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Jun-ichi Kuratsu and Yukitaka Ushio

✓ Platelet-derived growth factor (PDGF) is produced by glioma cells. However, there is heterogeneity among glioma cell lines in the production of PDGF. It has been demonstrated that U251MG cells produce a PDGF-like molecule while U105MG cells do not.

Trapidil, a specific antagonist of PDGF, competes for receptor binding with PDGF. Therefore, the inhibitory effect of trapidil on the proliferation of glioma cells was investigated in vitro using two glioma cell lines. At 100 µg/ml, trapidil significantly inhibited the proliferation of U251MG cells (which produce the PDGF-like molecule). At the same trapidil concentration, the proliferation of U105MG cells (which do not produce the PDGF-like molecule) was not inhibited. The inhibitory effect of trapidil was remarkable on Days 3 and 4 of culture. After 4 days of incubation, the proliferation of U251MG cells was 46% of the control preparation. Trapidil enhanced the antitumor effect of 3-((4-amino-2-methyl-5-pyrimidinyl)ethyl)-1-(2-chloroethyl)-1-nitro-sourea (ACNU) against U251MG cells. The enhancing effect was highest on Days 4 and 6 of culture. After 6 days of incubation in the presence of 100 µg/ml trapidil and 1 µg/ml ACNU, the proliferation of U251MG cells was 18% of the control preparation. These findings suggest that trapidil interrupts the autocrine loop at the PDGF and PDGF-receptor level and that combination therapy with trapidil and ACNU may be useful in the treatment of glioma.

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Jun-Ichi Kuratsu and Yukitaka Ushio

✓ This survey consists of 1117 residents of Kumamoto Prefecture who were diagnosed with primary intracranial tumors between 1989 and 1994. Age, sex, tumor type, and date of diagnosis were recorded in all cases; 79% of the diagnoses were confirmed histologically. The overall age-adjusted incidence rate was 9.47 per 100,000 population per year. Among males, the age-adjusted incidence rate was 8.24 per 100,000 per year, and the breakdown included 2.36 gliomas, 1.56 meningiomas, 1.46 pituitary tumors, and 0.99 neurinomas. Among females, the comparable overall rate was 10.7; that included a rate of 3.95 for meningiomas, 2.04 for gliomas, 2.16 for pituitary tumors, and 0.75 for neurinomas. Meningiomas were the most common tumor, with an average annual age-adjusted incidence of 2.76 per 100,000 population. The highest incidence of meningiomas was 13.02 per 100,000 among women aged 70 to 79 years. The highest incidence of gliomas (5.71 per 100,000 males and 5.29 per 100,000 females) was seen in patients between 60 and 69 years of age. Meningiomas, pituitary adenomas, and malignant lymphomas occurred at a higher rate in females (male/female ratio: 0.39, 0.68, and 0.81, respectively). On the other hand, gliomas, neurinomas, and germ-cell tumors occurred more often in males (male/female ratio: 1.16, 1.32, and 4.29, respectively). Meningiomas and germ-cell tumors tended to exhibit gender specificity.

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Microvascular decompression for hemifacial spasm

Patterns of vascular compression in unsuccessfully operated patients

Shinji Nagahiro, Akira Takada, Yasuhiko Matsukado and Yukitaka Ushio

✓ To determine the causative factors of unsuccessful microvascular decompression for hemifacial spasm, the follow-up results in 53 patients were assessed retrospectively. The mean follow-up period was 36 months. There were 32 patients who had compression of the seventh cranial nerve ventrocaudally by an anterior inferior cerebellar artery (AICA) or a posterior inferior cerebellar artery. Of these 32 patients, 30 (94%) had excellent postoperative results. Of 14 patients with more severe compression by the vertebral artery, nine (64%) had excellent results, three (21%) had good results, and two (14%) had poor results; in this group, three patients with excellent results experienced transient spasm recurrence. There were seven patients in whom the meatal branch of the AICA coursed between the seventh and eighth cranial nerves and compressed the dorsal aspect of the seventh nerve; this was usually associated with another artery compressing the ventral aspect of the nerve (“sandwich-type” compression). Of these seven patients, five (71%) had poor results including operative failure in one and recurrence of spasm in four. The authors conclude that the clinical outcome was closely related to the patterns of vascular compression.

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Hiroya Ikeda, Yukitaka Ushio, Toru Hayakawa and Heitaro Mogami

✓ An experimental model of spinal cord compression by epidural neoplasms was produced in rabbits by injecting a VX2 tumor-cell suspension anterior to the T-13 vertebral body. With this experimental model, edema and circulatory disturbance of the spinal cord compressed by epidural tumors were studied. The characteristic histopathological findings in the compressed spinal cord were edema and axonal swelling in the white matter. Water content and uptake of intravenously injected 99mTc pertechnetate in the compressed spinal cord were significantly greater than in the spinal cord distant from the tumor, and increased in proportion to the degree of neurological loss. Microangiography and fluorescein angiography demonstrated stenosis or obstruction of the epidural venous plexus and impairment of venous drainage in the compressed spinal cord at the early stage of neurological symptoms. It is suggested that venous stasis and subsequent vasogenic edema in the spinal cord play an important role in the symptomatology of metastatic epidural spinal cord compression.

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Yukitaka Ushio, Toru Hayakawa and Heitaro Mogami

✓ Malignant gliomas were induced in strain ddN mice by intracerebral implantation of a 20-methylcholanthrene pellet. The uptake and distribution of tritiated methotrexate (MTX-3H) in the tumor were investigated by radioactive assay and radioautography after single intravenous or intrathecal injections. By either route, a large amount of MTX-3H was taken up by gliomas, and a significantly higher concentration was observed in tumor than in the brain tissue. At 24 hours after intrathecal administration, the uptake of MTX-3H by gliomas exceeded that achieved after intravenous injection, although the drug dosage in the latter was 10 times that in the former.

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Jun-ichi Kuratsu, Masato Kochi and Yukitaka Ushio

Object. The increased use of computerized tomography (CT) and magnetic resonance (MR) technology has led to an increase in the detection of asymptomatic meningiomas, although the surgical indication for these tumors remains undetermined. The authors investigated the incidence of asymptomatic meningiomas and their clinical features.

Methods. An epidemiological survey was conducted of primary intracranial tumors diagnosed in Kumamoto Prefecture between 1989 and 1996. Follow-up neuroradiological imaging and clinical studies for asymptomatic meningiomas were performed.

Primary intracranial tumors were diagnosed in 1563 residents. Of these lesions, 504 (32.2%) were meningiomas, and of these meningiomas 196 (38.9%) were asymptomatic. The incidence of asymptomatic meningiomas was significantly higher in individuals older than 70 years of age. Furthermore, the incidence of asymptomatic meningiomas was significantly higher in female than in male patients. Of the asymptomatic meningiomas in 196 patients, 87 (44.4%) were surgically removed, whereas 109 (55.6%) were treated conservatively. Of these conservatively treated patients, 63 received follow-up care for more than 1 year. In 20 of these 63 cases, the tumors increased in size over the 27.8-month average follow-up period (range 12–87 months), whereas in the other 43 cases, the tumor size did not increase during a 36.6-month average follow-up period (range 12–96 months). There was no significant difference with respect to age, tumor size, and male/female ratio between the patient group in which the tumor size increased and the group in which it did not increase during the follow-up period. Asymptomatic meningiomas that evidenced calcification on CT scans and/or hypointensity on T2-weighted MR images appear to have a slower growth rate.

Conclusions. Among patients older than age 70 years who underwent operation for asymptomatic meningioma, the neurological morbidity rate was 23.3%; it was 3.5% among younger patients. This indicates that the advisability of surgery in elderly patients with asymptomatic meningiomas must be considered very carefully.

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Youichi Itoyama, Shodo Fujioka and Yukitaka Ushio

✓ A 69-year-old man presented with mild left-sided hemiparesis of 2 years' duration. A computerized tomography scan revealed a left-sided chronic subdural hematoma and a midline shift to the right. Magnetic resonance (MR) imaging obtained on admission to the hospital also disclosed a deformity of the right crus cerebri. After drainage and irrigation of the hematoma through a single burr hole, the left hemiparesis improved significantly. Magnetic resonance imaging performed 9 days after the operation revealed that the size of the subdural hematoma had diminished and the deformity of the crus cerebri had improved markedly. Kernohan's notch, caused by a supratentorial mass and producing ipsilateral hemiparesis or hemiplegia, is rarely demonstrated radiographically. This may be the first reported case in which Kernohan's notch in chronic subdural hematoma has been demonstrated on MR imaging.

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Shinji Nagahiro, Akira Takada, Satoshi Goto, Yutaka Kai and Yukitaka Ushio

✓ Results in three patients with thrombosed giant aneurysms of the vertebral artery are reported. Each of the aneurysms presented as a mass lesion. On postcontrast computerized tomography and magnetic resonance imaging, each aneurysm demonstrated a patent lumen and intrathrombotic vascular channels. Two patients died and were autopsied, and the other patient was successfully treated. Pathological examination revealed that the aneurysms had staged clots, an open lumen, intrathrombotic channels with endothelial lining, and aneurysmal walls with intimal thickening. The authors suggest that the development of the intrathrombotic capillary channels may be an important factor in the growth of thrombosed giant aneurysm of the vertebral artery. Trapping of the aneurysm followed by aneurysmectomy appears to be the best treatment for this type of aneurysm.

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Shinji Nagahiro, Jun-ichiro Hamada, Yuji Sakamoto and Yukitaka Ushio

✓ The authors assessed the reliability of magnetic resonance (MR) imaging contrast enhancement for the detection and follow-up evaluation of dissecting aneurysms of the vertebrobasilar circulation. Twenty consecutively admitted patients who underwent both gadolinium-enhanced MR imaging and conventional angiography were reviewed. Enhancement of the dissecting aneurysm was seen in all but one of the 20 patients, including 10 (71%) of 14 patients examined in the chronic phases, when the T1-hyperintensity signal that corresponded to the intramural hematoma was unrecognizable. The enhanced area corresponded to the “pearl sign” or aneurysm dilation noted on the comparable angiogram. On follow-up MR studies enhancement had spontaneously disappeared in four patients at a time when comparable vertebral angiograms revealed disappearance of the aneurysm dilation. The enhancement persisted in five of nine patients examined more than 24 weeks after symptom onset; in all five patients the aneurysm dilation remained on comparable angiograms. Dynamic MR studies showed rapid and remarkable enhancements with their peaks during the immediate dynamic phase after injection of the contrast material. The authors conclude that gadolinium-enhanced MR imaging is useful for the detection and follow-up evaluation of dissecting aneurysms of the vertebrobasilar circulation.

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Tatsuo Yoshida, Keiji Shimizu, Yukitaka Ushio, Heitaro Mogami and Yukiya Sakamoto

✓ Reserpine enhanced in vitro the cytotoxicity of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) in both the C6 glioma and its ACNU-resistant subline, C6/ACNU. Reserpine also enhanced the chemotherapeutic effect of ACNU in C6/ACNU-bearing (C6/ACNU-meningeal gliomatosis) rats, in which ACNU resistance could be modulated by combined ACNU and reserpine therapy.

When 10 μM reserpine was added to ACNU in culture, the concentration of drug required for 50% inhibition of cell growth (IC50) of ACNU for C6/ACNU cells decreased to the level of that for C6 cells. When 20 μM reserpine was added to the culture, intracellular uptake of ACNU in C6/ACNU cells increased further and the efflux of the drug from the cells decreased. In in vivo experiments in rats, combined chemotherapy with ACNU (1 mg/kg) and reserpine (250 μg/kg) by intrathecal injection significantly increased the life span of the rats as compared to results with ACNU chemotherapy alone. The enhanced cytotoxicity of ACNU in ACNU-resistant glioma cells in vitro and in vivo may be explained by the increase of intracellular concentration of ACNU resulting from the inhibition of ACNU efflux from the resistant cells by reserpine. It was concluded that ACNU resistance could be modulated in vitro and in vivo by combined therapy with ACNU and reserpine.