Akira Yamaura

Molecular Classification and Survival Prediction in Human Gliomas Based on Proteome Analysis

The biological features of gliomas, which are characterized by highly heterogeneous biological aggressiveness even in the same histological category, would be precisely described by global gene expression data at the protein level. We investigated whether proteome analysis based on two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry can identify differences in protein expression between high- and low-grade glioma tissues. Proteome profiling patterns were compared in 85 tissue samples: 52 glioblastoma multiforme, 13 anaplastic astrocytomas, 10 atrocytomas, and 10 normal brain tissues. We could completely distinguish the normal brain tissues from glioma tissues by cluster analysis based on the proteome profiling patterns. Proteome-based clustering significantly correlated with the patient survival, and we could identify a biologically distinct subset of astrocytomas with aggressive nature. Discriminant analysis extracted a set of 37 proteins differentially expressed based on histological grading. Among them, many of the proteins that were increased in high-grade gliomas were categorized as signal transduction proteins, including small G-proteins. Immunohistochemical analysis confirmed the expression of identified proteins in glioma tissues. The present study shows that proteome analysis is useful to develop a novel system for the prediction of biological aggressiveness of gliomas. The proteins identified here could be novel biomarkers for survival prediction and rational targets for antiglioma therapy.

Alcohol consumption and frontal lobe shrinkage: study of 1432 non-alcoholic subjects

OBJECTIVES To evaluate the influences of chronic alcohol consumption on brain volume among social drinkers, as it is well known that alcohol misusers have a high risk of brain shrinkage. METHODS Frontal lobe volumes on MRI were compared with the current alcohol habits of consecutive 1432 non-alcoholic subjects. RESULTS After adjusting for other variables, age was found to be the most powerful promoting factor for the shrinkage with a odds ratio of 2.8 (95% confidence interval (95% CI) 1.23–3.06) for each 10 years of age. Regarding alcohol habit, 667 of the subjects were abstainers, and 157, 362, and 246 of the subjects were light (average 88.2 g ethanol/week), moderate (181.2 g/week), and heavy (418.1 g/week) drinkers, respectively. Moderate alcohol consumption did not increase the incidence of frontal lobe shrinkage (odds ratio 0.98; 95% CI 0.73–1.33), whereas heavy drinkers were at a higher risk compared with abstainers (1.80; 1.32–2.46). The contributory rate of alcohol consumption for frontal lobe shrinkage was 11.3%. CONCLUSION The brain tends to shrink physiologically with age. Heavy alcohol consumption seems to exaggerate this shrinkage in social drinkers. Moderate alcohol consumption does not seem to affect brain volume.

Microsurgical anatomy and clinical significance of the anterior communicating artery and its perforating branches.

OBJECTIVE Precise identification of the anomalous anterior communicating artery (ACoA) or the perforating branches of the ACoA is usually difficult on preoperative angiograms because of the vascular complexity around the ACoA and its small-caliber branches. The purpose of this study was to review the microsurgical anatomy of the ACoA and its branches to show their importance for the interhemispheric trans-lamina terminalis approach and ACoA aneurysmal surgery. METHODS In 30 cadaver brains, the ACoA and its branches were examined under magnification using a surgical microscope. RESULTS The ACoA was evident in all specimens and had variations consisting of plexiform (33%), dimple (33%), fenestration (21%), duplication (18%), string (18%), fusion (12%), median artery of the corpus callosum (6%), and azygous anterior cerebral artery (3%). The perforating branches were also observed in all cadaver brains. They were classified into subcallosal, hypothalamic, and chiasmatic branches according to their vascular territories. The subcallosal branch, usually single and the largest, supplied the bilateral subcallosal areas, branching off to the hypothalamic area. The hypothalamic branches, multiple and of small caliber, terminated in the hypothalamic area. CONCLUSION The incidence of anomalous ACoA was higher than has been previously reported, and any segment of the anomalous ACoA may have perforating branches regardless of diameter. Among the three branches, the subcallosal branch is the most important because it feeds bilateral subcallosal areas branching to the hypothalamic area.

Conservative management, gamma-knife radiosurgery, and microsurgery for acoustic neurinomas: A systematic review of outcome and risk of three therapeutic options

Abstract Conservative management, gamma-knife (GK) radiosurgery, and microsurgery are therapeutic options for acoustic neurinomas (ANs). To determine the outcomes and risks of these methods this systematic review analyzed data from 903 patients with conservative management, 1475 with GK radiosurgery, and 5005 with microsurgery from 38 studies identified in MEDLINE searches. Conservative management over a 3.1-year period showed that 51% of ANs showed a tumor growth, an average tumor growth rate was 1.87 mm year-1 , 20% of ANs ultimately required surgical intervention, and a third of the patients lost useful hearing. GK radiosurgery significantly reduced the percentage of ANs that enlarged, to 8%, and reduced the percentage that underwent microsurgery to 4.6% over a 3.8-year period. Microsurgery removed 96% of ANs totally, with tumor recurrence, mortality, and major disability rates of 1.8%, 0.63%, and 2.9%, respectively. The majority of ANs grow slowly, but ultimately require intervention. Carrying the risk of hearing loss, conservative management should be supplemented with close follow-up. With a low rate of morbidity, GK radiosurgery suppresses tumor growth and provides good tumor control. Microsurgery provides the best tumor control, although mortality and morbidity are not completely eliminated.

Outcome prediction in severe head injury: analyses of clinical prognostic factors

Retrospective analysis of 272 patients with severe head injury was performed. Patient age, Glasgow Coma Scale (GCS) score, pupillary abnormalities, impaired oculocephalic response, presence of subarachnoid haemorrhage, and multiplicity of parenchymal lesions on computerised tomography (CT) were examined. The CT findings were divided into 2 groups, diffuse brain injury (DBI) and mass lesion, according to the classification of the Traumatic Coma Data Bank. The DBI, basically, has no high or mixed density lesion more than 25 ml on CT, and was classified into 4 subgroups: DBI I includes injuries where there is no visible pathology; DBI II includes all injuries in which the cisterns are present with a midline shift of less than 5 mm; DBI III includes injuries with swelling where the cisterns are compressed or absent and the midline shift is less than 5 mm; DBI IV includes injuries with a midline shift of more than 5 mm. The mass lesions were categorised into 3 subgroups: epidural haematoma; acute subdural haematoma; and intracerebral haematoma. Outcomes were determined at 6 months following trauma using the Glasgow Outcome Scale. All DBI I patients recovered well. In the DBI II group, age, GCS score and detection of multiple parenchymal lesions on CT were significantly correlated with outcome. For the DBI III and IV groups, the only significant prognostic factor was the GCS score. In patients with a mass lesion, the GCS score was the only significant prognostic factor in the epidural haematoma group, but the GCS score and the presence of subarachnoid haemorrhage were predictive factors in the acute subdural haematoma group. Outcomes were unfavourable in the majority of patients with intracerebral haematoma. GCS score could predict outcome in all groups. The confidence of the outcome prediction ranged from 75.8 to 92.1%, depending on logistic regression analysis.

Familial occurrence of moya-moya disease: report of three Japanese families

Three Japanese families with moya-moya disease in six patients are presented. These six patients were among 49 cases of confirmed moya-moya disease in our experience, and the familial incidence was more than 12%. A relatively high familial incidence (7%) was found in the total Japanese series emphasising the important hereditary components in the pathogenesis of the disease.

Cathepsin D Is a Potential Serum Marker for Poor Prognosis in Glioma Patients

Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling which can be secreted from cancer cells. To identify a potential serum marker for gliomas, we investigated the gene expression levels of cathepsin D in 87 tissue samples and measured the protein concentrations in sera of glioma patients. The tissue samples consisted of 43 glioblastomas, 13 anaplastic astrocytomas, 22 astrocytomas, and 9 normal brain tissues. The results of real-time quantitative reverse transcription-PCR analysis showed that cathepsin D transcript levels became significantly higher as the glioma grade advanced (P = 0.0466, glioblastoma and anaplastic astrocytoma; P = 0.0008, glioblastoma and astrocytoma; P = 0.0271, glioblastoma and normal brain tissue; unpaired t test). Immunohistochemical analysis with anti-cathepsin D antibody revealed dense and spotty staining in the tumor cells with high transcript levels. The low expression of cathepsin D significantly correlated with long survival of the glioma patients. Furthermore, the glioblastoma patients with high gene expression of cathepsin D lived significantly shorter than those with low expression (P = 0.0104, Cox-Mantel log-rank test) and frequently had leptomeningeal dissemination (P = 0.0016, chi2 test). The multivariate analysis confirmed that the cathepsin D expression level was an independent predictor for short survival (P = 0.0102, Cox proportional hazard regression model). Measurement of the serum cathepsin D concentrations by ELISA showed a significant increase in the patients with high-grade gliomas as compared with the low-grade tumors (P = 0.0081, chi2 test). These results collectively suggest that cathepsin D could be a potential serum marker for the prediction of aggressive nature of human gliomas.

High linear energy transfer carbon radiation effectively kills cultured glioma cells with either mutant or wild-type p53

PURPOSE A mutation in the p53 gene is believed to play an important role in the radioresistance of many cancer cell lines. We studied cytotoxic effects of high linear energy transfer (LET) carbon beams on glioma cell lines with either mutant or wild-type p53. METHODS AND MATERIALS Cell lines U-87 and U-138 expressing wild-type p53 and U-251 and U-373 expressing mutant p53 were used. These cells were irradiated with 290 MeV/u carbon beams generated by the Heavy Ion Medical Accelerator in the National Institute of Radiologic Science or X-rays. A standard colony-forming assay and flow cytometric detection of apoptosis were performed. Cell cycle progression and the expression of p53, p21, and bax proteins were examined. RESULTS High LET carbon radiation was more cytotoxic than low LET X-ray treatment against glioma cells. The effects of the carbon beams were not dependent on the p53 gene status but were reduced by G(1) arrest, which was independent of p21 expression. The expression of bax remained unchanged in all four cell lines. CONCLUSION These results indicate that high LET charged particle radiation can induce cell death in glioma cells more effectively than X-rays and that cell death other than p53-dependent apoptosis may participate in the cytotoxicity of heavy charged particles. Thus, it might prove to be an effective alternative radiotherapy for patients with gliomas harboring mutated p53 gene.

Clinical picture of intracranial non-traumatic dissecting aneurysm

Non‐traumatic intracranial arterial dissection has been accepted as a unique entity of ‘cerebral infarction in otherwise healthy young adults’, and is particularly prevalent in Western countries. A recent data collection and analysis have revealed additional clinical features. The nationwide study in Japan conducted in 1996 has provided new information on the natural history and current treatment of intracranial dissecting aneurysms in Japan. The incidence of symptomatic dissection was found to be much higher in the vertebrobasilar system than in the carotid system. The mean age of the patients was 51.3 years. Patients with carotid lesions were younger (mean 43.8 years). The male/female ratio was 2 : 1. Fifty‐eight percent of patients presented with subarachnoid hemorrhage. Recurrence was more frequent in patients with subarachnoid hemorrhage (14%) than in patients with no hemorrhage (4.2%). Common radiological findings were dilatation, ‘pearl and string’ sign and narrowing of the affected artery. Surgical treatment involved a variety of procedures including proximal occlusion, entrapment, wrapping and endovascular embolization. Patients with subarachnoid hemorrhage (61%) underwent surgical treatment more frequently than patients with no hemorrhage (17%). Good recovery was achieved in 64% of all patients. Outcome was better in patients with no subarachnoid hemorrhage compared with those with hemorrhage.

Establishment of interleukin 2 dependent cytotoxic T lymphocyte cell line specific for autologous brain tumor and its intracranial administration for therapy of the tumor

Autologous brain tumor specific CTLs were induced from the patients PBL by a mixed lymphocyte-tumor culture, and were maintained for more than 2 months in a medium containing exogenous ILr2. The autologous T cell line containing specific CTL was administered into the tumor-bed for the treatment of malignant glioma. In 2 cases out of 5, tumors regressed more than 50% in diameter. One of these patients is still alive now with full of his social activities, and it is 104 weeks after the initiation of the immunotherapy. Autologous T cell lines were safely administered in all cases without any complications nor toxicities.