CHB-related Hepatocellular Carcinoma Research Articles

Impact of metabolic dysfunction-associated steatotic liver disease on the efficacy of immunotherapy in patients with chronic hepatitis B-related hepatocellular carcinoma.

To investigate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). A total of 155 patients with CHB-related HCC who received ICI-based therapy (in the Department of Hepatology, Tianjin Second People's Hospital and Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute & Hospital) between April 2021 and December 2023 were evaluated. Patients were divided into two groups: MASLD concurrent with CHB [MASLD-CHB] (n = 38), and CHB (n = 117). The median progression-free survival (PFS, 6.9 months vs. 9.3 months; P = 0.001), progressive disease (57.89% vs. 37.61%; P = 0.028), and disease control rate (42.11% vs. 62.39%; P = 0. 028) in the MASLD-CHB group were significantly worse than the CHB group. The median overall survival was not attained. The percentage of CD4+PD1+ (17. 56% vs. 8.89%; P < 0.001) and CD8+PD1+ T cells (10.50% vs. 7.42%; P = 0.005) in patient samples from the MASLD-CHB group were significantly higher than the CHB group. Concurrent MASLD [hazard ratio (HR) = 1.921; 95% CI, 1.138-3.245; P = 0.015] and alpha-fetoprotein levels after 3 months of treatment (HR = 2.412; 95% CI, 1.360-4.279; P = 0.003) were independent risk factors for PFS in all patients. ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

A217 TREATMENT ADHERENCE OF CHRONIC HEPATITIS B PATIENTS WITH HEPATOCELLULAR CARCINOMA FROM THE CANHEPB NETWORK

BackgroundChronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide.AimsThe primary aim of this study is to explore the degree of treatment adherence to the American Association For The Study of Liver Disease (AASLD) HCC treatment guidelines for patients with CHB-HCC.MethodsThis is a retrospective, cross-sectional study of available data (2005–2020) in patients mono-infected with CHB collected from the Canadian HBV Network; a national consortium across 8 Canadian provinces. We analyzed data using descriptive statistics along with parametric and nonparametric statistical methods with a significance level of p < 0.05.ResultsOf the 6500 patients, 132 (2.0%) patients met inclusion criteria. The median age was 64 (IQR: 53.5- 71.5) with 101 (76%) being male. The median ALT was 40 (IQR: 26–59.5) and the median tumor number was 1(IQR: 1- 2) with a median tumor size of 2.6 cm (IQR: 1.9- 4.5). 98 (74.5%) patients were HBeAg negative with a median viral load of 3.8 logs (IQR 1.9 – 5.8). 58 (43%) patients had cirrhosis at diagnosis. 36% of patients were diagnosed with HCC on their first screening imaging whereas 39% were found to have HCC on repeated surveillance imaging. 116 (87.9%) were on treatment at the time of diagnosis or after (70 (60.3%) NA and 46 (39%) Combination therapy with double NA or NA plus interferon). Out of the 132 patients, BCLC stage 0, A, B, and C represented 30 (23%), 42 (32%), 17 (13%), and 5 (4%) patients, respectively, with 38 (28%) patients with unknown BCLC stage. The overall adherence to AASLD guidelines was 61%. The HCC treatment adherence rate for patients with BCLC stage 0, A, B were 63%, 97.5%, and 23.5%, respectively. BCLC stages C and D did not have a sufficient sample size for analysis. The adherence rate ranged from 53% (Eastern Canada) to 71% (Western Canada) across Canada.ConclusionsIn this retrospective nationwide cohort study of patients with CHB-related HCC, the overall treatment adherence rate to AASLD guidelines was low with notable regional differences. Further analysis will determine the cause of regional differences.Funding AgenciesNone

Reporting and Performance of Hepatocellular Carcinoma Risk Prediction Models: Based on TRIPOD Statement and Meta-Analysis

Background The performance of risk prediction models for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) was uncertain. The aim of the study was to critically evaluate the reports of transparent and external validation performances of these prediction models based on system review and meta-analysis. Methods A systematic search of the Web of Science and PubMed was performed for studies published until October 17, 2020. The transparent reporting of a multivariable prediction model for the individual prognosis or diagnosis (TRIPOD) tool was used to critically evaluate the quality of external validation reports for six models (CU-HCC, GAG-HCC, PAGE-B, mPAGE-B, REACH-B, and mREACH-B). The area under the receiver operator characteristic curve (AUC) values was to estimate the pooled external validating performance based on meta-analysis. Subgroup analysis and metaregression were also performed to explore heterogeneity. Results Our meta-analysis included 22 studies published between 2011 and 2020. The compliance of the included studies to TRIPOD ranged from 59% to 90% (median, 74%; interquartile range (IQR), 70%, 79%). The AUC values of the six models ranged from 0.715 to 0.778. In the antiviral therapy subgroups, the AUC values of mREACH-B, GAG-HCC, and mPAGE-B were 0.785, 0.760, and 0.778, respectively. In the cirrhosis subgroup, all models had poor discrimination performance (AUC < 0.7). Conclusions A full report of calibration and handling of missing values would contribute to a greater improvement in the quality of external validation reports for CHB-related HCC risk prediction. It was necessary to develop a specific HCC risk prediction model for patients with cirrhosis.

Impact of MAFLD on HBV-Related Stage 0/A Hepatocellular Carcinoma after Curative Resection.

Backgrounds and Aim: Metabolic-associated fatty liver dis-ease (MAFLD) is a novel term proposed in 2020 to avoid the exclusion of certain subpopulations, though the application of this term in the real world is very limited. Here, we aimed to evaluate the impact of MAFLD on hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. Methods: Patients with chronic hepatitis B (CHB)-related HCC who received hepatectomy between January 2010 and December 2019 were consecutively selected. The association between histologically proven concurrent MAFLD and clinical outcomes were retrospectively analyzed. Results: Among the 812 eligible patients with CHB-related HCC, 369 (45.4%) were diagnosed with concurrent MAFLD. After a mean follow-up of 65 months, 303 patients (37.3%) developed HCC recurrence, 111 (13.7%) died, and 12 (1.5%) received liver transplantation. Although no differences in the incidences of HCC recurrence (HR: 0.902, 95% CI: 0.719–1.131, p = 0.370) and death or liver transplantation (HR: 0.743, 95% CI: 0.518–1.006, p = 0.107) were observed between patients with and without MAFLD in multivariate analysis, the patients with MAFLD tended to achieve better recurrent-free survival compared to patients without MAFLD. Notably, lean MAFLD (BMI < 23 kg/m2) was a relative risk factor for tumor recurrence (HR: 2.030, 95% CI: 1.117–3.690, p = 0.020) among patients with MAFLD. Conclusions: The overall prognosis in HBV-related early-stage HCC, in terms of HCC recurrence and death or liver transplantation, was not significantly different between patients with and without MAFLD. Among patients with MALFD, lean-MAFLD was a risk factor for HCC recurrence. Further studies are warranted to validate these results.

Impact of tenofovir antiviral treatment on survival of chronic hepatitis B related hepatocellular carcinoma after hepatectomy in Chinese individuals from Qingdao municipality

The impact of different antiviral regimen on prognosis of chronic hepatitis B (CHB) related hepatocellular carcinoma (HCC) remains to be explored.A total of 479 CHB-related HCC patients after curative liver resection were enrolled receiving tenofovir (TDF, TDF group) or lamivudine, telbivudine, and entecavir (non-TDF group). Both the overall survival and diseases-free survival were analyzed and compared.A total of 242 patients received TDF treatment and 237 patients received other antiviral regimen. Child-Pugh score, serum α-fetoprotein (AFP) level, total bilirubin level, status of hepatitis B e antigen (HBeAg), and cirrhosis were compared between groups. Kaplan-Meier analysis revealed that patients with TDF treatment had significantly longer overall survival than those of patients with other regimen (P = .015). Similarly, compared with patients with non-TDF treatment, disease-free survival time was longer (P = .042) in those with TDF treatment. Multivariate analysis showed that TDF treatment (P = .04), AFP level (P = .03) were significant independent factors associated with overall survival of CHB-related HCC patients. While TDF treatment (P = .04) and serum AFP level (P = .03) were independent factors associated with disease-free survival.Anti-virus treatment with TDF benefits for both overall survival and disease-free survival of CHB-related patients than other Nucleos(t)ide analogues.

Prognostic impact of concurrent nonalcoholic fatty liver disease in patients with chronic hepatitis B-related hepatocellular carcinoma.

As the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, patients with both NAFLD and chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is also frequently found. This study aimed to investigate the clinical impact of concurrent NAFLD on the prognosis of patients with CHB-related HCC. Patients with CHB-related HCC who underwent surgical resection were consecutively selected from August 2009 to December 2013. The association between histologically proven concurrent NAFLD and clinical outcomes were analyzed. Propensity score (PS) matching was adapted to adjust for baseline characteristics. We also investigated the presence of nonalcoholic steatohepatitis (NASH) among patients with NAFLD and its association with clinical outcomes. Among 338 CHB-related HCC patients selected, 196 patients (58.0%) were diagnosed with concurrent NAFLD. The median follow-up duration was 74.9months. The patients with NAFLD tended to have better recurrence-free survival (RFS; log-rank, P=0.16) and had significantly better overall survival (OS; log-rank, P=0.004) than those without NAFLD. However, the survival benefit of the concurrent NAFLD was not significant in a multivariable Cox analysis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73, P=0.84) or an analysis after PS matching (log-rank, P=0.57). Regarding the presence or absence of NASH, no differences in the RFS (log-rank, P=0.61) and OS (log-rank, P=0.26) were found. Concurrent NAFLD was not associated with both RFS and OS in patients with CHB-related HCC after adjusting for baseline characteristics. Moreover, NAFLD patients with NASH did not have significantly different clinical outcomes compared with NAFLD patients without NASH.

Predictive validation of qualitative fibrosis staging in patients with chronic hepatitis B on antiviral therapy

The fibrosis in chronic hepatitis shows dynamic changes during antiviral therapy (AVT). We investigated whether P-I-R (progressive vs. indeterminate vs. regressive) staging is predictive of hepatocellular carcinoma (HCC) recurrence in patients with chronic hepatitis B (CHB) taking AVT who underwent resection. Patients with CHB-related HCC who underwent curative resection between 2004 and 2017 and had received ≥2 years AVT at the time of resection were eligible. Two pathologists performed P-I-R staging. In total, 104 patients with CHB-related HCC were enrolled. The mean age of the study population was 56.3 years. The mean duration of AVT at the time of resection was 62.6 months. During the follow-up period (mean, 45.5 months), 20 (19.2%) and 14 (13.5%) patients developed early and late recurrence of HCC, respectively. The cumulative incidence of late recurrence was significantly lower in patients with regressive patterns than in those with indeterminate and progressive patterns according to P-I-R staging (P = 0.015, log-rank test), although the cumulative incidence of overall recurrence according to P-I-R staging was similar. Hepatitis B virus DNA levels (hazard ratio [HR] = 3.200, P = 0.020) and the regressive P-I-R staging pattern (HR = 0.127, P = 0.047) independently predicted the risk of late recurrence. One-time assessment of the P-I-R staging at the time of curative resection in patients with CHB-related HCC receiving AVT independently predicted late HCC recurrence. Therefore, qualitative fibrosis assessment by P-I-R staging might be useful in predicting the outcomes of patients with CHB undergoing AVT.

Diagnostic value of angiopoietin-like protein 2 for CHB-related hepatocellular carcinoma.

PurposeAngiopoietin-like protein 2 (ANGPTL2) is a secretory glycoprotein with various functions in vascular biology, inflammation and tumor development. As shown in our previous studies, ANGPTL2 expression positively correlates with liver fibrosis stages in chronic hepatitis B (CHB) patients. The aim of this study was further to assess whether ANGPTL2 represents a potential biomarker for detecting hepatocellular carcinoma (HCC).Patients and methodsThis study enrolled 361 participants including healthy controls (HCs) and patients with CHB, liver cirrhosis (LC) and HCC. A discovery cohort consisted of 35 HCs and 55 patients with HCC. A total of 271 participants, including 45 HCs, 125 patients with CHB, 38 patients with LC, and 63 patients with HCC were enrolled in a validation cohort. Serum ANGPTL2 levels were detected using a human ANGPTL2 assay kit, and hepatic expression of ANGPTL2 was analyzed using immunohistochemistry.ResultsIn the discovery cohort, a significantly higher serum ANGPTL2 level was detected in HCC than in HCs (73.49±33.87 vs 30.54±9.86; p<0.001). The results of the receiver operating characteristic curve indicated a significantly higher area under the curve for the ability of the ANGPTL2 to predict HCC than alpha fetoprotein (AFP). In the validation cohort, serum ANGPTL2 level gradually increased with the progression of chronic hepatitis B virus infection and reached the highest level in HCC. Immunohistochemical staining also confirmed these findings. The serum ANGPTL2 displayed better diagnostic efficiency not only for differentiating HCC from HC but also for differentiating HCC from high-risk controls (CHB+LC). Furthermore, the combination of ANGPTL2 and AFP may increase the diagnostic accuracy for HCC compared to ANGPTL2 or AFP alone. Importantly, ANGPTL2 levels also correlated with the detection of AFP-negative HCC.ConclusionsANGPTL2 may be used as a promising biomarker for the diagnosis of CHB-related HCC.

Risk assessment of hepatocellular carcinoma development for indeterminate hepatic nodules in patients with chronic hepatitis B.

Background/AimsA risk prediction model for the development of hepatocellular carcinoma (HCC) from indeterminate nodules detected on computed tomography (CT) (RadCT score) in patients with chronic hepatitis B (CHB)-related cirrhosis was proposed. We validated this model for indeterminate nodules on magnetic resonance imaging (MRI).MethodsBetween 2013 and 2016, Liver Imaging Reporting and Data System (LI-RADS) 2/3 nodules on MRI were detected in 99 patients with CHB. The RadCT score was calculated.ResultsThe median age of the 72 male and 27 female subjects was 58 years. HCC history and liver cirrhosis were found in 47 (47.5%) and 44 (44.4%) patients, respectively. The median RadCT score was 112. The patients with HCC (n=41, 41.4%) showed significantly higher RadCT scores than those without (median, 119 vs. 107; P=0.013); the Chinese university-HCC and risk estimation for HCC in CHB (REACH-B) scores were similar (both P>0.05). Arterial enhancement, T2 hyperintensity, and diffusion restriction on MRI were not significantly different in the univariate analysis (all P>0.05); only the RadCT score significantly predicted HCC (hazard ratio [HR]=1.018; P=0.007). Multivariate analysis showed HCC history was the only independent HCC predictor (HR=2.374; P=0.012). When the subjects were stratified into three risk groups based on the RadCT score (<60, 60–105, and >105), the cumulative HCC incidence was not significantly different among them (all P>0.05, log-rank test).ConclusionsHCC history, but not RadCT score, predicted CHB-related HCC development from LI-RADS 2/3 nodules. New risk models optimized for MRI-defined indeterminate nodules are required.

Precancer antiviral treatment reduces microvascular invasion of early-stage Hepatitis B-related hepatocellular carcinoma

The impact of antiviral therapy before tumorigenesis on microvascular invasion (MVI) of Chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is still unknown. In this retrospective cohort study 3,276 HCC patients with early-stage who underwent curative resection were included. We investigated the effect of precancer antiviral therapy on the pathology, especially MVI, of CHB-related HCC. MVI occurrence rates of CHB-related HCC stratified by histopathologic inflammation grades of G1, G2, and G3 were 30.4%, 34.7%, and 38.6%, respectively, compared to 19.8% for CHB-negative HCC. Patients who received standard antiviral treatment showed much lower rates of MVI, higher tumor capsule integrity, less frequent satellite micronodules and lower AFP level compared to the no antiviral group. Moreover, precancer antiviral therapy prolonged the disease-free survival (DFS), which are also proved to be independent indicators of DFS. In addition, we show that antivirals may suppress early progression of HCC primarily by inhibition of HBV viral load, and influencing the expression levels of CK18, GPC3, OPN and pERK. Hence, we demonstrate that precancer antivirals significantly reduce the MVI rate of CHB-related HCC, reduce malignancy of early-stage HCC, and improve HCC prognosis. Thus, this study confirms the importance of antiviral therapy for CHB patients.

The different effects of adefovir dipivoxil and telbivudine on the prognosis of hepatitis b virus-related hepatocellular carcinoma patients after curative resection.

Numerous studies suggested that antiviral therapy could reduce the recurrence in hepatocellular carcinoma (HCC) patients after hepatectomy. The impact of nucleotide and nucleoside analogues on prognosis of chronic hepatitis B (CHB) related HCC remains to be explored. We aimed to investigate the role of the telbivudine and adefovir dipivoxil on the prognosis of CHB-related HCC patients after hepatectomy.One hundred eighty-eight CHB-related patients who received hepatectomy from February 2010 to February 2017 were divided into telbivudine (LdT) and adefovir dipivoxil (ADV) groups. The characteristics and survival information of both groups were retrospectively compared and analyzed.One hundred eleven and 77 patients received telbivudine and adefovir dipivoxil monotherapy, respectively. Alanine aminotransferase (ALT), total bilirubin level, status of hepatitis B e antigen (HBeAg), serum HBV-DNA level were compared between groups. OS and DFS in ADV-treatment group were significantly better than it in LdT-treatment group (P < .05). In the subgroups analysis, we found that ADV treatment was significantly associated with better DFS and OS among patients with cirrhosis, HBeAg-negative patients, or those with detectable HBV-DNA.CHB-related HCC patients receiving long-term ADV-treatment had a better OS and DFS than patients receiving LdT-treatment after hepatectomy.

Tenofovir disoproxil fumarate reduce incidence of HCC development in CHB-patients with compensated cirrhosis

BackgroundThe impact of different anti-virus regimens on prognosis of Chronic hepatitis B (CHB) related cirrhosis remains to be explored. We aim to investigate whether CHB-related HCC patients receiving nucleoside analogue regimen or not have a different prognosis.MethodsTwo hundred forty-two CHB-related compensated cirrhosis patients were attributed into groups regarding their anti-virus regimens containing tenofovir disoproxil fumarate (TDF) or not. The results of two groups were reviewed and investigated. The probability of hepatocellular carcinoma (HCC) development among each group were analyzed and compared.ResultsTwo hundred forty-two CHB-related compensated cirrhosis patients from 2008 June to 2011 December were included in our study. One hundred twenty-seven patients received anti-virus regimen containing TDF and 115 patients received anti-virus regimen without TDF. Child-Pugh score, alanine aminotransferase (ALT), total bilirubin level, status of hepatitis B e antigen (HBeAg) and serum HBV DNA level were compared between groups. The cumulative probability of HCC development in TDF-contained group were significantly lower than it in non-TDF-contained group (p < 0.05). Multi-variant analysis indicated that TDF-containing regimen treatment was significantly associated with lower probability of HCC development, (hazard ratio, 0.18; 95% confidence interval range, 0.07–0.45, p < 0.05).ConclusionAnti-virus regimen containing TDF benefits for the prognosis of CHB-related liver cirrhosis patients.

Tenofovir decrease hepatocellular carcinoma recurrence in chronic hepatitis B patients after liver resection

BackgroundTenofovir disoproxil fumarate (TDF) and entecavir (ETV) are recommended as the first-line choices regarding the treatment of chronic hepatits B. The impact of the two antiviral agents on prognosis of Chronic hepatitis B (CHB) related hepatocellular carcinoma (HCC) remains to be explored. We aim to investigate whether CHB-related HCC patients receiving TDF and ETV have a different prognosis.Methods233 CHB-related compensated cirrhosis patients were divided into groups according to the nucleut(s)ide patients received. The results of TDF and ETV groups were reviewed and compared. The disease-free survival (DFS) and overall survival (OS) of both groups were analyzed and compared.Results233 CHB-related compensated cirrhosis patients from 2013 October to 2014 November were included in our study. 107 and 126 patients received TDF and ETV monotherapy, respectively. Child-Pugh score, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin level, status of hepatitis B e antigen (HBeAg) and serum HBV DNA level were compared between groups. DFS in TDF-treatment group were significantly longer than it in ETV-treatment group (p < 0.05). multi-variant analysis indicated that TDF duration was significantly associated with lower probability of HCC development, (hazard ratio, 0.35; 95% confidence interval range, 0.33–0.84, p < 0.05).ConclusionAnti-virus regimen containing TDF benefits for the prognosis of CHB-related liver cirrhosis patients.

Comparison of anti-HBV regimen with or without adefovir on hepatocellular carcinoma development of Chronic hepatitis B patients with compensated cirrhosis: a retrospective cohort study

BackgroundThe impact of different anti-virus regimens on prognosis of Chronic hepatitis B (CHB) related cirrhosis remains to be explored. We aim to investigate whether CHB-related HCC patients receiving nucleoside analogue regimen or not have a different prognosis.Methods242 CHB-related compensated cirrhosis patients from 2008 June to 2011 December were included in our study and attributed into groups based on their anti-virus regimens containing adefovir (ADV) or not. The clinical parameters and virological response between ADV-containing regimen group and non-ADV containing regimen groups were reviewed and compared. The risk of hepatocellular carcinoma (HCC) development were analyzed and compared between two groups.Results127 patients received anti-virus regimen containing ADV and 115 patients received anti-virus regimen without ADV. The cumulative risk of HCC development among patients treated with ADV-contained therapy was significantly lower than that observed in patients with non-ADV-contained therapy (p<0.05). Multivariate analysis indicated that ADV-containing regimen treatment was significantly associated with lower probability of HCC development, (hazard ratio, 0.18; 95% confidence interval range, 0.07-0.45, p<0.05).ConclusionBoth anti-virus regimens were effective in reducing serum HBV DNA. Regimen containing ADV decreased the incidence of HCC development in CHB patients with compensated cirrhosis.

Evaluation of STAT3 rs1053004 single nucleotide polymorphism in patients with chronic hepatitis B and hepatocellular carcinoma

Chronic infection with hepatitis B (CHB) virus is one of the most important risk factors for Hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) causes liver cancer in various ways. One of these ways is increasing the expression of the signal transducer and activator of transcription 3 (STAT3) in Hepatocytes by HBV. The purpose of this research is to evaluate the single nucleotide polymorphism (SNP) rs1053004 in the STAT3 gene in CHB patients and individuals who suffer from HCC. In this research, 33 patients CHB-related HCC, 50 patients infected with chronic hepatitis B infection (CHB) without HCC and 50 healthy individuals were investigated for the presence of rs1053004 in the STAT3 gene according to the PCR-based differentiation of alleles test. Data analysis presented a different and significant distribution of alleles and genotypes (p&lt;0.05). When the HCC and CHB groups were compared from the point of the frequency of alleles, the frequency of the C allele and CC genotype in the HCC group were higher CHB and control groups. Analysis of our data in the genotype model (CC vs. TT + TC) showed, this meaningful relationship remained between the HCC group and the three groups of CHB, healthy and all controls. These results illustrate that perhaps rs1053004 polymorphisms in the STAT3 gene participated in the progression of hepatitis B to HCC in Iranian people.

Evaluation of STAT3 rs1053004 single nucleotide polymorphism in patients with chronic hepatitis B and hepatocellular carcinoma.

Chronic infection with hepatitis B (CHB) virus is one of the most important risk factors for Hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) causes liver cancer in various ways. One of these ways is increasing the expression of the signal transducer and activator of transcription 3 (STAT3) in Hepatocytes by HBV. The purpose of this research is to evaluate the single nucleotide polymorphism (SNP) rs1053004 in the STAT3 gene in CHB patients and individuals who suffer from HCC. In this research, 33 patients CHB-related HCC, 50 patients infected with chronic hepatitis B infection (CHB) without HCC and 50 healthy individuals were investigated for the presence of rs1053004 in the STAT3 gene according to the PCR-based differentiation of alleles test. Data analysis presented a different and significant distribution of alleles and genotypes (p&lt;0.05). When the HCC and CHB groups were compared from the point of the frequency of alleles, the frequency of the C allele and CC genotype in the HCC group were higher CHB and control groups. Analysis of our data in the genotype model (CC vs. TT + TC) showed, this meaningful relationship remained between the HCC group and the three groups of CHB, healthy and all controls. These results illustrate that perhaps rs1053004 polymorphisms in the STAT3 gene participated in the progression of hepatitis B to HCC in Iranian people.

Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection

Cirrhosis related to chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). The extent to which HCC occurs in U.S. in the absence of cirrhosis in CHB remains unclear. We identified CHB patients who were diagnosed with HCC in the national Veterans Administration (VA) between 2001 and 2013. We defined presence and absence of cirrhosis at the time of HCC diagnosis using explicit histological, radiological, endoscopic, and laboratory criteria. We used multivariable regression analysis to identify demographic and clinical characteristics associated with CHB-related HCC in the absence of cirrhosis. We also examined liver transplant-free survival in CHB-HCC patients with and without cirrhosis. Among 8539 CHB patients, 317 developed HCC of whom 30 (9.5%) did not have any evidence of cirrhosis at the time of HCC diagnosis. Compared to HCC patients with cirrhosis, HCC patients without cirrhosis were more likely to be non-white (African American, OR=6.78; 95% CI 2.05-22.4; Asian, OR 11.6, 95% CI 2.63-50.8), have a family history of HCC (OR 32.9, 95% CI 3.76-288), and hypertension (OR 3.15, 95% CI 1.02-9.75). There was no significant difference in the transplant-free survival between CHB-HCC patients with and without cirrhosis (hazard ratio 0.68, 95% CI 0.43-1.09). Fewer than 10% of U.S. based CHB-related HCC patients did not have cirrhosis. Race and family history of HCC were the main risk factors for HCC in the absence of cirrhosis in CHB. These factors may help guide the decision to initiate HCC surveillance in CHB patients without cirrhosis. Patients with chronic hepatitis B who are African American, or Asian, older than 40years of age with family members with liver cancer or high blood pressure are at a higher risk of developing liver cancer in the absence of cirrhosis. These patients should be included in the screening program for liver cancer.

Randomized clinical trial: Nucleos(t)ide analogues improved survival of CHB-related HCC patients via reducing severity and progression of malignancy.

BackgroundThe influence of nucleos(t)ide analogues (NAs) to treat Chronic hepatitis B (CHB) related hepatocellular carcinoma (HCC) remains to be explored.AimTo investigate if NAs reduce the severity and progression of CHB-related HCC.ResultsAmong 532 patients, there were 118 or 414 CHB-related HCC with or without NAs therapy, respectively. BCLC scores, serum level of ALT/AST and HBV DNA were compared. During follow-up, the survival period of CHB-related HCC patients with sustained NAs is significantly longer than that with NAs post-HCC and NAs naïve (p < 0.05). Factors significantly associated with the poor overall survival of CHB-related HCC include BCLC scores (hazard ratio, 1.84 [95% confidence interval, 1.57−2.15], p < 0.001), NAs post-HCC or NAs naïve (1.33 [1.07−1.65], p < 0.01), serum AST ≥ 40 IU/L (1.48 [1.03−2.12], p < 0.05) and HBV DNA ≥ 104 copies/ml (1.36 [1.01−1.83], p < 0.001).MethodsOutcomes of 532 CHB-related HCC patients with/without NAs were investigated. Overall survival of CHB-related HCC patients, NAs naïve (n = 156), NAs received post-HCC (n = 258) and NAs sustained (n = 118) were determined.ConclusionsNAs reduced severity of CHB-related HCC patients. Sustained NAs is an important factor associated with the extended survival of CHB-related HCC patients.

Single Nucleotide Polymorphisms in STAT3 and STAT4 and Risk of Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B.

Hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) development. Recent studies demonstrated that single nucleotide polymorphisms (SNPs) rs2293152 in signal transducer and activator of transcription 3 (STAT3) and rs7574865 in signal transducer and activator of transcription 4 (STAT4) are associated with chronic hepatitis B (CHB)-related HCC in the Chinese population. We hypothesized that these polymorphisms might be related to HCC susceptibility in Thai population as well. Study subjects were divided into 3 groups consisting of CHB-related HCC (n=192), CHB without HCC (n=200) and healthy controls (n=190). The studied SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the distribution of different genotypes for both polymorphisms were in Hardy-Weinberg equilibrium (P>0.05). Our data demonstrated positive association of rs7574865 with HCC risk when compared to healthy controls under an additive model (GG versus TT: odds ratio (OR) =2.07, 95% confidence interval (CI)=1.06-4.03, P=0.033). This correlation remained significant under allelic and recessive models (OR=1.46, 95% CI=1.09-1.96, P=0.012 and OR=1.71, 95% CI=1.13-2.59, P=0.011, respectively). However, no significant association between rs2293152 and HCC development was observed. These data suggest that SNP rs7574865 in STAT4 might contribute to progression to HCC in the Thai population.

SFRP-4, a potential novel serum marker for chronic hepatitis B-related hepatocellular carcinoma

The current methods used for diagnosing hepatocellular carcinoma (HCC) are unsatisfactory. Here, we assessed the serum levels of secreted frizzled related protein 4 (sFRP-4) for diagnosing HCC in patients infected with chronic hepatitis B (CHB). In 272 patients with CHB enrolled, 142 were patients with HCC. Thirty-three healthy subjects were recruited as healthy controls. The CHB patients were assigned to a test group or a validation group based on the time of enrollment. Human antibody arrays were used to screen 15 patients (8 CHB-related HCC patients, 7 CHB patients) for serum markers. Four markers and one candidate marker were assessed in the test group and validation group, respectively. Human antibody assays indicated that the serum levels of sFRP-4 in HCC patients were significantly higher than those in CHB patients (P<0.05). Additionally, serum sFRP-4 levels were significantly higher in the HCC patients than those in the non-HCC patients in both test group (79.7 vs 41.3 ng/mL; P<0.001) and validation group (89.0 vs 39.0 ng/mL; P<0.001). Areas under the Receiver Operating Characteristic curves (AUCs) for alpha-fetoprotein (AFP) and sFRP-4 were similar in both test group and validation group. In the test group, the combination of sFRP-4 (a sensitivity of 94.4%, a specificity of 60.5% at 46.4 ng/mL) and AFP (a sensitivity of 75.0%, a specificity of 87.2% at 11.3 ng/mL) showed better performance for diagnosing HCC (a sensitivity of 79.2% and a specificity of 95.3%). The AUC for combined sFRP-4 and AFP increased to 0.941 (95% CI: 0.908-0.975), and similar results were seen in the validation group. sFRP-4 is a candidate serum marker for diagnosing HCC in CHB patients, and the combination of sFRP-4 with AFP may improve the diagnostic accuracy of HCC.