Toshimitsu Aida

Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor α for the treatment of malignant gliomas

To elucidate the role of tumor necrosis factor α (TNFα) as a biological response modifier, we studied cellular and cytokine responses of the central nervous system to TNFα administered intracranially in a phase I clinical trial for patients with malignant gliomas. Six patients received injections of TNFα (1.25×103−10×103 U/injection) into the tumor cavities, and regional fluids (RF) and lumbar cerebrospinal fluids (CF) were serially sampled before and after the injections. Recruitment of neutrophils occurred, mostly peaking 8 h after TNFα injection, and fewer numbers of CD4+ T cells and monocytes/macrophages migrated, subsequently peaking at 24 h. The CF leukocytosis persisted for 48 h and was associated with an increased level of neutrophil chemotactic activity in the CF. This neutrophil chemotactic activity was attributed to interleukin-8 (IL-8) by HPLC. The level of IL-6 activity in the CF and RF consistently increased; beginning 2 h after TNFα injection and reaching the maximum between 8 h and 12 h. It returned to the basal level within 48 h. IL-1β was detected in the CF of three patients, its level peaking at 8 h. Prostaglandin E2 also increased after injection of TNFα, peaking between 4 h and 12 h and then gradually decreasing. Transforming growth factor γ was found in all cases tested and one patient showed a significant change after TNFα injection. IL-2 activity, interferon α (INFα) activity, IFNβ, and granulocyte/macrophage-colony-stimulating factor were not detected in the CF or RF. In conclusion, TNFα is biologically effective in inducing migration of immune cells and generating multiple cytokine responses in the human central nervous system.

Malignant melanotic neuroectodermal tumor arising from the pineal body.

SummaryA case of a melanotic neuroectodermal tumor arising from pineal region of a 4-year-old girl is presented. The tumor had spread diffusely to the meninges, consistent with malignant behavior. Histologically, the tumor consisted primarily of epithelial elements arranged in tubules, cords and nests separated by fibrous vascular tissue in addition to a small neuroblastomatous focus. Melanin pigment was frequently observed in the epithelial tumor cells, and melanin-laden macrophages were also often observed. No teratoid elements were found. Immunohistochemically, tumor cells were positive for neuron-specific enolase but were nonreactive for S-100 protein, epithelial membrane antigen, glial fibrillary acidic protein, vimentin, α-fetoprotein and human chorionic gonadotrophin. Ultrastructurally, the epithelial nature of the tumor cells could be easily demonstrated. In addition, melanosomes in various stages in maturation were observed, indicating melanogenesis of the tumor. On the basis of the tumor location and the histological similarities previously observed for the fetal pineal body, it is very likely that this melanotic epithelial tumor could have originated from the fetal pineal gland.

Responses of human glioblastoma cells to human natural tumor necrosis factor-α: Susceptibility, mechanism of resistance and cytokine production studies

SummaryResponses and susceptibility of 14 human glioblastoma cell lines to human natural tumor necrosis factor-α (TNF) were studiedin vitro.Susceptibility of glioblastoma cells to TNF varied in experimental conditions applied. Most of glioblastoma cell lines were resistant to cytotoxic activity of TNF in a MTT assay at concentrations below 16U/ml for 72 h exposure. However, TNF at higher dose, in prolonged exposure and against low density of target cells was antiproliferative for certain glioblastoma cultures. TNF exposure at 10U/ml for 48 h suppressed DNA synthesis in 9 of 14 glioblastoma cultures, but increased in 3 cultures. In addition, colony forming assay showed anti-clonogenic activity of TNF in 5 of 6 glioblastoma cell lines tested.In spite of their low susceptibility to TNF, glioblastoma cells well responded to TNF stimulation at low dose (10U/ml) for a short period in the absence of cell damage. Productions of Interleukin-6 (IL-6), IL-8-like activity, granulocyte-macrophage colony stimulating factor (GM-CSF), prostaglandin E2 (PGE2) and manganous Superoxide dismutase (Mn-SOD) were enhanced or induced by the low-dose TNF stimulation.Mn-SOD, a protein protective against oxidative cell damage, was well induced in time- and dose-dependent manner, however did not correlate with TNF resistance. Whereas the levels of PGE2 in TNF-susceptible cell lines, H-4 and SF-188, were higher than those of other lines.In conclusion, most of glioblastoma cells are resistant to TNF cytotoxic effects, but highly responsive to TNF stimulation. Its effect on glioblastoma cells appears to modulate cell differentiation rather than to kill the cells.

Modification of tumor blood flow and enhancement of therapeutic effect of ACNU on experimental rat gliomas with angiotensin II

Blood flow was measured in transplanted rat gliomas before and during a constant intravenous infusion of angiotensin II using hydrogen clearance methods. The brain tumor models were produced in syngeneic Wister-King-Aptekman male rats with stereotaxic inoculation of ethylnitrosourea-induced glioma cells (KEG-1). Induced hypertension up to 150 mmHg (mean arterial pressure) with the infusion of angiotensin II resulted in a significant increase of blood flow to tumor center compared to the normotensive state (p < 0.001). Blood flow measured simultaneously in brain tissue of tumor-free contralateral hemisphere did not change.The therapeutic effect of administration of the simultaneous 1-(4-Amino-2-methyl-5-pyrimidinyl)methyl3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and angiotensin II was evaluated in four experimental groups with the tumor-bearing rats. Twelve days after tumor implantation, the rats were administered angiotensin II to increase the mean arterial blood pressure to 150 mmHg, followed by intravenous injection of ACNU injection. The increased blood pressure was steadily maintained for 20 minutes. The ACNU/induced hypertension group showed a median survival time of 27.0 days, which was significant longer (p < 0.02) than that of an ACNU treatment group (22.0 days), a hypertension treatment group (19.0 days), or a no treatment group (18.5 days).The enhanced therapeutic effect can be attributed to improving chemotherapeutic drug delivery due to increased blood flow in the tumor.

Calcified vestibular schwannoma in the cerebellopontine angle.

Although vestibular schwannoma is a common tumor in the cerebellopontine angle, calcified vestibular schwannoma is rare. A 59-year-old woman with sudden onset epileptic seizures, was referred to Hokkaido Neurosurgical Memorial Hospital. Neurological examination revealed left Bruns nystagmus, left deafness and left cerebellar ataxia. Brain MRI revealed a mass, about 3cm in diameter, in the left cerebellopontine angle. The mass showed heterogeneous intensity on T1- and T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. Hydrocephalus was seen. On CT scan, the tumor was calcified. Preoperatively, vestibular schwannoma, meningioma, cavernous hemangioma, or thrombosed giant aneurysm were considered as differential diagnoses. The pathological diagnosis was schwannoma. For a calcified mass in the cerebellopontine angle, vestibular schwannoma should be considered in the differential diagnosis to plan appropriate treatment strategies.

Measurement of human blood viscosity by an electromagnetic spinning sphere viscometer

Abstract We herein applied an electromagnetic spinning sphere (EMS) viscometer to the measurement of human blood viscosity for the first time. We collected blood samples from 100 healthy outpatient volunteers in order to analyse viscosity dependence on blood cell parameters and on the shear rate with a simple approximation formula [ηi (γ)\, = Ai γ- pi + η0]. Viscosity dependence on blood cell parameters was relatively high at a high shear rate, but became lower as the shear rate decreased. The approximation formula with appropriate parameters of Ai and pi nearly faithfully reproduced actual blood rheological behaviour with a standard deviation of 1.5%. The distributions of Ai and pi values were broad, suggesting that the pattern of viscosity dependence on the shear rate varied with individual differences. The results obtained using the EMS viscometer suggest that blood viscosity values are individual-specific and actual individual measurements are important for understanding rheological conditions.

A case of cavernous angioma in the septum pellucidum

A 44-year-old man was admitted to Hokkaido Neurosurgical emorial Hospital because of memory disturbance. Eleven months efore admission, a hematoma in the septum pellucidum was ncidentally found on MRI in another hospital, which performed ollow-up for another asymptomatic cavernous angioma in the eft putamen. Because the hematoma was asymptomatic, he was ollowed up at an outpatient clinic. However, eight months after emorrhage, he noticed memory disturbance, and MRI revealed ngioma growth. He was referred to our hospital for surgery. He could not recall events that had happened a few minutes efore. MRI revealed a hematoma localizing in the septum pelluidum (Fig. 1) and a cavernous angioma with venous angioma in he left putamen. The lesion was completely removed through an anterior trancallosal approach. The hematoma was confined to the septum ellucidum, and there was no hematoma in the ventricle.

Small but Severe Residual Hypoperfusion Relates to Symptomatic Hemorrhage Even after Early Perfusion Improvement in Tissue Plasminogen Activator Therapy

Case Report A 70-year-old man who did not take any regular medication presented at the emergency room 73 min after the sudden onset of an impaired level of consciousness, dysarthria, left-sided hemiparesis and left-sided neglect. His NIHSS (National Institutes of Health Stroke Scale) score was 16. His blood pressure was 121/87 and his laboratory data showed glucose 126 mg/dl, a platelet count of 192,000/mm 3 and normal liver and kidney function. DWI showed small ischemic changes in the head of the right caudate nucleus, the periventricular area and the frontal cortical area ( fig. 1 a). MR angiography revealed occlusion of the M1 segment of the right-middle cerebral artery (MCA) ( fig. 1 b). Since the head of the caudate nucleus is usually supplied by the recurrent artery of Heubner, in addition to MCA, branches of the right anterior cerebral artery were thought to be occluded. After confirming that the patient met all eligibility criteria for tPA therapy, administration of a total dose of 0.6 mg/kg tPA with 10% of the dose given as a bolus was started at 140 min after onset according to the directions for the use of tPA in Japan. His symptoms improved from 30 min after the start of the tPA infusion and his NIHSS score was 7 by the end of it. 99m Tc-ethyl cysteinate dimer SPECT imaging 1 h after the end of the tPA infusion revealed a mild hypoperfusion in the cortex of the right MCA territory and a small but severe hypoperfusion in the head of the right caudate nucleus ( fig. 1 c, d). The early clinical improvement and the SPECT findings suggest that early perfusion improvement due to an increase in collateral flow or partial recanalization occurred in the MCA territory except for in the right caudate nucleus. Although posttreatment vital signs and the neurological status were uneventful, Background Symptomatic intracerebral hemorrhage (sICH) is the most unfavorable complication arising after intravenous tissue plasminogen activator (tPA) therapy. In multivariate analyses of sICH after tPA therapy, a high serum glucose level [1] , a large diffusionweighted imaging (DWI) lesion volume [2] and late reperfusion after persistent arterial occlusion [3] are regarded as independent predictors; however, we encountered a tPA-treated patient with sICH, which was not applicable to the above predictions. We present this case and discuss a relationship between the development of sICH and findings of early posttreatment single-photon emission computed tomography (SPECT). Published online: December 1, 2012

Immunohistochemical Analysis of Cerebral Intraparenchymal Choroid Plexus Tumor: Case Report

Background It is very rare for a choroid plexus tumor to occur intraparenchymally in the absence of a relation to the choroid plexus. Clinical Presentation A case of cerebral intraparenchymal choroid plexus tumor in a 30‐year‐old woman presenting with left hemiparesis is described. Brain magnetic resonance imaging depicted a large cystic mass in the right frontal lobe. Tumor resection was performed by right frontal craniotomy. No connection with the choroid plexus was observed during the operation. Histologically, the tumor exhibited a glandular structure with a papillary pattern suggesting a neoplasm of epithelial origin. Immunohistochemical analyses revealed the tumor as an atypical choroid plexus papilloma. Conclusion Immunohistochemical findings, especially regarding Kir7.1, are very important for the differential diagnosis of cerebral intraparenchymal choroid plexus tumors from metastatic tumors. The present case reveals that an atypical choroid plexus papilloma can occur intraparenchymally without an association with the choroid plexus. Intraparenchymal atypical choroid plexus papillomas may have previously been diagnosed incorrectly as metastatic adenocarcinomas of unknown origin.

Localized reversible high signal intensities on diffusion-weighted MRI in hypoglycemia: A study of 70 cases.

Introduction: It is well-known that localized reversible high signal intensities in the splenium of the corpus callosum or the basal ganglia appear on diffusion-weighted MRI in the presence of hypoglycemia. The aim of this study was to clarify the incidence and significance of such high signal intensity lesions. Results: We analyzed 70 cases of hypoglycemia with consciousness disturbance referred to our outpatient office. Localized reversible high signal intensities on diffusion-weighted MRI were noted in 6 cases (8.6%). They were at the splenium of the corpus callosum in four cases (5.7%), and right frontal cortex and bilateral frontal white matter in one each. Convulsions were noted in five cases, and right hemiparesis was noted in three. None of the three cases of hemiparesis showed localized reversible high signal intensities on diffusion-weighted MRI. These lesions are reversible if the patients undergo treatment without delay. Conclusion: The significance of these lesions is still unclear. However, when a high signal intensity lesion that is not reasonable for the symptom is detected on diffusion-weighted MRI, an immediate check of the blood sugar level is mandatory.