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Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease with a high mortality rate and is known as a disease that is hard to diagnose because it may be overlooked by noncontrast computed tomography (NCCT) examinations that are most frequently used for diagnosis. To create a system preventing this oversight of SAH, we trained artificial intelligence (AI) with NCCT images obtained from 419 patients with nontraumatic SAH and 338 healthy subjects and created an AI system capable of diagnosing the presence and location of SAH. Then, we conducted experiments in which five neurosurgery specialists, five nonspecialists, and the AI system interpreted NCCT images obtained from 135 patients with SAH and 196 normal subjects. The AI system was capable of performing a diagnosis of SAH with equal accuracy to that of five neurosurgery specialists, and the accuracy was higher than that of nonspecialists. Furthermore, the diagnostic accuracy of four out of five nonspecialists improved by interpreting NCCT images using the diagnostic results of the AI system as a reference, and the number of oversight cases was significantly reduced by the support of the AI system. This is the first report demonstrating that an AI system improved the diagnostic accuracy of SAH by nonspecialists.

Neurofibromatosis type 1 (NF1) is a rare disease with an incidence of approximately one in every 3000 births. NF1 is mainly recognized as a tumor suppressor. Vasculopathy in NF1 is well described in the literature, but the association between NF1 and cerebral aneurysm has not been determined. We report a case of a 67-year-old female with NF1 accompanied by 8 cerebral aneurysms. Two of the patient's unruptured aneurysms, the large distal anterior cerebral artery (ACA) aneurysm and anterior communicating artery aneurysm, were initially treated with microsurgical clipping. The peripheral ACA aneurysm gradually increased in size and ruptured after 5 years. Coil embolization was performed for the ruptured aneurysm. Four of the 5 remaining unruptured aneurysms were treated surgically. The patient is currently well, without neurological deficit, and coil embolization is scheduled for the last remaining aneurysm. NF1 is a probable risk factor for multiple cerebral aneurysms due to vessel wall vulnerability. Therapeutic indications for patients with NF1 who show multiple cerebral aneurysms include strict follow-up and aggressive treatment to avoid subarachnoid hemorrhage.

Frailty is an indispensable concept among elderly. The purpose of this study was to determine the association between modified frailty index (mFI) and the postoperative outcome of surgery for spontaneous intracerebral hemorrhage (sICH).Outcome measures included an unfavorable outcome (modified Rankin Scale score of 4-6) or mortality at 6-8 months after hemorrhage. The prognostic ability of mFI was assessed by comparing adjusted and nonadjusted effects with the Hemphill's ICH score. The performance of the ICH score combined with mFI was assessed for discriminative ability.In total, 156 patients satisfied the inclusion criteria. Multivariate analyses revealed that higher mFI was significantly associated with an unfavorable outcome (p-value = 0.004) and mortality (p-value0.001). Compared with the ICH score alone, the ICH score combined with mFI revealed significantly higher discriminative ability for predicting postoperative outcome.mFI was a useful and reliable predictor of postoperative unfavorable outcome for sICH. Frailty may be an important essence to be considered before operation for sICS in the aging society.

Hyperplastic anomaly of the anterior choroidal artery (hyperplastic AchA) and posterior communicating artery of duplicate origin (duplicated Pcom) are rare vessel anomalies. With some literature review, we here report three cases of hyperplastic AchA, one of which was considered a new type of hyperplastic AchA. This case was not categorized into Takahashi classification.

Background We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. Methods and results We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. Conclusions We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Background: Improving the quality of stroke care is an urgent issue worldwide. To facilitate the measurement of quality of stroke care in Japan, we aimed to develop the Close The Gap-Stroke initiative in the J-ASPECT Study. Methods and Results: Quality indicators (QIs) were developed by a multidisciplinary board between 2015 and 2017. The process involved a systematic review of domestic and international studies related to primary and comprehensive stroke care. Adherence rates for the defined QIs were calculated for 8,826 patients with acute ischemic stroke from 227 hospitals between 2013 to 2015. Seventeen and 12 measures were identified as QIs for primary and comprehensive stroke care (PSC and CSC), respectively. We analyzed adherence rates of all 17 QIs for PSC and 8 QIs for CSC related with acute ischemic stroke. We found NIHSS documentation (91.0 %), CT/MRI performed within 25min and 24hr (80.9 % and 99.1 %), evaluation of extracranial vascular imaging (90.4 %), treated in stroke unit (57.4 %), tPA administration (89.5 %), tPA performed within 1hr (37.4 %), early and discharge antithrombotics medication (75.1 % and 49.0 %), discharge anticoagulation for atrial fibrillation patients (76.2 %), discharge statin medication (32.7 %), discharge antihypertensive agents (54.3 %), deep vein thrombosis prophylaxis (34.5 %), early rehabilitation (57.0 %), dysphagia screening (76.6 %), smoking cessation (59.8 %) and stroke education (71.4 %) for primary stroke care; and median time to multimodal CT or MR brain and vascular imaging (33 min), proper endovascular recanalization (81.7 %), tPA before endovascular recanalization (65.7 %), TICI grade 2b/3 after endovascular recanalization (73.0 %), median time of door to puncture (105 min), symptomatic intracranial hemorrhage after thrombolytic or endovascular therapy (7.45 %), 90 days mRS documentation after thrombolytic or endovascular therapy (60.8 %), occurrence of complication within 24 hours of diagnostic neuroangiography (7.27 %) for comprehensive stroke care. Conclusion: This is a promising first step to measure the QIs related to primary and comprehensive stroke care at a national level in Japan.

Introduction Patients with stroke often experience pneumonia during the acute stage after stroke onset. Oral care may be effective in reducing the risk of stroke‐associated pneumonia (SAP). We aimed to determine the changes in oral care, as well as the incidence of SAP, in patients with intracerebral hemorrhage, following implementation of a learning health system in our hospital. Methods We retrospectively analyzed the data of 1716 patients with intracerebral hemorrhage who were hospitalized at a single stroke center in Japan between January 2012 and December 2018. Data were stratified on the basis of three periods of evolving oral care: period A, during which conventional, empirically driven oral care was provided (n = 725); period B, during which standardized oral care was introduced, with SAP prophylaxis based on known risk factors (n = 469); and period C, during which oral care was risk‐appropriate based on learning health system data (n = 522). Logistic regression analysis was performed to evaluate associations between each of the three treatment approaches and the risk of SAP. Results Among the included patients, the mean age was 71.3 ± 13.6 years; 52.6% of patients were men. During the course of each period, the frequency of oral care within 24 hours of admission increased (P

Background: We have been performing the clipping on crossed wrapping (COCW) method using 2 strips of cotton on patients with an internal carotid artery blood blister-like aneurysm (IC-BLA). This method is reliable in preventing the clips from slipping off and the aneurysm walls from being damaged during clipping, and it enables more appropriate and safer clipping. Here we report the technical details of this method and the long-term outcomes of patients receiving this procedure. Methods: Fifteen of 1275 (1.5%) patients with a ruptured cerebral aneurysm who received treatment at the Saiseikai Kumamoto Hospital during the period from January 1, 1999, to December 31, 2016, had an IC-BLA. All 15 patients were treated with COCW, except for the first patient, who was treated using a single strip of cotton. The long-term outcome of the treatment was analyzed. Results: The mean follow-up period was 74 months. The first patient experienced rerupture of an aneurysm 10 days after the operation. No complications or regrowth of an aneurysm were observed in the remaining 14 patients during the follow-up period, except for 1 patient who received a reoperation for the regrowth of an aneurysm. As the final outcome, the numbers of patients with a Modified Rankin Score of 0, 3, and 6 were 13, 1, and 1, respectively. Conclusions: It is suggested that COCW is a treatment that enables safe and long-term management of lesions in IC-BLAs. Key words: Blood blister-like aneurysm, Clipping on crossed wrapping, Clipping on wrapping, Direct surgery, Internal carotid artery aneurysm

Radiation therapy is associated with the subsequent development of cerebral aneurysms; however, stereotactic radiosurgery (SRS)-associated aneurysm cases have not been well documented, with only 18 cases reported to date. We present a case of intracranial aneurysms with the rupture occurring 20 years after SRS for a growth hormone-producing pituitary adenoma. This is the first report of aneurysms diagnosed following transsphenoidal surgery and SRS for pituitary adenoma. We believe that the aneurysm reported here is a consequence of the SRS treatment, and thus this may be a very rare long-term complication following radiation treatments.

Tokunaga T, Watanabe S, Terasaki T, Takita T, Yonehara T, Nishi T, Kanazawa C, Kawano S, Yamakuma K, Yamaga M, Hashimoto Y. A study of standard criteria for hospital admission fees using the Nichijo-seikatsu-kino-hyokahyo in Kaifukuki rehabilitation wards. Jpn J Compr Rehabil Sci 2013; 4: 88-96. Purpose: To consider methods, based on study results, which would allow the differences in severity distribution between hospitals to be reflected in the hospital admission fee standards, using the Nichijoseikatsu-kino-hyokahyo (NSKH). Methods: A sample of 3,389 patients with stroke was analyzed. Scores obtained from NSKH were divided into four categories: scores 0 to 4, 5 to 9, 10 to 14, and 15 to 19. The numbers of patients in the four categories, changes in NSKH score (NSKH gain), and the return home rates were computed for all the participating hospitals and for each of six and other hospitals. We calculated the adjusted NSKH gain and adjusted return home rate at each hospital, using a correction method based on the distribution of NSKH scores for patients in all the participating hospitals (the standard severity distribution). Results: The following differences were found between the hospitals. The percentage of patients identified as “critically ill” (with NSKH scores of 10 to 19) ranged from 29.4 to 44.8%. Patients with NSKH scores of 15 to 19 (severely critically ill patients) occupied 33.6 to 50.2% of the patients with NSKH scores of 10 to 19 (critically ill patients). The mean NSKH scores on admission ranged from 6.52 to 8.60, while the adjusted NSKH gain ranged from 2.23 to 3.50 points and the adjusted return home rates ranged from 58.3 to 74.3%. Conclusion: There may be a need to give higher evaluation to hospitals that show high mean NSKH scores at admission. In addition, adjustment by the standard severity distribution may have to be used in determining NSKH gain and the return home rate.

Background Delayed development of intracranial aneurysms is an extremely rare complication of gamma knife surgery (GKS), with only 6 cases been reported to date. There are no reported cases after GKS performed to treat trigeminal neuralgia (TN). Of the 6 aforementioned cases, none referred to the natural history or pathophysiology of GKS-related intracranial aneurysm formation. Case Description We treated 2 patients with subarachnoid hemorrhage (SAH) resulting from rupture of an intracranial aneurysm that developed long after GKS. Case 1 involved a 77-year-old man who had undergone GKS to treat recurrent TN after microvascular decompression surgery. At 13 years after the GSK, he developed SAH from a ruptured left anterior inferior cerebellar artery in close vicinity to the left trigeminal nerve. He died from a premature rupture before intervention could be instituted. Case 2 involved a 72-year-old woman who developed SAH at 9 years after undergoing GKS for TN. A ruptured left superior cerebellar artery aneurysm was treated successfully with endovascular occlusion of the parent artery. She recovered well after the surgery, and was discharged to the rehabilitation hospital with a modified Rankin Scale score of 2. Conclusion Long-term observations are necessary after GKS performed for TN owing to the possibility of formation of intracranial aneurysms near the irradiated region.

A 40-year-old male smoker presented with a ruptured saccular aneurysm that formed de novo 10 months after normal magnetic resonance (MR) angiography findings. Computed tomography of the head at the second admission showed subarachnoid hemorrhage in the interhemispheric fissure and anterior basal cistern. MR and conventional cerebral angiography revealed an aneurysm arising from the anterior communicating artery (AcomA). MR angiography performed 10 months earlier, when he experienced transient loss of consciousness, revealed no anomalies at the AcomA. Intraoperatively, the de novo aneurysm was found to be a typical saccular aneurysm with a fragile wall.

The ruptured blister-like aneurysm originating from the anterior wall of the internal carotid artery (BLA) was known to have several pitfalls in diagnosis and treatment. Because of their unusual size and shape, BLAs are apt to be overlooked in the initial conventional examination. Furthermore, BLAs with fragile walls can rupture easily during microsurgery and cause postoperative fatal rebleeding more frequently than other aneurysms. We retrospectively reviewed 8 patients with BLA seen at our institution during the past 8 years to discuss couterplans for pitfalls in diagnosis and treatment. Seven of 8 patients were women between the age of 28 and 62 years (mean 48.6 years). BLAs were localized in the right side in 6 patients. In 4 patients, multiple angiographies were required to confirm the diagnosis because of lack of awareness of these lesions. We believe the key point to avoid misdiagnosis is to focus on the anterior wall of the internal carotid artery using several 3-dimensional images such as 3D-CTA. We treated all the BLAs with the so-called clipping on wrapping method (CWM). All patients except the first 1, who died of postoperative rebleeding due to incomplete obliteration of the neck, achieved favorable clinical outcomes. We describe the detailed procedure of CWM, which we modified to prevent poor clinical outcomes.

Object The aim of this study was to assess the quality of life (QOL) of patients who underwent surgery for asymptomatic unruptured intracranial aneurysms (UIAs). Methods The authors assessed QOL in 149 patients who had undergone microsurgical clipping of asymptomatic UIAs. They surveyed these patients using universal methods such as the 36-Item Short Form Health Survey (SF-36) for health-related QOL and the Hospital Anxiety and Depression Scale for anxiety and depression assessments. Results The patients' mean scores for each of the eight domains of SF-36 were comparable to those of a Japanese reference population. Analysis of data from the average-QOL and low-QOL subgroups showed that the low-QOL group contained a higher number of patients with preexisting heart diseases and restricted activities of daily living. Operative procedures and complications did not affect QOL. Conclusions Because 86% of the patients who underwent surgery manifested a QOL similar to the reference population, the authors suggest that elective surgery for asymptomatic UIAs is a reasonable treatment, especially in patients who are troubled by the risk of rupture. Postoperative decreases in QOL are not invariably attributable to the operation or its associated complications, but may be correlated with other chronic disorders. To select the appropriate treatment for asymptomatic UIAs, neurosurgeons and patients need information on the expected postoperative QOL.

Clipping an aneurysmal neck is considered an optimal treatment modality for ruptured and unruptured cerebral aneurysms. However, various anatomical variations in the relationships of parent artery, branched arteries, shape of the aneurysmal dome and aneurysmal neck frequently make it difficult to apply a simple clipping method using a single clip. To achieve safe and effective neck clipping, we use several techniques such as the clipping on wrapping method (COW method), tentative parallel clipping method (TPC method) and combination clipping with fenestrated clips (CCFC method). In this study, we analyzed the safety and effectiveness of these methods. In 515 surgeries for cerebral aneurysm performed between January 2001 and December 2003, the COW method, TPC method and CCFC method were used in 61 cases, 11 cases and 26 cases, respectively. In patients treated by the COW method, slight stenosis of the parent arteries was found on long-term follow-up studies in only 2 patients. In patients treated by the TPC method and/or CCFC method, complete obliteration of the aneurysm and preservation of blood flow through the parent arteries and branched arteries were confirmed. These 3 techniques are safe and effective methods for aneurysmal neck clipping.

Murin-double-minute 2 (MDM2) is an important negative regulator of the p53 tumor suppressor, and affects the p53 protein level and transcriptional activity. The genotype of the single nucleotide polymorphism in the promoter region of MDM2 (single nucleotide polymorphism [SNP] 309) is associated with the MDM2 protein expression level and the onset age of several types of cancer. The SNP309 genotype was investigated in 254 Japanese patients with glioma and 50 healthy subjects. The genotype frequency of SNP309 was T/T homozygous in 62 patients (24%), T/G heterozygous in 126 (50%), and G/G homozygous in 66 (26%) of the glioma patients, and was similar in the healthy subjects. The G/G ratio was higher in our Japanese subjects than in Western populations. Immunohistochemical study of glioma tissues showed that the G/G genotype was associated with higher expression of MDM2 protein compared to the T/T genotype, suggesting that SNP309 attenuates MDM2 protein expression in vivo. However, no association was found between the SNP309 genotype and the histological grade of glioma, age at disease onset, or p53 gene mutation rate. In our study population, SNP309 affected MDM2 protein level, but had no significant involvement in glioma tumorigenesis.

Objective: To compare the preoperative and postoperative health-related quality of life (QOL) and psychological state of patients with asymptomatic unruptured intracranial aneurysms (ICAs) who underwent elective surgery. Methods: Out of 67 patients who underwent neck clipping of ICAs, we assessed the QOL of 61 patients using Short Form-36 (SF-36); their psychological state was rated on the Hospital Anxiety and Depression Scale (HADS) before, 3 months, and 1 and 3 years after treatment. Results: The preoperative mean scores for each of the eight SF-36 domains except bodily pain were significantly lower in the study population than in the reference population. 14 (20.9%) patients experienced surgical complications defined as neurological deterioration and/or abnormal CT findings within 30 days of the operation. Despite some complications, the QOL of all operated patients returned to the mean level of the reference population 3 years after treatment. At 3 months after surgery, the scores for psychosocial activities and general health perception were transiently below the preoperative levels. According to the HADS, the patients experienced mild anxiety before the operation; it disappeared by the third postoperative month. Conclusions: Preoperatively, patients with unruptured ICAs reported a significantly decreased QOL. It further declined transiently after elective surgery, but it returned to the mean level recorded for the reference population within 3 years. Our findings suggest that these patients derived significant QOL benefits from their surgery. Hence subjective QOL issues should be considered in deciding whether treatment-related risks and their natural history, such as their potential rupture, warrant surgery of asymptomatic unruptured ICAs.

We report a 14-year-old boy with cavernous malformation of the optic chiasm. He had a 2-year history of gradually worsening visual disturbance. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a suprasellar mass, findings compatible with craniopharyngioma. The mass was biopsied and histological examination confirmed cavernous malformation. On the second day after the biopsy, he suffered chiasmal apoplexy due to intratumoural haemorrhage, lost visual acuity and developed a field cut. Cavernous malformations arising from the optic nerve and chiasm are extremely rare; only 29 cases have been reported to date. Most patients manifested acute visual acuity and visual field disturbances. Although MRI findings of cavernous malformations in the brain parenchyma have been reported, MRI findings on the optic nerve and chiasm may not be completely diagnostic. Of the 29 documented patients, 16 underwent total resection of the lesion without exacerbation of their preoperative symptoms; in some cases, resection was complicated by risk of damage to the surrounding neural tissue. As patients may suffer intratumoural haemorrhage after biopsy or partial removal of the lesion, the advisability of surgical treatment of cavernous malformations of the optic nerve and chiasm must be considered carefully.

We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c mice were subjected to repeated EGT treatments consisting of intratumoral co-injection of naked plasmids encoding the cytokine interleukin-12 (IL-12) (p35 and p40 subunits) and the suicide gene herpes simplex virus thymidine kinase (HSV-tk), followed by in vivo electroporation. The early anti-tumor effect was always stronger, and the rate of cure, as seen in the long-term follow-up, was always greater in the groups treated with combination EGT than in those treated with IL-12 or HSV-tk EGT alone. Systemic levels of IL-12 and IFN-gamma increased in both combination and IL-12-alone EGT-treated groups. Moreover, combination EGT for established subcutaneous tumors strongly reduced hematogenous lung metastases and increased survival time when live CT26 tumor cells were injected through the tail vein. Limited experiments on C57/B16 mice with murine melanoma also showed very similar trends. These results suggest that this simple and safe method of plasmid-mediated combination EGT may provide a potentially effective gene therapy for cancer.

Background: Muscarinic M3 (M3) receptor has been recognized as a major muscarinic receptor for smooth muscle contractions of the urinary bladder. Under the hypothesis that overexpression of M3 receptor in the urinary bladder would enhance urinary bladder contractions, we have transferred the M3 receptor gene into rat bladders using electroporation (EP) and evaluated the functional expression of the transferred gene. Methods: Plasmids expressing luciferase, a green fluorescence protein and M3 receptor were injected into the rat bladder and square-wave electric pulses were immediately applied. Two days after gene transfer, we analyzed gene expression. Immunohistochemical staining was performed and the contractile responses from isolated bladder strips, which were induced KCl, carbachol and electrical field stimulation (EFS), were evaluated. Results: The optimal conditions of electroporation were 8 pulses, 45 voltages, 50 milliseconds/pulses and 1 Hz. Under these conditions, luciferase gene expression was enhanced approximately 300-fold, compared to an injection of DNA only. Regarding immunohistochemistry with an anti-M3 receptor, an increase in immunoactivity was observed in the M3 receptor gene transferred rat bladder, compared to the bladder of the control rat. In rats with the transferred M3 receptor gene, carbachol- and EFS-induced maximum contractile responses of bladder smooth muscle strips significantly increased. Conclusions: These findings suggest that an in vivo EP procedure is an useful method for gene transfer into the bladder and that an overexpression of M3 receptor in the rat bladder enhances bladder contractility. This technique may become a new treatment modality for detrusor underactivity.

OBJECTIVE To investigate the possibility of in vivo gene transfer by attempting to transfer the neuronal nitric oxide synthase (nNOS) gene into rat bladder using electroporation. MATERIALS AND METHODS The bladder was exposed through an abdominal midline incision in 8-week-old male rats. Plasmid DNA of the marker genes green fluorescent protein (GFP) and luciferase, and the nNOS gene, was then injected into the subserosal space of the bladder and electroporation applied. At 72 h after gene transfer, GFP and luciferase were assayed in the isolated bladder and immunohistochemical staining used to detect nNOS; NOx released from isolated bladder strips was also assessed using microdialysis and high-performance liquid chromatography. RESULTS From the luciferase assay, 45 V, 1 Hz, 50 ms and eight pulses were selected as the optimum conditions for electroporation. Bladder specimens with GFP genes injected by electroporation showed bright and numerous sites of GFP expression in the smooth muscle layer. In rats with the nNOS gene injected by electroporation there was marked nNOS immunoreactivity, and NOx released from bladder strips was significantly greater than in the control groups. CONCLUSIONS These results suggest that electroporation is a useful technique for in vivo gene transfer into rat bladder smooth muscles, and that the nNOS gene transferred by this procedure functionally expresses and contributes to NO production.

Neurofibromin, the neurofibromatosis type 1 (NF1) gene product, contains a central domain homologous to a family of proteins known as Ras-GTPase-activating proteins (Ras-GAPs), which function as negative regulators of Ras. The loss of neurofibromin function has been thought to be implicated in the abnormal regulation of Ras in NF1-related pathogenesis. In this study, we found a novel role of neurofibromin in neuronal differentiation in conjunction with the regulation of Ras activity via its GAP-related domain (GRD) in neuronal cells. In PC12 cells, time-dependent increases in the GAP activity of cellular neurofibromin (NF1-GAP) were detected after NGF stimulation, which were correlated with the down-regulation of Ras activity during neurite elongation. Interestingly, the NF1-GAP increase was due to the induction of alternative splicing of NF1-GRD type I triggered by the NGF-induced Ras activation. Dominant-negative (DN) forms of NF1-GRD type I significantly inhibited the neurite extension of PC12 cells via regulation of the Ras state. NF1-GRD-DN also reduced axonal and dendritic branching/extension of rat embryonic hippocampal neurons. These results demonstrate that the mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance.

BACKGROUND Although the overall prognosis of patients with metastatic brain tumors is dismal, a small number survive longer than 10 years after craniotomy. We report 5 patients who survived for more than 10 years after undergoing treatment for metastatic brain tumor. METHODS The 5 patients who survived for more than 10 years after undergoing craniotomy were among 56 consecutively treated patients with solitary metastatic brain tumors. We retrospectively examined their clinical course, treatment, and variables associated with their longer survival and compared these 5 patients with other reported cases of metastatic brain tumor. RESULTS The histologic tumor types and the sites of origin of the primary tumor varied: two were from lung cancer and one each was from colon cancer, renal cell, and cervical carcinoma of the uterus. Common features among the long-term survivors were: systemic disease was absent, the metastatic tumor was located in the non-eloquent area of the non-dominant hemisphere, they were in good neurologic condition before surgery, there was a long interval between the diagnosis and treatment of the primary lesion and the diagnosis of the brain metastasis, and the patients received postoperative irradiation/chemotherapy. CONCLUSION Aggressive surgical treatment may be justified in young patients with a solitary metastatic brain tumor, as long as they are free of active systemic metastases.

The quaking gene family encodes single KH domain RNA-binding proteins that play vital roles in cell differentiation, proliferation, and apoptotic processes. The human quaking gene, Hqk, maps to 6q25-q26, where cytogenetic alterations associated with a variety of human malignancies, including gliomas have been reported. To assess possible relationships of Hqk with human diseases such as glial tumors, we first isolated the Hqk gene, characterized its structure and expression pattern, and carried out mutational analysis of Hqk in primary tumor samples. The Hqk gene contains 8 exons spanning a approximately 200 kb genomic region, and generating at least four alternatively spliced transcripts, Hqk-5, Hqk-6, Hqk-7 and Hqk-7B, of which Hqk-7 is abundantly expressed in brain. Analysis of primary tumors demonstrated a high incidence of expression alterations of Hqk in gliomas (30%; 6/20), but not in other tumors such as schwannomas (0/3), or meningiomas (0/8). Among the tumor samples showing expression alterations, two were devoid of all three major transcripts, one was missing only the Hqk-5 message, and only the Hqk-7 message was absent in two cases. Our results thus imply the involvement of Hqk in human glial tumor progression.

Objective: To evaluate the efficacy and safety of non-suture dural closure using a novel dural substitute (GM111) consisting of polyglycolic acid felt with a fibrin-glue-coated area commensurate in size with the dural defect. Methods: This was a non-controlled, open-label, multicenter clinical trial. The efficacy evaluation endpoints were 1) GM111's intra-operative capability to close dural defects and 2) prevention of cerebrospinal fluid (CSF) leakage and subcutaneous CSF retention throughout the postoperative period (evaluated by diagnostic imaging). Patients meeting the following three preoperative and two intra-operative selection criteria were enrolled: 1) between 12 and

Background: Esophageal carcinoma (EC) is a major malignancy with a poor prognosis. Although esophageal cancers rarely metastasize to the brain, the number of patients diagnosed with brain metastases (BM) from EC is steadily increasing. Therefore, the risk factors for BM from EC should be known. Here we reviewed our experiences and the previous literature regarding BM from EC. Methods: Between 2000 and 2013, we retrospectively reviewed the clinical features and neurological findings of 19 patients diagnosed with and treated for BM from EC to determine the clinical risk factors and features. Results: In all patients, the lesions were partially or completed located in the thoracic esophagus, and the average size of the EC lesion at diagnosis was 5.8 ± 2.9 cm, which was smaller than the previously reported size of EC lesions accompanied by BM. Patients without lung metastases were more common than those with lung metastases. The lesions in the 13 patients included squamous cell carcinoma (SqCC) in 9 (69.2%) and small cell carcinoma (SmCC) in 3 (23.0%). Six patients were not examined. Although there was no trend toward a higher incidence of BM in patients with adenocarcinoma and SqCC, this trend was observed in patients with SmCC. Excluding a single patient with SmCC, all patients had beyond stage III disease at EC diagnosis. Conclusions: Our study suggests that BM can occur in patients with EC lesions smaller than those previously reported; moreover, SmCC may be a risk factor for BM from EC.

A 73-year-old woman who suddenly developed left hemiparesis was admitted to our hospital. Ultrasonography on admission showed a free-floating thrombus (FFT) attached to an ulcerative plaque in the right common carotid artery. The FFT almost disappeared during treatment with intravenous anticoagulation therapy for acute stroke, but it reappeared when the therapy was discontinued. She underwent endarterectomy on day 13, after which she was free from stroke recurrence.

BACKGROUND Hemangioblastoma (HBL) in the suprasellar region is extremely rare. CASE DESCRIPTION A suprasellar mass was found in a 33-year-old woman with retinal HBL and bilateral adrenal pheochromocytomas. The diagnosis of von Hippel-Lindau (VHL) disease was confirmed preoperatively not only by these clinical manifestations but also by germline mutation study. The existence of VHL disease indicated a diagnosis of HBL for the suprasellar mass. The results of our mutation study indicated that this patient had type II VHL disease, suggesting that careful follow-up is essential for the early detection of renal cell carcinoma, which is often associated with type II VHL disease. Here, we summarize the previously reported features of sellar and suprasellar HBLs. CONCLUSIONS HBLs in this region may be one manifestation of VHL disease. Genetic testing of the VHL gene of our patient could provide useful information to determine appropriate medical care and management.

We report on an antitumor treatment involving electrogene therapy (EGT), a newly developed in vivo gene transfer method using electroporation. We carried out in vivo EGT in a subcutaneous model of CT26 colon carcinoma cells, using plasmid DNAs encoding interleukin 12 (IL-12) subunits. For this purpose, we developed two IL-12 expression systems: a cotransfer system using a plasmid encoding the IL-12 p40 subunit and a plasmid encoding the IL-12 p35 subunit, and a single-vector system using a plasmid expressing a p40-p35 fusion protein. Both transfer systems significantly inhibited the growth of CT26 tumor. Immunohistochemical analysis of IL-12 EGT-treated tumors revealed enhanced infiltration of CD8(+) cells into the tumor tissue, while reverse transcriptase-polymerase chain reaction confirmed the increased expression of interferon gamma within treated tumors. The same IL-12 EGT applied to the nude mouse model was not effective, suggesting the critical role of T cell infiltration in this treatment. The inhibitory effects revealed in experiments in which previously treated mice were rechallenged with a second inoculation of CT26 tumor cells suggested that IL-12 EGT may also establish partial systemic antitumor immunity. The growth of IL-12 EGT-treated Renca tumors, a renal cell carcinoma, was also significantly inhibited. These findings suggest that EGT of the IL-12 gene has the potential to be an effective anticancer gene therapy.

Background Although mutational inactivation and allelic loss in the NF2 gene appear to be causal events in the majority of vestibular schwannomas, involvement of another potentially important mechanism, transcriptional inactivation, has not been investigated. Results We cloned and functionally characterized the 5′-flanking region of the human NF2 gene and identified the molecular mechanisms that regulate NF2 expression. Luciferase assay and site-directed mutagenesis demonstrated that a 70-base pair (bp) region (−591 to −522 bp from the translation start site) was essential for the basic expression of the NF2 gene. A gel mobility shift assay indicated recognition by nuclear protein of the unusually long (≈66 bp) sequences in this region. Recognition was inhibited by either mutation of the binding core sequence or by methylation of three CpG sites. Point mutations at these CpG sites significantly decreased promoter activity, suggesting the importance of these sites. In 14 of 23 vestibular schwannomas, these three CpG sites were methylated in a site-specific manner and the methylation status was consistent with the expression of NF2 mRNA. Conclusion Suppressed expression by aberrant methylation or mutation of the promoter elements could be an alternative mechanism for inactivation of the NF2 gene.

This prospective randomized trial was performed to compare the effectiveness of intra-arterial ACNU with intravenous ACNU in newly diagnosed patients with supratentorial glioblastoma. The primary end points were overall survival and progression-free survival. Within 3 weeks after surgery, patients were randomly assigned to receive either intravenous or intra-arterial ACNU (80 mg/m2) once every 6 weeks concomitant with radiotherapy. Intra-arterial ACNU was administered for the first 3 courses followed by intravenous administration. Eighty-four patients were enrolled onto this study and among them 82 patients who passed eligibility criteria were analyzed. Patients characteristics were not different significantly between 2 treatment arms. Median survival and progression-free survival time was 59 and 24 weeks, respectively for intra-arterial arm and 56 and 45 weeks, respectively for intravenous arm. There was no significant difference respectively between two treatment arms. Among the prognostic variables including age, Karnofsky performance status, extent of surgery and treatment arm, Cox's proportional hazards model showed that age was the only significant factor for both survival and progression-free survival (P=0.003 and 0.016, respectively). With regard to toxicity, there was no significant difference between two treatment arms. Leukoencephalopathy was not observed in intra-arterial arm. In conclusion, intra-arterial ACNU when administered by the method in this study does not increase the survival and progression-free survival of newly diagnosed patients with glioblastoma over that afforded by intravenous ACNU.

A cytoplasmic protein tyrosine phosphatase (PTPase) designated as striatal enriched phosphatase with a molecular weight of 46 kDa (STEP46) is highly expressed in striatal neurons with dopamine D1-receptors. To examine the hypothesis that STEP46 is involved in the neuronal functions modulated by the cyclic adenosine 3', 5'-monophosphate (cAMP)-signaling system, we introduced the complementary DNA of STEP46 into the pheochromocytoma cell line PC12, which exhibits neuronal differentiation characterized by neurite outgrowth in response to cAMP and nerve growth factor stimulation, and we established subclonal cell lines that constitutively overexpress STEP46 protein with PTPase activity. The subclones expressing STEP46 showed increased neurite outgrowth during differentiation induced by a cAMP analogue (dibutyryl cAMP). The positive regulatory role of STEP46 in the cAMP-induced neuronal differentiation of PC12 cells indicates that STEP46 may play a role in neuronal processes modulated by the cAMP-signaling cascade as a PTPase.