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Tsukagoshi M.,Gunma University | Wada S.,Gunma University | Wada S.,Kanagawa Cancer Center | Yokobori T.,Gunma University | And 9 more authors.
Cancer Science | Year: 2016

The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain-related proteins A and B (MICA/B), unique long 16 binding protein (ULBP) 1, and ULBP2/5/6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA/B or ULBP2/5/6 correlated with overall and disease-free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease-free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease-free survival than that observed with the overexpression of any one NKG2D ligand. Co-expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co-overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC. © 2016 Japanese Cancer Association.

Tsutsumi S.,Gunma University | Ishibashi K.,Saitama University | Uchida N.,Red Cross | Ojima H.,Gunma Cancer Center | And 7 more authors.
Oncology (Switzerland) | Year: 2012

Objectives: BRiTE and ARIES (observational cohort studies) provided valuable information on continued use of bevacizumab (BV) beyond progression (BBP). This trial evaluates the efficacy and safety of BBP for patients with metastatic colorectal cancer that progressed on first-line chemotherapy. Methods: A total of 39 patients received FOLFIRI + BV (after FOLFOX + BV) or FOLFOX + BV (after FOLFIRI + BV) as protocol treatment. The primary endpoint was the response rate. Secondary endpoints were overall survival (OS), total survival from initiation of first-line treatment (TS), progression-free survival (PFS), and safety. Results: All 39 treated patients were evaluated for toxic effects. Two patients did not meet all of the eligibility criteria and were excluded from efficacy analyses. The response rate was 16.2%. The disease control rate was 76%. The median PFS was 150 days (range 117-224). The median OS was 417 days (range 233-813). The median TS was 988 days (range 600-1,268). Grade 3/4 adverse events (% of patients) related to treatment were neutropenia (33%), fatigue (23%), and hypertension (18%). Conclusions: This is the first report to show the effect of BBP in patients who had progressive disease on first-line treatment including BV confirmed by RECIST criteria. This analysis suggests the possibility of prolonged survival with continued use of BV. Copyright © 2012 S. Karger AG, Basel.

Shimura T.,Fukushima Medical University | Kofunato Y.,Fukushima Medical University | Okada R.,Fukushima Medical University | Yashima R.,Fukushima Medical University | And 6 more authors.
Annals of Cancer Research and Therapy | Year: 2016

Background: Although intraductal papillary mucinous neoplasms (IPMNs) have become recognized as the most common cystic tumors of the pancreas, evaluations of the prognostic factors of invasive IPMN have not yet been firmly established. Furthermore, the significance of galectin-3 expression in the prognosis of IPMN has not yet examined. Materials and Methods: We retrospectively examined galectin-3 expression immunohistochemically in 53 patients with IPMNs who underwent resection: 28 patients with non-invasive IPMN (including 3 patients with IPMN with carcinoma in situ component), and 25 patients with invasive IPMN. Results: The intranuclear accumulation of galectin-3 (gal-3-INA) was more frequently encountered in patients with invasive IPMN than with non-invasive IPMN (P = 0.038). Incidences of background fibrosis and dilatation of the main pancreatic duct were higher in the high-galectin-3 expression group than in the low-galectin-3 expression group (P = 0.0041 and 0.006, respectively). Incidence of background fibrosis was also higher in patients with gal-3-INA than without gal-3-INA (P = 0.011). The presence of gal-3-INA was higher in the high-galectin-3 expression group than in the low-galectin-3 expression group (P = 0.014). The high-galectin-3- expression group and the patients with gal-3-INA had a significantly poorer prognosis than the low-galectin-3-expression group and those without gal-3-INA (P = 0.020 and P = 0.014, respectively). Multivariate analysis using a Cox regression model revealed that gal-3-INA was an independent prognostic factor (hazard ratio: 5.162, 95% confidential interval: 1.033-25.807, P = 0.046). Conclusions: The presence of gal-3-INA is an independent prognostic factor for patients with invasive IPMN. © 2016, PJD Publications Ltd. All rights reserved.

Mochiki E.,Gunma University | Ogata K.,Gunma University | Ohno T.,Gunma University | Toyomasu Y.,Gunma University | And 7 more authors.
British Journal of Cancer | Year: 2012

Background: A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1paclitaxel with S-1cisplatin in this setting. Methods: Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m -2 twice daily) on days 1-14 plus paclitaxel (60 mg m -2) on days 1, 8, and 15 of a 4-week cycle (S-1paclitaxel) or S-1 (40 mg m -2 twice daily) on days 1-21 plus cisplatin (60 mg m -2) on day 8 of a 5-week cycle (S-1cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 83 patients were eligible for safety and efficacy analyses. In the S-1paclitaxel and S-1cisplatin groups, RRs (52.3% vs 48.7%; P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1paclitaxel and S-1cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1paclitaxel and 19.5% with S-1cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1paclitaxel and 17.1% with S-1cisplatin. Conclusion: S-1paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials. © 2012 Cancer Research UK All rights reserved.

Watanabe A.,Gunma University | Suzuki H.,Gunma University | Yokobori T.,Gunma University | Altan B.,Gunma University | And 8 more authors.
Cancer Science | Year: 2013

Extrahepatic cholangiocarcinoma (EHCC) is a cancer with a poor prognosis, and the postoperative survival of patients depends on the existence of invasion and metastasis. The epithelial-to-mesenchymal transition (EMT) is an important step in EHCC invasion and metastasis. Forkhead box protein C2 (FOXC2) is a transcription factor that has been reported to induce the EMT. Therefore we examined the correlation between FOXC2 expression and clinical pathological factors, and analysed the function of FOXC2. The expression of FOXC2 in 77 EHCC cases was investigated by immunohistochemical staining, and the relationship between FOXC2 expression and clinicopathological factor was assessed. Knockdown by small interfering RNA (siRNA) was performed to determine the roles of FOXC2 in EHCC cell line. FOXC2 expression correlated with lymph node metastasis (P = 0.0205). Patients in the high FOXC2 expression group had a poorer prognosis than the patients in the low FOXC2 expression group. Moreover, FOXC2 knockdown inhibited cell motility and invasion, and decreased the expression of EMT markers (N-cadherin, and matrix metalloproteinase (MMP) -2) and Angiopietin-2 (Ang-2). The EMT inducer FOXC2 contributes to a poor prognosis and cancer progression. FOXC2 may be a promising molecular target for regulating EHCC metastasis. © 2013 Japanese Cancer Association.

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