Chinese Hepatocellular Carcinoma Patients Research Articles

Efficacy of transcatheter arterial chemoembolization (TACE) in combination with sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients.

279 Background: The purpose of this prospective trial is to evaluate the efficacy and safety of the concurrent use of TACE and sorafenib in a group of patients with unresectable HCC.The treatment outcomes of this group of patients were also compared in a retrospective fashion with a group of HCC patients with similar characteristics of patient and disease in a case controlled setting. Methods: A total of 45 patients (BCLC stage B/C: 16/29) with unresectable HCC were enrolled between June 2008 and Feb 2011 as experimental group and were treated with combination of sorafenib and TACE according to an institutional protocol. To evaluate the efficacy of the combination therapy, a group of 45 HCC patients (n=45, BCLC stage B/C: 17/28) with comparable baseline characteristics who had been treated with TACE alone in our institute were retrospectively selected as control group to compare the treatment outcomes. Median overall survival was compared between the two groups. Adverse events related to sorafenib were assessed according to CTCAE3.0 to observe safety endpoints. The study was approved by the Institutional Ethics Committee at Zhongshan Hospital, Fudan University, China. Results: The median follow-up time for the entire group of patients was 21 months (12.66 - 29.33). The median survival time for the TACE/sorafenib group was 27 months (21.89 - 32.10), and that for TACE alone group was 17 months (8.9 - 25.04) (P<0.05). The most common adverse events associated with sorafenib were hand-foot skin reaction (82.2%), rash (57.94%) and diarrhea (48.91%). Most of the drug-related adverse events were manageable with dose modification, and no CTCAE Grade 4 adverse event was observed. Conclusions: The combination treatment of TACE and sorafenib significantly prolonged median survival in Chinese patients with unresectable HCC, with well tolerated safety profile.

ABO Blood Group and the Risk of Hepatocellular Carcinoma: A Case-Control Study in Patients with Chronic Hepatitis B

BackgroundStudies have observed an association between the ABO blood group and risk of certain malignancies. However, no studies of the association with hepatocellular carcinoma (HCC) risk are available. We conducted this hospital-based case-control study to examine the association with HCC in patients with chronic hepatitis B (CHB).MethodsFrom January 2004 to December 2008, a total of 6275 consecutive eligible patients with chronic hepatitis B virus (HBV) infection were recruited. 1105 of them were patients with HBV-related HCC and 5,170 patients were CHB without HCC. Multivariate logistic regression models were used to investigate the association between the ABO blood group and HCC risk.ResultsCompared with subjects with blood type O, the adjusted odds ratio (AOR) for the association of those with blood type A and HCC risk was 1.39 [95% confidence interval (CI), 1.05–1.83] after adjusting for age, sex, type 2 diabetes, cirrhosis, hepatitis B e antigen, and HBV DNA. The associations were only statistically significant [AOR (95%CI) = 1.56(1.14–2.13)] for men, for being hepatitis B e antigen positive [AOR (95%CI) = 4.92(2.83–8.57)], for those with cirrhosis [AOR (95%CI), 1.57(1.12–2.20)], and for those with HBV DNA≤105copies/mL [AOR (95%CI), 1.58(1.04–2.42)]. Stratified analysis by sex indicated that compared with those with blood type O, those with blood type B also had a significantly high risk of HCC among men, whereas, those with blood type AB or B had a low risk of HCC among women.ConclusionsThe ABO blood type was associated with the risk of HCC in Chinese patients with CHB. The association was gender-related.

Correlation of LAPTM4B polymorphisms with hepatocellular carcinoma in Chinese patients

Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality in many countries. Evaluation of new susceptibility risk factors is therefore warranted in order to explore means to improve the survival rate. Here, we report on a novel HCC-related gene known as lysosomal protein transmembrane 4 beta (LAPTM4B) that has two alleles designated LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains one copy of a 19-bp sequence, whereas this sequence is duplicated in allele *2 in exon 1 of LAPTM4B. In this study, we aimed to investigate the relationship between LAPTM4B allelic variation and HCC susceptibility. The LAPTM4B genotype was analyzed in the blood samples from 102 HCC patients and 135 healthy individuals by PCR. The genotypic distribution of LAPTM4B was analyzed using the chi-squared test. The frequencies of allele *2 were 38.24 and 24.07% in the HCC group and control group, respectively, representing a significant difference between these two groups (P<0.001). Thus, allele *2 of LAPTM4B appears to be associated with genetic susceptibility of HCC and may therefore be considered as a risk factor.

Prognostic factors after liver resection for hepatocellular carcinoma: a single-center experience from China

BackgroundThis study aimed to clarify the risk factors for survival and recurrence of hepatocellular carcinoma (HCC) in a cohort of Chinese HCC patients after hepatectomy and to compare 6 developed staging systems. MethodsA retrospective analysis was performed on 165 consecutive patients. The Kaplan–Meier method was used to calculate survival. Postoperative prognostic factors were evaluated using univariate and multivariate analyses. The overall predictive power of each staging system was evaluated by the area under the receiver operating characteristic curve. ResultsThe overall survival rates of 1, 3, and 5 years were 81.2%, 58.6%, and 56.7%, respectively, and the corresponding disease-free survival rates were 52.9%, 23.3%, and 15.5%, respectively. α-fetoprotein level and blood transfusion were correlated significantly with patients' overall survival, and portal vein thrombosis and tumor size (>5 cm) were correlated significantly with poor disease-free survival. ConclusionsThe French staging system is better for predicting the prognosis of HCC patients receiving surgical treatment.

Serum MicroRNAs as Biomarkers for Hepatocellular Carcinoma in Chinese Patients with Chronic Hepatitis B Virus Infection

BackgroundMicroRNAs (miRNAs) have been shown to anticipate great cancer diagnostic potential. Recently, circulating miRNAs have been reported as promising biomarkers for various pathologic conditions. The objective of this study was to investigate the potential of serum miRNAs as novel biomarkers for hepatocellular carcinoma (HCC).Methodology/Principal FindingsThis study was divided into four phases: (I) Ten candidate serum miRNAs were detected by using real-time RT-PCR, corresponding 10 HCC patients with chronic hepatitis B virus (HBV) infection and 10 age- and sex-matched healthy subjects. (II) Marker validation by real-time RT-PCR on HBV patients with (n = 48) or without HCC (n = 48), and healthy subjects (n = 24). (III) Marker detection by real-time RT-PCR in sera from another 14 HCC patients before and 1 month after surgical resection. (IV) We examined the correlation between the expressions of candidate serum miRNAs with clinical parameters of HCC patients. Although miR-222, miR-223 or miR-21 were significantly up- or down-regulated between HCC patients and healthy controls, no significant difference was observed in the levels of these miRNAs between HBV patients without and with HCC. MiR-122 in serum was significantly higher in HCC patients than healthy controls (p<0.001). More importantly, it was found that the levels of miR-122 were significantly reduced in the post-operative serum samples when compared to the pre-operative samples. Although serum miR-122 was also elevated in HBV patients with HCC comparing with those without HCC, the difference was at the border line (p = 0.043).Conclusions/SignificanceOur results suggest that serum miR-122 might serve as a novel and potential noninvasive biomarker for detection of HCC in healthy subjects, moreover, it might serve as a novel biomarker for liver injury but not specifically for detection of HCC in chronic HBV infection patients.

Clinicopathologic and gene expression parameters predict liver cancer prognosis

BackgroundThe prognosis of hepatocellular carcinoma (HCC) varies following surgical resection and the large variation remains largely unexplained. Studies have revealed the ability of clinicopathologic parameters and gene expression to predict HCC prognosis. However, there has been little systematic effort to compare the performance of these two types of predictors or combine them in a comprehensive model.MethodsTumor and adjacent non-tumor liver tissues were collected from 272 ethnic Chinese HCC patients who received curative surgery. We combined clinicopathologic parameters and gene expression data (from both tissue types) in predicting HCC prognosis. Cross-validation and independent studies were employed to assess prediction.ResultsHCC prognosis was significantly associated with six clinicopathologic parameters, which can partition the patients into good- and poor-prognosis groups. Within each group, gene expression data further divide patients into distinct prognostic subgroups. Our predictive genes significantly overlap with previously published gene sets predictive of prognosis. Moreover, the predictive genes were enriched for genes that underwent normal-to-tumor gene network transformation. Previously documented liver eSNPs underlying the HCC predictive gene signatures were enriched for SNPs that associated with HCC prognosis, providing support that these genes are involved in key processes of tumorigenesis.ConclusionWhen applied individually, clinicopathologic parameters and gene expression offered similar predictive power for HCC prognosis. In contrast, a combination of the two types of data dramatically improved the power to predict HCC prognosis. Our results also provided a framework for understanding the impact of gene expression on the processes of tumorigenesis and clinical outcome.

Association Betweenpri-miR-218Polymorphism and Risk of Hepatocellular Carcinoma in a Han Chinese Population

MicroRNAs are noncoding RNA molecules of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. The aim of this study was to investigate whether pri-miR-218 rs11134527 A/G polymorphism influences the risk of hepatocellular carcinoma (HCC) or not. pri-miR-218 rs11134527 A/G was genotyped in 302 HCC patients and 513 control subjects using the polymerase chain reaction-restriction fragment length polymorphism assay. The AG genotype of pri-miR-218 rs11134527 A/G was associated with family history (p=0.018, odds ratio [OR]=2.96, 95% confidence interval [CI]: 1.16-7.56) and elevated serum α-fetoprotein (serum alpha-fetoprotein [AFP]) levels (≥20 ng/mL; p=0.009, OR=1.92, 95% CI: 1.17-3.14) in HCC patients. These findings suggested that the AG genotype of pri-miR-218 rs11134527 might relate to genetic predisposition and be involved in regulating the expression of AFP in Chinese HCC patients.

Low Frequency of PIK3CA Gene Mutations in Hepatocellular Carcinoma in Chinese Population

PI3K/AKT constitutes an important pathway regulating the signaling of multiple biological processes and plays a critical role in carcinogenesis. PIK3CA gene missense mutations have been reported in many human cancer types. The mutation of it in hepatocellular carcinoma cases varies with different races and regions. In this study, we investigated PIK3CA mutation in Chinese hepatocellular carcinoma patients. A total 90 Chinese patients of hepatocellular carcinoma were recruited in this study. Exons 9 and 20 hotspots mutations of PIK3CA gene were detected by PCR-based DNA sequencing. Two point mutations (E542K and D549H) in exon 9 were found in only one patient (1/90; 1.11%), no mutation was found in exon 20 in any cases. 57 patients are associated with HBV infection (57/90; 63.3%), and 8 patients with HCV infection (8/90; 8.9%). The frequency of the PIK3CA mutations in hepatocellular carcinoma seems to be lower in Chinese hepatocellular carcinoma patients. These findings suggest that PI3K mutations may not play a major role in hepatic carcinogenesis in Chinese. HBV infection has close relationship with HCC in Chinese.

Comparison of 12 current staging systems for advanced hepatocellular carcinoma not amendable to locoregional therapy as inclusion criteria for clinical trials.

2567 Background: The life expectancy of patients with advanced hepatocellular carcinoma (HCC) enrolled in clinical trials should be at least 3 month to test drug response. However, the prognosis of these patients was poor with median overall survival (OS) shorter than 3 months. This study was aimed to evaluate different prognosis score systems for HCC in predicting prognosis and 3-month OS of patients with advanced HCC. Methods: From November 2008 to April 2010, a total of 208 patients with advanced HCC who were not amendable to locoregional therapy were included in this study. Data were collected to classify patients according to Japan Integrated Staging scoring system, TNM stage by liver Cancer Study Group of Japan criteria, National Comprehensive Cancer Network Stage system, Cancer of the liver Italian Program scoring system for hepatocelluar carcinoma (CLIP), Advanced Liver Cancer Prognostic System (ALCPS), model of end-stage liver disease, French scoring system, Chinese University Prognostic Index staging system for HCC (CUPI), OKUDA score system, Tokyo score system, Barcelona Clinic Liver Cancer staging for hepatocelluar carcinoma at diagnosis. OS and 3-month OS were the end points used in the analysis. Survival analysis, Cox regression, relative operating characteristic (ROC), and logistic regression were utilized to access the prognostic value of each score system. Results: ROC analysis confirmed that ALCPS was the best prognostic system for 3-month OS. The cut-off point for ALCPS was 14 with sensitivity of 81.82% and specificity of 79.01%, which was reinforced by the survival variation on the two subgroups divided by ROC analysis generated cutoff point. CLIP and CUPI presented no statistical difference in prognostic discrimination with ALCPS, however, with relatively lower accuracy. Conclusions: ALCPS was the best score system in prediction of OS and 3-month OS among the 12 systems analyzed and a proper inclusion criteria for clinical trials for Chinese advanced HCC patients.

Global Regulation on microRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma

Recent work has revealed the causative links between deregulation of microRNAs (miRNAs) and cancer development. In hepatocellular carcinoma (HCC), aberrant expression of miRNAs has been observed, but the molecular mechanisms that contribute to such changes remains to be elucidated. Here, we reported the analysis of miRNA expression in 94 pairs of tumor and adjacent nontumor tissues from HBV-associated HCC in Chinese patients. We found miRNAs were aberrantly expressed in HCC tissues. To investigate the cause of such deregulation, we detected changes in DNA copy number by measuring locus-specific hybridization intensity, and found changes in expression of several miRNAs are correlated with genomic amplification or deletion. For example, the genomic regions of miR-30d and miR-151 were amplified in ∼50% of HCC tumor tissues, and the expressions of these miRNAs are significantly correlated with DNA copy number. We also employed cDNA microarray data, and provide evidence that key regulators of the miRNA biosynthetic pathway, including DROSHA, DGCR8, AGO1, and AGO2, are frequently overexpressed in HCC. This study provides molecular clues that may contribute to the global changes of miRNA expression in HCC.

A variant in microRNA-196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis

Cirrhosis is an important risk factor for hepatocellular carcinoma (HCC) in China, while little is known of the genetic susceptibility to hepatocarcinogenesis. Traditional approaches to identification of novel genetic predisposition genes have focused on protein encoding genes. There is evidence to suggest that microRNAs (miRNA) may play an important role in tumorigenesis. Recent studies have implicated that the rs11614913 SNP in miR-196a2 may be associated with susceptibility to lung cancer, congenital heart disease, breast cancer, as well as reduced survival in non-small cell lung cancer. This study aims to assess whether this functional polymorphism can influence susceptibility to and the progression of cirrhosis-related HCC. 532 patients with hepatic cirrhosis (310 patients with HCC and 222 patients without HCC) were enrolled. DNA was extracted from blood specimens, and miR-196a2 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In addition, tumour tissues of liver (n=59) were obtained from the studied HCC patients for measurement of miR-196a expression levels. The frequency of the CC genotype among HCC patients was higher than that in the control group, implying that the cirrhotic patients with the CC genotype or C allele containing genotypes (CT and CC) may have a higher risk of HCC. However, in a subsequent analysis of the association between this polymorphism and clinicopathological characteristics, there was an association between rs11614913 genotype and tumour size (p=0.046), but not with tumour number, grade, stage, invasiveness or Child-Pugh grade. In a genotype-phenotype correlation analysis using 59 tumour tissues of liver, rs11614913 CC or carrying at least one C allele was associated with significantly increased mature miR-196a expression (p=0.006 or =0.002). Our results suggest, for the first time, that miR-196a2 polymorphism may contribute to cirrhosis-related HCC susceptibility in Chinese patients through influencing mature miR-196a expression.

PEBP1 downregulation is associated to poor prognosis in HCC related to hepatitis B infection

Phosphatidylethanolamine-binding protein 1 (PEBP1, also RKIP) plays a pivotal role in cancer by regulating multiple cellular signaling processes and suppressing metastasis in animal models. We examined whether PEBP1 expression in hepatocellular carcinoma (HCC) correlated with the risk of recurrence and survival after resection. A randomly selected cohort of 240 Chinese HCC patients, predominantly hepatitis B related, formed the basis of the study. PEBP1 expression levels were evaluated by immunohistochemistry and real-time reverse-transcriptase PCR. Survival analysis was performed by univariate and multivariate analyses. The results were further validated in an independent series of 403 patients. The relevance of PEBP1 to phospho-ERK was determined by Western blot analysis on clinical samples and hepatoma cell lines. PEBP1, prevalently down-regulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, lack of encapsulation, poor differentiation and large size). Both PEBP1 protein and mRNA levels were independent predictors for tumor recurrence (hazard ratio (HR) = 1.877, p=0.001; HR = 2.633, p = 0.001; respectively), and patient survival (HR = 1.796, p = 0.004; HR = 1.730, p = 0.044; respectively). The prognostic value of PEBP1 was then confirmed in the validation cohort. In addition, Western blot suggested that loss of PEBP1 led to hyperactivity of MAPK signaling. Down-regulation of PEBP1 in HCC indicated aggressive tumor behaviors and predicted a worse clinical outcome, which may be a useful biomarker to identify the patients at high risk of post-operative recurrence.

Comparison of four staging systems in predicting outcomes and guiding option of treatment for patients with hepatocellular carcinoma

Objective To compare the Barcelona clinic liver cancer staging classification (BCLC), the Japan integrated staging score (JIS), the cancer of the liver Italian program score (CLIP) and Chinese staging system in terms of their ability to predict outcomes and to guide option of therapy in patients with hepatocellular carcinoma (HCC) in China.Methods Clinical data of 861 HCC patients from Zhongshan Hospital between 2001 and 2002 were retrospectively analyzed. Patients were classified acccording to different staging systems. Survival for patients in different stages and the effects of therapeutic methods on survival time were compared. Results BCLC, JIS and Chinese staging system showed the ability in predicting survival for patients in different staging. CLIP failed to show significant difference in survival rates for each subgroup. There was no significant difference in survival rate between surgery and transarterial chemoembolization (TACE)/transarterial embolization (TAE) for patients classified as BCLC stage C, CLIP scores more than 3 or Chinese stage Ⅲ a.The survival rate, however, was higher in patients received operation than those received TACE/TAE if they were classified as earlier stages. Conclusions The BCLC, JIS and Chinese staging systems show prospective ability for Chinese HCC patients in prediction outcomes, whereas the BCLC and the Chinese staging systems are better at both predicting outcomes and guiding the option of treatment. Key words: Hepatocellular carcinoma; Staging systems; Prognostic ability; Therapeutic guiding ability

Abstract 1983: TP53 mutations in hepatocellular carcinoma: Association with survival and stem cell-like gene expression traits

Abstract PURPOSE Mutations of TP53, a tumor suppressor gene, are associated with prognosis of many cancers. However, the prognostic value of TP53 mutations in hepatocellular carcinoma (HCC) is still unclear, largely because of the enormous heterogeneity in the geographic and etiological backgrounds of the HCC patients. Here, we analyzed the prognostic values of TP53 mutations. Gene expression profiling analysis was performed to evaluate the effect of TP53 mutations at the molecular level. PATIENTS AND METHODS TP53 mutations were investigated in a total of 409 HCC patients including Chinese (n=336) and Caucasian (n=73) patients using direct sequencing method. RESULTS A total of 125 TP53 mutations were found in Chinese HCC patients (37.2 %). HCC patients harboring TP53 mutations showed shorter overall survival compared to patients with wild-type TP53 (Hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.37-2.52; P&amp;lt;0.001). The hotspot mutations at R249S and V157F were significantly associated with worse prognosis in both univariate (HR, 2.11; 95% CI, 1.51-2.94; P&amp;lt;0.001) and multivariate analyses (HR, 1.79; 95% CI, 1.29-2.51; P&amp;lt;0.001). In addition, gene expression profile analysis revealed the expression of stem cell-like traits in TP53 mutated tumors. This finding was validated in breast and lung cancers with TP53 mutations. CONCLUSION TP53 mutations, particularly hotspot mutations, are associated with poor prognosis in HCC. The acquisition of stem cell-like gene expression traits may contribute to the aggressive behavior of the TP53 mutated tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1983.

Diabetes mellitus and hepatocellular carcinoma: Comparison of Chinese patients with and without HBV-related cirrhosis

To determine the role of diabetes mellitus (DM) and other associated factors in Chinese hepatocellular carcinoma (HCC) patients with cirrhosis, compared with those HCC patients without cirrhosis, in the single setting of hepatitis B virus (HBV) infection, after other known concomitant diseases were excluded. A total of 482 patients, treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period January 2003 to June 2009, and with a hospital discharge diagnosis of HCC, were included. Demographic, clinical, laboratory, metabolic and instrumental features were analyzed. Of the total, 310 patients were diagnosed with HBV infection and, following the inclusion and exclusion criteria, 224 were analyzed, including 122 patients (54.5%) with cirrhosis (the case group) and 102 patients without cirrhosis (the control group). Twenty-seven patients (12.1%) were diabetic, including 19 in the case group and 8 in the control group (19/122 = 15.6% vs 8/102 = 7.8%, P = 0.077). Thirty-one possible relevant parameters were compared by univariate analysis, and 9 variables were selected for multivariable analysis, including DM (P = 0.077), past history of HBV infection (P = 0.005), total bilirubin (P < 0.001), albumin level (P < 0.001), international normalized ratio (INR) (P < 0.001), alanine aminotransferase (P = 0.050), platelet (P < 0.001), total cholesterol (P = 0.047), and LDL cholesterol (P = 0.002) levels. Diabetes showed a statistical difference by multivariable analysis [odds ratio (OR) 4.88, 95% confidence interval (CI): 1.08-21.99, P = 0.039], although no significant difference was found in univariate analysis. In addition, three cirrhosis-related parameters remained statistically different, including INR (OR 117.14, 95% CI: 4.19-3272.28, P = 0.005), albumin (OR 0.89, 95% CI: 0.80-0.99, P = 0.027), and platelet count (OR 0.992, 95% CI: 0.987-0.999, P = 0.002). Besides the three cirrhosis-related parameters, DM was found to be the sole independent factor associated with HCC in patients with HBV-related cirrhosis, compared with those without cirrhosis.

Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters

BackgroundSurgical resection is one important curative treatment for hepatocellular carcinoma (HCC), but the prognosis following surgery differs substantially and such large variation is mainly unexplained. A review of the literature yields a number of clinicopathologic parameters associated with HCC prognosis. However, the results are not consistent due to lack of systemic approach to establish a prediction model incorporating all these parameters.MethodsWe conducted a retrospective analysis on the common clinicopathologic parameters from a cohort of 572 ethnic Chinese HCC patients who received curative surgery. The cases were randomly divided into training (n = 272) and validation (n = 300) sets. Each parameter was individually tested and the significant parameters were entered into a linear classifier for model building, and the prediction accuracy was assessed in the validation setResultsOur findings based on the training set data reveal 6 common clinicopathologic parameters (tumor size, number of tumor nodules, tumor stage, venous infiltration status, and serum α-fetoprotein and total albumin levels) that were significantly associated with the overall HCC survival and disease-free survival (time to recurrence). We next built a linear classifier model by multivariate Cox regression to predict prognostic outcomes of HCC patients after curative surgery This analysis detected a considerable fraction of variance in HCC prognosis and the area under the ROC curve was about 70%. We further evaluated the model using two other protocols; leave-one-out procedure (n = 264) and independent validation (n = 300). Both were found to have excellent prediction power. The predicted score could separate patients into distinct groups with respect to survival (p-value = 1.8e-12) and disease free survival (p-value = 3.2e-7).ConclusionThis described model will provide valuable guidance on prognosis after curative surgery for HCC in clinical practice. The adaptive nature allows easy accommodation for future new biomarker inputs, and it may serve as the foundation for future modeling and prediction for HCC prognosis after surgical treatment.

Association between epidermal growth factor 61A/G polymorphism and hepatocellular carcinoma susceptibility in Chinese patients

Chronic hepatitis B virus (HBV) infection is an important risk factor for hepatocellular carcinoma (HCC) development in China, while little is known of the genetic susceptibility to hepatocarcinogenesis. The epidermal growth factor (EGF) pathway plays an important role in tumorigenesis, including HCC. EGF polymorphisms are associated with susceptibility to several types of cancers. Therefore, this study aimed to assess whether EGF genetic polymorphisms can influence HCC development. A total of 338 chronic HBV-infected patients (186 HCC patients and 152 cirrhotic patients) and 186 healthy individuals were enrolled in this study. EGF 61A/G polymorphisms of all subjects and 12 cell lines were assayed with polymerase chain reaction-restriction fragment length polymorphism and the sequencing method. Furthermore, EGF protein levels were measured in the serum and the results were compared with the different genotypes. EGF expression in the liver tissue of the HCC patients was detected by immunohistochemical analysis. EGF 61A and 61G allele frequencies in healthy subjects were 28.76 and 71.24%. EGF 61GG and G allele frequencies in the HCC group were higher than those in the cirrhosis group. EGF protein levels with the GG genotype were significantly higher than those with either the GA or the AA genotype. About 59.09% of HCC liver tumour tissues assayed showed EGF protein expression. The EGF 61 GG genotype might be associated with a high risk for the development of chronic HBV infection-related HCC in Chinese patients.

No association of EGF 5'UTR variant A61G and hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection

Epidermal growth factor (EGF) has many biological functions, including mitogenesis, tumorigenesis, and proliferation of epidermal tissues. Previous studies have reported that the EGF +61 (A/G) single nucleotide polymorphism in the 5'-untranslated region of the EGF gene is functional, and is associated with development of hepatocellular carcinoma (HCC) in liver cirrhosis and various malignancy. Our aim was to investigate whether EGF gene A61G polymorphism could be implicated in susceptibility to and/or clinicopathological characteristics of HCC in Chinese patients with chronic hepatitis B virus (HBV) infection. This polymorphism was studied in 387 patients with chronic HBV infection and in 208 healthy volunteers using restriction fragment-length polymorphism. The patients were divided into two groups: those without (n = 172) and those with HCC (n = 215). These 215 HCC patients with chronic HBV infection were designated as cases, and the remaining 172 patients without HCC served as controls. There were no significant differences in EGF genotype or allelic frequencies between cases and controls nor was EGF genotype or allelic frequencies associated with tumour number, size, growth phase, stage, and invasiveness. We also found ethnic heterogeneity in the functional EGF polymorphism. The present results show that although EGF gene A61G polymorphism is associated with development of HCC in liver cirrhosis, it is not sufficient for HCC in Chinese patients with chronic HBV infection.

Indicators of prognosis after liver transplantation in Chinese hepatocellular carcinoma patients

To identify prognostic factors of patients with hepatocellular carcinoma (HCC), who were treated by orthotopic liver transplantation (OLT). From January 2000 to October 2006, 165 patients with HCC underwent OLT. Various clinicopathological risk factors for actuarial and recurrence-free survival were identified using the Kaplan-Meier method with the log-rank test. The Cox proportional hazards model was used to identify independently predictive factors for actuarial and recurrence-free survival, which were used to propose new selection criteria. We compared the outcome of the subgroup patients meeting different criteria. Survival analysis was performed using the Kaplan-Meier method with the log-rank test. The median follow-up was 13.0 mo (2.8-69.5 mo). Overall, 1-, 2-, 3- and 5-year actuarial survival was 73.3%, 45.6%, 35.4% and 32.1%, respectively. One-, 2-, 3- and 5-year overall recurrence-free survival was 67.0%, 44.3%, 34.5% and 34.5%, respectively. In univariate analysis, number of tumors, total tumor size, lobar distribution, differentiation, macrovascular invasion, microvascular invasion, capsulation of the tumor, and lymph node metastasis were found to be associated significantly with actuarial and tumor-free survival. By means of using the multivariate Cox proportional hazards model, total tumor size and macrovascular invasion were found to be independent predictors of actuarial and tumor-free survival. When the selection criteria were expanded into the proposed criteria, there was no significant difference in 1-, 2-, 3- and 5-year actuarial and tumor-free survival of the 49 patients who met the proposed criteria (97.6%, 82.8%, 82.8% and 82.8%, and 90.7%, 82.8%, 68.8% and 68.8%, respectively) compared with that of patients who met the Milan or University of California, San Francisco (UCSF) criteria. Macrovascular invasion and total tumor diameter are the strongest prognostic factors. The proposed criteria do not adversely affect the outcome of liver transplantation for HCC, compared with the Milan or UCSF criteria.

Comparison of four current staging systems for Chinese patients with hepatocellular carcinoma undergoing curative resection: Okuda, CLIP, TNM and CUPI

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, there is no general consensus as to which staging system is the most reliable for predicting the survival of patients with HCC. The aims of this study were to compare commonly-used staging systems in a cohort of Chinese HCC patients undergoing curative resection. From January 1991 to June 2002, 234 Chinese patients undergoing curative resection for HCC from one medical center were evaluated. All patients were classified by the Okuda, Cancer of the Liver Italian Program (CLIP), tumor node metastasis (TNM) (6th edition) and the Chinese University Prognostic Index (CUPI) staging systems. Survival curves were calculated using the Kaplan-Meier method and were examined using log-rank testing. The overall predictive power for patient survival with each staging system was evaluated by the area under the receiver operating characteristic (ROC) curve. The overall median survival of the entire cohort was 24.9 months (95% confidence interval (CI) 18.15-31.65 months) and the estimated survival rates at 1, 3, and 5 years were 69.66% 3.01%, 41.02% 3.31%, and 29.08% 3.55%, respectively. In our patient cohort, the log-rank test demonstrated that the TNM and Okuda staging systems gave better results than the other staging systems in the prognosis stratification. The prognostic predictive powers of the TNM staging for survival, evaluated by ROC curve areas, was also superior. For HCC patients undergoing curative resection, the TNM staging system (6th edition) proved the best for prognostic stratification and prognosis prediction.