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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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Jun-ichi Kuratsu, Yasuhiko Matsukado and Masaki Miura

✓ A prolactin-secreting pituitary adenoma containing amyloid substance was studied by light and electron microscopy. The tumor was found in a 32-year-old woman who presented with a short history of amenorrhea and galactorrhea. Pituitary adenoma containing amyloid substance is a very rare entity, and the implications of this association are discussed. Previous reports, suggesting that mesenchymal cells or hormone-secreting tumor cells in pituitary adenomas produce amyloid substances, are reviewed.

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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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Shigetoshi Yano, Jun-ichi Kuratsu and the Kumamoto Brain Tumor Research Group

Object

To determine the indications for surgery in patients harboring asymptomatic meningiomas, the authors retrospectively analyzed the natural course and surgical outcome of asymptomatic meningiomas and then compared these to the natural course and surgical outcome of symptomatic meningiomas.

Methods

Between 1989 and 2003, 1434 patients harboring meningiomas, who were treated in Kumamoto Prefecture, Japan, were enrolled in this study. Six hundred three patients had asymptomatic lesions and 831 had symptomatic ones. The authors analyzed the sizes of the lesions at detection, their growth over time, and any appearances of symptoms associated with previously asymptomatic meningiomas. The authors then compared the surgery-related morbidity rates associated with asymptomatic and symptomatic meningiomas arising at different locations.

Of the 603 asymptomatic meningiomas, 351 (58.2%) were treated conservatively. Tumor growth was observed in 25 (37.3%) of 67 patients who participated in follow up for longer than 5 years, and symptoms developed in 11 (16.4%) of the 67 patients over a mean follow-up period of 3.9 years. Among the 213 patients with surgically treated asymptomatic meningiomas, the morbidity rate was 4.4% in patients younger than 70 years of age and 9.4% in those 70 years of age or older. Although the total morbidity rate was lower in patients with asymptomatic lesions than in those with symptomatic ones, it exceeded 6% in patients whose asymptomatic tumors were located at the convexity or falx.

Conclusions

Approximately 63% of asymptomatic meningiomas did not exhibit tumor growth, and only 6% of all patients with these lesions experienced symptoms during the observation period. To avoid surgery-related incidences of morbidity in patients with asymptomatic meningiomas, conservative treatment with close follow-up review may be the best therapeutic strategy.

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Takuichiro Hide, Shigetoshi Yano, Naoki Shinojima and Jun-ichi Kuratsu

OBJECT

To avoid disorientation during endoscopic endonasal transsphenoidal surgery (ETSS), the confirmation of anatomical landmarks is essential. Neuronavigation systems can be pointed at exact sites, but their spatial resolution power is too low for the detection of vessels that cannot be seen on MR images. On Doppler ultrasonography the shape of concealed arteries and veins cannot be visualized. To address these problems, the authors evaluated the clinical usefulness of the indocyanine green (ICG) endoscope.

METHODS

The authors included 38 patients with pituitary adenomas (n = 26), tuberculum sellae meningiomas (n = 4), craniopharyngiomas (n = 3), chordomas (n = 2), Rathke's cleft cyst (n = 1), dermoid cyst (n = 1), or fibrous dysplasia (n = 1). After opening the sphenoid sinus and placing the ICG endoscope, the authors injected 12.5 mg of ICG into a peripheral vein as a bolus and observed the internal carotid arteries (ICAs), cavernous sinus, intercavernous sinus, and pituitary.

RESULTS

The ICA was clearly identified by a strong fluorescence signal through the dura mater and the covering thin bone. The intercavernous and cavernous sinuses were visualized a few seconds later. In patients with tuberculum sellae meningiomas, the abnormal tumor arteries in the dura were seen and the vague outline of the attachment was identified. At the final inspection after tumor removal, perforators to the brain, optic nerves, chiasm, and pituitary stalk were visualized. ICG fluorescence signals from the hypophyseal arteries were strong enough to see and spread to the area of perfusion with the passage of time.

CONCLUSIONS

The ICA and the patent cavernous sinus were detected with the ICG endoscope in real time and at high resolution. The ICG endoscope is very useful during ETSS. The authors suggest that the real-time observation of the blood supply to the optic nerves and pituitary helps to predict the preservation of their function.

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Takashi Kamezawa, Jun-Ichiro Hamada, Masaki Niiro, Yutaka Kai, Koichi Ishimaru and Jun-ichi Kuratsu

Object. The authors reviewed angiograms obtained in patients with cavernous malformations to identify and characterize coexisting venous drainage.

Methods. Fifty-seven patients with cavernous malformations treated at the authors' institutions between 1994 and 2002 were classified into three groups according to the venous system adjacent to the malformation on angiography studies. In Group A patients (23 patients) the malformations had no venous drainage; in Group B patients (14 patients) the lesions were associated with typical venous malformations; and in Group C patients (20 patients) the lesions had atypical venous drainage (AVD). The risk of hemorrhage based on the type of associated venous drainage was analyzed, and the usefulness of magnetic resonance (MR) imaging compared with digital subtraction (DS) angiography in demonstrating associated AVD was determined.

Fifty-seven patients harbored 67 cavernous malformations: Group A patients had 29 cavernous malformations with no associated venous drainage; Group B patients had 17 lesions associated with venous malformations; and Group C patients harbored 21 lesions, 20 of which manifested AVD. Symptomatic hemorrhage was present in 10 (43.5%) of 23 Group A patients and in 28 (82.4%) of 34 Groups B and C patients. Although high-resolution MR imaging revealed the presence of associated venous malformations in 11 (78.6%) of 14 Group B patients, such studies demonstrated AVD in only two (10%) of 20 Group C patients.

Conclusions. Patients harboring cavernous malformations plus venous malformations or AVD are more likely to present with symptomatic hemorrhage than are patients with cavernous malformation alone. The actual incidence of associated venous drainage may be underestimated when MR imaging alone is used rather than combined with DS angiography.

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Kyoichi Sato, Jun-Ichi Kuratsu, Hideo Takeshima, Teizo Yoshimura and Yukitaka Ushio

✓ Monocyte chemoattractant protein-1 (MCP-1), purified from glioma cell line (U-105MG) culture fluid, attracts monocytes but not neutrophils. Macrophage accumulation is one of the pathological features of meningioma. To investigate the mechanism of macrophage infiltration into meningioma, the expression and localization of MCP-1 in 16 cases of meningioma were studied using Northern blot analysis and immunohistochemistry. Seven of 16 meningiomas expressed MCP-1 messenger ribonucleic acid and protein, and some degree of macrophage infiltration was seen in all 16 meningiomas.

There was a relationship between MCP-1 expression and the degree of macrophage infiltration; MCP-1 was strongly expressed in meningiomas with a high degree of macrophage infiltration. Sometimes the meningioma was accompanied by perifocal edema; a correlation between macrophage infiltration into brain tumors and perifocal edema has already been reported. It was found that the degree of MCP-1 expression is not correlated with the extent of perifocal edema.

The authors' findings suggest that MCP-1 plays an important role in macrophage infiltration into meningioma.

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Hideo Takeshima, Jun-Ichi Kuratsu, Motohiro Takeya, Teizo Yoshimura and Yukitaka Ushio

✓ Expression of monocyte chemoattractant protein-1 (MCP-1) in human glioma cell lines and surgical specimens was studied by Northern blot analysis, reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. The samples tested consisted of 11 human glioma cell lines and eight specimens of human malignant glioma (seven from glioblastomas and one from a malignant ependymoma).

Messenger ribonucleic acid (mRNA) of MCP-1 was detected by either Northern blot or reverse-transcription polymerase chain reaction analysis in all cell lines and tumor specimens examined. In vivo expression of MCP-1 mRNA and protein was found predominantly in glioma cells with large and pleomorphic nuclei rather than in areas of small nucleated glioma cells. Adjacent brain tissue did not produce a significant level of MCP-1 mRNA or protein. Tumor vessels with endothelial proliferation expressed a moderate level of MCP-1 protein. Macrophages were found among the glioma cells, and the degree of macrophage infiltration was grossly correlated with the level of MCP-1 expression. The study results suggest that MCP-1 produced by the glioma cells may mediate macrophage infiltration into the glioma tissue.

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Masaji Murakami, Yukitaka Ushio, Yosuke Mihara, Jun-Ichi Kuratsu, Seikoh Horiuchi and Yoshimasa Morino

✓ Low-density lipoprotein (LDL) is a carrier of the cholesterol found in human plasma. Cells utilize cholesterol for membrane synthesis by taking up LDL via receptor-mediated endocytosis. In the present study, interactions of LDL with human malignant glioma cell lines (U-251MG and KMG-5) were investigated biochemically and morphologically. The LDL, labeled with the fluorescent dyes 1, l′-dioctadecy1–3,3,3′,3′-tetramethylindocarbocyanine (DiI) and fluorescein isothiocyanate (FITC), was internalized by both cell processes and cell bodies. Reductive methylation of DiI-labeled LDL, which abolishes the ability of the cell to bind to the LDL receptor, prevented the internalization of the cholesterol moiety of LDL. Cellular binding of 125I-LDL to U-251MG cells at 4°C revealed the presence of a specific saturable-associated receptor (dissociation constant (Kd) approximately 38 µg/ml). Endocytic uptake of 125I-LDL or 3H-cholesterol oleate-labeled LDL (3H-LDL) at 37°C demonstrated the cell-associated 125I-LDL and 3H-LDL increase. The intracellular degradation of protein moiety increased linearly with time. Reductive methylation of 3H-LDL led to a remarkable decrease in the cell-associated cholesterol moiety of LDL. The difference in uptake of the cholesterol moiety of LDL between U-251MG cells and KMG-5 cells showed that the U-251MG cells, which proliferate more actively than KMG-5 cells, take up more of the cholesterol moiety of LDL than do the KMG-5 cells.

Thus, LDL cholesterol seems to be endocytosed predominantly via the LDL receptor present on the plasma membrane of malignant glioma cells. In addition, for growth, these cells may require large amounts of the cholesterol moiety of LDL.