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Background/aims: Patients with active cancer frequently develop venous thromboembolism (VTE). However, there is little data about VTE in patients with advanced cholangiocarcinoma (CCA). Therefore, we investigated the clinical significance of VTE in patients with advanced CCA., Methods: We analyzed the data of a total of 332 unresectable CCA patients diagnosed between 2010 and 2020 in this retrospective study. We investigated the incidence and risk factors for VTE, and its effect on survival in patients with advanced CCA., Results: During a median follow-up of 11.6 months, 118 patients (35.5%) developed VTE. The cumulative incidence of VTE was 22.4% (95% confidence interval [CI], 0.18 to 0.27) at 3 months and 32.8% (95% CI, 0.27 to 0.38) at 12 months. Major vessel invasion was an independent risk factor for VTE (hazard ratio, 2.88; 95% CI, 1.92 to 4.31; p<0.001). Patients who developed VTE during follow-up had shorter overall survival than patients who did not (11.50 months vs 15.83 months, p=0.005). In multivariable analysis, VTE (hazard ratio, 1.58; 95% CI, 1.23 to 2.02; p<0.001) was associated with poor overall survival., Conclusions: Major vessel invasion is related to the occurrence of VTE in advanced CCA. The development of VTE significantly decreases the overall survival and is an important unfavorable prognostic factor for survival.

Background/aim: Cholangiocarcinoma is a devastating malignancy with limited treatment options and poor prognosis. Natural products have gained considerable attention for showing antitumor effects with less toxicities. Flavokawain B (FKB), a natural product, has been studied for its antitumor effects on various cancer cells. However, the anti-tumor effect of FKB on cholangiocarcinoma cells remains unknown. This study aimed at investigating the antitumor effect of FKB on cholangiocarcinoma cells in vitro and in vivo., Materials and Methods: SNU-478, a human cholangiocarcinoma cell line, was used in this study. Effects of FKB on cell growth inhibition and apoptosis were investigated. The synergistic anti-tumor effect of FKB and cisplatin in combination was also evaluated. Western blotting was performed to examine the underlying molecular mechanisms of the effect of FKB. A xenograft mouse model study was performed to investigate the effect of FKB in vivo., Results: FKB inhibited cell proliferation of cholangiocarcinoma cells in a concentration- and time-dependent manner. FKB also induced cellular apoptosis additively in combination with cisplatin. Akt pathway was suppressed by FKB either alone or in combination with cisplatin. In the xenograft model, FKB treatment in combination with cisplatin/gemcitabine significantly inhibited tumor growth of SNU-478 cells., Conclusion: FKB showed an antitumor effect through the induction of apoptosis, which was mediated by suppressing the Akt pathway in cholangiocarcinoma cells. However, the synergistic effect of FKB and cisplatin was not definite., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Several systemic inflammatory response (SIR) markers, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and albumin-to-globulin ratio (AGR), have emerged as prognostic markers in various cancers. The aim of this study was to explore the impact of SIR markers on the survival outcomes of unresectable intrahepatic cholangiocarcinoma (IHC) patients., Methods: Patients with histologically confirmed, unresectable IHC treated with gemcitabine plus cisplatin (GP) chemotherapy in a single tertiary hospital from 2012 to 2016 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) were determined using unadjusted Kaplan-Meier and adjusted Cox-proportional-hazards analysis. Time-dependent receiver operating characteristic (ROC) analysis was performed to compare the performance of the SIR markers in predicting OS., Results: A total of 137 patients received a median of six cycles (interquartile range [IQR], 3-11) of GP chemotherapy with a median observation time of 9.9 months (range, 1.8-54.7 months). The median PFS and OS of all patients were 7.8 months and 9.9 months, respectively. Among the SIR markers, high PLR (> 148) and high NLR (> 5) were associated with a short PFS (Hazard ratio [HR] 1.828, P = 0.006; HR 1.738, P = 0.030, respectively) and short OS (HR 2.332, P < 0.001; HR 2.273, P < 0.001, respectively). Low LMR (< 3.5) and low AGR (< 1.2) were associated with a short OS (HR 2.423, P < 0.001; HR 1.768, P = 0.002, respectively). In multivariable cox-regression analysis, high PLR (HR 1.766, P = 0.009) and distant lymph node (LN) metastasis (HR 2.085, P = 0.001) were associated with a short PFS. High PLR (HR 1.856, P = 0.002) was an independent predictor of a short OS, along with distant LN metastasis (HR 1.929; P < 0.001), low LMR (HR 1.691; P = 0.041), and low level of serum albumin (< 3.5 g/dL) (HR 1.632; P = 0.043). Time-dependent ROC analysis revealed that the area under the curve of PLR for predicting overall survival was greater than that of NLR, LMR, and AGR at most time points., Conclusions: High PLR was an independent prognostic factor of a short PFS and OS in patients with unresectable IHC receiving GP chemotherapy.

Since conventional chemotherapy (gemcitabine and cisplatin) has marginal survival benefit in patients with advanced cholangiocarcinoma (CCA), an effective targeted therapeutic agent is urgently required. Activation of the PI3K/Akt/mTOR signaling pathway is frequently observed in CCA, and thus, PI3K and mTOR are promising therapeutic targets in CCA. Recently a new dual PI3K/mTOR inhibitor GDC-0980 (apitolisib) was introduced. This study was undertaken to examine the activity of apitolisib against CCA cells in vitro and in vivo. Apitolisib treatment strongly reduced Akt and mTOR active phosphorylation levels and attenuated cell growth in two different CCA cell lines (SNU478 and SNU1196). In addition, the cytotoxic activity of apitolisib enhanced the effects of gemcitabine or cisplatin in vitro and increased PARP cleavage. Moreover, we observed these co-treatments significantly reduced colony formation by SNU478 and SNU1196 cells and potently inhibited tumor growth in a mouse xenograft model. The results of the present study show that apitolisib effectively reduces CCA cell growth by suppressing the PI3K/Akt/mTOR pathway. In addition, co-treatments with apitolisib and gemcitabine or cisplatin synergistically enhanced apitolisib activity, which suggests a means of improving the chemotherapeutic sensitivity of CCA., Competing Interests: Declaration of competing interest Biochemical and Biophysical Research Communications. 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. Please note that all Biochemical and Biophysical Research Communications authors are required to report the following potential conflicts of interest with each submission. If applicable to your manuscript, please provide the necessary declaration in the box above. (1) All third-party financial support for the work in the submitted manuscript. (2) All financial relationships with any entities that could be viewed as relevant to the general area of the submitted manuscript. (3) All sources of revenue with relevance to the submitted work who made payments to you, or to your institution on your behalf, in the 36 months prior to submission. (4) Any other interactions with the sponsor of outside of the submitted work should also be reported. (5) Any relevant patents or copyrights (planned, pending, or issued). (6) Any other relationships or affiliations that may be perceived by readers to have influenced, or give the appearance of potentially influencing, what you wrote in the submitted work. As a general guideline, it is usually better to disclose a relationship than not., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/aims: Recurrent pyogenic cholangitis (RPC) is a chronic progressive disease frequently accompanied by cholangiocarcinoma (CCA). This study aimed to investigate the natural course of RPC and identify factors associated with CCA., Methods: From January 2005 to December 2016, 310 patients diagnosed with RPC at Seoul National University Hospital were included. Complications and management during follow-up were recorded. CCA-free probability was estimated by Kaplan-Meier method, and risk factors associated with CCA were analyzed using log-rank test and Cox’s proportional hazard regression model., Results: Mean age at diagnosis was 59.1±10.9 years and mean follow-up duration was 84.0±64.1 months. An intrahepatic duct stone was found in 253 patients (81.6%). Liver atrophy was identified in 185 patients (59.7%) and most commonly located at the left lobe (65.4%). Acute cholangitis, liver abscesses, cirrhotic complications, and CCA developed in 41.3%, 19.4%, 9.7%, and 7.4%, respectively. During follow-up, complete resolution rate after hepatectomy, biliary bypass surgery, and choledocholithotomy with T-tube insertion reached 82.3%, 55.2%, and 42.1%, respectively. None of the patients who maintained complete resolution by the last follow-up day developed CCA. In univariate analysis, female, both-sided intrahepatic duct stones, and liver atrophy at any location were associated with increased risk of CCA. Multivariate analysis revealed that both-sided atrophy significantly increased risk of CCA (hazard ratio, 4.56; 95% confidence interval, 1.48 to 14.09; p=0.008). In 21 patients who developed intrahepatic CCA, tumor was located mostly in the atrophied lobe (p=0.023)., Conclusions: In RPC patients, acute cholangitis, liver abscess, cirrhotic complications, and CCA frequently developed. Both-sided liver atrophy was a significant risk factor for developing CCA.

Background: Bilateral stent-in-stent (SIS) self-expandable metal stent placement is technically challenging for palliation of unresectable malignant hilar obstruction. In the SIS technique, the uniform large cell type biliary stent facilitates contralateral stent deployment through the mesh of the first metallic stent. This study aimed to assess the technical success and clinical effectiveness of this technique with a uniform large cell type biliary stent., Methods: Thirty-one patients who underwent bilateral SIS placement using a large cell type stent were reviewed retrospectively. All patients showed malignant hilar obstruction (Bismuth types II, III, IV) with different etiologies., Results: Sixteen (51.6%) patients were male. The mean age of the patients was 67.0+/-14.0 years. Most patients were diagnosed as having hilar cholangiocarcinoma (58.1%) and gallbladder cancer (29.0%). Technical success rate was 83.9%. Success was achieved more frequently in patients without masses obstructing the biliary confluence (MOC) than those with MOC (95.2% vs 60.0%, P=0.03). Functional success rate was 77.4%. Complications occurred in 29.0% of the patients. These tended to occur more frequently in patients with MOC (50.0% vs 19.0%, P=0.11). Median time to recurrent biliary obstruction was 188 days and median survival was 175 days., Conclusions: The large cell type stent can be used efficiently for bilateral SIS placement in malignant hilar obstruction. However, the risk of technical failure increases in patients with MOC, and caution is needed to prevent complications for these patients.

Background: Cholangiocarcinoma (CCA) is a malignancy with poor prognosis and limited therapeutic options. Effective prevention and treatment of CCA require developing novel anticancer agents and improved therapeutic regimens. As natural products are concidered a rich source of potential anticancer agents, we investigated the anticancer effect of fisetin in combination with gemcitabine., Materials and Methods: Cytotoxic effect of fisetin and gemcitabine on a human CCA cell line SNU-308 was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptosis assay using propidium iodine and annexin V. Molecular mechanisms of fisetin action in CCA were investigated by western blotting., Results: Fisetin was found to inhibit survival of CCA cells, through strongly phosphorylating ERK. It also induced cellular apoptosis additively in combination with gemcitabine. Expression of cellular proliferative markers, such as phospho-p65 and myelocytomatosis (MYC), were reduced by fisetin., Conclusion: These results suggest fisetin in combination with gemcitabine as a candidate for use in improved anticancer regimens., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Little is known of the prognostic value of CEA/CA 19-9 kinetics during chemotherapy in patients with advanced cholangiocarcinoma (CCA)., Methods: A total of 236 patients with pathologically confirmed advanced CCA received gemcitabine-based chemotherapy were reviewed, and 179 were eligible for analysis. Baseline, pre-, and post-treatment (after two cycles of chemotherapy) CEA and CA 19-9 values were checked, and survival was compared according to various cutting points of baseline measurement or extent of change of tumor marker level., Results: Patients with a ≥ 50% decline in CA 19-9 level had better survival than the others (16.0 vs 9.0 months). However, CEA decline did not predict survival gain. Significant favorable prognostic factors of survival in multivariable analysis included initial treatment response (HR 0.61), distal location of tumor (HR 0.46), baseline CA 19-9 level ≤ 1000 U/mL (HR 0.58), and ≥ 50% decline in CA 19-9 level (HR 0.50). Subgroup analysis was conducted in 114 patients with pre-treatment CA 19-9 > 37 U/mL and bilirubin ≤ 2 mg/dL. Decline ≥ 50% in CA 19-9 level still showed an independent prognostic significance (HR 0.45)., Conclusion: CA 19-9 but not CEA kinetics serves as a predictor of better survival in patients with advanced CCA on gemcitabine-based chemotherapy. A ≥ 50% decline in CA 19-9 level after two cycles of chemotherapy may have clinical utility as an early indicator of better response to gemcitabine-based chemotherapy., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The blood neutrophil-to-lymphocyte ratio (NLR) is reported to be a prognostic marker in several cancers. However, the prognostic role of NLR in patients with advanced cholangiocarcinoma on chemotherapy is unknown. A total of 221 patients with pathologically confirmed locally advanced or metastatic cholangiocarcinoma receiving first-line palliative chemotherapy were enrolled. Associations between baseline clinical and laboratory variables including NLR and survival were investigated. Patients were classified into two groups according to the NLR level (≤ 5 vs. >5). Median overall survival (OS) and time to progression (TTP) in patients with NLR ≤ 5 were 10.9 and 6.7 months, respectively, and 6.8 and 4.1 months in patients with NLR > 5 (P < 0.001, P = 0.002, respectively). In multivariate analysis, number of cycles of chemotherapy was a significant predictor of longer OS (HR 0.86, P < 0.001), whereas adverse prognostic factors for OS were CA 19-9 > 300 (HR 1.43, P = 0.025), CEA > 5 (HR 1.44, P = 0.029), higher stage (HR 1.69, P = 0.004), and NLR > 5 (HR 1.87, P < 0.001). NLR > 5 was also associated with reduced TTP (HR 1.66, P = 0.007). Among 50 patients with initial NLR > 5, 33 patients had NLR ≤ 5 after two cycles of chemotherapy and they had significantly better survival than the others (HR 0.48, P = 0.015). NLR independently predicts survival in patients with advanced cholangiocarcinoma undergoing chemotherapy. Considering cost-effectiveness and easy availability, NLR may be a useful biomarker for prognosis prediction.

Background and Aim: Although the large cell-sized biliary stent facilitates contralateral stent deployment through the mesh of the first metallic stent for stent-in-stent (SIS) technique, there are concerns about its vulnerability to tumor ingrowth. The aim of the present study was to compare the clinical outcomes of endoscopic bilateral SIS placement according to the cell size of a self-expandable metallic stent (SEMS)., Methods: A total of 58 patients were enrolled who underwent endoscopic bilateral SIS placement of SEMS for malignant hilar biliary obstruction as a result of cholangiocarcinoma or gallbladder cancer. Finally, 43 patients who underwent successful stent insertion were included in the analysis and divided into the small cell-sized stent (SCS; n = 21) and the large cell-sized stent (LCS; n = 22) groups. We retrospectively compared comprehensive clinical and laboratory data in both groups., Results: There were no significant differences between the two groups in successful drainage (SCS vs LCS, 100% vs 100%, respectively), early complications (38.1% vs 18.2%), late complications (14.3% vs 22.7%), stent occlusion (42.9% vs 45.5%), tumor ingrowth (33.3% vs 45.5%) or overgrowth (9.5% vs 0%). Duration of stent patency and overall survival were not significantly different between the two groups (P = 0.086 and P = 0.320, respectively)., Conclusions: Endoscopic bilateral SIS placement for malignant hilar biliary obstruction shows no differences in stent patency, survival, complications and clinical course according to the cell size of SEMS., (© 2015 The Authors. Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society.)

Background: Aberrant Hedgehog (HH) signaling activation is important in cancer growth and mediates the interaction between cancer cells and the surrounding stromal cells. This study investigated the role of HH signaling on the growth of cholangiocarcinoma (CC), focusing on the interaction of CC cells with stromal cells., Methods: To evaluate the interaction between human CC cells (SNU-1196, SNU-246, SNU-308, SNU-1079, and HuCCT-1) and stromal cells (hepatic stellate cell line, Lx-2), co-culture proliferation, migration, and invasion assays were performed. In vivo nude mice experiments were conducted using two groups-HuCCT-1 single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2., Results: When HuCCT-1 cells were co-cultured with Lx-2 cells, the expression of HH signaling-related proteins increased in both HuCCT-1 and Lx-2 cells. Co-culture with Lx-2 cells stimulated the proliferation, migration, and invasion of CC cells, and these effects were mediated by HH signaling. Co-culture of HuCCT-1 and Lx-2 cells increased the secretion of several cytokines. In an ectopic xenograft model, Lx-2 co-implantation increased CC tumor growth and stimulated angiogenesis. Cyclopamine attenuated tumor growth in the CX group, but not in the HuCCT-1 mono-implant (SX) group. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased tumor necrosis in the CX group, but not in the SX group., Conclusion: Hepatic stellate cells stimulate the proliferation, migration, and invasion of CC cells, promote angiogenesis through HH signaling activation, and render CC more susceptible to necrosis by HH inhibitor.

Extrahepatic cholangiocarcinoma (EHC) is usually difficult to diagnose by bile cytology because of cellular disintegration. However, DNA samples from bile fluid can provide sufficient materials to screen for the presence of EHC. We developed DNA methylation marker panels that can be used for MethyLight assay-based detection of EHC in bile fluid specimens. The methylation status of 59 DNA methylation markers was investigated in 20 EHC and 20 non-neoplastic gallbladder tissue samples with MethyLight assay to determine cancer-specific DNA methylation markers. Through assaying cancer-specific DNA methylation markers in a training set (n = 40) and validation set (n = 45) of bile fluid specimens from patients with EHC or those without cancer, we selected suitable marker panels that were assessed for their performance in a third set (test set; n = 40). Four marker panels showed a sensitivity of 60% or more and a specificity of 100% in both the training and validation sets, whereas bile cytology displayed a sensitivity of 40% to 46% and a specificity of 100%. In an independent test set of bile fluid samples, a five-gene panel (CCND2, CDH13, GRIN2B, RUNX3, and TWIST1) detected EHC at a sensitivity of 83%, which was far higher than that of bile cytology (46%, P = 0.004). Using bile fluids, a methylation assay consisting of a five-gene panel may be useful for detecting EHC and in helping to increase the sensitivity of preoperative diagnoses., (Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Endoscopic or percutaneous biliary drainage with self-expandable metallic stents (SEMS) is widely used for the palliation of cholestasis in patients with advanced hilar cholangiocarcinoma. However, little is known about which is the better option in patients with advanced hilar cholangiocarcinoma. We compared the clinical outcomes of these 2 methods of biliary decompression in these patients., Design and Setting: Multicenter retrospective study., Patients: A total of 85 patients with newly diagnosed advanced hilar cholangiocarcinoma (Bismuth III or Bismuth IV) and who did not receive an operation, chemotherapy, or radiotherapy were retrospectively reviewed. Forty-four of the 85 received endoscopic SEMS and 41 received percutaneous SEMS., Interventions: Endoscopic SEMS or percutaneous SEMS., Main Outcome Measurements and Results: Baseline characteristics were similar in the 2 groups, but the rate of successful biliary decompression was significantly higher in the percutaneous SEMS group than in the endoscopic SEMS group (92.7% vs 77.3%, respectively, P= .049). Overall rates of procedure-related complications were similar for the 2 groups, but 1 death (from biliary sepsis) occurred in the endoscopic SEMS group. Median survival of patients in whom biliary drainage was successful initially, regardless of which procedure was performed, was much longer than that of patients who had failed biliary drainage (8.7 months vs 1.8 months, respectively, P< .001). Once successful biliary decompression had been achieved, median survival and stent patency duration were similar in the 2 study groups., Limitation: Retrospective study., Conclusions: Percutaneous SEMS may be chosen for initial biliary drainage in patients with advanced type III or IV hilar cholangiocarcinoma, given higher initial success rate and low level of procedure-related cholangitis.

Background: Ampullary carcinoma is often considered to have a better prognosis than distal extrahepatic cholangiocarcinoma. However, studies that directly compare the recurrence and histopathological features between the two groups are rare., Methods: Clinicopathologic factors and the long-term outcomes of 163 patients with ampullary carcinoma after radical resection were retrospectively evaluated and compared with those of 91 patients with distal extrahepatic cholangiocarcinoma., Results: Among the 163 ampullary carcinomas, T1 stage, well-differentiated tumors and perineural invasion were 45 (28%), 73 (45%), and 23 (14%), respectively, whereas, only five (6%) were T1 stage, 15 (17%) were well differentiated, and 63 (69%) showed perineural invasion (p < 0.001, for all) in distal extrahepatic cholangiocarcinomas. More patients with distal extrahepatic cholangiocarcinoma had liver metastasis than ampullary carcinoma (24% vs. 10%, p = 0.004). Multivariate analysis identified venous invasion and perineural invasion as risk factors for recurrence of ampullary carcinoma after radical resection. Only lymph node involvement was identified as a risk factor for recurrence of distal extrahepatic cholangiocarcinoma by multivariate analysis. Overall five-year survival of patients with ampullary cancer was higher than that of patients with distal extrahepatic cholangiocarcinoma (68% vs. 54%; p = 0.033). In patients without lymph node metastasis, a significant difference in survival was also observed between the two groups (p = 0.049)., Conclusion: Earlier diagnosis and the less frequent occurrence of pathological factors associated with tumor invasiveness in ampullary carcinoma than in distal extrahepatic cholangiocarcinoma may explain its association with a better prognosis.

Cholangiocarcinomas are intrahepatic bile duct carcinomas that are known to have a poor prognosis. Sesquiterpene lactone parthenolide, which is the principal active component in medicinal plants, has been used to treat tumors. Parthenolide effectively induced apoptosis in all four cholangiocarcinoma cell lines in a dose-dependent manner. However, the sarcomatous SCK cells were more sensitive to parthenolide than the other adenomatous cholangiocarcinoma cells. Therefore, this study investigated whether or not the expression of p53, the Fas/Fas ligand (FasL), Bcl-2/Bcl-X(L) determines the enhanced drug susceptibility of SCK cells. The results showed that Bcl-2 family molecules, such as Bid, Bak, and Bax, are involved in the parthenolide-induced apoptosis and that the defective expression of Bcl-X(L) might contribute to the higher parthenolide sensitivity in the SCK cells than in the other adenomatous cholangiocarcinoma cells. SCK cells, which stably express Bcl-X(L), were resistant to parthenolide, whereas Bcl-X(L)-positive Choi-CK cells transfected with the antisense Bcl-X(L) showed a higher parthenolide sensitivity than the vector control cells. Molecular dissection revealed that Bcl-X(L) inhibited the translocation of Bax to the mitochondria, decreased the generation of intracellular reactive oxygen species, reduced the mitochondrial transmembrane potential (deltapsi(m)), decreased the release of cytochrome c, decreased the cleavage of poly(ADP-ribose) polymerase, and eventually inhibited apoptotic cell death. These results suggest that parthenolide effectively induces oxidative stress-mediated apoptosis, and that the susceptibility to parthenolide in cholangiocarcinoma cells might be modulated by Bcl-X(L) expression in association with Bax translocation to the mitochondria.

Backgrounds: The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions.Methods: Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics.Results: The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P  = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups.Conclusions: Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans. [ABSTRACT FROM AUTHOR]

Gemcitabine is a principal chemotherapeutic agent for biliary tract cancer (BTC). Expression of human equilibrative nucleoside transporter 1 (hENT1) is regarded as a potential predictive biomarker for a gemcitabine response in some cancers. This study was conducted to investigate the association between hENT1 expression and the effects of gemcitabine on BTC cell lines and on patients with advanced BTC receiving gemcitabine-based chemotherapy. A total of four BTC cell lines, HuCCT1, SNU-478, SNU-1079, and SNU-1196, were tested. mRNA and protein expression levels of hENT1 were measured by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively. Cell viability after gemcitabine treatment was measured in a chemosensitivity assay. For clinical assessment, 40 patients with unresectable or recurrent BTC who were treated with gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) between June 2012 and May 2014 were enrolled. Among the four cell lines, SNU1196 showed the highest mRNA and protein levels of hENT1. Expression of hENT1 showed a linear correlation with the log value of the half-maximal inhibitory concentration of gemcitabine. During incubation with gemcitabine, pretreatment with hENT1-specific small interfering RNA (siRNA) resulted in higher cell viability than that in samples pretreated with control siRNA. In a clinical evaluation, the median progression-free survival was 24 and 11 weeks among patients with strong and weak intratumoral hENT1 immunohistochemical staining (P = 0.05), and the median overall survival was 52 and 26 weeks (P = 0.15), respectively. In conclusion, this study showed that increased hENT1 expression is associated with a stronger toxic effect of gemcitabine on BTC cell lines. The clinical outcomes in this study suggest that increased intratumoral hENT1 immunohistochemical staining is a possible biomarker predicting better therapeutic effects of gemcitabine on patients with advanced BTC. Further studies are needed to determine the precise role of hENT1 in BTC. [ABSTRACT FROM AUTHOR]