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Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

14-3-3 proteins are ubiquitous adapters combining with phosphorylated serine/threonine motifs to regulate multiple cellular processes. As a negative regulator, 14-3-3 proteins could sequester the phosphorylated YAP1 in cytoplasm to inhibit its activity. In this study, we identified the K50 acetylation (K50ac) of 14-3-3ε protein and investigated its roles and mechanism in cholangiocarcinoma progression. The NAD (+)-dependent protein deacetylases inhibitor, NAM treatment significantly up-regulated the K50ac of 14-3-3ε. K50R mutation resulted in the decrease of K50ac of 14-3-3ε. The K50ac of 14-3-3ε was reversibly mediated by PCAF acetyltransferase and sirt1 deacetylases. K50ac had no obvious effect on the protein stability of 14-3-3ε, but inhibited the combination of 14-3-3ε with phosphorylated YAP1, which resulted in the activation of YAP1 in cholangiocarcinoma. K50R significantly decreased cholangiocarcinoma cell proliferation in vitro and the growth of tumor xenograft in vivo compared with WT (wild type) 14-3-3ε. The level of K50ac were higher in cholangiocarcinoma tissues accompanied by the accumulation of YAP1 in nuclear than para-carcinoma tissues. Our study revealed the underlying mechanism of K50ac of 14-3-3ε and its roles in cholangiocarcinoma, providing a potential targeting for cholangiocarcinoma therapy., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The distant metastasis (DM) mode and treatment efficacies in the advanced biliary tract cancer (BTC) were obscure, and a credible evaluation is urgently needed., Method: A total of 6348 advanced BTC patients (ICC, intrahepatic cholangiocarcinoma, n = 1762; PHCC, perihilar cholangiocarcinoma, n = 1103; GBC, gallbladder cancer, n = 2580; DCC, distal cholangiocarcinoma, n = 538; AVC, carcinoma of Vater ampulla, n = 365) were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) process was carried out for less bias., Result: The proportion of M1 patients in each subtype at first diagnosis was 26.4% (ICC), 37.2% (PHCC), 41. 0% (GBC), 24.5% (DCC), and 12.7% (AVC), and the constitution of DM sites in different subtypes varied apparently. Moreover, the survival of metastasis sites was different (P < .05 in all the subtypes) where the multi-metastasis and distant lymph node (dLN) only always indicated the worst and best prognosis, respectively. Chemotherapy presented the most significant survival impact with the lowest hazard ratio by multivariate cox model and still provided a survival improvement after PSM (all P < .001) in all subtypes. However, the median months manifested different between patients with and without chemotherapy among the subtypes (ICC, from 5 to 9; PHCC, from 6 to 10; AVC, from 4 to 9; GBC, from 6 to 7; DCC from 6 to 8)., Conclusion: We provided a landscape about the detailed DM mode of the advanced BTC in a large population, found the survival differences among DM sites, and revealed the different chemotherapy efficacies in the BTC subtypes., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Tumor-infiltrating neutrophils (TIN) carry out quite significant but opposite functions in different cancers, and their function in biliary cancer has not been fully characterized. To investigate the prognostic significance of TIN in biliary cancer, a training set (n = 118) and a validation set (n = 127) were involved in this study. TIN were evaluated by immunohistochemical staining of CD66b, and then defined as low (neutrophils <18/high-power field [HPF]) vs high (neutrophils ≥18/HPF). Kaplan-Meier curve, Cox proportional hazards models and receiver operating characteristic curve were used to assess the prognostic significance. TIN was identified as an independent prognostic factor for overall survival in the training set (HR: 4.720; 95% CI: 2.623-8.493; P < .001) which was confirmed in the validation set (HR: 4.993; 95% CI: 2.626-9.492; P < .001). Notably, among patients with stage III and IV disease, those with low TIN could benefit from adjuvant chemotherapy, with a reduced risk of compromised survival compared with those with high TIN (HR: 0.294; 95% CI: 0.099-0.873; P = .047 in the training set; and HR: 0.100; 95% CI: 0.022-0.462; P = .006 in the validation set). In addition, TIN were negatively related to biological pathways as regulation of activated T-cell proliferation and lymphocyte-mediated immunity, and showed a negative correlation with CD8 +  T cells (r = -.324, P < .001). Taken together, our results implicate TIN as an independent marker of prognosis and indicator of patients who would benefit from adjuvant chemotherapy in biliary cancer., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cholangiocarcinoma is a rare, but highly fatal malignancy. However, the intrinsic mechanism involved in its tumorigenesis remains obscure. An urgent need remains for a promising target for cholangiocarcinoma biological therapies. Based on comparative proteomical technologies, we found 253 and 231 different spots in gallbladder tumor cell lines and cholangiocarcinoma cell lines, respectively, relative to non-malignant cells. Using Mass Spectrometry (MS) and database searching, we chose seven differentially expressed proteins. High Stathmin expression was found in both cholangiocarcinoma and gallbladder carcinoma cells. Stathmin expression was validated using immunohistochemistry and western blot in cholangiocarcinoma tissue samples and peritumoral tissue. It was further revealed that high Stathmin expression was associated with the repression of staurosporine-induced apoptosis in the cholangiocarcinoma cell. Moreover, we found that Stathmin promoted cancer cell proliferation and inhibited its apoptosis through protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) signaling. Integrin, β1 appears to serve as a partner of Stathmin induction of ERK and Akt signaling by inhibiting apoptosis in the cholangiocarcinoma cell. Understanding the regulation of anti-apoptosis effect by Stathmin might provide new insight into how to overcome therapeutic resistance in cholangiocarcinoma.

Background: This population-based study examined surgical outcomes and hospital and post-acute care resource use after operations of cholangiocarcinoma during 2005-2012., Study Design: Using New York State hospital claims, we identified subjects with intrahepatic tumor who underwent hepatectomy only (n = 2089), subjects with perihilar tumor who underwent hepatectomy and biliary-enteric anastomosis (BEA; n = 389) or BEA only (n = 3721), and subjects with distal cholangiocarcinoma undergoing pancreatectomy or pancreaticoduodenectomy (n = 228). We performed trend analyses for each group and calculated overall risk-adjusted mortality, complication, and 30-day readmission rates for hospitals using multivariable logistic regressions., Results: Mortality rate was roughly 12 % over years for perihilar cases undergoing hepatectomy and BEA, significantly higher than the rates of other 3 groups (p = 0.000). The overall complication rate was 40 % for subjects undergoing both hepatectomy and BEA, more than doubling the rate for subjects undergoing hepatectomy or BEA alone (p = 0.000). Average LOS declined markedly for perihilar cases undergoing hepatectomy and BEA (from 21 days in 2005 to 16 days in 2012) and subjects with distal cholangiocarcinoma (from 22 days in 2005 to 16 days in 2012), but other outcomes did not change dramatically. Risk-adjusted hospital outcome rates varied substantially., Conclusions: Surgical patients with cholangiocarcinoma incur considerable mortality, postoperative complications, and resource uses, especially among those undergoing hepatectomy and BEA for perihilar tumors.

Purpose: 18F-FDG PET/MR has been applied to the diagnosis and preoperative staging in various tumor types; however, reports using PET/MR in hilar cholangiocarcinoma (HCCA) are rare. We investigated the value of PET/MR for preoperative staging and compared it with PET/CT in HCCA. Methods: Fifty-eight patients with HCCA confirmed by pathology were retrospectively analyzed. 18F-FDG PET/CT imaging was performed first, followed with whole-body PET/MR imaging. SUVmax of tumor and normal liver tissue were measured. Paired T test was used to compare SUVmax of tumor and normal liver tissue of PET/CT and PET/MR. In addition, McNemar test was used to compare the accuracy of TNM staging and Bismuth-Corlette typing between PET/CT and PET/MR. Results: There was no significant difference in SUVmax between PET/CT and PET/MR in primary tumor lesions (6.6 ± 5.5 vs. 6.8 ± 6.2, P = 0.439). SUVmax of PET/CT and PET/MR in normal liver parenchyma was significantly different (3.0 ± 0.5 vs. 2.1 ± 0.5, P < 0.001). The accuracy of PET/MR in diagnosing T staging and N staging was significantly higher than those of PET/CT (72.4% vs. 58.6%, P = 0.022 and 84.5% vs. 67.2%, P = 0.002). There was no significant difference between PET/CT and PET/MR in M staging (94.8% vs. 98.3%, P = 0.5). The classification accuracy of PET/MR in Bismuth-Corlette was significantly higher than that of PET/CT (89.7% vs. 79.3%), P = 0.031. Conclusions: The diagnostic accuracy of 18F-FDG PET/MR was superior to that of PET/CT in preoperative T staging, N staging, and Bismuth–Corlette classification of HCCA. In M staging, the diagnostic accuracy of PET/MR was similar to that of PET/CT. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the role of dual-time point 18F-FDG PET/CT imaging in the primary diagnosis and staging of hilar cholangiocarcinoma (HCCA). Methods: Dual-time point FDG PET/CT findings, including early phase whole-body scanning and abdominal delayed phased performed 1 and 2 h after radiotracer injection, respectively, were retrospective reviewed in 69 patients conformed HCCA by histology. PET/CT was evaluated based on visual interpretation and the semiquantitative index of SUVmax and tumor-to-normal liver tissue ratio (TNR) for both early and delayed images. Results: For all 69 HCCA patients, the mean SUVmax of the lesion and TNR in delayed phase was significantly higher than that in early phase (6.1 ± 4.7, 2.2 ± 1.7, vs 5.1 ± 3.4, 1.6 ± 1.1; P < 0.001). The sensitivity and accuracy value of detection primary lesions was 69.6% and 70% in early phase vs 76.8% and 76.8% in delay phase, respectively. There was a significant correlation between lesion SUVmax and Ki67 index in both dual-time imaging (r = 0.462, P < 0.001 in early phase vs r = 0.47, P < 0.001 in delay phase). The sensitivity, specificity and accuracy value of metastatic lymph nodes prediction was 50%, 67.3% and 71% in early phase vs 62.5%, 73.3% and 76.8% in delayed phase, respectively. The sensitivity, specificity and accuracy of FDG PET/CT in detecting distant metastasis in our study was 75%, 100% and 97.1%. There was no difference of predicting distant metastasis between early phase and delayed phase. Conclusion: Delayed phase in dual-time point 18F-FDG PET/CT scan provides additional usefulness for detection primary tumor and lymph nodes metastases in HCCA, but there was no added benefit of delayed PET/CT imaging in detection of distant metastases in this study. SUVmax in early and delayed phase could be used to assess tumor aggressiveness in pre-treatment HCCA. [ABSTRACT FROM AUTHOR]

Background: The prognostic benefits and safety of extended lymphadenectomy for hilar cholangiocarcinoma remain uncertain. The available evidence is still insufficient concerning its retrospective aspect. The aim of this study is to explore the clinical effect and safety of extended lymphadenectomy compared to regional lymphadenectomy in patients with hilar cholangiocarcinoma.Methods: The Relay-HC trial is a prospective, multicenter, and randomized controlled trial. Seven hundred and thirty-four eligible patients with resectable perihilar cholangiocarcinoma across 15 tertiary hospitals in China will be randomly assigned (1:1) to receive either regional lymphadenectomy or extended lymphadenectomy. The primary objective is to determine the overall survival after the two approaches. Secondary objectives of the study include the evaluation of perioperative mortality, postoperative complication, and disease-free survival. This study has been approved by the ethics committee of each participating hospital.Discussion: The Relay-HC trial is designed to investigate the prognostic benefits and safety of expanded lymphadenectomy for hilar cholangiocarcinoma. Currently, it has never been investigated in a prospective randomized controlled clinical trial.Trial Registration: Chinese Clinical Trial Registry (ChiCTR), ChiCTR1800015688 . Registered on 15 April 2018. [ABSTRACT FROM AUTHOR]