective molecular therapeutic approaches. In this study, we report the development of mouse models for spontaneous gliomas representing distinct progressive stages of disease that are governed by defined genetic alterations. Neural stem/progenitor cell (NPC)-specific constitutive Ras activation in vivo plus p53 deficiency led to development of primarily anaplastic astrocytoma (grade III), whereas combined loss of p53 plus p16Ink4a/p19Arf led to development of GBM (grade IV) at 100% penetrance within 6 weeks. These glioma models showed enhanced stem cell properties (stemness) accompanied by malignant progression. Notably, we determined that, in our models and in human specimens, downregulation of the homeodomain transcription factor NKX2.2, which is essential for oligodendroglial differentiation, was correlated with increased tumor malignancy. NKX2.2 overexpression by GBM-derived glioma-initiating cells (GIC) induced oligodendroglial differentiation and suppressed self-renewal capacity. By contrast, Nkx2.2 downregulation in mouse NPCs accelerated GBM formation. Importantly, the inhibitory effects of NXK2.2 on GIC self-renewal were conserved in human cells. Thus, our mouse models offer pathobiologically significant advantages to investigate the nature of brain tumors, with improved opportunities to develop novel mechanism-based therapeutic approaches. Cancer Res; 71(3); 1135–45. ©2010 AACR.

Background: Recurrence of glioma frequently occurs within the marginal area of the surgical cavity due to invading residual cells. 5-Aminolevulinic acid (5-ALA) fluorescence-guided resection has been used as effective therapeutic modalities to improve discrimination of brain tumour margins and patient prognosis. However, the marginal areas of glioma usually show vague fluorescence, which makes tumour identification difficult, and the applicability of 5-ALA-based photodynamic therapy (PDT) is hampered by insufficient therapeutic efficacy in glioma tissues. Methods: To overcome these issues, we assessed the expression of ferrochelatase (FECH) gene, which encodes a key enzyme that catalyses the conversion of protoporphyrin IX (PpIX) to heme, in glioma surgical specimens and manipulated FECH in human glioma cell lines. Results: Prominent downregulation of FECH mRNA expression was found in glioblastoma tissues compared with normal brain tissues, suggesting that FECH is responsible for PpIX accumulation in glioblastoma cells. Depletion of FECH by small interference RNA enhanced PpIX fluorescence after exposure to 5-ALA concomitant with increased intracellular PpIX accumulation in glioma cells. Silencing of FECH caused marked growth inhibition and apoptosis induction by PDT in glioma cells. Conclusion: These results suggest that knockdown of FECH is a potential approach to enhance PpIX fluorescent quality for optimising the subjective discrimination of vague fluorescence and improving the effect of 5-ALA-PDT.

In order to realize a less invasive robotic neurosurgery for the deeply seated tumor, a force detecting gripper with a flexible micro manipulator has been developed. Gripping force applied on the gripper is detected by strain gages fit on the gripper clip. Signal is conducted to the amplifier by the cables through the inner pipe of the manipulator. In order to approach to the deeply seated tumor through a narrow hole, a micro manipulator which can flex at the end part to face the gripper for the target and can rotate the closing direction of the gripper at the end of the manipulator has been developed. Some operation test showed that the developed manipulator can approach flexibly to the target, and the taking out force of a target on the soft material was detected clearly. © 2011 IEEE.

We evaluated the radiologic and clinical outcome of unruptured intracranial aneurysms treatment by using double microcatheters into the aneurysm. Between October 2006 and December 2009, 30 patients with 30 aneurysms were treated, including 12 patients treated by using double microcatheters and 18 patients treated by using a single microcatheter. The volume embolization ratio (VER) ―percentage of the coil volume occupying the aneurysmal lumen―was used as an index to evaluate the radiologic results. The VER of aneurysms treated with double-microcatheter technique was 25.2±4.8%, and the VER of aneurysms treated with the single-microcatheter technique was 21.6±3.9% (PAlthough in the aneurysms with a long aneurysmal diameter/short aneurysmal diameter (L/S) ratio less than 1.5, there were no significant differences between the 2 groups, in the aneurysms with a L/S ratio of 1.5 or greater, the VER of aneurysms treated with the double-microcatheter technique was 27.6±4.3%, and the VER of aneurysms treated with single-catheter technique was 19.7±3.4% (PThe double microcatheter technique is an effective and safe treatment for unruptured aneurysms.

We experienced an unusual case of a 15-year-old girl who suffered acute bilateral blindness caused by a frontal lobe tumour. She underwent emergent operation, after which her vision recovered. This case emphasizes that a brain mass can cause sudden onset blindness and an emergency intervention might save the patient's sight.

金沢大学医薬保健研究域医学系, Background: The retrochiasmatic region is one of the most challenging areas to surgically expose. The authors evaluated the transcrusal approach, which involves removal of the superior and posterior semicircular canal from the ampulla to the common crus, to expose the retrochiasmatic region and compared it with the retrolabyrinthine approach, both of which are a variation of the posterior petrosal approach with hearing preservation, with a special emphasis on the influence of temporal lobe retraction. Methods: Six sides of silicone-injected cadaveric heads were dissected using two approaches: the transcrusal approach and the retrolabyrinthine approach. For each craniotomy, 3 exposure parameters in the retrochiasmatic region were measured: (1) horizontal distance, (2) vertical distance, and (3) triangular area of exposure, at three different levels of temporal lobe retractions: 0, 5, and 10 mm of retraction from the level of the tentorial incisura. Results: Without temporal lobe retraction, only the transcrusal and not the retrolabyrinthine approach provided a direct exposure of the retrochiasmatic region, especially in the horizontal distance (p < 0.001). At all levels of temporal lobe retraction, the transcrusal approach provided greater exposure in the horizontal and vertical distances and in the area of exposure. Nonetheless, in the horizontal distance, the difference between the transcrusal and retrolabyrinthine approaches decreased along with increased temporal lobe retraction, and almost no difference was obtained at 10 mm of retraction. Conclusions: Posterior petrosal approaches can provide an excellent exposure of the retrochiasmatic region. Of these two approaches, namely, transcrusal and retrolabyrinthine with hearing preservation, the transcrusal approach offers greater exposure than the retrolabyrinthine approach. The beneficial effect of partial labyrinthectomy of the transcrusal approach to the retrochiasmatic region is accentuated in the exposure of the horizontal distance with less temporal lobe retraction. © 2010 Springer-Verlag.

BACKGROUND: Although the treatment of intracranial aneurysms with detachable coils is now widely accepted, the problem of coil compaction and recanalization remains to be solved. OBJECTIVE: To prevent recanalization by inducing intra-aneurysmal organization through prepared platinum coils coated with a novel cyclic peptide, SEK-1005, which can accelerate wound healing. METHODS: Using a rat aneurysm model, we examined the tissue response to these coils. An SEK-1005-coated coil (SC) or unmodified coil was inserted into the ligated external carotid artery (ECA) sac of rats. The sacs were removed on day 14 or 42 after coil insertion and subjected to conventional and immunohistochemical examination. We evaluated the tissue response in the ECA sacs and compared the percentage of organized areas in the ECA sacs of rats with SCs and unmodified coils. RESULTS: In SC rats, tissue organization was accelerated and the proliferation of α-smooth muscle actin- and vimentin-positive cells was promoted. On days 14 and 42, tissue organization was significantly greater in the ECA sacs of rats with SCs. CONCLUSION: SCs accelerated intra-aneurysmal organization in our rat aneurysm model suggesting that platinum coils coated with the novel cyclic peptide SEK-1005 may prevent recanalization and improve the clinical outcome in patients treated by coil embolization.

A retro-odontoid pseudotumor (ROP) is commonly associated with atlantoaxial subluxation (AAS). Here, we report a patient with ROP but without AAS. The patient was a 72-year-old man who did not have a history of rheumatoid arthritis or trauma to the head and neck. The patient was admitted to our hospital with gait disturbance, progressive motor weakness in both upper extremities and sensory disturbance in all four extremities. MRI showed a retro-odontoid mass with severe compression of the cervical spinal cord. A CT scan showed spondylotic changes in C5, C6, and C7 and bilateral facet fusion between C3 and C4. Dynamic radiography showed no evidence of AAS; there was loss of mobility at C2-C7 and excessive mobility at C1. Intraoperative pathological examination revealed that the lesion was a pseudotumor; therefore, posterior C1-C2 fixation was performed. MRI performed 6 months after the operation revealed that the pseudotumor was markedly reduced. To the best of our knowledge, patients with ROP without AAS are uncommon.

A 5-year-old male presented with scrotal migration of the catheter from a ventriculoperitoneal shunt manifesting as left scrotal swelling 4 months after implantation. Surgical obliteration of the patent peritoneal processus vaginalis that forms a corridor from the peritoneum to the scrotum was performed to avoid shunt malfunction. Review of the 26 reported cases including the present case revealed that most patients were up to 18 months old. Our patient was the oldest. Migration tended to occur within 6 months after implantation (mean 3.8 months, median 1.0 month). Involvement of the right side of the scrotum was prevalent (23 of 26 cases). Patent processus vaginalis and small peritoneal cavity probably contribute to scrotal catheter migration.

A 65-year-old man presented with a hyperplastic anomalous anterior choroidal artery (AChA) associated with a ruptured internal carotid artery aneurysm at the origin of a perforating artery manifesting as sudden onset of headache and vomiting. The aneurysm was too small for endovascular embolization, so we performed open surgery via the left pterional approach. Aneurysm clipping with preservation of the perforator was impossible, so we clipped the aneurysm neck and sacrificed the perforator. We also performed dome clipping because dome puncture resulted in continuous bleeding. Head computed tomography obtained 3 days after the operation showed cerebral infarction at the territory of the sacrificed perforator, but the patient suffered no neurological deficits. This case of internal carotid artery aneurysm with a perforating artery arising from the aneurysm dome shows that sacrifice of the perforator may be necessary to prevent rebleeding.

Four patients presented with intracerebral hemorrhage secondary to ventriculoperitoneal (VP) shunt insertion. VP shunt insertion was performed for idiopathic normal-pressure hydrocephalus (Case 1), hydrocephalus after cerebellar hemorrhage (Case 2), and subarachnoid hemorrhage followed by meningitis (Cases 3 and 4). Cerebral hemorrhage was confirmed 4 hours (Case 1), 2 days (Case 2), 7 days (Case 3), and 13 days (Case 4) after the operation. Cases 1 and 2 required intraoperative hemostasis for bleeding from the cortical vein. The 7 previous and our 4 patients were divided according to early (within 2 days after shunt placement, n = 6, Group 1) and delayed (5-13 days post-shunting, n = 5, Group 2) hemorrhage. Bleeding was attributable to venous occlusion due to intraoperative manipulation in Group 1, and to the vulnerability of brain tissue induced by a primary brain disease in Group 2.

A 69-year-old woman developed hydrocephalus after the embolization of an incidentally detected unruptured large internal carotid artery aneurysm with bare platinum coils. Endovascular embolization resulted in near-total aneurysm occlusion. She complained of mild headache 18 hours after the procedure and magnetic resonance (MR) imaging performed on the 6th post-treatment day revealed wall enhancement and perianeurysmal brain edema. Follow-up MR imaging showed recanalization of the aneurysm and gradual ventricular enlargement. She presented with typical symptoms of hydrocephalus including disorientation, gait disturbance, and urine incontinence at 7 months post-embolization. We removed 30 ml of cerebrospinal fluid by lumbar tap, which improved her condition without symptom recurrence for 2 months. She did not require shunt placement. Post-interventional hydrocephalus is known in patients with unruptured aneurysms embolized with bioactive second-generation coils. This case shows that hydrocephalus can occur after aneurysm embolization with bare platinum coils without intracranial hemorrhage.

Controversy remains over whether the cancer stem cell (CSC) theory applies to all tumors. To determine whether cells within a highly aggressive solid tumor are stochastically or hierarchically organized, we combined a reporter system where the nucleostemin (NS) promoter drives GFP expression (termed NS-GFP) with a mouse brain tumor model induced by retroviral Ras expression on a p16 Ink4a /p19 Arf -deficient background. The NS-GFP system allowed us to monitor the differentiation process of normal neural stem/precursor cells by analyzing GFP fluorescence intensity. In tumor-bearing mice, despite the very high frequency of tumorigenic cells, we successfully identified the NS-GFP + cells as tumor-initiating cells (T-ICs). The clonal studies conclusively established that phenotypical heterogeneity can exist among the cells comprising a genetically homogeneous tumor, suggesting that this aggressive brain tumor follows the CSC model. Detailed analyses of the NS-GFP + brain tumor cells revealed that T-ICs showed activation of the receptor tyrosine kinase c-Met, which functions in tumor invasiveness. Thus, the NS-GFP system provides a powerful tool to elucidate stem cell biology in normal and malignant tissues.

Dural arteriovenous fistulae (DAVF) occasionally lead to cognitive disorders whose reversibility after DAVF treatment remains unclear. We studied changes on pre- and post-treatment magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) scans in ten patients with cognitive disorder due to DAVF.We studied the symptoms, pre- and post-treatment MRI scans, SPECT findings, and mini-mental state examination (MMSE) and treatment results in ten patients with cognitive disorder due to DAVF. They were divided into two groups; the post-treatment MMSE score exceeded 25 points in group 1 (n = 6) and was lower than 24 points in group 2 (n = 4).In the six group 1 patients, pretreatment diffusion-weighted images (DWI) showed hyperintense areas, and SPECT scans demonstrated the preservation of vasoreactivity after acetazolamide challenge. In the four group 2 patients, pretreatment SPECT demonstrated hypoperfusion areas that coincided with the hyperintense areas seen on DWI; there were areas with marked disturbance in vasoreactivity. The post-treatment MMSE score in groups 1 and 2 improved by 13.7 +/- 2.4 and 3.8 +/- 1.0 points, respectively; the difference was significant at p0.01.In patients with cognitive disorder due to DAVF, the preservation of vasoreactivity on SPECT after acetazolamide challenge indicates that their cognitive disorder may be reversible by DAVF treatment.

To clarify the important factors contributing to outcome of moyamoya disease patients showing ischemia onset, we analyzed the long-term outcomes of 59 (24 males, 35 females) young moyamoya patients. The mean follow-up period and mean age was 11.1±7.8 years and 7.0±3.9 years old, respectively. Forty-three cases received bypass operations and 4 cases refused. The distribution of Glasgow Outcome Scale of all cases at onset and at follow-up showed no statistical difference. Eight cases (2 females, 6 males) showed neurological deterioration during the follow-up period, and the causes of worsened outcomes were 4 infarctions, 1 hemorrhage and 3 other complications. No cerebral hemisphere that received bypass surgery suffered infarction. Thus, it is concluded that the most important factor contributing to poor neurological outcome is infarction and that bypass surgery (direct or indirect bypass) can effectively prevent infarction over long terms. To clarify the important angiographic findings contributing to infarction occurrence, we analyzed the relationship between angiographical findings and cerebral infarction. In 143 bilateral hemispheres, we identified the presence of infarction (n=57) and transient ischemic attack (TIA, n=43). Forty-three hemispheres were asymptomatic. We analyzed the relationship between the occurrence of infarction and the status of stenosis/occlusion in the internal carotid artery (ICA) and PCA in each hemisphere of moyamoya disease patients. The incidence of PCA stenotic/occlusive lesions was significantly higher in infarcted (78.9%) than non-infarcted hemispheres (TIA: 14.0%; asymptomatic: 9.4%; p

A 48-year-old man presented with a pseudoaneurysm at the cervical portion of the left internal carotid artery (ICA) secondary to infection in the deep neck space. Magnetic resonance (MR) imaging demonstrated enhancement of the wall of the ICA and a pseudoaneurysm, considered to be sequelae of infection spread. ICA occlusion occurred on the next day resulting in sudden onset of right hemiparesis and motor aphasia. The ICA pseudoaneurysm shrank gradually and his neurological deficits improved with conservative therapy. One month later, he presented with aneurysm regrowth. The common carotid artery was occluded with Guglielmi detachable coils to block arterial flow into the pseudoaneurysm. There were no neurological complications. Marked enhancement of the ICA wall on computed tomography and MR imaging may indicate the possibility of vascular complications such as rupture, pseudoaneurysm development, or ICA occlusion, and consequent neurological deficits. ICA occlusion caused by spread of infection in the deep neck space may cause accelerated coagulopathy due to ICA wall inflammation.

We investigated the mechanism of phorbol 12-myristate 13-acetate (PMA)-induced migration of glioblastoma cells focusing on the p38 mitogen-activated protein kinase (MAPK)/heat shock protein 27 (Hsp27) pathway. PMA-induced cell migration and activation of p38MAPK in A172 glioblastoma cells. PMA-induced formation of lamellipodia and focal complexes was blocked by inhibiting p38MAPK with SB203580 or small interfering RNA (siRNA). Furthermore, activation of p38MAPK resulted in phosphorylation of an F-actin polymerization regulator, Hsp27. Immunohistochemical analysis showed that upon PMA stimulation, both unphosphorylated and phosphorylated Hsp27 were translocated to the lamellipodia. SB203580 or p38MAPK siRNA blocked these phenomena, indicating that Hsp27 phosphorylation and translocation from cytosol to membrane were mediated by p38MAPK. To address the question of whether endogenous Hsp27 participates in PMA-induced migration, we inhibited the expression of Hsp27 using Hsp27 siRNA. Although knockdown of Hsp27 by siRNA had little effect on p38MAPK activation, lamellipodia and focal complex formation was markedly inhibited. Migration was also abolished in Hsp27 siRNA-transfected cells. In conclusion, p38MAPK activation followed by Hsp27 phosphorylation was required for PMA-induced migration. Furthermore, Hsp27 itself played critical roles in PMA-induced migration. Our data provide substantial evidence for a model elucidating the molecular mechanisms of regulation of actin dynamics and migration by PMA-activated protein kinase C in glioblastoma cells.

External manual carotid compression is a non-invasive method to treat patients with cavernous sinus dural arteriovenous fistulae (CS-DAVF). We studied a group of patients with CS-DAVF to identify factors that made cure by compression therapy possible. We treated 23 patients with CS-DAVF without cortical venous drainage or a recent decline in visual acuity by compression therapy. All were followed up by magnetic resonance angiography (MRA) at one, three, six, and 12 months after treatment and the characteristics of the imaging findings, their neurological symptoms, and the patterns of symptom improvement were examined. In group A (n=8), cure was achieved by manual carotid compression; in the other 15 patients (group B), cure was not obtained. Group B manifested significantly higher ocular pressure and a significantly longer interval between symptom onset and treatment by manual carotid compression. In group A, venous drainage was via the superior orbital vein (SOV) with/without involvement of the inferior petrosal sinus (IPS); closure of the CS-DAVF occurred within 4.1 months after the start of treatment. In three patients symptom improvement progressed steadily and gradually. The other five cured patients experienced transient worsening of their symptoms at two to four months after the start of treatment, these resolved within four to seven months Manual carotid compression was effective in patients without retrograde venous CS-DAVF drainage or a severe decline in visual acuity. The factors that rendered cure by compression therapy possible were lower ocular pressure and a shorter interval between symptom onset and the start of treatment. Venous drainage in those patients was exclusively via the SOV without involvement of the IPS.

Background As direct surgery to treat giant aneurysms of the ICA is difficult, ICA occlusion is the conventional treatment in patients with BTO tolerance. To determine whether bypass surgery should be performed after carotid occlusion by trapping or proximal occlusion, we developed a treatment strategy that includes BTO and SPECT. Methods We report 19 patients with symptomatic giant aneurysms in the cavernous portion of ICA. The appropriate type of bypass surgery was determined by the results of BTO and SPECT. The type of ICA occlusion selected was based on the evaluation of retrograde filling of the aneurysm during BTO. Results In all 19 patients, the ICA was sacrificed; 10 patients also underwent bypass surgery (low-flow bypass with STA-MCA anastomosis, n = 7; medium-flow bypass with radial artery graft, n = 2; high-flow bypass with vein graft, n = 1). Coil trapping was performed in 11 patients; proximal occlusion in 8. In 18 patients, there were no ischemic complications after treatment; 1 patient who had been treated by proximal ICA occlusion developed transient ischemia due to an intra-aneurysmal thrombus. Cranial nerve palsies were improved in 16 patients. Conclusions Based on our experience, we recommend that patients with giant aneurysms in the cavernous portion of the ICA be evaluated by BTO and SPECT. In conjunction with bypass surgery, ICA trapping or proximal occlusion constitutes an effective treatment strategy.

Two patients with ruptured aneurysm associated with fenestrated basilar artery (BA) were treated using the endovascular approach. Angiography showed these patients had different types of BA bifurcation. One type had two points of bifurcation and a bridging artery in the BA fenestration, with the aneurysm at the bifurcation of the right loop of the fenestration. The aneurysm had different appearances on right and left vertebral angiograms. The other type had only one point of bifurcation, and the appearance of this aneurysm was similar on both angiograms. To ensure successful embolization, bilateral vertebral angiography should be performed for complete assessment of the morphological characteristics of aneurysm associated with fenestrated BA.

OBJECTIVE: Because it is difficult to predict the compaction of Guglielmi detachable coils (GDCs) after endovascular surgery for aneurysms, we studied the relationship between the coil packing ratio and compaction. Here, we propose a simple method for the preoperative estimation of coil compaction. Using follow-up angiograms, we studied the timing and degree of coil compaction in small terminal and side-wall aneurysms with narrow necks. METHODS: We studied 62 patients with acute ruptured intracranial aneurysms that were small ( RESULTS: Of the 62 patients, 16 (25.8%) manifested angiographic coil compaction (10 minor and 6 major compactions); the mean coil packing ratio was 51.9 ± 13.4%. The mean coil packing ratio in the other 46 patients was 80.5 ± 20.2%, and the difference was statistically significant (P < 0.01). In all 6 patients with major compaction, the mean packing ratio was less than 50% and all underwent re-embolization after a mean of 24.9 ± 1.1 months. The 10 patients with minor compaction were conservatively treated, and the degree of compaction did not change during a mean period of 24 months. We detected 93.8% of the compactions within 12 months of coil placement. The aneurysm was of the terminal type in 5 of the 6 patients with major coil compaction. CONCLUSION: In patients who underwent embolization with GDC-10s of aneurysms that were small and had a small neck, the optimal coil packing ratio could be identified with the formula 0.3 × a × b × c. The probability of coil compaction was significantly higher when the coil packing ratio was less than 50%. To detect coil compaction after embolization, follow-up angiograms must be examined regularly for at least 12 months. To detect major coil compaction in patients with terminal type aneurysms, angiographic follow-up should not be shorter than 24 months.

Background Hydrocephalus associated with intracranial germ cell tumors or disseminated medulloblastoma has been treated with ventriculoperitoneal shunt. However, this procedure has a potential risk of intraperitoneal metastasis of these brain tumors. To prevent this potential risk and to minimize the risk of infection, we developed a percutaneous long-tunneled ventricular drainage (PLTVD). To confirm the effectiveness, we retrospectively analyzed the results of this procedure. Methods From 1979 to 2003, we have treated 96 patients with germ cell tumors and medulloblastoma in our hospital. Of 96 patients, 59 (germ cell tumor, 31; medulloblastoma, 28) had hydrocephalus and 13 needed long-term cerebrospinal fluid drainage to manage the obstructive hydrocephalus due to persistent tumor or communicating hydrocephalus due to dissemination. We performed PLTVD for these cases using a flow-controlled shunt device and percutaneous long-tunneled shunt tube (peritoneal catheter) exiting at the upper abdomen and connecting to a closed drainage system. The occurrence of extraneural metastasis and the incidence of infection were evaluated. Results The average duration of drainage was 74 days (range, 34-115 days). All 13 cases received full-dose chemotherapy and radiotherapy without infectious complications or extraneural metastasis. Conclusions Percutaneous long-tunneled ventricular drainage was an effective method to manage long-lasting obstructive or communicating hydrocephalus with germ cell tumors and medulloblastoma.

We report 17 patients with symptomatic giant aneurysms in the cavernous portion of the internal carotid artery (ICA) who were treated by trapping the ICA on either side of the aneurysmal orifice or proximal occlusion using detachable coils. In all 17 patients, the ICA was sacrificed; 9 patients subsequently underwent bypass surgery (STA-MCA bypass, n=7; high-flow bypass with vein graft, n=1 and median flow bypass with radial artery graft, n=1). The other 8 patients did not. Coil trapping was performed in 10 patients and proximal occlusion in 7 patients. In 16 patients, there were no ischemic complications after treatment; 1 patient who had been treated by proximal occlusion of the ICA developed transient ischemia due to an intra-aneurysmal thrombus. Cranial nerve palsies were improved in 15 patients. ICA trapping or proximal occlusion using detachable coils was a highly successful treatment method, and we found the detachable coils effective and easy to use in this series of 17 patients.

Late-onset idiopathic aqueductal stenosis (LIAS) has been recognized as one of the clinical entities of adulthood hydrocephalus for decades, although there have been no radiological reports that show normal ventricular systems before the development of LIAS. We present here an adolescent case of LIAS with a previously normal ventricular system on magnetic resonance imaging (MRI). A 17-year-old boy had been suffering from chronic headaches and mild intellectual disability (MID) since he became a teenager, and this had prevented him from leading an ordinary school life. MRIs on admission showed triventriculomegaly from the aqueductal stenosis that had not been detected on previous MRIs, at least until the age of 6. An endoscopic third ventriculostomy was successfully performed, which improved both the headache and the MID. The developmental mechanism of LIAS remains unclear, although the membranous ependymal-like tissue observed in the aqueduct suggested the preceding existence of an inflammatory process around this region. To the best of our knowledge, this case was noteworthy because the development of LIAS was clearly demonstrated on MRI for the first time.