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Ryo Nishikawa and Masao Matsutani

Primary intracranial germ cell tumors (GCTs) comprise 3.1% of all brain tumors and 13.6% of those in patients younger than 15 years of age in Japan. They are classified into five basic histological types: germinoma, teratoma, choriocarcinoma, yolk sac tumor, and embryonal carcinoma; or into mixed tumor types when they consist of two or more components. Radiation therapy with or without chemotherapy has proven effective in the treatment of germinoma, whereas there is a poor prognosis for choriocarcinoma, yolk sac tumor, embryonal carcinoma, and mixed tumors having components of the group of malignant intracranial GCTs. The underlying mechanisms for such different responses to radio- and chemotherapies of intracranial GCTs remain unknown.

In this study, the authors analyzed the expression of p53 and p21WAF1/Cip1 proteins by immunohistochemical analysis in 35 intracranial GCTs. Expression of p53 protein was observed in 33 (94%) of 35 intracranial GCTs. Expression of p21WAF1/Cip1 was detected in seven (20%) of 35 intracranial GCTs. None of the 15 germinomas was immunoreactive for p21WAF1/Cip1 protein, whereas in a group of malignant intracranial GCTs, four (80%) of five cases showed immunoreactivity for p21WAF1/Cip1 protein. Analysis of the data suggests that overexpression of p21WAF1/Cip1 in intracranial GCTs may correlate with decreased sensitivity to radio- and chemotherapy and suggest a poor prognosis.

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Taichi Tachikawa, Jun-ichi Adachi, Ryo Nishikawa and Masao Matsutani

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Kohei Fukuoka, Takaaki Yanagisawa, Tomonari Suzuki, Kenji Wakiya, Masao Matsutani, Atsushi Sasaki and Ryo Nishikawa

Congenital intracranial immature teratomas carry a dismal prognosis, and the usefulness of chemotherapy for these tumors has not been elucidated. The authors report on the successful management of a case of congenital intracranial immature teratoma by using neoadjuvant chemotherapy and surgery after the failure of an initial attempt at resection.

The patient was an infant who had begun vomiting frequently at the age of 12 days and had been admitted to a hospital at the age of 18 days with continued vomiting, increased head circumference, and disturbance of consciousness. A CT scan of the brain revealed a large mass in his posterior fossa and hydrocephalus. Surgery was performed on an emergent basis, but only minor tumor resection could be performed due to massive intraoperative hemorrhage. The histopathological diagnosis was immature teratoma. Postoperatively, the infant was in critical condition due to severe postoperative complications, and when he was transferred to the authors' institution 43 days after birth, his respiratory condition was still unstable because of lower cranial nerve palsy. Chemotherapy with carboplatin and etoposide resulted in moderate shrinkage of the tumor. Further chemotherapy led to improvement in the patient's general condition and weight gain, which allowed for a second attempt at resection. During this second surgery, which was performed when the child was 8 months of age, after 8 courses of chemotherapy, the tumor was completely resected with little bleeding. Histological findings from the second operation were consistent with mature teratoma.

This case indicates that upfront chemotherapy may be effective for the initial management of such cases. Although the objective response to the treatment was modest, chemotherapy reduced the hemorrhagic nature of the tumor, facilitated improvement of the patient's general condition, and allowed for successful resection.

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Kohei Fukuoka, Takaaki Yanagisawa, Yuko Watanabe, Tomonari Suzuki, Masao Matsutani, Ichiei Kuji and Ryo Nishikawa

Although 11C-methionine (MET)-PET has been used to diagnose intracranial germ cell tumors (GCTs) arising in the basal ganglia, whether this imaging technique is useful in assessing treatment response and residual tumor is still unclear. The authors report 3 cases of basal ganglia GCTs in which the residual MET uptake at the end of treatment did not develop into a relapse, even without additional treatment. Case 1 is a 22-year-old man who had a second relapse of a left basal ganglia germinoma with diffuse dissemination on the walls of both of his lateral ventricles. MET-PET revealed high MET accumulation around tumors and their surroundings (maximum standardized uptake value [SUVmax] 3.3). After all treatments, MET-PET demonstrated mild tracer accumulation in both basal ganglia (SUVmax 2.2). Progression-free survival was 56 months from the second relapse without any further treatment. Case 2 is a 17-year-old boy with a left basal ganglia germinoma that showed increased MET uptake (SUVmax 4.2). After treatment, MET-PET revealed residual MET uptake (SUVmax 2.4) along the left posterior limb of the internal capsule. Progression-free survival was 52 months from the start of treatment. Case 3 is a 7-year-old boy with a left basal ganglia choriocarcinoma with increased tumor MET uptake (SUVmax 2.5). A minor enhanced mass remained on MRI after treatment with residual MET accumulation (SUVmax 1.4). Progression-free survival was 44 months. Treatment strategies based on MET uptake on PET should be carefully designed in patients with basal ganglia GCTs to avoid overtreatment and complications.

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Kohei Fukuoka, Takaaki Yanagisawa, Tomonari Suzuki, Mitsuaki Shirahata, Jun-ichi Adachi, Kazuhiko Mishima, Takamitsu Fujimaki, Hideki Katakami, Masao Matsutani and Ryo Nishikawa

OBJECTIVE

Human chorionic gonadotropin (HCG) can be detected in a certain population of patients with a germinoma, but the frequency of germinoma HCG secretion and the prognostic value of HCG in the CSF are unknown.

METHODS

The authors measured HCG levels in sera and CSF in patients with a histologically confirmed germinoma by using a highly sensitive assay known as an immune complex transfer enzyme immunoassay (EIA), which is more than 100 times as sensitive as the conventional method, and they analyzed the correlation between HCG levels and the prognoses of patients with a germinoma.

RESULTS

HCG levels in sera and CSF of 35 patients with a germinoma were examined with the immune complex transfer EIA. The median CSF HCG levels in patients with a germinoma during the pretreatment and posttreatment evaluations were 192.5 pg/ml (range 1.2–13,116.5 pg/ml) and 18.7 pg/ml (1.2–283.9 pg/ml), respectively. Before treatment, the CSF HCG level was greater than the cutoff value in 85.7% of the patients with a germinoma. The authors compared survival rates among the patients by using a CSF HCG cutoff level of 1000 pg/ml, and the difference was statistically significant between the groups (p = 0.029, log-rank test).

CONCLUSIONS

Results of this study demonstrate that most germinomas secrete HCG. Patients with a germinoma that secretes higher amounts of HCG in their CSF experienced recurrence more frequently than those with lower CSF HCG levels.

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Tomonari Suzuki, Satoru Wada, Hidetaka Eguchi, Jun-ichi Adachi, Kazuhiko Mishima, Masao Matsutani, Ryo Nishikawa and Masahiko Nishiyama

Object

Gliomas contain aggressive malignant cancer, and resection rate remains an important factor in treatment. Currently, fluorescence-guided resection using orally administered 5-aminolevulinic acid (5-ALA) has proved to be beneficial in improving the prognosis of patients with gliomas. 5-ALA is metabolized to protoporphyrin IX (PpIX) that accumulates selectively in the tumor and exhibits strong fluorescence upon excitation, but glioma cells do not always respond to 5-ALA, which can result in incomplete or excessive resection. Several possible mechanisms for this phenomenon have been suggested, but they remain poorly understood. To clarify the probable mechanisms underlying the variable induction of fluorescence and to improve fluorescence-guided surgery, the authors searched for key negative regulators of fluorescent signal induced by 5-ALA.

Methods

A comprehensive gene expression analysis was performed using microarrays in 11 pairs of tumor specimens, fluorescence-positive and fluorescence-negative tumors, and screened genes overexpressed specifically in fluorescence-negative tumors as the possible candidates for key negative regulators of 5-ALA–induced fluorescence. The most possible candidate was selected through annotation analysis in combination with a comparison of expression levels, and the relevance of expression of the selected gene to 5-ALA–induced fluorescence in tumor tissues was confirmed in the quantified expression levels. The biological significance of an identified gene in PpIX accumulation and 5-ALA–induced fluorescence was evaluated by in vitro PpIX fluorescence intensity analysis and in vitro PpIX fluorescence molecular imaging in 4 human glioblastoma cell lines (A1207, NMCG1, U251, and U373). Knockdown analyses using a specific small interfering RNA in U251 cells was also performed to determine the mechanisms of action and genes working as partners in the 5-ALA metabolic pathway.

Results

The authors chose 251 probes that showed remarkably high expression only in fluorescent-negative tumors (median intensity of expression signal > 1.0), and eventually the cadherin 13 gene (CDH13) was selected as the most possible determinant of 5-ALA–induced fluorescent signal in gliomas. The mean expression level of CDH13 in the fluorescence-negative gliomas was statistically higher than that in positive ones (p = 0.027), and knockdown of CDH13 expression enhanced the fluorescence image and increased the amount of PpIX 13-fold over controls (p < 0.001) in U251 glioma cells treated with 5-ALA. Comprehensive gene expression analysis of the CDH13-knockdown U251 cells demonstrated another two genes possibly involved in the PpIX biosynthesis: ATP-binding cassette transporter (ABCG2) significantly decreased in the CDH13 knockdown, while oligopeptide transporter 1 (PEPT1) increased.

Conclusions

The cadherin 13 gene might play a role in the PpIX accumulation pathway and act as a negative regulator of 5-ALA–induced fluorescence in glioma cells. Although further studies to clarify the mechanisms of action in the 5-ALA metabolic pathway would be indispensable, the results of this study might lead to a novel fluorescent marker able to overcome the obstacles of existing fluorescence-guided resection and improve the limited resection rate.