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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.


Osuga K.,Osaka University | Arai Y.,University of Tokyo | Anai H.,Nara Medical University | Takeuchi Y.,University of Tokyo | And 12 more authors.
Journal of Vascular and Interventional Radiology | Year: 2012

Purpose: A multicenter phase I/II study of transarterial chemoembolization with a fine cisplatin powder and gelatin particles (GPs) for multifocal hepatocellular carcinoma (HCC) was conducted. Primary endpoints were dose-limiting toxicity (DLT) and recommended dose (RD). Secondary endpoints were the incidence and severity of adverse events and tumor response. Materials and Methods: Nonselective transarterial chemoembolization was performed until all tumor enhancement disappeared. Lipiodol was not used. In the phase I study, the cisplatin dose was escalated from 35 mg/m2 to 65 mg/m2 in 15-mg/m2 increments to determine DLT and RD. In the phase II study, 40 patients were treated with the RD. Toxicity was assessed by Common Toxicity Criteria for Adverse Effects (version 3.0), and tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) and European Association for the Study of the Liver (EASL) criteria. Results: A total of 46 patients were enrolled. As no DLT occurred at any dose level in the phase I study, RD was determined as 65 mg/m2. In the phase II study, the treatment was discontinued in one patient as a result of vasovagal response. Toxicities of grade 3 or higher included nausea (2.2%), pancreatitis (2.2%), cholecystitis (2.2%), thrombocytopenia (8.7%), hyperbilirubinemia (2.2%), and increased aspartate aminotransferase (28.3%) and alanine aminotransferase (21.7%) levels. Tumor response rates under RD were 25.6% and 64.1% by RECIST and EASL criteria, respectively. Conclusions: Nonselective transarterial chemoembolization with fine cisplatin powder and GPs was well tolerated and effective in patients with multifocal HCC at the RD of 65 mg/m2. © 2012 SIR.


Ohue M.,Japan National Cardiovascular Center Research Institute | Hamaguchi T.,National Cancer Center Hospital | Ito Y.,National Cancer Center Hospital | Sakai D.,Osaka University | And 6 more authors.
International Journal of Clinical Oncology | Year: 2015

Background: The purpose of this phase I study of the dose escalation of oxaliplatin in combination with oral S-1 and pelvic radiation preoperatively for poor-risk lower rectal cancer was to determine the dose-limiting toxicity (DLT) and recommended dose of oxaliplatin. Methods: Patients with cT4 and lateral pelvic lymph node metastasis, and without distant metastasis (cM0), were treated with weekly oxaliplatin, oral S-1 40 mg/m2 twice daily for 5 days a week, and radiation. A total of 5 weekly doses of oxaliplatin were planned. RT was administered to a total dose of 50.4 Gy in 28 fractions. Results: We enrolled 11 patients between December 2009 and January 2012. DLTs were observed at dose level 1 (50 mg/m2) in two patients, one of whom experienced grade 3 aspartate aminotransferase elevation and a grade 3 alanine aminotransferase increase, and the other developed grade 4 hypokalemia and a grade 3 alanine aminotransferase increase. Five patients at dose level 2 (60 mg/m2) showed no DLTs. The hematological toxicities in all patients were mild and reversible. One patient showed distant metastasis after chemoradiation. Ten of the 11 patients achieved R0 resection by mesorectal resection and lateral lymph node dissection; three of the 10 underwent combined resection of the other organs. Conclusion: This phase I trial of preoperative S-1 in combination with oxaliplatin and radiation for lower rectal cancer with T4 and lateral pelvic lymph node metastasis revealed that the recommended dose of oxaliplatin was 60 mg/m2 weekly. © 2014, Japan Society of Clinical Oncology.


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.


Niwakawa M.,Shizuoka Cancer Center Hospital | Hashine K.,National Hospital Organization | Yamaguchi R.,Shizuoka Cancer Center Hospital | Yamaguchi R.,Teikyo University | And 5 more authors.
Investigational New Drugs | Year: 2012

Background We investigated the safety, pharmacokinetics, tumor response, and immunological parameters of sorafenib plus interferon á-2a (IFN) in Japanese patients with advanced RCC. Patients and methods After 2 weeks of IFN-alone treatment, eligible patients received 28-day cycles of continuous sorafenib 200 mg (Cohort 1) or 400 mg (Cohorts 2 and 3) twice daily combined with intramuscular IFN 6 (Cohorts 1 and 2) or 9 (Cohort 3) million international units (MIU) three times a week. Results A total of 18 patients received at least one dose of sorafenib plus IFN. Five patients had dose-limiting toxicities (DLTs). The most common DLT was fatigue, experienced in four DLT patients. All 18 patients experienced at least one treatment-emergent adverse event (AE). The most common treatment-emergent AEs included fatigue, fever, platelets, leukocytes, hemoglobin, weight loss and anorexia. Five patients had confirmed partial response and 11 had stable disease, a response rate of 27.8%. IFN had no relevant impact on the pharmacokinetics of sorafenib. Conclusions Sorafenib administered in combination with IFN was well tolerated, with promising results in efficacy. Continuous sorafenib 400 mg twice daily in combination with IFN 6 MIU three times a week is recommended in Japanese patients with advanced RCC. © 2012 Springer Science+Business Media, LLC.


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.


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.


Ando J.,Tochigi Cancer Center Hospital | Kitamura T.,Tochigi Cancer Center Hospital | Kuroki Y.,Tochigi Cancer Center Hospital | Igarashi S.,Tochigi Cancer Center Hospital
Breast Cancer | Year: 2010

Background: The purpose of this study was to describe the preoperative diagnosis of the axillary arch with multidetector row computed tomography (MDCT) in patients who underwent sentinel lymph node (SLN) biopsy. In addition, we investigated anatomical problems of SLN biopsy in the cases that diagnosed this anomaly. Methods: From 2003 to 2008, combined procedures with blue dye SLN biopsy and MDCT-assisted axillary node sampling were performed in 550 clinically axilla-negative patients with primary operable breast cancer. We use MDCT for not only the diagnosis of the axillary arch, but also the planning and navigation of SLN biopsy. Results: The axillary arches were preoperatively diagnosed with MDCT in 59 patients (10.8%) as follows: a single ordinary axillary arch (n = 44), another anomalous muscle besides the ordinary axillary arch (n = 13), and other rare axillary arches (n = 2). The SLN identification failure rate was 1.8% (9/491) for patients without the axillary arch and 5.1% (3/59) for patients with the axillary arch (chi-square test, P = 0.11). Three patients with an axillary arch in whom a SLN could not be identified were observed in 13 patients who had another anomalous muscle besides the ordinary axillary arch (3/13, 23.1%). In the examination of 56 patients with an axillary arch in whom a SLN was identified, variations of the SLN location and/or anomalous muscles covering a SLN were observed in 16 patients (28.5%). Conclusions: MDCT is useful for a diagnosis of the axillary arch. The axillary arch should be kept in mind during SLN biopsy because this anomaly would be related to anatomical variations that affect SLN biopsy. © 2009 The Japanese Breast Cancer Society.

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