Yong Fa Zhang

Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus

OBJECTIVE To compare the outcomes of hepatic resection and transcatheter arterial chemoembolization for resectable hepatocellular carcinoma with hepatic vein tumor thrombus. METHODS From January 2006 to November 2013, 28 patients initially diagnosed with resectable hepatocellular carcinoma combined with hepatic vein tumor thrombus received hepatic resection. These patients were compared with 56 case-matched controls (1:2 ratio) selected from a pool of 91 patients who received transcatheter arterial chemoembolization as an initial treatment during the same period. Clinical characteristics, adverse events, overall survival and survival-related factors were analyzed. RESULTS The 1-, 2- and 3-year overall survival rates were 66.5, 37.4 and 28.5% for the hepatic resection group and 32.3, 18.7 and 15.6% for the transcatheter arterial chemoembolization group (P = 0.015), respectively. No significant difference was found between the two groups in terms of complications and mortality. Multivariate analyses revealed combined portal vein tumor thrombosis (HR = 2.116; 95% CI: 1.26-3.57; P = 0.005) and treatment allocation (hepatic resection = 2.289; 95% CI, 1.30-4.02; P = 0.004) as risk factors for overall survival. CONCLUSIONS Hepatic resection provides a good prognosis for hepatocellular carcinoma patients with hepatic vein tumor thrombus compared with patients undergoing transcatheter arterial chemoembolization, and the most important factor related to survival was co-existence with portal vein invasion.

Optimal surgical strategy for hepatocellular carcinoma with portal vein tumor thrombus: A propensity score analysis

Objectives The optimal surgical resection method for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) that maximizes both safety and long-term outcome has not yet been determined. The aim of this study was to compare the clinical outcomes following peeling off versus en bloc resection for PVTT. Methods From 2005 to 2012, 252 patients with HCC and type I/II PVTT who underwent hepatic resection were divided into two groups according to whether they received en bloc resection (n = 113) or peeling off resection (n = 139). The clinical outcomes were compared before and after propensity score matching. Results The propensity model matched 113 patients with en bloc resection for further analyses. After matching, overall survival (OS) and disease-free survival (DFS) rates were significantly increased in the en bloc group compared with the peeling off group (p = 0.011 and p = 0.015). A multivariate analysis indicated that en bloc resection independently improved both OS and DFS (HR = 1.471, 95% CI: 1.071-2.018, p = 0.017 and HR = 1.415, 95% CI: 1.068-1.874, P=0.016). The adverse events were not significantly different between the two groups. However, the peeling off group showed a significantly increased recurrence rate of vascular invasion compared with the en bloc group (23.9% vs. 9.7%, p = 0.005). Similar results were also demonstrated prior to the matched analysis. Conclusions An en bloc resection is safe and confers a survival advantage compared with a peeling off resection in HCC patients with PVTT; thus, en bloc resection should be recommended as a standard treatment for these patients when possible.

Elevated expression of Cripto-1 correlates with poor prognosis in hepatocellular carcinoma

Cripto-1 could promote tumorigenesis in a wide range of carcinomas, yet little is known in hepatocellular carcinoma (HCC). The expression of Cripto-1 and MMP-9 were assessed by immunohistochemistry in 205 HCC specimens. The correlation between Cripto-1 and MMP-9, clinicopathological/prognostic value in HCC was examined. Cripto-1 overexpression was correlated with larger tumor, TNM stage, BCLC stage and tumor recurrence. In multivariate analyses, Cripto-1 was an independent predictor for overall survival (OS) and time to recurrence (TTR). Cripto-1 expression was increased in TNM and BCLC stage-dependent manner. Cripto-1 overexpression was associated with poor prognosis in patients subgroups stratified by tumor size, tumor differentiation, TNM and BCLC stage. In addition, Cripto-1 was positively correlated with MMP-9 among 205 HCC samples. Patients with Cripto-1 upregulation had poor OS and shorter TTR in low and high aggressiveness groups. Furthermore, Cripto-1 had predictive validity for early and late recurrence in HCC patients. Combination of Cripto-1 and serum AFP was correlated with OS and TTR. In conclusion, Cripto-1 overexpression contributes to aggressiveness and poor prognosis of HCC. Cripto-1/AFP expression could be a potential prognostic biomarker for survival in HCC patients.

MicroRNA-34c-3p promotes cell proliferation and invasion in hepatocellular carcinoma by regulation of NCKAP1 expression

Purpose Our previous miRNA profiling study indicated that microRNA-34c-3p (miR-34c-3p) was overexpressed and associated with survival in HCC. This study is aimed to confirm its clinical significance and explore the function and underlying mechanism of miR-34c-3p in HCC.MethodsWe first evaluated miR-34c-3p expression and its relationship with prognosis in HCC patients. We then established stable HCC cell lines with miR-34c-3p overexpression and knockdown by the lentiviral packaging systems and performed the functional assays in vitro and in vivo, respectively. We next identified the target of miR-34c-3p by using microRNA target databases and dual-luciferase assay. Finally, the correlation between the expression of miR-34c-3p and the target gene was analyzed by immunohistochemistry and qRT-PCR in HCC tissues and hepatoma xenografts.ResultsOverexpressed miR-34c-3p was confirmed in HCC tissues and significantly associated with poor survival of HCC patients. miR-34c-3p expression was also recognized as an independent risk factor for DFS and OS in multivariate analysis. Ectopic expression of miR-34c-3p significantly promotes the proliferation, colony formation, invasion and cell cycle regression of HCC cell lines. Knockdown of miR-34c-3p remarkably blocked hepatoma growth in the xenograft model. miRNA target databases and luciferase reporter assay showed that NCKAP1 was a direct target of miR-34c-3p in HCC cells and the high expression of NCKAP1 in HCC tissues is significantly correlated with low expression of miR-34c-3p and associated with a favorable prognosis of HCC patients.ConclusionThe current study demonstrates that miR-34c-3p functions as a tumor promoter by targeting NCKAP1 that is associated with prognosis in HCC. miR-34c-3p and NCKAP1 may be new potential molecular targets for HCC therapy.

Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus

Objective To compare the treatment outcomes of sorafenib plus transarterial chemoembolization (TACE) vs TACE alone in patients with hepatocellular carcinoma (HCC) and hepatic vein tumor thrombus (HVTT). Methods Twenty patients who were initially diagnosed with HCC and HVTT and received TACE combined with sorafenib during February 2009 to October 2013 were included in the study. To minimize selection bias, these patients were compared with 60 case-matched controls selected from a pool of 81 patients (in a 1:3 ratio) who received TACE alone during the same period. The primary end point was overall survival (OS). The secondary end points were time to progression, disease control rate, and adverse events. Results After a median follow-up period of 12.5 months (range, 1.03–44.23 months), the OS of the combined group was found to be significantly higher compared with the monotherapy group (14.9 vs 6.1 months, P=0.010). The time to progression was found to be significantly longer in the combined group (4.9 vs 2.4 months, P=0.016). Univariate and multivariate analyses revealed that the treatment allocation was an independent predictor of OS. Conclusion Sorafenib plus TACE was well tolerated and was more effective in treating patients with advanced HCC and HVTT. Future trials with prospective larger samples are required to validate these results.

MEP1A contributes to tumor progression and predicts poor clinical outcome in human hepatocellular carcinoma

Although many staging classifications have been proposed for hepatocellular carcinoma (HCC), determining a patients prognosis in clinical practice is a challenge due to the molecular diversity of HCC. We investigated the relationship between MEP1A, a candidate oncogene, and clinical outcomes of HCC patients; furthermore, we explored the role of MEP1A in HCC. In this report, it was demonstrated by quantitative real‐time polymerase chain reaction that MEP1A messenger RNA levels were significantly elevated in HCC tumor tissues compared with matched adjacent nonneoplastic tissues and nonmalignant liver disease tissues. Immunohistochemical analyses of tissue samples from two independent groups of 394 HCC patients showed that positive expression of MEP1A in tumor cells was an independent and significant risk factor affecting survival after curative resection in both cohort 1 (hazard ratio = 2.05, 95% confidence interval 1.427‐2.946; P < 0.001) and cohort 2 (hazard ratio = 1.89, 95% confidence interval 1.260‐2.833; P = 0.002). Analysis of Barcelona Clinic Liver Cancer stage 0‐A subgroup further showed that patients with positive MEP1A expression in tumor cells had poorer surgical prognoses than those with negative MEP1A expression in tumor cells (cohort 1 P = 0.001, cohort 2 P < 0.001). Both in vitro and in vivo assays showed that MEP1A promoted HCC cell proliferation, migration, and invasion. Further analyses found that MEP1A played an important role in regulating cytoskeletal events and induced epithelial‐mesenchymal transition in HCC cells. Conclusion: MEP1A is a novel prognostic predictor in HCC and plays an important role in the development and progression of HCC. (Hepatology 2016;63:1227‐1239)

Intermediate-stage hepatocellular carcinoma treated with hepatic resection: the NSP score as an aid to decision-making.

Background:The subgroups of patients with intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) who would truly benefit from hepatic resection (HR) are unknown. An objective point score was established to guide the selection of these patients for HR.Methods:In all, 255 consecutive patients with intermediate-stage HCC treated with HR were evaluated retrospectively and included in this study (the training cohort). The variables on overall survival (OS, log-rank test) were investigated and a point score (the NSP score) was developed by using a Cox-regression model and validated in an independent external cohort from another institution (n=169).Results:The NSP score differentiated two groups of patients (⩽1, >1 point) with distinct prognoses (median OS, 61.3 vs 19.3 months; P<0.001). A high NSP score was associated with increased major adverse events after HR (5.6 vs 13.8%, P=0.027). Its predictive accuracy as determined by the area under the receiver operating characteristic curve (AUC) at 1, 3, and 5 years (AUCs 0.688, 0.739, and 0.732) was greater than the other six staging systems for HCC (0.513–0.677). The findings were supported by the validation cohort.Conclusions:The NSP scoring system is more accurate in selecting patients with intermediate-stage HCC for HR.

A prognosis model for patients with hepatocellular carcinoma and portal vein tumor thrombus following hepatic resection

The present study aimed to identify the risk factors influencing the survival of patients with hepatocellular carcinoma (HCC) affected by portal vein tumor thrombus (PVTT), following hepatic resection, and to establish a prognostic model. Between March 2001 and May 2008, 234 cases of HCC with PVTT that underwent hepatic resection were randomly divided into experimental or validation groups. The association between the clinicopathological factors and disease-free survival (DFS) and overall survival (OS) was analyzed, and the significant factors involved were used to establish a prognostic model, which was then validated. Tumor rupture, number of tumors and macroscopic vascular invasion were observed to be independent risk factors of DFS and OS. In the prognostic model, the DFS and OS of low-, medium- and high-risk patients in the experimental group were observed to be significantly different, compared to those in the validation group. In conclusion, the present study established a prognostic model for patients with HCC affected by PVTT following hepatectomy, and demonstrated that the model may be used to guide the treatment of these patients and predict their prognosis.

Matrix metalloproteinase 12 expression is associated with tumor FOXP3+ regulatory T cell infiltration and poor prognosis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is among the most fatal types of cancer worldwide due to its high rates of recurrence and metastasis. The molecular processes involved in HCC progression require further investigation to identify biomarkers for use in diagnosis and treatment. In the present study, the significance and prognostic value of matrix metallopeptidase 12 (MMP12) expression in human HCC was investigated. MMP12 mRNA expression was investigated using reverse transcription-quantitative polymerase chain reaction analysis of 42 pairs of tumor and non-tumor liver tissues obtained from patients with HCC following surgical treatment. Immunohistochemical staining was used to detect MMP12 and forkhead box P3 (FOXP3) expression in 158 paraffin-embedded HCC tissues. The prognostic value of MMP12 expression was determined using Kaplan-Meier analysis and the Cox proportional hazards model. MMP12 mRNA levels were significantly higher in liver tumor tissues compared with matched non-tumor liver tissues. MMP12 expression and FOXP3+ regulatory T cell (Treg) infiltration was positively correlated (r=0.302; P<0.001). MMP12 protein overexpression was positively correlated with tumor size (P=0.018), high serum alpha-fetoprotein levels (P=0.005) and poor overall survival time (P=0.012) in patients with HCC. Furthermore, MMP12 protein level was an independent predictive factor for overall survival time of patients with HCC who underwent curative resection. In conclusion, these results suggest that MMP12 may increase FOXP3+ Treg infiltration into tumor tissues, and promote tumor progression and immune evasion of HCC. The overexpression of MMP12 protein is, therefore, a valuable prognostic indicator in patients with HCC.

Prognostic significance of sodium-potassium ATPase regulator, FXYD3, in human hepatocellular carcinoma

The clinical significance of the sodium-potassium ATPase regulator FXYD domain-containing ion transport regulator 3 (FXYD3) has been demonstrated in a number of types of cancer. However, the role of this protein in human hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, 217 HCC tissue samples were analyzed to evaluate the expression and prognostic significance of FXYD3 in HCC. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA expression of FXYD3 in 80 primary HCC specimens and paired non-cancerous liver tissue samples, while western blotting was used to analyze the protein expression level of FXYD3 in another 24 pairs. These analyses demonstrated that the expression level of FXYD3 was significantly increasedb at the mRNA and protein levels in HCC tumor tissues compared with adjacent non-cancerous tissues. Immunohistochemical analysis of 137 paraffin-embedded HCC tissue samples indicated that the expression of FXYD3 was associated with HCC clinicopathological characteristics. Kaplan-Meier analysis demonstrated that patients with high FXYD3 protein expression (n=60) experienced significantly poorer overall survival time compared with patients with low FXYD3 protein expression (n=77) (P<0.001). Multivariate analysis demonstrated that FYXD3 protein expression level (hazard ratio, 2.137; 95% confidence interval, 1.224–3.732; P=0.008) was an independent prognostic factor in patients with HCC. Overall, the results indicated that FXYD3 expression levels were higher in HCC tumor tissues than in adjacent non-cancerous tissues, and that the FXYD3 protein may serve as a prognostic marker for HCC.