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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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Masato Kochi, Youichi Itoyama, Shoji Shiraishi, Isao Kitamura, Toru Marubayashi and Yukitaka Ushio

Object. The goal of this study was to confirm the effectiveness of our novel treatment strategy, neoadjuvant therapy (NAT) consisting of combined chemo- and radiotherapy, which are performed before complete excision of residual tumor in patients with intracranial nongerminomatous malignant germ cell tumors (NGMGCTs).

Methods. The authors treated 11 consecutive patients with NGMGCTs by applying NAT consisting of combined platinum-based chemotherapy and radiotherapy, followed by complete excision of residual tumors. The pretreatment diagnosis, based on tumor markers with or without biopsy, was yolk sac tumor in five patients, embryonal carcinoma in one patient, immature teratoma in one patient, and mixed germ cell tumor containing malignant tumor components in four patients.

Among the 11 patients, NAT achieved a complete response in two and a partial response in six patients; two patients manifested no change and one suffered disease progression. Residual tumors that occurred post-NAT were surgically removed in nine patients. Of the 11 patients, 10 are currently alive without recurrence of their disease, 30 to 177 months (mean 96 months) after diagnosis. In one patient a leptomeningeal tumor recurred and he died of the disease 21 months after diagnosis.

Conclusions. Neoadjuvant therapy, consisting of combined chemo- and radiotherapy, followed by complete excision of residual tumors is highly effective in patients with intracranial NGMGCTs.

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Osamu Miyanohara, Hideo Takeshima, Masatomo Kaji, Hirofumi Hirano, Yutaka Sawamura, Masato Kochi and Jun-Ichi Kuratsu

Object. Overexpression of the protooncogene c-kit has been suggested in a gonadal germ cell tumor (GCT). Recently, the soluble isoform of c-kit (s-kit) has been expressed in a variety of cell types. The goal of this study was to investigate the expression of c-kit and the clinical significance of s-kit in patients with GCTs.

Methods. The authors first conducted an immunohistochemical investigation of the expression of the c-kit protein in 27 surgical specimens. In all 18 specimens that contained germinomas, c-kit was diffusely expressed on the cell surface of the germinoma cells, but was not found on lymphocytes or interstitial cells. In seven of eight immature teratomas, only some mature components, such as cartilage and glands, were immunoreactive for c-kit. Syncytiotrophoblastic giant cells (STGCs) demonstrated negative findings as well, suggesting that primarily germinoma cells express c-kit. Next, 47 cerebrospinal fluid (CSF) samples collected from 32 patients with GCTs (15 samples from patients with pure germinomas, 16 from patients with STGC germinomas, 14 from patients with teratomas, and two from a patient with a choriocarcinoma) were analyzed using a sandwich enzyme-linked immunosorbent assay. The level of s-kit was significantly higher in CSF collected from patients with germinomas and STGC germinomas than in CSF collected from patients with teratomas or non—germ cell brain tumors, or in CSF collected from controls. The concentration of s-kit in CSF was correlated with the patient's clinical course; it was significantly higher in pretreatment samples obtained before and in samples obtained at the time of tumor recurrence than in samples collected from patients in whom the tumor was in remission. The level of s-kit was remarkably high in CSF collected from patients with subarachnoid tumor dissemination.

Conclusions. These results indicate that the concentration of s-kit in CSF may be a useful clinical marker for germinomas, especially for detecting recurrence or subarachnoid dissemination of these lesions.

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Yukitaka Ushio, Masato Kochi, Jun-ichi Kuratsu, Youichi Itoyama and Toru Marubayashi

✓ The authors evaluated the effect of adjuvant therapy (preoperative chemotherapy combined with radiotherapy) followed by radical tumor removal in the treatment of children with primary intracranial yolk sac tumor, embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor components.

Between 1988 and 1995, five consecutive patients were treated with adjuvant therapy followed by total tumor removal. The diagnosis was based on markedly elevated concentrations of serum α-fetoprotein (AFP) and/or β-human chorionic gonadotropin (β-HCG) in four children and the results of biopsy sampling in one child. The chemotherapy regimen consisted of cisplatin (20 mg/m2) and etoposide (60 mg/m2) daily for 5 days (one course) given three times at 4-weeks intervals. Radiotherapy consisted of 30 to 40 Gy to the whole brain or an area including all ventricles and a 15- to 20-Gy boost to the tumor site. Spinal radiation of 25 Gy was added in one patient. In all patients the serum level of AFP and β-HCG gradually decreased during the adjuvant therapy and disappeared completely on its completion. In two of the five patients the tumor disappeared as well. In the other three patients the tumor size was moderately or markedly reduced and the remaining tumor was totally removed; there were no neurological deficits. Chemotherapy was maintained after the initial treatment and was repeated every 2 to 4 months for less than 2 years. All children are alive and well without recurrence at 33 to 118 months (average 88 months) after the start of adjuvant therapy.

Our preliminary results indicate that adjuvant therapy consisting of combination chemotherapy with cisplatin and etoposide and concomitant radiotherapy, followed by removal of the tumor, is highly effective in the treatment of pediatric patients with primary intracranial yolk sac tumor, embryonal carcinoma, or mixed germ cell tumors containing yolk sac tumor components.

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Masaji Murakami, Jun-ichi Kuratsu, Masato Kochi, Naoko Kunitoku, Akihito Hashiguchi and Yukitaka Ushio

The authors report on two cases of pineal germinomas with granulomatous inflammation (granulomatous germinomas). Macroscopically, both tumors were relatively hard and grayish in color. Histological examination revealed a germinoma with multinucleated giant cells and Schaumann bodies in one case, and a germinoma with the background of acellular fibrillated matrix in the other. On immunohistochemical analysis, the granulomatous germinomas were shown to contain many macrophages, T- and B-lymphocytes, and glial fibrillary acid protein-positive cells infiltrating the specimens, compared to nongranulomatous germinomas. Analysis of Masson's trichrome staining tests showed that large areas of the granulomatous germinomas were occupied by a collagenous component; this was not the case in cases of nongranulomatous germinomas. Analysis of monoclonal anti-human Ki-67 results showed that the granulomatous germinomas had a lower score than nongranulomatous germinomas (p < 0.05, unpaired t-test), indicating that germinomas with granulomatous inflammation may have a better prognosis.

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Hideo Nakamura, Keishi Makino, Masato Kochi, Yukitaka Ushio and Jun-ichi Kuratsu

Object

The authors evaluated the effectiveness of a neoadjuvant therapy (NAT) consisting of combined chemoand radiotherapy followed by complete resection of the residual tumor in patients with nongerminomatous malignant germ cell tumors (NGMGCTs).

Methods

The authors treated 14 consecutive patients in whom NGMGCTs were diagnosed based on elevated levels of the tumor markers α-fetoprotein, human chorionic gonadotropin, and the β-subunit of human chorionic gonadotropin (β-HCG). Chemotherapy and radiotherapy were performed, and after the serum tumor markers level was in the normal or near-normal range, the residual tumors were completely resected.

Results

Residual tumors were confirmed in 11 of the 14 patients after NAT, and total removal was successful in 10 of the 11 patients. In the other patient the residual tumor could not be completely excised because it was attached to a deep vein. The follow-up duration ranged from 1.2 to 22.2 years. The 5-year event-free and total survival rates were 86% and 93%, respectively. Although 3 patients died, 2 of tumor recurrence and 1 of a radiation-induced secondary tumor (glioblastoma), the other 11 are alive and without evidence of tumor recurrence.

Conclusions

The authors consider their NAT protocol for NGMGCT to be highly effective in relation to survival for the patients with NGMGCT, but there are several quality of life issues that need to be resolved.

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Naoki Shinojima, Kazutaka Ohta, Shigetoshi Yano, Hideo Nakamura, Masato Kochi, Yasuji Ishimaru, Youichi Nakazato and Yukitaka Ushio

✓ Myofibroblastoma is a rare type of benign mesenchymal tumor; only two cases of intracranial myofibroblastoma have been reported in the literature. The authors report on the case of a 34-year-old woman with a myofibroblastoma in the suprasellar region who presented with the complaint of sudden onset of headache followed within 2 weeks by progressively worsening visual disturbance. Computerized tomography scanning demonstrated a mixed low- and high-density mass in the suprasellar region and contrast-enhanced magnetic resonance imaging revealed the mass to be of mixed intensity with heterogeneous enhancement. The tumor was subtotally removed via a right frontobasal translamina—terminalis approach and her vision improved immediately. Histologically, the tumor was characterized by alternating areas of spindle-shaped and round cells that were separated by collagen fibers. The diagnosis of myofibroblastoma was based on the tumor's intense immunoreactivity for α—smooth-muscle actin and the ultrastructural identification of myofibroblasts. The tumor was thought to have originated from the meninges in the suprasellar region.

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Takanori Kamiryo, Kenji Tada, Shoji Shiraishi, Naoki Shinojima, Hideo Nakamura, Masato Kochi, Jun-ichi Kuratsu, Hideyuki Saya and Yukitaka Ushio

Object. One of the most frequent genetic abnormalities found in patients with glioblastoma multiforme (GBM) is homozygous deletion of the p16 tumor suppressor gene. The authors investigated whether this deletion is associated with prognosis in patients with GBM.

Methods. In 46 adult patients with supratentorial GBM, homozygous deletion of the p16 gene in tumor DNA was examined using the multiplex polymerase chain reaction assay. The deletion was confirmed in 14 (30.4%) of 46 patients, eight (30.8%) of 26 men and six (30.0%) of 20 women. Cox proportional hazard regression analysis, adjusted for age at surgery, the Karnofsky Performance Scale score, extent of resection, and the MIB-1 labeling index, revealed that homozygous deletion of the p16 gene was significantly associated with overall survival and progression-free survival in men, but not in women.

Conclusions. The results of this study suggest that p16 homozygous deletion is a significant unfavorable prognostic factor in male patients with GBM.

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Kenji Tada, Shoji Shiraishi, Takanori Kamiryo, Hideo Nakamura, Hirofumi Hirano, Jun-Ichi Kuratsu, Masato Kochi, Hideyuki Saya and Yukitaka Ushio

Object. The most frequent genetic abnormality in human malignant gliomas is loss of heterozygosity (LOH) on chromosome 10. Candidate genes on chromosome 10 that are associated with the prognosis of patients with anaplastic astrocytoma (AA) and glioblastoma (GBM) were evaluated.

Methods. The authors used 12 fluorescent microsatellite markers on both arms of chromosome 10 to study LOH in 108 primary astrocytic tumors. The LOH on chromosome 10 was observed in 11 (32%) of 34 AAs and 34 (56%) of 61 GBMs. No LOH was detected in 13 low-grade gliomas. Loss of heterozygosity was not detected in any AA in the seven patients younger than 35 years, but it was discovered in 41% of the patients older than 35 years. The prognostic significance of LOH at each locus was evaluated in 89 patients older than 15 years; 33 (37%) had supratentorial AAs and 56 (63%) had supratentorial GBMs. The Cox proportional hazards model, adjusted for patient age at surgery, the preoperative Karnofsky Performance Scale score, and the extent of surgical resection revealed that LOH on marker D10S209 near the FGFR2 and DMBT1 genes was significantly associated with shorter survival in patients with AA. The LOH on markers D10S215 and D10S541, which contain the PTEN/MMAC1 gene between them, was significantly associated with shorter survival in patients with GBM.

Conclusions. In the present study it is found that LOH on chromosome 10 is an age-dependent event for patients with AAs and that LOH on marker D10S209 near the FGFR2 and DMBT1 loci is a significantly unfavorable prognostic factor. It is also reported that LOH on the PTEN/MMAC1 gene is a significantly unfavorable prognostic factor in patients with GBM.

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Naoki Shinojima, Masato Kochi, Jun-Ichiro Hamada, Hideo Nakamura, Shigetoshi Yano, Keishi Makino, Hiromasa Tsuiki, Kenji Tada, Jun-Ichi Kuratsu, Yasuji Ishimaru and Yukitaka Ushio

Object. Glioblastoma multiforme (GBM) remains incurable by conventional treatments, although some patients experience long-term survival. A younger age, a higher Karnofsky Performance Scale (KPS) score, more aggressive treatment, and long progression-free intervals have been reported to be positively associated with long-term postoperative patient survival. The aim of this retrospective study was the identification of additional favorable prognostic factors affecting long-term survival in surgically treated adult patients with supratentorial GBM.

Methods. Of 113 adult patients newly diagnosed with histologically verified supratentorial GBM who were enrolled in Phase III trials during the period between 1987 and 1998, six (5.3%) who survived for longer than 5 years were defined as long-term survivors, whereas the remaining 107 patients served as controls. All six were women and were compared with the controls; they were younger (mean age 44.2 years, range 31–60 years), and their preoperative KPS scores were higher (mean 85, range 60–100). Four of the six patients underwent gross-total resection. In five patients (83.3%) the progression-free interval was longer than 5 years and in three a histopathological diagnosis of giant cell GBM was made. This diagnosis was not made in the other 107 patients.

Conclusions. Among adult patients with supratentorial GBM, female sex and histopathological characteristics consistent with giant cell GBM may be predictive of a better survival rate, as may traditional factors (that is, younger age, good KPS score, more aggressive resection, and a long progression-free interval).