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A retrospective cohort study was conducted to identify risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. A total of 317 patients who had received curative resection of pathologically proven small HCC (< or = 3 cm in diameter) were analyzed to ascertain the factors affecting recurrence. The median follow-up period was 33.7 months. Cumulative recurrence rates at 1, 3, and 5 years after resection were 23.5%, 49.5%, and 65.5%, respectively. Male sex, alpha-fetoprotein (AFP) > or = 400 ng/mL, HBV DNA level > or = 4 log(10) copies/mL, prolonged prothrombin time, tumor size > or = 2 cm, microvascular invasion, absence of capsular formation, moderate/poor tumor differentiation, and absence of postoperative interferon-alpha (IFN-alpha) treatment were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV DNA level > or = 4 log(10) copies/mL (P < 0.001, hazard ratio (HR) 2.110), AFP > or = 400 ng/mL (P = 0.011, HR 1.574), microvascular invasion (P < 0.001, HR 1.767), and postoperative IFN-alpha treatment (P = 0.022, HR 0.562) remained to be independently associated with HCC recurrence. Those contributing to late recurrence (>2 years) were older age and HBV DNA level > or = 4 log(10) copies/mL. Patients with persistent HBV DNA level > or = 4 log(10) copies/mL at resection and follow-up had the highest recurrence risk (P < 0.001, HR 4.129). HBV DNA level > or = 4 log(10) copies/mL at the time of resection was the most important risk factor for recurrence. Postoperative IFN-alpha treatment significantly decreased the recurrence risk after resection. [ABSTRACT FROM AUTHOR]

Clinical response of hepatocellular carcinoma (HCC) to arsenic trioxide (ATO) has been poor. Promyelocytic leukemia protein (PML) is central to ATO treatment efficacy of acute promyelocytic leukemia. We examine impacts of PML expression on the effectiveness of ATO treatment in HCC. We show that increased PML expression predicts longer survival and lower cancer recurrence rates after HCC resection. However, high PML expression dampens the anti-tumor effects of ATO in HCC cells. Gene microarray analysis shows that reduced PML expression significantly down-regulates expression of aldehyde dehydrogenase 3 family member A1 (ALDH3A1). ALDH3A1 depression facilitates accumulation of ATO-induced reactive oxygen species. Chromatin immunoprecipitation analysis and promoter activity assays confirm that PML regulates ALDH3A1 expression through binding to the promoter region of ALDH3A1. Clinically, ATO treatment decreases the disease progression rate in advanced HCC patients with negative PML expression. In conclusion, PML confers a favorable prognosis in HCC patients, but it induces ATO resistance through ALDH3A1 up-regulation in HCC cells. ATO is effective for HCC patients with negative PML expression. Combined with an ALDH3A1 inhibitor, ATO may be efficacious in patients with positive PML expression. [ABSTRACT FROM AUTHOR]

Upregulation of CXCR2 in tumor cells has been documented in several types of cancer. As one of its ligands, CXCL5 is associated with neutrophil infiltration and poor prognosis in hepatocellular carcinoma (HCC). However, little is known about the role of the CXCR2/CXCL5 axis in the invasion and metastasis of HCC cells. In this study, we examined CXCR2 expression in human HCC cell lines and in three independent cohorts of HCC patients. The molecular effects of high expression levels of CXCR2 and CXCL5 in HCC cells were determined using qRT-PCR, western blot analysis, immunofluorescence, matrigel invasion assay, and xenograft mouse models. We found that high levels of CXCR2 correlated with progression and poor prognosis in human HCC. CXCR2/CXCL5 together promoted cell spreading by inducing the epithelial–mesenchymal transition (EMT) through activation of the PI3K/Akt/GSK-3β/Snail signaling pathway. In clinical HCC samples, high expression of both CXCR2 and CXCL5 showed a significant correlation with the activation of PI3K/Akt/GSK-3β/Snail signaling and EMT phenotype. In conclusion, our data showed that the CXCR2/CXCL5 axis contributes to EMT of HCC cells through activating PI3K/Akt/GSK-3β/Snail signaling, and it may serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Immunoglobulin G4 (IgG4)-associated disease is a recently recognized disease entity that is characterized by elevated serum IgG4 concentrations, abundant IgG4 lymphoplasmacytic infiltration, and dramatic steroid responses. IgG4-associated cholangitis is one manifestation of IgG4-associated disease. However, it is clinically challenging to make a preoperative differentiation between this rare disease and cholangiocarcinoma, especially for those with serum concentrations of IgG4 in the normal range. This article reports on a 57-year-old man with jaundice and upper abdominal discomfort. Imaging examination showed biliary stricture that closely resembled cholangiocarcinoma, and the patient's serum IgG4 concentration was normal. The patient underwent a laparoscopic choledochectomy with Roux-en-Y hepaticojejunostomy using an intracorporeal hand-sewn technique. He recovered quickly without any complications. We also present our experience in laparoscopic intracorporeal hand-sewn hepaticojejunostomy. [ABSTRACT FROM AUTHOR]

Aim: To verify if detailed analysis of temporal enhancement patterns on contrast enhanced ultrasound (CEUS) may help differentiate intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) in cirrhosis. Methods: Thirty three ICC and fifty HCC in cirrhosis were enrolled in this study. The contrast kinetics of ICC and HCC was analyzed and compared. Results: Statistical analysis did not reveal significant difference between ICC and HCC in the time of contrast first appearance and arterial peak maximum time. ICC displayed much earlier washout than that of HCC (47.93±26.45 seconds vs 90.86±31.26 seconds) in the portal phase, and most ICC (87.9%) showed washout before 60 seconds than HCC (16.0%). Much more ICC (78.8%) revealed marked washout than HCC (12.0%) while most HCC (88.0%) showed mild washout or no washout in late part of the portal phase (90–120 seconds). Twenty six out of thirty three ICC (78.8%) demonstrated both early washout(<60seconds) and marked washout in late part of the portal phase, whereas, only six of fifty HCC (12.0%)showed these temporal enhancement features (p = 0.000).When both early washout and marked washout in the portal phase are taken as diagnostic criterion for ICC, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 78.8%,88.0%,81.3%,86.3%,and 84.3% respectively by CEUS. Conclusions: Analysis of detailed temporal enhancement features on CEUS is helpful differentiate ICC from HCC in cirrhosis.If a nodule in cirrhotic liver displays hyper-enhancement in the arterial phase followed by early and marked washout in the portal phase, the nodule is highly suspicious of ICC rather than HCC. [ABSTRACT FROM AUTHOR]

Studies have highlighted important features of the nucleocytoplasmic transport of mRNAs and proteins. Nuclear RNA export factor 3 (NXF3) is a member of the nuclear RNA export factor family that plays a role in mediating the export of cellular mRNA from the nucleus to the cytoplasm for translation. However, little is known about the clinical significance of NXF3 in human tumors. To evaluate the prognostic significance of NXF3 in hepatocellular carcinoma (HCC), the expression levels of NXF3 in a cohort of 112 patients with primary HCC who had undergone hepatectomy for histologically confirmed HCC were assessed by immunohistochemistry. It was identified that the expression levels of NXF3 were higher in the primary HCC tissues compared with those in paired peritumoral liver tissues. The overexpression of NXF3 in the HCC tissues was correlated with decreased survival time [hazard ratio (HR) = 1.954, 95% confidence interval (CI) = 1.034-3.695, P=0.039] and earlier tumor recurrence (HR = 2.101, 95% CI = 1.186-3.722, P=0.011) in postoperative patients with HCC. Notably, overexpression of NXF3 was correlated with a poor survival time and increased recurrence following HCC resection in male patients (P=0.020 and P=0.007, respectively) but not in female patients (P=0.916 and P=0.821, respectively). In conclusion, the findings provide evidence that implicates NXF3 as a prospective predictor of HCC prognosis as well as a potential therapeutic target for cancer treatment. [ABSTRACT FROM AUTHOR]

Background: To report the feasibility, efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for the treatment of portal vein tumor thrombosis (PVTT) and/or inferior vena cava tumor thrombosis (IVCTT) in patients with advanced hepatocellular carcinoma (HCC). Materials and methods: Forty-one patients treated with SBRT using volumetric modulated arc therapy (VMAT) for HCC with PVTT/IVCTT between July 2010 and May 2012 were analyzed. Of these, 33 had PVTT and 8 had IVCTT. SBRT was designed to target the tumor thrombosis and deliver a median total dose of 36 Gy (range, 30–48 Gy) in six fractions during two weeks. Results: The median follow-up was 10.0 months. At the time of analysis, 15 (36.6%) achieved complete response, 16 (39.0%) achieved partial response, 7 (17.1%) patients were stable, and three (7.3%) patients showed progressive disease. No treatment-related Grade 4/5 toxicity was seen within three months after SBRT. One patient had Grade 3 elevation of bilirubin. The one-year overall survival rate was 50.3%, with a median survival of 13.0 months. The only independent predictive factor associated with better survival was response to radiotherapy. Conclusions: VMAT-based SBRT is a safe and effective treatment option for PVTT/IVCTT in HCC. Prospective randomized controlled trials are warranted to validate the role of SBRT in these patients. [ABSTRACT FROM AUTHOR]

Purpose: An immune function assay has been proposed as a new strategy to monitor immunosuppression after organ transplantation. However, there are limited data regarding its role in liver transplant recipients with hepatocellular carcinoma (HCC). In this study, we sought to determine the utility of this functional assay in assessing the risk of infection, rejection, and tumor recurrence in liver transplant recipients. Methods: Immune function was determined by ImmuKnow assay that measures the amount of adenosine triphosphate (ATP) produced by CD4 (+) T cells to monitor the global immune status in 342 whole blood samples from 105 liver transplant recipients. The association between ATP value and post-transplant tumor recurrence was evaluated in 60 HCC patients. The ATP value in predicting tumor recurrence in other independent cohort of 92 recipients with HCC was analyzed prospectively. Results: The mean ATP values of liver transplant recipients with infection (145.2 ± 87.0 ng/ml) or acute rejection (418.9 ± 169.5 ng/ml) were different from those with stable state (286.6 ± 143.9 ng/ml, P < 0.05). In recipients with HCC who developed recurrent tumors, the values were significantly lower than those without recurrence (137.8 ± 66.4 vs. 289 ± 133.9 ng/ml, P < 0.01); the optimal threshold value to predict post-transplant tumor recurrence was 175 ng/ml. Comparing with the patients in lower immune group (ATP ≤ 175 ng/ml), patients in the higher immune group (ATP > 175 ng/ml) experienced significantly better disease-free survival ( P < 0.01). Multivariate Cox regression analysis showed the ATP value was an independent predictor of HCC recurrence. Conclusions: The immune function assay has the potential to assess the risk of infection and rejection in liver transplantation and to predict post-transplant tumor recurrence in recipients with HCC. [ABSTRACT FROM AUTHOR]

Background: Recurrence prediction of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) present a great challenge because of a lack of biomarkers. Genetic variations play an important role in tumor development and metastasis. Methods: Oligonucleotide microarrays were used to evaluate the genetic characteristics of tumor DNA in 30 HBV-related HCC patients who were underwent LT. Recurrence-related single-nucleotide polymorphism were selected, and their prognostic value was assessed and validated in two independent cohorts of HCC patients (N = 102 and N = 77), using pretransplant plasma circulating DNA. Prognostic significance was assessed by Kaplan-Meier survival estimates and log-rank tests. Multivariate analyses were performed to evaluate prognosis-related factors. Results: rs894151 and rs12438080 were significantly associated with recurrence (P = .003 and P = .004, respectively). Multivariate analyses demonstrated that the co-index of the 2 SNPs was an independent prognostic factor for recurrence (P = .040). Similar results were obtained in the third cohort (N = 77). Furthermore, for HCC patients (all the 3 cohorts) exceeding Milan criteria, the co-index was a prognostic factor for recurrence and survival (P<.001 and P = .002, respectively). Conclusions: Our study demonstrated first that genetic variations of rs894151 and rs12438080 in pretransplant plasma circulating DNA are promising prognostic markers for tumor recurrence in HCC patients undergoing LT and identify a subgroup of patients who, despite having HCC exceeding Milan criteria, have a low risk of post-transplant recurrence. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to define individualized internal target volume (ITV) for hepatocellular carcinoma (HCC) using 4D computed tomography (4DCT), and to determine the geometric and dosimetric benefits of respiratory gating. Gross tumor volumes (GTVs) were contoured on 10 respiratory phases of 4DCT images for 12 patients with HCC. Three treatment plans were prepared using different planning target volumes (PTVs): (1) PTV3D, derived from a single helical clinical target volume (CTV) plus conventional margins; (2) PTV10 phases, derived from ITV10 phases, which encompassed all 10 CTVs plus an isotropic margin of 0.8 cm; (3) PTVgating, derived from ITVgating, which encompassed three CTVs within gating-window at end-expiration plus an isotropic margin of 0.8 cm. The PTV3D was the largest volume for all patients. The ITV-based plans and gating plans spared more normal tissues than 3D plans, especially the liver. Without increasing normal tissue complication probability of the 3D plans, the ITV-based plans allowed for increasing the calculated dose from 50.8 Gy to 54.7 Gy on average, and the gating plans could further escalate the dose to 58.5 Gy. Compared with ITV-based plans, the dosimetric gains with gating plan strongly correlated with GTV mobility in the craniocaudal direction. The ITV-based plans can ensure target coverage with less irradiation of normal tissues compared with 3D plans. Respiratory-gated radiotherapy can further reduce the target volumes to spare more surrounding tissues and allow dose escalation, especally for patients with tumor mobility >1 cm. [Copyright &y& Elsevier]

The optimum strategy, hepatic resection (HR) or liver transplantation (LT), for treatment of early hepatocellular carcinoma (HCC) associated with liver diseases of Child–Pugh A is far from established. The aim of this study was to compare and determine which strategy is optimal for HCC fulfilling the Milan criteria. Consecutive data were collected in 1,018 HCC patients treated with HR and 89 HCC patients listed for LT (1 drop out for HCC progression) between January of 2003 and December of 2007. The independent prognostic factors identified by multivariate analysis were tumor size-plus-number, microscopic venous invasion, and operation type (LT or HR). When tumor size-plus-number was ≤4 or microscopic venous invasion was absent, there was no significant difference in overall survival (OS) between the LT and HR group. When tumor size-plus-number was >4 or microscopic venous invasion was present, OS was higher in the LT group. Since the pathological microscopic venous invasion was not easily available before operation which is limitation for widespread clinical use, thus in practice, we concluded that, for early HCC associated with Child–Pugh A cirrhosis, when tumor size-plus-number is >4, LT provides the best cure; when it is ≤4, HR remains the initial treatment of choice. [ABSTRACT FROM AUTHOR]

Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC. MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation, and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model tumor to explore the effect of sirolimus on tumor growth and metastatic progression. In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group. Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared to untreated control cells following anoxia. The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received a liver transplant for HCC. [ABSTRACT FROM AUTHOR]

To evaluate the prognostic value of tumor-associated macrophages (TAM), individually or synergistically with CD45RO + memory T cells (TM), in hepatocellular carcinoma (HCC) patients following resection. The infiltration of TAM and TM was assessed by immunohistochemistry in tissue microarray containing 302 HCC specimens. Correlations between TAM/TM infiltration and clinicopathologic features, disease-free survival (DFS) and overall survival (OS) were statistically analyzed. High TAM infiltration was associated with both improved DFS ( P = 0.0021) and OS ( P = 0.0481). Multivariate analysis identified TAM infiltration as independent prognostic factor for DFS ( P = 0.004) and OS ( P = 0.049). A second analysis clarified the synergistic effect of TAM&TM infiltration for DFS ( P = 0.004) and OS ( P = 0.040). Both TAM infiltration alone and concomitant infiltration of TAM&TM are associated with improved DFS/OS, suggesting that TAM could protect HCC patients from recurrence/metastasis and prolong survival by distinct mechanisms. [ABSTRACT FROM AUTHOR]

To investigate the most suitable housekeeping genes for quantifying a change in mRNA expression levels due to hepatitis virus B related hepatocellular carcinoma (HCC). Expression of mRNA encoding ACTB, GAPDH, B2M, HPRT and TBP was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in matched malignant and non-malignant tissues obtained from 65 non-treated HCCs. The software programs geNorm and NormFinder were used to ascertain the most suitable reference gene combination. All candidate genes showed significantly different expression between malignant and non-malignant samples. GAPDH and ACTB, genes most frequently used for normalization, were heavily regulated during HCC carcinogenesis and progression. B2M expression levels varied with hepatitis infection status. The combination of HPRT and TBP expression levels were the most stable, regardless of differences in tumor stage and cirrhotic and malignancy status. It is necessary to select reference genes based on tissue and disease specific expression profile and to further identify novel reference genes with greater expression stability for use in HBV related HCC gene expression studies. [ABSTRACT FROM AUTHOR]

Purpose: T cell transcription factors are nuclear effectors of the Wnt signaling transduction pathway and play crucial roles in embryonic and malignant development. Our precious study showed increased expression level of Tcf mRNA in liver cancer. In the present paper, antisense Tcf RNA was used to explore the possible therapeutic effect on liver cancer cells by interrupting the abnormal Wnt pathway. Methods: Antisense expression vectors containing the conserved sequence of Tcf cDNA were constructed and transfected into a human liver cancer cell line SMMC-7721. Tumorigenic potential was determined by cellular growth assay and tumor growth in nude mice. Results: The stable transfection of antisense Tcf in SMMC-7721 cells significantly reduced Tcf expression at both mRNA and protein levels compared with parental and mock-transfected cells. Antisense- mediated suppression of Tcf inhibited the in vitro proliferation and in vivo tumor formation ability. Furthermore, the apoptosis rate of antisense transfected cells was significantly higher than that of control, indicating that antisense RNA suppressed malignant growth by induction of apoptosis. Concclusion: Our studies demonstrate the critical role of Wnt signaling pathway in the neoplastic growth of liver cancer cells and suggest that inhibition of Tcf activity with antisense Tcf RNA may be a potential new gone therapy method for liver cancer. [ABSTRACT FROM AUTHOR]