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Keisuke Takai, Tetsuhiro Nishihara, Shigeru Nemoto, Keisuke Ueki, Hiroshi Miyauchi, Kazuhiko Mishima, Ichiro Suzuki and Takaaki Kirino

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Kazuhiko Mishima, Masanao Nakamura, Hirohiko Nakamura, Osamu Nakamura, Nobuaki Funata and Nobuyuki Shitara

✓ A case of surgically treated pilocytic astrocytoma in the cerebellar vermis is reported in a patient who subsequently demonstrated multiple subarachnoid nodular masses in the cerebrum and spinal cord 6 years after the initial surgery. The nodular tumors did not indicate a growth tendency on computerized tomography or magnetic resonance imaging over a 2-year observation period. The histology of the nodular masses in the cerebrum and spinal cord was similar to that of the original tumor. The bromodeoxyuridine labeling index indicated low proliferative activity (0.5%). The peculiar pattern of dissemination of the pilocytic astrocytoma is described.

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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.

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Motoo Nagane, Yoshitaka Narita, Kazuhiko Mishima, Alexander Levitzki, Antony W. Burgess, Webster K. Cavenee and H. J. Su Huang

Object. Activation of signaling by the epidermal growth factor receptor (EGFR) through gene amplification or rearrangement is common in human malignancy, especially in a large fraction of de novo glioblastomas multiforme (GBMs). The most common mutant EGFR, (ΔEGFR, also known as de2–7 EGFR and EGFRvIII) lacks a portion of the extracellular domain, enhances tumorigenicity in vivo, and causes resistance to the chemotherapeutic drug cisplatin (CDDP). This resistance is due to the suppression of CDDP-induced apoptosis by the constitutively active tyrosine kinase activity of the receptor. The authors have investigated whether inhibition of AEGFR signaling by the tyrosine kinase inhibitor, tyrphostin AG1478, could sensitize tumor xenografts to CDDP and, thereby, enhance its therapeutic efficacy in animals.

Methods. Nude mice were inoculated either subcutaneously or intracerebrally with human GBM cells expressing ΔEGFR and were then systemically treated with CDDP and/or AG1478. Tumor volumes were monitored and tumor sections were analyzed by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assays or MIB-1 staining.

Expression of ΔEGFR, but not wild-type EGFR, conferred CDDP resistance to the cells in vivo. Inhibition of receptor signaling by the EGFR-specific tyrosine kinase inhibitor, AG1478, sensitized the xenografts to the cytotoxic effects of CDDP. This combined CDDP/AG1478 treatment significantly suppressed growth of subcutaneous xenografts in nude mice in a synergistic manner (p < 0.01 compared with vehicle control) without causing generalized toxicity, whereas treatments with CDDP or AG1478 alone were ineffective. The synergistic growth suppression by the CDDP/AG1478 combination was not observed in xenografts overexpressing wild-type EGFR or kinase-deficient ΔEGFR. The combined CDDP/AG1478 treatment induced tumor growth suppression, which correlated with increased apoptosis and reduced proliferation. This treatment also extended the life span of mice bearing intracerebral xenografts (p < 0.01 compared with controls).

Conclusions. The results of this study may provide the basis for the development of a novel and safe therapeutic strategy for the very aggressive ΔEGFR-expressing GBM.

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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.