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BackgroundCD36, a multi-ligand scavenger receptor, has been associated with several cancers. Many studies have revealed that CD36 contributed to cancer malignancy. This study aimed to reveal the function of CD36 expression in pancreatic ductal adenocarcinoma (PDAC).MethodsCD36 expression was characterized using immunohistochemistry in 95 clinical specimens resected from patients with PDAC. We divided patients into two groups, with different CD36 expression levels, and analyzed and compared their prognoses. CD36 expression was also assessed in PDAC cell lines. Gemcitabine-resistant (GR) PDAC cell lines were transfected with small interfering RNA (siRNA) that specifically targeted CD36 to evaluate chemoresistance and apoptosis.ResultsIn resected PDAC samples, CD36 expression was significantly correlated with microinvasion into the venous system (p = 0.0284). Patients with high CD36 expression had significantly lower overall survival (OS) and recurrence-free survival (RFS) rates than patients with low expression; thus, CD36 was an independent prognostic factor for OS and RFS. In subgroup analyses, CD36 was an independent risk factor for OS and RFS in 59 patients treated with gemcitabine adjuvant chemotherapy. CD36 expression was upregulated in PDAC–GR cell lines compared with the PDAC parent cell line. Transduction with siRNA downregulated CD36, which reduced PDAC cell resistance to gemcitabine and inhibited anti-apoptosis proteins.ConclusionCD36 expression influenced gemcitabine resistance by regulating anti-apoptosis proteins. High CD36 expression was a significant, unfavorable prognostic factor in PDAC. Anti-CD36 treatment might serve as an optional treatment for lowering resistance to gemcitabine.

CXCL9, an IFN‐γ inducible chemokine, has been reported to play versatile roles in tumor‐host interrelationships. However, little is known about its role in intrahepatic cholangiocarcinoma (iCCA). Here, we aimed to elucidate the prognostic and biological implications of CXCL9 in iCCA. Endogenous CXCL9 expression and the number of tumor‐infiltrating lymphocytes were immunohistochemically assessed in resection specimens. These data were validated in mice treated by silencing CXCL9 with short hairpin RNA. In addition, the induction of endogenous CXCL9 and the effects of CXCL9 on tumor biological behaviors were evaluated in human cholangiocarcinoma cell lines. Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor‐infiltrating natural killer (NK) cells. In fact, due to the trafficking of total and tumor necrosis factor‐related apoptosis‐inducing ligand‐expressing NK cells into tumors, CXCL9‐sufficient cells were less tumorigenic in the liver than CXCL9‐deficient cells in mice. Although CXCL9 involvement in tumor growth and invasion abilities differed across cell lines, it did not exacerbate these abilities in CXCL9‐expressing cell lines. We showed that CXCL9 was useful as a prognostic marker. Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9‐expressing iCCA by augmenting anti–tumor immune surveillance. CXCL9, an IFN‐γ inducible chemokine, plays versatile roles in the tumor‐host interrelationship. In this study, we demonstrated that elevated intratumoral CXCL9 expression was associated with a large number of tumor‐infiltrating NK cells, leading to favorable postoperative survival in patients with intrahepatic cholangiocarcinoma. Upregulation of CXCL9 might be an immunotherapeutic approach for treating intrahepatic cholangiocarcinoma.

PurposeIn this study, we aim to clarify whether exosomes secreted from hepatocellular carcinoma (HCC) cells under hypoxia affect angiogenesis in endothelial cells.MethodsExosomes derived from human liver cancer cell lines were cultured under hypoxic or normoxic conditions for 24 h, isolated using ExoQuick-TC®, and co-cultured with HUVECs to evaluate angiogenic activity. We also evaluated the expression of miR-155 in the exosomes from 40 patients with HCC.ResultsExosomes under hypoxia remarkably enhanced tube formation of HUVECs. Both cellular and exosomal miR-155 were significantly up-regulated under hypoxic conditions. Knockdown of miR-155 in HCC cells attenuated the promotion of tube formation by exosomes under hypoxia in HUVECs, and high expression of exosomal miR-155 in preoperative plasma was significantly correlated with early recurrence.ConclusionThese results suggest that exosomes derived from HCC cells under hypoxia induce tube formation of HUVECs and that exosomal miR-155 may affect angiogenic activity in HCC.

BackgroundF-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) has been used to diagnose and stage various cancers. In regard to biliary tract cancer (BTC), due to cholangitis it is difficult to evaluate FDG uptake caused by cancer. We previously showed that FDG-positive lymph nodes (LNs) of resectable BTC had a possibility of predicting postoperative prognosis. ObjectiveThis study aimed to validate the usability of FDG-PET for LNs using another cohort and to investigate in detail the relationship between FDG-positive LNs and the prognosis of BTC.MethodsWe measured the preoperative maximum standardized uptake value (SUVmax) at each of the 190 surgically dissected LN areas in 67 patients and investigated the prognosis using our previously determined SUVmax cut-off values of ≥ 2.8.ResultsRegarding the prognosis of patients with resectable BTC, a LN SUVmax ≥ 2.8 [PET N (+)] was a poor prognostic factor for recurrence-free survival (RFS) compared with a LN SUVmax < 2.8 [PET N (−)]. It was confirmed that the hazard ratio forest plot [PET N (+)/PET N (−)] for RFS indicated a similar tendency among subcategories. Moreover, we investigated patients with pN0 disease and demonstrated that the PET N (+) group also had a significantly worse RFS outcome compared with the PET N (−) group. Recurrence of the PET N (+) group has significantly occurred more often in LNs than that of the PET N (−) group.ConclusionHigh LN SUVmax was confirmed to be the preoperatively diagnosed prognostic risk factor for RFS in resectable BTC and could be helpful for clinical decision making regarding the perioperative treatment strategy.

Background/AimWe previously demonstrated that inflammatory cytokine interleukin-6 (IL-6) was produced during cancer progression, worked together with transforming growth factor-beta 1 (TGF-β1), and induced the epithelial–mesenchymal transition (EMT) with chemo-resistance against gemcitabine (GR) at the invasion front of biliary tract cancers (BTCs). However, the significance of cytokine-induced T cell accumulation at the tumor microenvironment in biliary tract cancer (BTC) is not well understood. Because these cytokines (IL-6 and TGF-β1) are able to differentiate naïve T cells into Foxp3-expressing T cells (Tregs) and/or IL-17–producing T helper 17 (Th17) cells, we investigated the relationship between heterogeneous, cancer-producing cytokines and T cell differentiation.MethodsIn total, 127 curative resected specimens from patients with BTCs at Osaka University Hospital between 2000 and 2012 were evaluated for IL-6, TGF-β1, Tregs, and Th17 cells by immunohistochemistry. The ability of BTC–GR cells to undergo T cell differentiation was investigated in vitro.ResultsTregs accumulated at the tumor center and Th17 cells accumulated at the invasion front during cancer progression and/or metastasis; each signaled poor prognosis. Treg accumulation was related to TGF-β1 expression by cancer cells, and Th17 cell accumulation was related to IL-6 expression by cancer cells, in resected specimens; this was confirmed in vitro. Compared with parent cells, GR cells produced IL-6 but not TGF-β1 in a time-dependent manner, had EMT features, and induced T cell differentiation to Th17 cells but not Tregs.ConclusionCytokines produced by cancer cells (IL-6 and TGF-β1) induced heterogeneity of Tregs and Th17 cells in the tumor microenvironment, supporting progression of BTC.

Aim The aim of this study was to evaluate the intra‐abdominal status related to postoperative pancreatic fistula by combining postoperative fluid collection and drain amylase levels. Methods We retrospectively reviewed the data of 203 patients who underwent distal pancreatectomy and classified their postoperative abdominal status into four groups based on postoperative fluid collection size and drain amylase levels. We also evaluated the incidence of clinically relevant postoperative pancreatic fistula in each group according to C‐reactive protein values. Results The incidence of clinically relevant postoperative pancreatic fistula in the entire cohort (n = 203) was 28.1%. Multivariate analysis revealed that postoperative fluid collection, drain amylase levels, and C‐reactive protein levels are considerable risk factors for clinically relevant postoperative pancreatic fistula. In the subgroup with large postoperative fluid collection and high drain amylase levels, 65.9% of patients developed clinically relevant postoperative pancreatic fistula. However, no significant difference was observed in C‐reactive protein levels between patients with clinically relevant postoperative pancreatic fistula and those without it. In contrast, in the subgroup with a large postoperative fluid collection size or a high amylase level alone, a significant difference was observed in C‐reactive protein values between the patients with clinically relevant postoperative pancreatic fistula and those without it. Conclusion Postoperative fluid collection status and the C‐reactive protein value provide a more precise assessment of intra=abdominal status related to postoperative pancreatic fistula after distal pancreatectomy. This detailed analysis may be a clinically reasonable approach to individual drain management. We identified PFCs, postoperative drain amylase levels, and C‐reactive protein (CRP) levels as significant risk factors for CR‐POPF after DP. Detailed assessments of the size of PFC combined with drain amylase level (PFC status) revealed potentially different clinical meanings of drain amylase level and pathogenesis of PFCs. Furthermore, we demonstrated the different clinical significances of CRP levels according to the PFC status.

The efficacy of preoperative treatment for pancreatic cancer (PC) has been reported in randomized controlled trials, but the optimal regimen and the appropriateness of combining radiotherapy remain controversial. Therefore, predicting the efficacy of preoperative treatment using biomarkers and determining whether to combine chemotherapy or radiotherapy based on the biology of individual tumors could help personalize treatment and maximize therapeutic outcomes. In this study, a microRNA (miRNA) microarray analysis was performed using peripheral blood plasma exosomes from 10 PC patients who underwent neoadjuvant chemoradiotherapy, leading to the identification of miR-6855-5p as a candidate miRNA. miR-6855-5p was found to induce radioresistance in PC cells. In another cohort of 28 patients, it was observed that those with higher expression levels of miR-6855-5p in peripheral blood plasma exosomes tended to have increased radioresistance ( r  = − 0.5964). In future, measuring plasma exosomal miR-6855-5p before treatment could potentially lead to precision medicine by personalizing the decision of whether to include radiotherapy in the treatment plan.