Proposal of new expanded selection criteria using total tumor size and ^(18)F-fluorodeoxyglucose- positron emission tomography/computed tomography for living donor liver transplantation in patients with hepatocellular carcinoma:The National Cancer Center K

AIM: To expand the living donor liver transplantation(LT) pool of eligible patients with hepatocellular carcinoma(HCC) using new morphological and biological criteria.METHODS: Patients with HCC who underwent living donor LT(LDLT) from March 2005 to May 2013 at the National Cancer Center Korea(NCCK) were enrolled. We performed the 18F-fluorodeoxyglucose positron emission tomography/computed tomography(PET/CT)before LDLT. Overall and disease-free survival analysis was done in patients to evaluate the usefulness of new NCCK criteria using PET/CT and total tumor size(10 cm).RESULTS: We enrolled a total of 280 patients who pathologically confirmed to have HCC and performed the PET/CT before transplantation. Among them, 164(58.6%) patients fulfilled the NCCK criteria and 132 patients(47.1%) met the Milan criteria. Five-year overall and disease-free survival rates for patients who fulfilled the NCCK criteria showed 85.2% and 84.0%, respectively, and were significantly higher than those beyond the NCCK criteria(60.2% and 44.4%, respectively; P < 0.001). The correlation analysis between preoperative imaging tests and pathologic reports using Cohen's Kappa demonstrated the better results in the NCCK criteria than those in the Milan criteria(0.850 vs 0.583). The comparison of diseasefree analysis among the NCCK, Milan, and University of California, San Francisco(UCSF) criteria using the receiver operating characteristics curves revealed the similar area under the curve value criteria(NCCK vs Milan, P = 0.484; NCCK vs UCSF, P = 0.189 at 5-years).CONCLUSION: The NCCK criteria using hybrid concept of both morphological and biological parameters showed an excellent agreement between preoperative imaging and pathological results, and favorable survival outcomes. These new criteria might select the optimal patients with HCC waiting LDLT and expand the selection pool.

Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression.A tumor subpopulation called liver cancer stem cells(CSCs)significantly accounts for the initiation,metastasis,therapeutic resistance,and recurrence of liver cancer.Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses.This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression,as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment.Finally,we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

Pretransplant absolute monocyte count in peripheral blood predicts posttransplant tumor prognosis in patients undergoing liver transplantation for hepatocellular carcinoma

BACKGROUND: Preoperative absolute monocyte count in peripheral blood(AMCPB) is closely associated with prognoses in not only various malignancies but also hepatocellular carcinoma(HCC). The purpose of this study was to evaluate whether pretransplant AMCPB predicts posttransplant outcomes in patients with HCC undergoing liver transplantation(LT).METHOD: We retrospectively analyzed relationships between clinicopathologic factors involving pretransplant AMCPB and tumor recurrence or survival in 256 patients who had undergone LT for HCC between January 2005 and April 2012.RESULTS: ROC curve analysis showed that AMCPB >200/mm3was a risk factor for tumor recurrence; 43 patients showed higher AMCPB(>200/mm3), whereas 213 showed lower AMCPB(≤200/mm3) at the time of LT. On multivariate analysis,pretransplant high AMCPB, positive findings in pretransplant18F-FDG PET/CT, pathological maximal tumor size >5 cm,intrahepatic metastasis, moderately or poorly differentiated tumor and microvascular invasion were independent factors affecting recurrence-free survival. When we performed subgroup analysis based on the Milan criteria, high AMCPB was an independent factor for predicting HCC recurrence in patients with tumor beyond the Milan criteria(P=0.004), and not for patients within the criteria.CONCLUSION: This study demonstrated that pretransplant AMCPB could predict tumor recurrence after LT for HCC,especially in patients with tumor beyond the Milan criteria.

High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation

AIM: To investigate the impact of high-dose hepatitis B immunoglobulin(HBIG) on hepatocellular carcinoma(HCC) and hepatitis B virus(HBV) recurrence and overall survival after living donor liver transplantation(LDLT).METHODS: We investigated 168 patients who underwent LDLT due to HCC, and who were HBV-DNA/hepatitis B e antigen(HBe Ag)-positive, from January 2008 to December 2013. After assessing whether the patients met the Milan criteria, they were assigned to the low-dose HBIG group and high-dose HBIG group. Using the propensity score 1:1 matching method, 38 and 18 pairs were defined as adhering to and not adhering to the Milan criteria. For each pair, HCC recurrence, HBV recurrence and overall survival were analyzed by the Kaplan-Meier method and the log rank test according to the HBIG dose. RESULTS: Among those who met the Milan criteria, the 6-mo, 1-year, and 3-year HCC recurrence-free survival rates were 88.9%, 83.2%, and 83.2% in the low-dose HBIG group and 97.2%, 97.2%, and 97.2% in the high-dose HBIG group, respectively(P = 0.042).In contrast, among those who did not meet the Milan criteria, HCC recurrence did not differ according to the HBIG dose(P = 0.937). Moreover, HBV recurrence and overall survival did not differ according to the HBIG dose among those who met(P = 0.317 and 0.190, respectively) and did not meet(P = 0.350 and 0.987, respectively) the Milan criteria. CONCLUSION: High-dose HBIG therapy can reduce HCC recurrence in HBV-DNA/HBe Ag-positive patients after LDLT.

Surgical outcome of pancreatic cancer using radical antegrade modular pancreatosplenectomy procedure

AIM:To evaluate the surgical outcomes following radical antegrade modular pancreatosplenectomy (RAMPS) for pancreatic cancer. METHODS:Twenty-four patients underwent RAMPS with curative intent between January 2005 and June 2009 at the National Cancer Center, South Korea. Clinicopathologic data, including age, sex, operative findings, pathologic results, adjuvant therapy, postop-erative clinical course and follow-up data were retro-spectively collected and analyzed for this study. RESULTS:Twenty-one patients (87.5%) underwent distal pancreatectomy and 3 patients (12.5%) underwent total pancreatectomy using RAMPS. Nine patients (37.5%) underwent combined vessel resection, including 8 superior mesenteric-portal vein resections and 1 celiac axis resection. Two patients (8.3%) underwent combined resection of other organs, including the colon, stomach or duodenum. Negative tangential margins were achieved in 22 patients (91.7%). The mean tumor diameter for all patients was 4.09 ± 2.15 cm. The 2 patients with positive margins had a mean diameter of 7.25 cm. The mean number of retrieved lymph nodes was 20.92 ± 11.24 and the node positivity rate was 70.8%. The median survival of the 24 patients was 18.23 ± 6.02 mo. Patients with negative margins had a median survival of 21.80 ± 5.30 mo and those with positive margins had a median survival of 6.47 mo (P = 0.021). Nine patients (37.5%) had postoperative complications, but there were no postoperative mortalities. Pancreatic fistula occurred in 4 patients (16.7%):2 patients had a grade A fistula and 2 had a grade B fistula. On univariate analysis, histologic grade, positive tangential margin, pancreatic fistula and adjuvant therapy were significant prognostic factors for survival. CONCLUSION:RAMPS is a feasible procedure for achieving negative tangential margins in patients with carcinoma of the body and tail of the pancreas.

Graft-to-recipient weight ratio lower to 0.7% is safe without portal pressure modulation in right-lobe living donor liver transplantation with favorable conditions

BACKGROUND: The low graft-to-recipient weight ratio(GRWR) in adult-to-adult living donor liver transplantation(LDLT) is one of the major risk factors affecting graft survival. The goal of this study was to evaluate whether the lower limit of the GRWR can be safely reduced without portal pressure modulation in right-lobe LDLT. METHODS: From 2005 to 2011, 317 consecutive patients from a single institute underwent LDLT with right-lobe grafts without portal pressure modulation. Of these, 23 had a GRWR of less than 0.7%(group A), 27 had a GRWR of ≥0.7%, 【0.8%(group B), and 267 had a GRWR of more than and equal to 0.8%(group C). Medical records, including recipient, donor, operation factors, laboratory findings and complications were reviewed retrospectively. RESULTS: The baseline demographics showed low model for end-stage liver disease score(mean 16.3±8.9) and high percentage of hepatocellular carcinoma(231 patients, 72.9%). Three groups by GRWR demonstrated similar characteristics except recipient body mass index and donor gender. For smallforsize syndrome, there were 3(13.0%) in group A, 1(3.7%) in group B, and 2 patients(0.7%) in group C(P【0.001). Hepatic artery thrombosis was more frequently observed in group A than in groups B and C(8.7% vs 3.7% vs 1.9%, P=0.047). However, among the three groups, graft survival rates at 1 year(100% vs 96.3% vs 93.6%) and 3 years(91.7% vs 73.2% vs 88.1%) were not different(P=0.539). In laboratory measurements,there was no group difference in total bilirubin and albumin. However, prothrombin time was longer in group A within postoperative 1 week and platelet count was lower in groups A and B within postoperative 1 month. CONCLUSION: A GRWR lower to 0.7% is safe and does not need to modulate portal pressure in adult-to-adult LDLT using the right-lobe in favorable conditions including low model for end-stage liver disease score.

Outcomes after liver transplantation in accordance with ABO compatibility: A systematic review and meta-analysis

AIM To evaluate the differences in outcomes between ABOincompatible(ABO-I) liver transplantation(LT) and ABO-compatible(ABO-C) LT.METHODS A systematic review and meta-analysis were performed by searching eligible articles published before November 28, 2016 on MEDLINE(Pub Med), EMBASE, and Cochrane databases. The primary endpoints were graft survival, patient survival, and ABO-I-related complications. RESULTS Twenty-one retrospective observational studies with a total of 8247 patients were included in this metaanalysis. Pooled results of patient survival for ABO-I LT were comparable to those for ABO-C LT. However, ABO-I LT showed a poorer graft survival than ABO-C LT(1-year: OR = 0.66, 95%CI: 0.57-0.76, P < 0.001; 3-year: OR = 0.74, 95% CI 0.64-0.85, P < 0.001; 5-yearr: OR =0.75, 95%CI: 0.66-0.86, P < 0.001). Furthermore, ABO-I LT was associated with more incidences of antibody-mediated rejection(OR = 74.21, 95%CI: 16.32-337.45, P < 0.001), chronic rejection(OR =2.28, 95%CI: 1.00-5.22, P = 0.05), cytomegalovirus infection(OR = 2.64, 95%CI: 1.63-4.29, P < 0.001), overall biliary complication(OR = 1.52, 95%CI: 1.01-2.28, P = 0.04), and hepatic artery complication(OR = 4.17, 95%CI: 2.26-7.67, P < 0.001) than ABO-C LT. In subgroup analyses, ABO-I LT and ABO-C LT showed a comparable graft survival in pediatric patients and those using rituximab, and ABO-I LT showed an increased acute cellular rejection in cases involving deceased donor grafts.CONCLUSION Although patient survival in ABO-I LT was comparable to that in ABO-C LT, ABO-I LT was inferior to ABO-C LT in graft survival and several complications. Graft survival of ABO-I LT could be comparable to that of ABO-C LT in pediatric patients and those using rituximab.

A comparison of desensitization methods: Rituximab with/without plasmapheresis in ABO-incompatible living donor liver transplantation

Background: Plasmapheresis is a desensitization method used prior to ABO-incompatible(ABO-I) living donor liver transplantation. However, studies on its usefulness in the rituximab era are lacking.Methods: Fifty-six adult patients underwent ABO-I living donor liver transplantation between January2012 and October 2015. A single dose of rituximab(300 mg/m~2) was administered 2 weeks before surgery with plasmapheresis in all patients until February 2014(RP group, n = 26). Patients were administered rituximab only, without plasmapheresis between March 2014 and October 2015(RO group, n = 30).Results: The 6-, 12-and 18-month overall survival rates were 92.3%, 80.8% and 76.9% in the RP group and 96.6%, 85.4% and 85.4% in the RO group, respectively(P = 0.574). When the initial isoagglutinin titers < 16, neither group showed a rebound rise of isoagglutinin titers. For patients with initial isoagglutinin titers ≥ 16, the rebound rise of isoagglutinin titers was more prominent in the RP group. There was no difference in time-dependent changes in B cell subpopulations and ABO-I-related complications.Conclusions: Sufficient desensitization for ABO-I living donor liver transplantation can be achieved using rituximab alone. This desensitization strategy does not affect the isoagglutinin titers, ABO-I-related complications and patient survival.

The Gut Microbiota, Tumorigenesis, and Liver Diseases

一个多世纪以前,科学家们就首次发现了肿瘤区域中细菌的存在。但是,微生物在肿瘤发生中的作用近年来才被认识到。近几十年来,与肠道菌群失调相关的疾病代表了全世界最严重的一些公共卫生问题。大量的流行病学研究表明,肠道菌群与某些常见肿瘤密切相关。然而,肠道菌群与肿瘤相关联的具体分子机制仍不明确。研究表明,肠道菌群的改变有助于确定肝癌、酒精相关肝病、非酒精性脂肪肝和肝硬化的发生和发展。鉴于益生菌是一种可通过调节免疫系统促进人类健康的药物,其可能会为肝细胞癌(HCC)和非酒精性脂肪肝的治疗提供新方向。本文总结了肠道菌群在肿瘤及肝病中的研究进展,综述了肠道菌群与肿瘤和肝病之间的关系。此外,考虑到细菌内稳态的重要性,我们也对益生菌进行了概述,旨在为相关疾病的治疗提供指导。

Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients

Once-daily extended-release tacrolimus （Tac-OD） has been introduced as a useful therapeutic option to increase patient adherence to immunosuppressive therapy. This study aimed to evaluate the safety, efficacy and immunosuppressant adherence of conversion from twice-daily tacrolimus （Tac-BID） to Tac-OD in stable adult living donor liver transplant （LDLT） recipients in a single institution. METHODS： Between February and May 2013, Tac-BID was converted to Tac-OD in recipients followed up for at least 12 months after transplantation and without previous rejection episodes. The switching policy was based on a dose ratio of 1：1 with dose adjustment target trough levels at 3-5 ng/mL. Tacro- limus trough levels, laboratory parameters, metabolic disor- ders, and adverse events were assessed. RESULTS： A total of 229 patients were enrolled in the study. The median age at conversion was 53 years （range 31-73）. The median transplant duration was 35.3 months （range 12.0-95.4）. During a median follow-up of 13.5 months after conversion, 9 patients returned to Tac-BID because of adverse events. No acute rejection episodes were observed. Of 214 patients still on Tac-OD at 12 months, 12 （5.6%） received a reduced dose and 95 （44.4%） required an increased dose over baseline. Overall adherence was 82.2% at the end of follow-up. CONCLUSION： The conversion from Tac-BID to Tac-OD with similar target trough levels after conversion is safe and effec- tive for long-term stable LDLT patients.

Methodology of drug screening and target identification for new necroptosis inhibitors

Apoptosis has been considered as the only form of regulated cell death for a long time. However, a novel form of programmed cell death called necroptosis was recently reported. The process of necroptosis is regulated and plays a critical role in the occurrence and development of multiple human diseases. Thus,the study on the molecular mechanism of necroptosis and its effective inhibitors has been an attractive field for researchers. Herein, we introduce the molecular mechanism of necroptosis and focus on the literature about necroptosis drug screening in recent years. In addition, the identification of the critical drug targets of the necroptosis is also discussed.

A new hemostatic clip for endoscopic surgery that can maintain blood flow after clipping

AIM: To develop a new hemostatic device for endoscopic surgery that can control the bleeding without completely occluding the bleeding vessel. METHODS: A hemostatic clip and its applier that can stanch bleeding while maintaining blood flow through the clipped vessel was introduced, and the performance of the proposed clip was evaluated using in vitro and in vivo experiments. RESULTS: During in vitro experiments, no leakage was found after clipping at cuts made in artificial vessels, and flow was maintained through the clipped artificial vessels. In experiments on rats, all the implanted clips occluded the target vessels successfully, and no bleeding or tissue damage was observed at the operative site after the rats were euthanized on postoperative day 7. In experiments on pigs, bleeding stopped immediately after partial clipping of a damaged vessel, and some amount of blood flow was consistently maintained through the clipped vessel after hemostasis. CONCLUSION: We believe that the proposed hemostatic clip and clip applier can enhance patient safety during laparoscopic surgery.

Transarterial chemoembolization versus percutaneous microwave coagulation therapy for recurrent unresectable intrahepatic cholangiocarcinoma:Development of a prognostic nomogram

Background:Transarterial chemoembolization(TACE)and percutaneous microwave coagulation therapy(PMCT)are commonly used to treat intrahepatic recurrent liver cancers.However,there is no informa-tion regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma(ICC)after resection.Methods:A total of 275 patients with localized recurrent ICC who received either TACE(n=183)or PMCT(n=92)were studied.A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT.Prognostic factors for TACE and PMCT were identified respectively.Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values.Results:Both TACE and PMCT provided curativeness in partial patients(5-year overall survival:21.4%and 6.1%,respectively),but TACE provided better survival benefit in both overall patients(hazard ratio[HR]=0.71;95%confidence interval[CI]:0.50–0.97;P=0.034)and propensity score matching analysis(HR=0.69;95%CI:0.47–0.98;P=0.041).Independent prognostic factors for TACE were tumor size>5 cm,poor differentiation,and major resection,whereas poor differentiation,hepatitis B virus infection,cholelithiasis,and lymph node metastasis were identified for PMCT.Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70,respectively.Conclusions:TACE provided better survival benefits compared to PMCT.However,there was a disparity in prognostic factors,suggesting evaluation of the two nomograms may be supportive in modality selection.Further prospective validation studies are required for the results to be applied in clinical medicine.

Successful living donor liver transplantation with a graft-to-recipient weight ratio of 0.41 without portal flow modulation:A case report

BACKGROUND There have been numerous efforts to lower the limit of minimum graft size to meet the metabolic demand of recipients in adult-to-adult living donor liver transplantation(LDLT).We experienced a successful case of LDLT using a verysmall-for-size graft without portal flow modulation such as splenectomy or portocaval shunt.CASE SUMMARY A 49-year-old man(weighing 91 kg)suffering hepatocellular carcinoma accompanied with hepatitis B virus related cirrhosis underwent LDLT.The one and only voluntary donor was his 17-year-old daughter whose body weight was 50 kg with a body mass index(BMI)of 18.3.The procured right liver graft was 411 g with a real graft-to-recipient weight ratio(GRWR)of 0.41%,the smallest to be reported in the literature.Both the recipient and donor had an uneventful recovery and were discharged on days 15 and 8,respectively,with normal liver function.The father and daughter have had no complication so far and are still in good health with normal liver function 81 mo after LDLT.CONCLUSION Satisfactory outcomes can be achieved in LDLT with a GRWR as low as 0.41%even without using portal flow modulation in highly selected patients.

An Approach to the Simultaneous Detection of Multiple Biomarkers for the Early Diagnosis of Liver Cancer Using Quantum Dot Nanoprobes

Biomarker-based early diagnosis of liver cancer is of high clinical value for reducing the mortality rate.However,it has been challenging to establish early detection methods with a single biomarker such as alpha-fetoprotein(AFP)because of limited diagnostic sensitivity and specificity.Therefore,developing multiplexed biomarker detection assays is crucially important for early diagnosis.Yet,simultaneous detection methods involving three or more biomarkers have been scarce.Here we suggest employing the serological biomarker panel of glypican-3(GPC3),dickkopf-1(DKK1),and AFP for liver cancer detection.We present a rapid simultaneous detection approach for the biomarker panel labeled with three fluorescent quantum dot nanoprobes(emission wavelengths at 565 nm,605 nm,and 655 nm).As a proof-of-concept,simultaneous fluorescence detection of the biomarker panel was demonstrated using mixed reference samples containing human recombinant GPC3,DKK1,and AFP antigens.Our simultaneous detection approach conferred a linear range of 0.625–2.5 ng·mL^(-1)for the entire biomarker panel,which merits further clinical validation for the simultaneous and accurate determination of the biomarker panel in human serum samples.

肝胆肿瘤中肿瘤特异性CircRNA衍生抗原肽的鉴定

基于肿瘤抗原的免疫治疗的应用受到验证免疫原性肽稀缺性的阻碍。本研究旨在研究环状RNA(circRNA)在肝胆肿瘤类器官中作为肿瘤抗原肽新来源的潜力。使用RNA测序(RNA-seq)和基于算法的评分工具,预测3950个翻译的肿瘤特异性环状RNA在27个类器官中产生18971个抗原肽。从抗原格局来看,11个氨基酸长度(mer)肽和人白细胞抗原(HLA)-A结合肽具有最高的免疫原性相关评分。在分析的3/5类器官中,有13个预测抗原肽通过质谱(MS)免疫肽组学被直接确认为HLA-A、HLA-B和HLA-C(HLA-ABC)结合肽。在流式细胞术和酶联免疫吸附试验(ELISA)中,由HLA-ABC分子呈递的circRNA衍生的肿瘤特异性肽刺激CD8(CD8)T细胞,显示CD107a干扰素γ(IFNγ)共表达和IFNγ分泌增加。免疫原性环状RNA衍生肽诱导的靶向类器官的细胞毒性T细胞活性在杀伤实验中得到验证。值得注意的是,来自circTBC1D15的抗原肽YGFNEILKK不仅被认为是类器官的HLA-ABC呈递肽,而且还显著降低了肿瘤类器官的存活率。本研究的发现强调了产生肿瘤抗原的一个关键亚群,这对靶向肿瘤特异性circRNA具有重要意义。

Diverse functions of sox9 in liver development and homeostasis and hepatobiliary diseases

The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative capacities.The hepatobiliary system originates from the foregut endoderm,in which cells undergo multiple events of cell proliferation,migration,and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription factors.Studies on liver development and diseases have revealed that SRY-related high-mobility group box 9(SOx9)plays an important role in liver embryogenesis and the progression of hepatobiliary diseases.sox9 is not only a master regulator of cell fate determination and tissue morphogenesis,but also regulates various biological features of cancer,including cancer stemness,invasion,and drug resistance,making Sox9 a potential biomarker for tumor prognosis and progression.This review systematically summarizes the latest findings of sox9 in hepatobiliary development,homeostasis,and disease.We also highlight the value of sox9 as a novel biomarker and potential target for the clinical treatment of major liverdiseases.

Clinicopathological features and prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgery

BACKGROUND： Combined hepatocellular carcinoma and cholangiocarcinoma （cHCC-CC） is a rare subtype of primary liver cancer consisting of both hepatocellular carcinoma （HCC） and cholangiocarcinoma （CC）. Because of the rarity of this tumor, its feature is poorly understood. The present study aimed to evaluate the clinicopathological features and long-term prognosis of patients with cHCC-CC after surgery and to compare with those of the patients with stage-matched HCC and CC. METHODS： The dinicopathological features of the patients who underwent surgery for cHCC-CC at our center during the period of 2001-2010 were retrospectively analyzed and compared with those of stage-matched HCC and CC patients. Cancer staging was performed according to the AJCC Cancer Staging Manual （6th ed.）. Overall survival and disease-free survival were compared among the groups and prognostic factors of cHCC-CC were evaluated. RESULTS： Significant differences were observed in clinico- pathological features among 42 patients with cHCC-CC, 90 patients with HCC and 45 patients with CC. Similar to HCC patients, cHCC-CC patients had frequent hepatitis B virus antigen positivity, microscopic vessel invasion, cirrhosis and high level of serum alpha-fetoprotein. Similar to CC patients, cHCC-CC patients showed increased bile duct invasion and decreased capsule. The 1-, 3-, and 5-year overall survival and disease- free survival of patients with cHCC-CC were not significantly different from those with stage-matched patients with CC;but significantly poorer than those with HCC. In subanalysis of patients with stage Ⅱ, the overall survival in patients with cHCC-CC or CC was significantly poorer than that in patients with HCC. We did not find the difference in patients with other stages. Univariate analysis of overall and disease-free survival of patients with cHCC-CC showed that the vascular invasion and intrahepatic metastasis were the significant predictive factors. CONCLUSION： Patients with cHCC-CC showed similar dinico- pathological features as those with HCC or CC, and patients with cHCC-CC or CC had a poorer prognosis compared with those with HCC, especially at matched stage Ⅱ.

Endoscopic management of occluded metal biliary stents:Metal versus 10F plastic stents

AIM:To compare the efficacy of self-expandable metal stents(SEMSs) with 10F plastic stents(PSs) in the endoscopic management of occluded SEMSs.METHODS:We retrospectively reviewed the medical records of 56 patients who underwent SEMS insertion for palliation of unresectable malignant biliary obstruction between 2000 and 2007 and subsequent endoscopic retrograde biliary drainage(ERBD) with SEMS or PS for initial SEMS occlusion between 2000 and 2008.RESULTS:Subsequent ERBD with SEMS was performed in 29 patients and with PS in 27.The median time to stent occlusion after subsequent ERBD was 186 d in the SEMS group and 101 d in the PS group(P= 0.118).Overall median stent patency was 79 d for the SEMS group and 66 d for the PS group(P = 0.379).The mean number of additional biliary drainage procedures after subsequent ERBD in patients that died(n = 50) during the study period was 2.54 ± 4.12 for the SEMS group and 1.85 ± 1.95 for the PS group(P = 0.457).The mean total cost of additional biliary drainage procedures after the occlusion of subsequent SEMS or PS was $410.04 ± 692.60 for the SEMS group and $630.16 ± 671.63 for the PS group(P = 0.260).Tumor ingrowth as the cause of initial SEMS occlusion was the only factor associated with a shorter time to subsequent stent occlusion(101 d for patients with tumor ingrowth vs 268 d for patients without tumor ingrowth,P = 0.008).CONCLUSION:Subsequent ERBD with PSs offered similar patency and number of additional biliary drainage procedures compared to SEMSs in the management of occluded SEMS.

ATP-citrate lyase regulates stemness and metastasis in hepatocellular carcinoma via the Wnt/β-catenin signaling pathway

Background: Hepatocellular carcinoma(HCC) is one of the most highly malignant tumors. Liver tumor-initiating cells(LTICs) have been considered to contribute to HCC progression and metastasis. ATP-citrate lyase(ACLY), as a key enzyme for de novo lipogenesis, has been reported to be upregulated in various tumors. However, its expression and role in HCC and LTICs remain unknown. Methods: The expressions of ACLY in HCC tissues were detected by quantitative real-time PCR(q RT-PCR), Western blotting and immunohistochemistry. Kaplan-Meier curves and Chi-square test were used to determine the clinical significance of ACLY expression in HCC patients. A series of assays were performed to determine the function of ACLY on stemness, migration and invasion of HCC cells. Luciferase reporter assay, Western blotting and immunoprecipitation were used to study the regulation of the Wnt/β-catenin signaling by ACLY. Rescue experiments were performed to investigate whether β-catenin was the mediator of ACLY-regulated stemness and migration in HCC cells. Results: ACLY was highly expressed in HCC tissues and LTICs. Overexpression of ACLY was significantly correlated with poor prognosis, progression and metastasis of HCC patients. Knockdown of ACLY remarkably suppressed stemness properties, migration and invasion in HCC cells. Mechanistically, ACLY could regulate the canonical Wnt pathway by affecting the stability of β-catenin, and Lys49 acetylation of β-catenin might mediate ACLY-regulated β-catenin level in HCC cells. Conclusions: ACLY is a potent regulator of Wnt/β-catenin signaling in modulating LTICs stemness and metastasis in HCC. ACLY may serve as a new target for the diagnosis and treatment of HCC.