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Yamaguchi K.,Shizuoka Cancer Center | Shijubo N.,JR Sapporo Hospital | Kodama T.,Tochigi Cancer Center Hospital | Mori K.,Tochigi Cancer Center Hospital | And 6 more authors.
Japanese Journal of Clinical Oncology | Year: 2011

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline ®) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life. © The Author (2010). Published by Oxford University Press. All rights reserved.

Hishida T.,Research Center for Innovative Oncology | Hishida T.,National Cancer Center Hospital East | Ishii G.,Research Center for Innovative Oncology | Kodama T.,Tochigi Cancer Center Hospital | And 8 more authors.
Pathology International | Year: 2011

Lung adenocarcinomas that exhibit endobronchial polypoid growth and arise from the central portion of the respiratory tree are extremely rare and their clinicopathological features are not well understood. We report the clinicopathological characteristics of five cases of centrally located adenocarcinomas. Histologically, in three cases (cases 1, 2, and 3) the tumor had a papillary, acinar, and solid structure. In the other two cases (cases 4 and 5) histological examination revealed a mucin-filled glandular and cystic structure resembling mucoepidermoid carcinoma, although the lesions lacked a squamoid cell component. Immunohistochemical staining revealed that the tumor cells in all five cases were positive for MUC1 and Cytokeratin 7. The tumor cells in cases 4 and 5 were positive for MUC5AC and MUC6, and the expression pattern in these two cases was similar to that of mucoepidermoid carcinoma of the lung. Our findings allowed us to identify two distinct subtypes of centrally located adenocarcinomas with distinct morphological and immunohistochemical characteristics; these should provide new insight into the pathogenesis of central adenocarcinoma of the lung. © 2010 The Authors. Pathology International © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

Wolff E.M.,University of Southern California | Chihara Y.,University of Southern California | Pan F.,University of Southern California | Weisenberger D.J.,University of Southern California | And 6 more authors.
Cancer Research | Year: 2010

Urothelial cancer (UC) develops along two different genetic pathways, resulting in noninvasive or invasive tumors. However, it is unknown whether there are also different epigenetic pathways in UC. UC is also characterized by a high rate of recurrence, and the presence of a field defect has been postulated. In this study, we compared the DNA methylation patterns between noninvasive and invasive UC and the DNA methylation patterns between normal-appearing urothelium from bladders with cancer and urothelium from cancer-free bladders. We used the Illumina GoldenGate methylation assay at 1,370 loci in 49 noninvasive urothelial tumors, 38 invasive tumors with matched normal-appearing urothelium, and urothelium from 12 age-matched UC-free patients. We found distinct patterns of hypomethylation in the noninvasive tumors and widespread hypermethylation in the invasive tumors, confirming that the two pathways differ epigenetically in addition to genetically. We also found that 12% of the loci were hypermethylated in apparently normal urothelium from bladders with cancer, indicating an epigenetic field defect. X-chromosome inactivation analysis indicated that this field defect did not result in clonal expansion but occurred independently across the urothelium of bladders with cancer. The hypomethylation present in noninvasive tumors may counterintuitively provide a biological explanation for the failure of these tumors to become invasive. In addition, an epithelium-wide epigenetic defect in bladders with cancer might contribute to a loss of epithelial integrity and create a permissible environment for tumors to arise. ©2010 AACR.

Miyake M.,Tochigi Cancer Center Research Institute | Miyake M.,Nara Medical University | Ishii M.,Tochigi Cancer Center Research Institute | Koyama N.,Tochigi Cancer Center Research Institute | And 6 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Activating mutation of the fibroblast growth factor receptor-3 (FGFR3) gene is known as a key molecular event in both oncogenesis and cell proliferation of low-grade noninvasive human bladder urothelial carcinoma (UC), which is characterized by frequent intravesical recurrence. In this study, we investigated the antitumor potentiality of 1-tert-butyl-3-[6-(3,5-dimethoxy- phenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea (PD173074), a small-molecule FGFR3-selective tyrosine kinase inhibitor (TKI), as a therapeutic modality using eight UC cell lines. In our in vitro cell proliferation assay, PD173074 suppressed cell proliferation remarkably in two cell lines, namely, UM-UC-14 and MGHU3, which expressed mutated FGFR3 protein. In contrast, the other six cell lines expressing wild-type FGFR3 or without FGFR3 expression were resistant to PD173074 treatment. Cell cycle analysis revealed the growth inhibitory effect of PD173074 was associated with arrest at G1-S transition in a dose-depending manner. Furthermore, we observed an inverse relationship between Ki-67 and p27/Kip1 expression after PD173074 treatment, suggesting that up-regulation of p27 recruited UC cells harboring activating FGFR3 mutations in G1 that was analogous with the other receptor TKIs acting on the epidermal growth factor receptors. In the mouse xenograft models using subcutaneously transplanted UM-UC-14 and MGHU3, orally administered PD173074 suppressed tumor growth and induced apoptotic changes comparable with the results of our in vitro assay. These findings elucidated the effectiveness of molecular targeted approach for bladder UC harboring FGFR3 mutations and the potential utility to decrease the intravesical recurrence of nonmuscle invasive bladder UC after transurethral surgical resection. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

Miyake M.,Tochigi Cancer Center Research Institute | Miyake M.,Nara Medical University | Sugano K.,Tochigi Cancer Center Research Institute | Sugino H.,Tochigi Cancer Center Research Institute | And 10 more authors.
Cancer Science | Year: 2010

The fibroblast growth factor receptor (FGFR)-3 gene encodes a receptor tyrosine kinase that is frequently mutated in non-muscle invasive bladder cancer (NMIBC). A sensitive and quantitative assay using peptide nucleic acid-mediated real-time PCR was developed for detecting FGFR3 mutations in the urine samples and evaluated as a molecular marker for detecting intravesical recurrence of NMIBC in patients undergoing transurethral resection of bladder tumor. FGFR3 mutation was examined in tumor tissues and serially taken pre- and postoperative urine sediments in 45 NMIBC patients with a median follow up of 32 months. FGFR3 mutations were detected in 53.3% (24/45) of primary tumor tissues, among which intravesical recurrence developed in 37.5% (9/24) of cases. FGFR3 mutation in the primary tumor was not a significant prognostic indicator for recurrence, while the proportion of FGFR3 mutation (i.e. tumor cellularity was ≥11%) in the preoperative urine sediments was a significant indicator for recurrence in patients with FGFR3 mutations in the primary tumors. FGFR3 mutations were detected in 78% (7/9) of postoperative urine samples from recurrent cases with FGFR3 mutations in the tumor, while no mutations were detected in the urine of 15 non-recurrent cases. Urine cytology was negative in all cases with FGFR3 mutations in the primary tumors, while the sensitivity of cytological examination was as high as 56% (5/9) in cases showing wild-type FGFR3 in the primary tumors. Urine FGFR3 mutation assay and cytological examination may be available in the future as complementary diagnostic modalities in postoperative management of NMIBC. © 2009 Japanese Cancer Association.

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