BackgroundLittle is known about the roles of Notch signaling in cholangiocarcinoma (CC). The expression of hairy and enhancer of split 1 (Hes-1) has not been investigated yet in resected specimens of CC. Notch signaling has been reported to be related to cancer stem cell (CSC) like properties in some malignancies. Our aim is to investigate the participation of Notch signaling in resected specimens of extrahepatic CC (EHCC) and to evaluate the efficacy of CC cells with CSC-like properties by Notch signaling blockade.MethodsFirst, the expression of Notch1, 2, 3, 4 and Hes-1 was examined by immunohistochemistry in 132 resected EHCC specimens. The clinicopathological characteristics in the expression of Notch receptors and Hes-1 were investigated. Second, GSI IX, which is a γ-secretase-inhibitor, was used for Notch signaling blockade in the following experiment. Alterations of the subpopulation of CD24+CD44+ cells, which are surface markers of CSCs in EHCC, after exposure with GSI IX, gemcitabine (GEM), and the combination of GSI IX plus GEM were assessed by flow cytometry using the human CC cell lines, RBE, HuCCT1 and TFK-1. Also, anchorage-independent growth and mice tumorigenicity in the cells recovered by regular culture media after GSI IX exposure were assessed.ResultsNotch1, 2, 3, 4 and Hes-1 in the resected EHCC specimens were expressed in 50.0, 56.1, 42.4, 6.1, and 81.8 % of the total cohort, respectively. Notch1 and 3 expressions were associated with poorer histological differentiation (P = 0.008 and 0.053). The patients with the expression of at least any one of Notch1-3 receptors, who were in 80.3 % of the total, exhibited poorer survival (P = 0.050). Similarly, the expression of Hes-1 tended to show poor survival (P = 0.093). In all of the examined CC cell lines, GSI IX treatment significantly diminished the subpopulation of CD24+CD44+ cells. Although GEM monotherapy relatively increased the subpopulation of CD24+CD44+ cells in all lines, GSI IX plus GEM attenuated it. Anchorage-independent growth and mice tumorigenicity were inhibited in GSI IX-pretreated cells in RBE and TFK-1 (P < 0.05).ConclusionAberrant Notch signaling is involved with EHCC. Inhibition of Notch signaling is a novel therapeutic strategy for targeting cells with CSC-like properties.

Aim Endoscopic decompression using the self‐expandable metallic colonic stent (SEMS) or transanal decompression tube (TDT) can convert emergency surgery into elective one‐stage surgery for obstructive colorectal cancer (OCRC). The aim of the present study was to clarify the effect of SEMS and TDT on long‐term oncological outcomes. Methods We retrospectively analyzed 76 consecutive pathological stage II and III OCRC patients who were inserted with SEMS or TDT as a bridge to curative surgery between 2009 and 2018. Results There were 53 SEMS cases and 23 TDT cases. The tumor was located in the left colon in 58 cases and in the right colon in 18 cases. The interval between the decompression and the surgery was 16.5 days in the SEMS group and 13.0 days in the TDT group (P = 0.09). Technical and clinical success rates were 100% and 100% for SEMS, and 95% and 91% for TDT, respectively. Stoma was created in four patients in the SEMS group, and in five in the TDT group (P = 0.08). Three‐year overall survival rates of the SEMS and TDT groups were 82% and 86% (P = 0.94), and disease‐free survival rates were 68% and 62% (P = 0.79), respectively. The recurrence pattern was not significantly different. Conclusion This study found no statistically significant differences between the effects of SEMS and TDT for OCRC as a bridge to surgery on long‐term outcomes.

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