Compliance with enhanced recovery after surgery predicts long-term outcome after hepatectomy for cholangiocarcinoma

BACKGROUND Enhanced recovery after surgery(ERAS)program has been proved to improve postoperative outcome for many surgical procedures,including liver resection.There was limited evidence regarding the feasibility and benefit of ERAS in patients who underwent liver resection for cholangiocarcinoma.AIM To evaluate the feasibility of ERAS in patients who underwent liver resection for cholangiocarcinoma and its association with patient outcomes.METHODS We retrospectively analyzed 116 cholangiocarcinoma patients who underwent hepatectomy at Srinagarind Hospital,Khon Kaen University between January 2015 and December 2016.The primary outcome was the compliance with ERAS.To determine the association between ERAS compliance and patient outcomes.the patients were categorized into those adhering more than and equal to 50%(ERAS≥50),and below 50%(ERAS<50)of all components.Details on type of surgical procedure,preoperative and postoperative care,tumor location,postoperative laboratory results,and survival time were evaluated.The compliance with ERAS was measured by the percentage of ERAS items achieved.The Kaplan-Meier curve was used for survival analysis.RESULTS The median percentage of ERAS goals achieved was 40%(±12%).Fourteen patients(12.1%)were categorized into the ERAS≥50 group,and 102 patients were in the ERAS<50 group.Postoperative hospital stay was significantly shorter in the ERAS≥50 group[8.9 d,95%confidence interval(CI):7.3-10.4 d]than in the ERAS<50 group(13.7 d,95%CI:12.2-15.2 d)(P=0.0217).No hepatobiliary-related complications or in-hospital mortality occurred in the ERAS≥50 group.Overall survival was significantly higher in the ERAS≥50 group.The median survival of the patients in the ERAS<50 group was 1257 d(95%CI:853.2-1660.8 d),whereas that of the patients in the ERAS≥50 group was not reached.CONCLUSION Overall ERAS compliance for patients who underwent liver resection for cholangiocarcinoma is poor.Greater ERAS compliance could predict in-hospital,short-term,and long-term outcomes of the patients.

Annexin A1: A new immunohistological marker of cholangiocarcinoma

AIM: To evaluate a new immunohistological marker, annexin A1 (ANXA1), in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC). METHODS: Expression of ANXA1 protein was investigated in liver tissues from patients with CCA and HCC by immunohistochemistry. Its expression on differences stages of tumor development was investigated in hamster CCA tissues induced by Opisthorchis viverrini and N -nitrosodimethylamine. Moreover, mRNA expression of ANXA1 was assessed in CCA cell lines by quantitative real-time polymerase chain reaction and silencing of ANXA1 gene expression using small interfering RNA. RESULTS: In human CCA tissue arrays, immunohistochemical analysis revealed that the positive expression of ANXA1 was 94.1% (64/68 cases) consisting of a high expression (66.2%, 45/68 cases) and a low expression (33.8%, 23/68 cases). However, expression of ANXA1 protein was negative in all histologic patterns for HCC (46/46 cases) and healthy individuals (6/6 cases). In hamster with opisthorchiasis-associated CCA, the expression of ANXA1 was observed in the cytoplasm of inflammatory cells, bile duct epithelia and tumor cells. Grading scores of ANXA1 expression were significantly increased with tumor progression. In addition, mRNA expression of ANXA1 significantly increased in all of the various CCA cell lines tested compared to an immortalized human cholangiocyte cell line (MMNK1). Suppressing the ANXA1 gene significantly reduced the matrix metalloproteinase (MMP) 2 and MMP9, and transforming growth factor-β genes, but increased nuclear factor-kB gene expression. CONCLUSION: ANXA1 is highly expressed in CCA, but low in HCC, suggesting it may serve as a new immunohistochemical marker of CCA. ANXA1 may play a role in opisthorchiasis-associated cholangiocarcinogenesis.

Outcome of curative resection for perihilar cholangiocarcinoma in Northeast Thailand

AIM: To examine survival outcomes of perihilar cholangiocarcinoma(PCCA) resection including mortality, morbidity and prognostic factors. METHODS: Multivariate analyses were carried out based on the survival data of all patients with histologically confirmed PCCA who underwent curative resection at Srinagarind Hospital from January 2006 to December 2011. RESULTS: There were 29(19%) cases of intrahepatic CCA that involved hilar and 124(81%) with hilar bileduct cancer. R0 resection was carried out on 66(43.1%) patients of whom 50(32.7%) also had lymph node metastasis. The other patients underwent R1 resection. The overall 5-year survival rate was 20.6%(95%CI: 13.8-28.4) and median survival time was 19.9 mo. Postoperative mortality was 2%, and 30% of patients had complications. Patients without lymph node metastasis were 60% less likely to die than those with metastasis. Achieving R0 led to a 58% reduction in the chance of mortality as compared to R1. CONCLUSION: To achieve a better survival outcome, focus should center on performing radical surgery and detection of patients with early stage cancer.

Expression of sialyl Lewis^a relates to poor prognosis in cholangiocarcinoma

AIM: High levels of serum sialyl Lewisa (sLea) are frequently found in cholangiocarinnoma (CCA) patients and have been suggested to be a serum marker for CCA. However, the significance of this antigen in CCA is unknown. In this study,the clinical significance of sLea expression in CCA tissues and the possible role of sLea in vascular invasion in vitro were elucidated.METHODS: Expression of sLea in tumor tissues of 77patients with mass-forming CCA and 33 with periductal infiltrating CCA was determined using immunohistochemistry.The in vitro assays on adhesion and transmigration of CCA cells to human umbilical vein endothelial cells were compared between CCA cell lines with and without sLea expression.RESULTS: sLea was aberrantly expressed in 60% of CCA tumor tissues. A significant relationship was found between the frequency of sLea expression and the mass-forming type CCA (P = 0.041), well differentiated histological grading (P = 0.029), and vascular invasion (P = 0.030). Patients with positive sLea expression had a significantly poorer prognosis (21.28 wk, 95% CI = 16.75-25.81 wk) than those negative for sLea (37.30 wk, 95% CI = 27.03-47.57 wk)(P＜0.001). Multivariate analysis with adjustment for all covariates showed that patients positive for sLea possessed a 2.3-fold higher risk of death than patients negative for sLea (P＜0.001). The role of sLea in vascular invasion was demonstrated using in vitro adhesion and transmigration assays. KKU-M213, a human CCA cell-line with a high expression of sLea, adhered and transmigrated to IL-1β-activated endothelial cells of the human umbilical vein more than KKU-100, the line without sLea expression (P＜0.001).These processes were significantly diminished when the antibodies specific to either sLea or E-selectin were added to the assays (P＜0.001).CONCLUSION: This study demonstrates the clinical significance of sLea expression in vascular invasion, and an unfavorable outcome in CCA. The role of sLea in vascular invasion which may lead to poor prognosis is supported by the in vitro adhesion and transmigration studies.

Amplification of D22S283 as a favorable prognostic indicator in liver fluke related cholangiocarcinoma

瞄准：为了分析目标基因 NF2， TIMP3， ST13， TOB2， BIK，和 TP 和参考的 DNA 拷贝数字，在肝吸虫在 22q12-qter 上印射的微卫星标记 D22S283， D22S423，和 D22S274 联系了 cholangiocarcinoma (CCA ) 并且与临床的参数定义它的关联。方法：量的实时 PCR (qPCR ) 被用于决定在 65 肝吸虫的突变而产生之遗传的不平衡联系了 CCA 纸巾。在突变而产生之遗传的不平衡和 clinicopathological 参数之间的统计关联，即年龄，性别，肿瘤阶段，组织学的类型，血管侵略，神经侵略和淋巴的侵略借助于 chi2 测试被评估。考克斯回归分析被用于决定病人的幸存。结果： TP ( 22q13.33 )的扩大， TOB2 ( 22q13.2-13.31 )， D22S283 ( 22q12.3 )， TIMP3 ( 22q12.3 )和 NF2 ( 22q12.2 )在 35 被发现(53.8%)， 28 (43.1%)， 27 (41.5%)， 24 (36.9%)，并且 24 (36.9%)，分别地。在 D22S423 (22q13.1-13.2 ) 和 BIK (22q13.31 ) 的损失在 26 被检测(40%) 并且 23 (35.4%) 分别地。重要关联在淋巴的侵略和 BIK 的突变而产生之遗传的损失之间被观察(P = 0.025 ) 并且 D22S283 (P = 0.041 ) 。 Univariate 并且多，变量考克斯回归分析作为好预后的一个独立预言者揭示了 D22S283 扩大( P = 0.006 ，死亡危险比率= 0.411 ，95% CI = 0.217-0.779 )并且是的血管侵略一个独立人士差的预示的因素( P = 0.042 ，死亡危险比率= 1.911 ，95% CI = 1.022-3.571 )在 CCA 病人。结论：这研究提供证据因为在肝吸虫的染色体 22q 上的基因扩大和删除的参与联系了 CCA。当在肝吸虫的有利预后的独立指示物联系了 CCA，这是 D22S283 扩大的第一份报告。

Orotate phosphoribosyl transferase mRNA expression and the response of cholangiocarcinoma to 5-fluorouracil

AIM:To determine whether expression of certain enzymes related to 5-fluorouracil(5-FU)metabolism predicts 5-FU chemosensitivity in cholangiocarcinoma(CCA).METHODS:The histoculture drug response assay(HDRA)was performed using surgically resected CCA tissues.Tumor cell viability was determined morphologically with hematoxylin and eosin-and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-stained tissues.The mRNA expression of thymidine phosphorylase(TP),orotate phosphoribosyl transferase(OPRT),thymidylate synthase(TS),and dihydropyrimidine dehydrogenase(DPD)was determined with realtime reverse transcriptase-polymerase chain reaction.The levels of gene expression and the sensitivity to 5-FU were evaluated.RESULTS:Twenty-three CCA tissues were obtained from patients who had been diagnosed with intrahepatic CCA and who underwent surgical resection at Srinagarind Hospital,Khon Kaen University from 2007 to 2009.HDRA was used to determine the response of these CCA tissues to 5-FU.Based on the dose-response curve,200μg/mL 5-FU was selected as the test concentration.The percentage of inhibition index at the median point was selected as the cut-off point to differentiate the responding and non-responding tumors to 5-FU.When the relationship between TP,OPRT,TS and DPD mRNA expression levels and the sensitivity of CCA tissues to 5-FU was examined,only OPRT mRNA expression was significantly correlated with the response to 5-FU.The mean expression level of OPRT was significantly higher in the responder group compared to the non-responder group(0.41±0.25 vs 0.22±0.12,P<0.05).CONCLUSION:OPRT mRNA expression may be a useful predictor of 5-FU chemosensitivity of CCA.Whether OPRT mRNA could be used to predict the success of 5-FU chemotherapy in CCA patients requires confirmation in patients.

Repeated praziquantel treatment and Opisthorchis viverrini infection:a population-based cross-sectional study in northeast Thailand

Background:Opisthorchis viverrini infection is highly prevalent in northeast Thailand.This liver fluke is classified as a carcinogen due to its causal links with cholangiocarcinoma(CCA)development.Although treatment with praziquantel(PZQ)effectively cures O.viverrini infection,the prevalence remains high due to the traditional consumption of raw fish.Therefore,re-infection is common in the endemic community,leading to severe hepatobiliary morbidities including the fatal CCA.In this study,we evaluate the association between the frequency of previous PZQ treatment and current O.viverrini infections among Thai adults living in the endemic area of northeast Thailand.Methods:This study includes all participants who were screened for O.viverrini infection in the Cholangiocarcinoma Screening and Care Program(CASCAP),northeast Thailand.History of PZQ treatment was recorded using a health questionnaire.O.viverrini infections were diagnosed using urine antigen detection.Associations between PZQ and O.viverrini were determined by adjusted odds ratio(aOR)and 95%confidence interval(CI)using multiple logistic regression.Results:Among participants,27.7%had previously been treated once with PZQ,8.2%twice,2.8%three times,and 3.5%more than three times.Current O.viverrini prevalence was 17%(n=524).Compared with participants who never used PZQ,the aOR for infection among those who used the drug once was 1.09(95%CI:0.88-1.37),twice was 1.19(95%CI:0.85-1.68),three times was 1.28(95%C/:0.74-2.21),and more than three times was 1.86(95%C/:1.18-2.93;P=0.007).Conclusions:The population with a frequent history of PZQ use and still continued raw fish consumption showed high levels of repeated reinfection with O.viverrini.They were infected,treated and re-infected repeatedly.These findings suggest that certain participants continue raw fish consumption even after previous infection.This is a particular problem in highly endemic areas for O.viverrni and increases the risk of CCA.

Correction to:Repeated praziquantel treatment and Opisthorchis viverrini infection:a population-based crosssectional study in northeast Thailand

In the original publication of this article[1],there is an error in the section of‘Ethics approval and consent to participate’at the end of the article,the correct Ethics reference number should be HE551404 rather than HE591067.