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Background Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis. Methods We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo. Results CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups. Conclusions Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.

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Objectives Understanding the effect of lymph node metastasis (LNM) on prognosis in pancreatic neuroendocrine neoplasm is helpful for surgery and follow-up. In this study, we investigated the significance of LNM in well-differentiated pancreatic neuroendocrine tumors (PanNETs) according to the World Health Organization 2017 classification. Methods We retrospectively collected data for 95 consecutive patients with PanNET who underwent pancreatic resection with curative intent between January 2008 and December 2017 at 6 institutions. The clinicopathological factors were compared in patients with and without LNM, and prognostic factors were analyzed. Results Lymph node metastasis was significantly associated with malignant potential of PanNET, such as larger tumor size, higher Ki-67 index, higher tumor grade, and higher incidence of lymphatic, vessel, and neural invasion. Lymph node metastasis was also associated with disease-free but not overall survival. Multivariate analysis identified NET grade 2 (G2) and G3 as independent risk factors for recurrence after curative resection. Conclusions World Health Organization 2017 classification was the most independent prognostic factor in patients with resectable well-differentiated PanNETs. Patients with G2 and higher-grade tumors require lymph node dissection to improve prognosis.

Intensive surgical care is necessary for high-risk patients with hemodialysis, psychiatric disorder, high CONUT count and/or low skeletal muscle quality to reduce postoperative complication.

AimPostoperative ascites is one of the most common complications after hepatic resection and is related to liver fibrosis. Mac‐2 binding protein glycosylation isomer (M2BPGi) is a reliable and non‐invasive marker for assessing liver fibrosis. This study aimed to evaluate whether preoperative M2BPGi level can predict postoperative refractory ascites in patients with curative hepatic resection for hepatocellular carcinoma.MethodsThe present study retrospectively evaluated 59 patients between January 2016 and June 2018. We assessed the relationship between preoperative M2BPGi levels, expressed as the cut‐off index, and postoperative ascites.ResultsThe median M2BPGi level was 1.36 (range 0.34–11.56). Postoperative ascites occurred in seven patients (11.9%). Among them, refractory ascites, defined as diuretic‐resistant ascites, occurred in four patients (6.8%). Uni‐ and multivariate analysis showed that preoperative M2BPGi level was the only independent risk factor of postoperative ascites (odds ratio 3.28, P = 0.033). The cut‐off values of M2BPGi for postoperative ascites and refractory ascites were 2.41 and 3.10, respectively. Remarkably, there were no patients with postoperative ascites and refractory ascites when the preoperative M2BPGi levels were less than each cut‐off value.ConclusionOur results suggest that M2BPGi level is a reliable and non‐invasive surrogate marker for predicting postoperative ascites before curative resection for hepatocellular carcinoma.

CKLF‐like MARVEL transmembrane domain–containing protein 6 (CMTM6) maintains membrane PD‐L1 expression by controlling its endosomal recycling. However, in patients with hepatocellular carcinoma (HCC), the correlation among CMTM6, B7 family ligands, and CD8‐positive cytotoxic T lymphocytes (CTLs), and the molecular function of CMTM6 in HCC have not been established. We performed immunohistochemistry to evaluate the relationships among CMTM6 expression, clinicopathological factors, B7 family ligands expression, and CTL infiltration in HCC samples. Moreover, we established CMTM6‐knockout human HCC cell lines to evaluate the function of human CMTM6 in immune regulation and tumor viability. CMTM6 expression was positively associated with membrane B7 family ligands expression and CTL infiltration in HCC samples. High CMTM6 expression in HCC tissues was associated with the expression of the proliferation marker Ki‐67 and shorter recurrence‐free survival. In vitro analysis showed the downregulation of membrane B7 family ligands and proliferation potency in the CMTM6‐knockout human HCC cell line. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family ligands expression. Thus, CMTM6 might be a biomarker to predict the risk of HCC recurrence and a therapeutic target to suppress tumor growth and increase CTL activity.

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