Takuhiro Hotta

O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications

SummaryActivity of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) is an important determinant of responsiveness of tumor cells to chloroethylnitrosoureas (CENUs), representative chemotherapeutic agents for primary malignant gliomas. In order to assess the real states of this repair protein in human malignant gliomas, we assayed AGT activity in surgically extirpated 42 malignant glioma samples and studied the distribution of the activity under certain clinical conditions. There were wide variations in AGT activity between individuals. No significant difference in AGT activity on average was seen either between glioblastoma and anaplastic astrocytoma, nor between primary and recurrent tumors. Among 42 malignant gliomas, 7 samples (16.7%) had low AGT activity less than 0.1 pmoles/mg protein. In the case of glioblastoma, tumors possessing higher AGT activity tended to be less responsive to post-operation remission-induction therapy including CENUs. The result of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) chemosensitivity assay by using the corresponding surgical specimens suggested a close relationship between cellular resistance to CENUs and AGT activity. It was found to be unlikely that a short term administration of CENUs had a significant effect on AGT activity of brain tumors in human body. We could detect a bit of definite evidences of the relevance of AGT to resistance to CENUs and need to conduct further investigations for other resistance factors.

Intracranial germ-cell tumor with synchronous lesions in the pineal and suprasellar regions: Report of six cases and review of the literature

The features of intracranial germ-cell tumor with synchronous lesions in the pineal and suprasellar regions (GCTSPS) in six patients were investigated. GCTSPS accounted for 12.8% of all germ-cell tumors (GCT) in our brain tumor study group. In all cases, the initial symptoms were attributable to the suprasellar lesion, and symptoms due to the pineal GCT developed only after admission. Five of the six cases were histologically diagnosed as germinoma. In all cases, tumors of both regions disappeared after irradiation, resulting in no recurrence for an average of 55.3 months. Our experience and reports in the literature suggest that GCTSPS is highly sensitive to radiation in most cases, although some reports indicated that recurrence is frequent after radiation therapy alone. It is suggested that histological diagnosis in one of the GCTSPS lesions is undertaken to make a plan for the following treatment.

Penetration of etoposide into human malignant brain tumors after intravenous and oral administration

SummaryPenetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55–65 mg/m2) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50–150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 μg/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44–4.99 μg/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7%±0.5%, 3.4%±1.0%, and 7.2% ± 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04–4.80 μg/g) was 14.0%±2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.

Multi-detector-row CT angiography as a preoperative evaluation for spinal arteriovenous fistulae

The role of multi-detector-row computed tomographic angiography (MDCTA) in spinal vascular malformations has not yet been determined. We present a report on a short series of spinal arteriovenous fistulae (AVF) evaluated by MDCTA. With 4-row and 16-row MDCTA, three cases of spinal dural AVF and one case of perimedullary AVF were examined. Each case was also examined by magnetic resonance (MR) imaging and spinal catheter angiography. In two patients with spinal dural AVF, including one patient with angiographically occult AVF, MDCTA successfully located the site of the AVF in a multi-planar reformation image. MDCTA failed to locate the remaining case of spinal dural AVF, probably due to the small amount of shunting blood volume at the fistula. In a patient with perimedullary AVF, MDCTA visualized the broad range of the lesion, including the anterior spinal artery as a single feeder, the fistulous point, and the single perimedullary draining vein. In conclusion, although conventional spinal angiography might be still essential, MDCTA provides useful information for the surgeon in treatment of the spinal dural AVF. Further accumulation of clinical cases is required to determine the potential of MDCTA for perimedullary AVF. MDCTA should be considered as a choice of investigation in the evaluation of spinal AVFs.

Spontaneous rupture of craniopharyngioma cysts. A report of five cases and review of the literature.

Reports of spontaneous rupture of a craniopharyngioma cyst are extremely rare. Five cases of spontaneous rupture of a craniopharyngioma cysts are reported. Clinical symptoms included chemical meningitis in three patients, alleviation of headache in one, and improvement in a visual disturbance in one. Reduction in cyst size was confirmed by computed tomography or magnetic resonance imaging in three of five patients, and the histopathological diagnosis was confirmed histologically in four patients. Cerebrospinal fluid findings were abnormal in the three patients with chemical meningitis. Spontaneous rupture of craniopharyngioma cysts tended to occur more frequently in adult males. Computed tomography and magnetic resonance imaging were useful in diagnosing cyst rupture, and cerebrospinal fluid findings, especially the presence of cholesterol crystals and an elevated cholesterol concentration, are suggestive, even when no reduction in cyst size is observed radiologically.

Ganglioglioma of the optic pathway: A case report

A case of ganglioglioma of the optic pathway associated with congenital exophthalmos and strabismus is presented. Since the tumor extended from the right optic nerve to the right geniculate body, it was diagnosed as an optic glioma before operation. However, optic nerve biopsy showed that the lesion was a ganglioglioma. Although a literature review yielded two previous cases of ganglioglioma of the optic pathway, this is the first case in which the tumor involved the whole optic pathway.

Interhemispheric arachnoid cyst in the elderly: case report and review of the literature

BACKGROUND Preoperative differential diagnosis of interhemispheric cysts is sometimes difficult. CASE DESCRIPTION We recently experienced a case of symptomatic interhemispheric arachnoid cyst in a 62-year-old woman. We reviewed interhemispheric arachnoid cysts in the elderly and the management of symptomatic interhemispheric arachnoid cysts in elderly patients. Symptomatic interhemispheric arachnoid cysts in the elderly are predominantly located on the right side, have a long history of progressive symptomology, occur predominantly in females, and have no communication with the subarachnoid space. Interhemispheric arachnoid cysts are usually not associated with agenesis of the corpus callosum in elderly patients, whereas interhemispheric nonarachnoid cysts are usually associated with agenesis of the corpus callosum, which will be clearly demonstrated on magnetic resonance imaging. CONCLUSIONS It is highly possible that an interhemispheric cyst without agenesis of the corpus callosum in an adult is an arachnoid cyst.

De novo distal posterior cerebral artery aneurysm.

BACKGROUND De novo aneurysms in the posterior circulation are very rare. The authors describe a first case of ruptured de novo posterior cerebral artery (PCA) aneurysm in the P3 portion. CASE DESCRIPTION A 52-year-old woman with ruptured de novo P3 aneurysm was treated by early endovascular obliteration using Guglielmi Detachable Coils (GDC). To prevent vasospasm, she received postoperative treatment with a hypertensive hypervolemia dilution and a calcium antagonist. She was discharged without neurologic deficits. CONCLUSIONS Aneuryms arising from peripheral segment of PCA are rare, and delayed surgical clipping has been recommended for these lesions. This is the first report of a de novo P3 ruptured aneurysm treated by endovascular embolization using GDC in the acute stage of subarachnoid hemorrhage. The characteristics of de novo posterior circulation aneurysms and the strategy for the distal PCA aneurysms are discussed.

Interrelationship between O6-alkylguanine-DNA alkyltransferase activity and susceptibility to chloroethylnitrosoureas in several glioma cell lines

SummaryIn order to study the dynamic relationship in glioma cells between O6-alkylguanine-DNA alkyltransferase (AGT) activity and resistance to the cytotoxic effect of chloroethylnitrosoureas (CENUs), we investigated the changes in sensitivity to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) after modulation of AGT activity. In ACNU-resistant rat glioma cell lines (9LR1, 9LR3, and 9LR12) and a human glioma cell (HNG-1), O6-methylguanine enhanced cytotoxicity to ACNU following a depletion of AGT activity. But no enhancement of cytotoxicity was seen in an ACNU-sensitive rat glioma cell line (9L). In the 9L and 9LR12 cells, equivalently sublethal doses of ACNU similarly depleted AGT activity but the regeneration rates of this repair protein were different. In the case of a 7-day pretreatment with human recombinant interferon-β (HuIFN-β), although it could modulate AGT activity in HNG-1 cells, no definite influence on cellular sensitivity to CENUs was observed. However, a 50-day pretreatment with HuIFN-β conferred resistance to CENUs on them despite its effect to reduce AGT activity. Thus, diversity was seen in the relation between AGT activity and resistance to CENUs when AGT activity was modulated by HuIFN-β. The results of this study suggest that AGT activity is one of factors affecting cellular sensitivity to CENUs but that alternative mechanisms of tolerance may be induced depending upon some environmental effects.

Analysis and Distribution of Etoposide in Rat Brain Tumor Model: Intracarotid Versus Intracarotid with Angiotensin II—Induced Hypertension

The brain tissue distribution of etoposide has been investigated in 9L gliosarcoma-bearing rats with or without hypertension induced by angiotensin II (AT II). The rat brain tumor models were divided into the following two groups according to etoposide administration route: intracarotid injection (IC) group and intracarotid injection with hypertension induced by AT II (IHIC) group. Ten mg/kg of etoposide was given, and 30 min and 2, 4, 8, and 24 hr later the rats were sacrificed. The drug concentrations in the serum, tumor, and normal brain tissue were analyzed by high-pressure liquid chromatography. The etoposide concentration in the serum, tumor, and normal brain tissue peaked at 30 min in both groups. The serum concentration was similar between the two groups. The etoposide concentration in the tumor was at least 2.2 times higher in the IHIC group than in the IC group at 30 min and 2 hr. The area under drug concentration curve (AUC) in the tumor in the IHIC group was about 2.2 times higher than that in the IC group. The etoposide concentration in the normal brain on the drug injection side changed only slightly from 0.5 hr to 4 hr and was about 3 times higher in the IHIC group than in the IC group. The etoposide concentration in the contralateral normal brain was very low in both groups at 30 min and disappeared thereafter. Intracarotid injection of anticancer drugs with AT II-induced hypertension further increases the drug concentration and AUC in the tumor compared with intracarotid injection alone and can be useful in treatment of malignant brain tumors.