Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the most common histological form of primary liver cancer; the tumor cells having retained features of hepatocytic differentiation. It is important to emphasize the heterogeneity of the histological background on which the tumor develops. Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other; being much higher in the southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated in the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. A large number of epidemiological and molecular studies have indeed clearly demonstrated the prime importance of environmental factors to the development of primary liver cancers in humans. Chronic hepatitis B (HBV) and C (HCV) infections are major risk factors. This review will mainly analyse the impact of chronic HBV infection but it is important to emphasize the potential synergistic effects between HBV and HCV, as well as between viral infections and other environmental factors, such as alcohol, chemical carcinogens (see review by Dr Wogan) and other, still poorly defined, hormonal factors which may account for the higher incidence of the tumor in man. Finally the review by Dr Buendia highlights the emerging issue of liver-cancer genetics.     

Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients

BACKGROUND: Occult hepatitis B virus (HBV) infection frequently occurs in patients with HBV surface antigen (HBsAg)-negative chronic liver disease, and much evidence suggests that it is a risk factor for hepatocellular carcinoma (HCC) development. However, to the authors' knowledge, no follow-up study has been performed to date evaluating HCC occurrence over time in chronic hepatitis patients with or without occult HBV infection. METHODS: A cohort of the 380 HBsAg-negative chronic hepatitis patients attending the study institution between 1991-2000 were evaluated and tested for occult HBV DNA by analysis of liver biopsy specimens. RESULTS: There were 135 patients (35.5%) with occult HBV and 245 patients (64.5%) without occult HBV. Cirrhosis was significantly associated with occult HBV infection (P = 0.01). One hundred thirty-four of these patients were followed for a minimum of 50 months (median, 82.8 +/- 32.6 mos). Fifty-three patients (39%) were occult HBV carriers and 81 (61%) were not. Nine patients developed HCC during the follow-up; eight were positive and one was negative for occult HBV (P = 0.002). CONCLUSIONS: The current observational cohort study showed that, among the HBsAg-negative patients with chronic hepatitis, HCC develops for the most part in carriers of occult HBV. Therefore, the evaluation of HBV genomes in chronic hepatitis patients appears to be a powerful tool for the identification of individuals at higher risk of HCC development.     

Type 2 diabetes and hepatocellular carcinoma: a case-control study in patients with chronic hepatitis B

Type 2 diabetes has been suggested as an independent risk factor for the development of hepatocellular carcinoma (HCC). However, the role of Type 2 diabetes on the development of HCC in the presence of chronic hepatitis B (CHB) remains inconclusive. We conducted this hospital-based case-control study to evaluate the roles of Type 2 diabetes in HCC development in patients with CHB. From January 2004 to December 2008, a total of 6,275 eligible consecutive patients with chronic hepatitis B virus (HBV) infection were recruited. A total of 1,105 of them were patients with HBV-related HCC and 5,170 patients were CHB but without HCC. We used multivariate logistic regression models to investigate the association between Type 2 diabetes and HCC risk. The prevalence of Type 2 diabetes is higher among HCC patients without cirrhosis than among those with cirrhosis (12.1% vs. 6.7%, p=0.003). Type 2 diabetes was associated with a significantly high risk of HCC in female patients after adjusting for age, family history of HCC, city of residence, hepatitis B e antigen and cirrhosis with an odds ratio (95% confidence interval, CI) of 1.9 (1.1-3.4). Restricted analyses among female patients without cirrhosis indicated that Type 2 diabetes was strongly associated with HCC risk with adjusted odds ratio (95% CI) of 5.6 (2.2-14.1). In conclusion, Type 2 diabetes is independently associated with the increased risk of HCC in female CHB patients. Female CHB patients with Type 2 diabetes are of a high HCC risk population and should be considered for HCC close surveillance program.     

基于深度学习算法开发和验证的肝细胞癌预后预测模型：一项大样本队列和外部验证研究

目的 基于深度学习算法开发和验证可评估肝细胞癌（hepatocellular carcinoma,HCC）患者预后的预测模型,并评估其价值。方法 选择2011年1月—2015年12月美国国立癌症研究所的监测、流行病学和最终结果（Surveillance,Epidemiology and Results,SEER）数据库中经病理确诊的HCC患者为训练队列用于构建模型,选择同期在本院经病理确诊的HCC患者为外部验证队列用于评估模型。主要预测结局为1、3、5年总生存率。分别使用深度学习算法DeepSurv、随机生存森林（RFS）、Cox比例风险回归开发模型,使用C-index评价模型的区分度,一致性曲线评估模型的校准度,log-rank检验评估危险分层能力。结果 训练队列9 730例患者和外部验证队列405例患者被纳入分析。在训练队列中,DeepSurv算法1、3、5年的C-index分别为0.85 （95%CI：0.80~0.90）、0.82 （95%CI：0.77~0.89）、0.80 （95%CI：0.73~0.87）,在外部验证队列中分别为0.83 （95%CI：0.78~0.87）、0.79 （95%CI：0.74~0.83）、0.72 （95%CI：0.67~0.77）。无论在训练队列还是外部验证队列中,DeepSurv算法的C-index和校准度均优于RFS、Cox回归和TNM分期（均P<0.05）;log-rank检验显示,DeepSurv算法具有良好的危险分层能力（P<0.001）。结论 基于深度学习算法DeepSurv开发的预测模型可有效预测HCC患者死亡率,且优于常规的算法和预后评价指标。       

乙型肝炎病毒感染与原发性肝癌相关的危险度分析

目的:分析原发性肝癌(PHC)患者血清中乙型肝炎病毒(HBV)标志情况,探讨HBV感染与PHC危险性的关系。方法:收集在中国医科大学附属第一医院介入科住院的PHC患者224例作为病例组,同时期在此科住院的其他非肝病患者280例作为对照组,记录其血清HBV标志,与既往乙型肝炎和肝硬化等情况进行病例对照研究。结果:PHC组HBV总感染率为68.22%(146/214),以HBsAg阳性(65.42%,140/214)和抗-HBe阳性(30.84%,66/214)为主,对照组总感染率为7.63%(20/262),其中以HBsAg(3.44%,9/262)和抗-HBe(7.63%,20/262)为主。病例组感染率明显高于对照组(χ2=200.1,P<0.000 1),优势比OR=27.4(95%CI为16.0~46.9)。结论:HBV慢性感染是PHC的一个危险因素,在HBV慢性感染者中进行PHC筛查,对早期诊断PHC提高其临床疗效有重要意义。     

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Chronic hepatitis B (CHB) accounts for approximately 50% of the underlying etiologies for the development of hepatocellular carcinoma (HCC) worldwide. We reviewed the primary, secondary, and tertiary measures for the prevention of HCC in CHB patients. First, the most effective method is preventing the acquisition of CHB through global vaccination of infants. However, in patients already chronically infected, antiviral treatment using interferon or nucleoside analogs can prevent disease progression to cirrhosis or HCC. Studies have found viral replications indicated by a HBV DNA level to be a strong predictor for cirrhosis and HCC, irrespective of other viral and biochemical factors. Additionally, periodic surveillance using ultrasonography and serum α-fetoprotein every 3-6 months for earlier detection of HCC is also important so that curative treatments can be used. Once HCC occurs, hepatic resection is the mainstay of curative treatments. To prevent tumor recurrence after resection, adjuvant interferon treatments have been tried with promising results based on the assumption that they not only suppress viral activity but also have tumoricidal, antiangiogenetic, and antiproliferative effects. Using nucleoside analogs also has its rationale for preventing de novo tumor development in remnant liver, considering that viral replications are a strong risk factor for HCC. Optimal preventive plans should be further investigated in future studies.     

首诊乙型肝炎病毒相关肝细胞癌发生门静脉癌栓和肝外转移的危险因素及预测列线图

目的 分析首诊乙型肝炎病毒相关肝细胞癌(HBV-HCC)患者发生门静脉癌栓(PVTT)和肝外转移(EHM)的独立危险因素,构建并评价风险预测列线图.方法 选取200例首诊HBV-HCC患者,采用单因素和多因素Logistic回归分析其发生PVTT和EHM的独立危险因素.用R软件构建风险评分列线图,绘制受试者工作特征(R...     

Optimize nucleot(s)ide analogues' to prevent hepatocellular carcinoma in patients with chronic hepatitis B: a lesson from real-world evidence

The goal of antiviral treatment for chronic hepatitis B (CHB) is to reduce the risk of liver-related complications, including liver cirrhosis, hepatic decompens...     

Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma

This study investigated whether conformal radiotherapy affects hepatitis B virus (HBV) reactivation, and the risk factors for HBV reactivation in patients with HBV‐related hepatocellular carcinoma (HCC). Sixty‐nine patients with HCC were included in this retrospective study. Before radiotherapy (RT), all patients underwent imaging examinations and some baseline examinations, including CBC, liver function test, renal function test, α‐fetoprotein level, hepatitis B (HB) surface antigen, HB surface Ab, HB e antigen, HB e Ab, and serum HBV DNA quantification. During the period of RT and at least 16 weeks after the end of RT, CBCs were carried out weekly and the other tests were monitored monthly or more frequently if necessary. The clinical features and dosimetric parameters of RT were recorded. Univariate and multivariate logistic regression algorithms were used to analyze the risk factors of HBV reactivation. The incidence of complications in the study population was as follows: radiation‐induced liver disease, 17.4%; HBV reactivation, 24.6%; and HBV reactivation‐induced hepatitis, 21.7%. The HBV DNA level and dose volume parameters including normal liver volume, V20, and mean dose were associated with HBV reactivation. There was a relatively high incidence of HBV reactivation in HCC patients after the end of conformal RT. The serum HBV DNA level and some dosimetric parameters related to normal liver, including normal liver volume, V20, and mean dose, were the prognosis factors of HBV reactivation and should be carefully considered before conformal RT.     

Independent factors and predictive score for extrahepatic metastasis of hepatocellular carcinoma following curative hepatectomy

Background.

Postoperative extrahepatic metastasis (EHM) contributes to a poor prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. This study was aimed to develop a practical method that can be used to predict postoperative EHM.

Methods.

In total, 578 patients were enrolled. We analyzed the clinicopathological features of the tumors and did a long-term follow-up to observe HCC recurrence. Postoperative EHM was detected in 136 patients, and multivariate analysis was used to confirm independent risk factors for postoperative EHM. After the factors were identified, a predictive scoring system was constructed as a weighted sum of these factors. The cutoff value that determines a high risk for EHM was defined by maximizing the Youden''s index of the receiver operating characteristic curve.

Results.

Microvascular invasion, incomplete capsule, and larger tumor diameter were the three independent factors predictive for a high risk for EHM. The scoring system was derived with an area under the curve (AUC) of 0.81 for postoperative 10-year EHM prediction. A cutoff value of 43 was derived and validated with a sensitivity >90% and specificity >60% to predict the development of EHM. This system was further verified in a subgroup of Barcelona Clinic Liver Cancer stage 0–A patients with an AUC of 0.82. When the cutoff value was set at 43, the sensitivity and specificity were 90.38% and 64.88%, respectively.

Conclusions.

Our predictive scoring system may be used to identify HCC patients who have a high risk for EHM following curative hepatectomy.     

Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives

BACKGROUND: Familial predisposition as a risk factor for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers has not been thoroughly explored. METHODS: The HCC risk associated with having parents and/or siblings with HCC was evaluated by use of a cohort study of 4808 male HBV carriers. A case-control family study was also conducted on data from first-degree relatives of 553 HBV carriers who had newly diagnosed HCC (case subjects) and 4684 HBV carriers without HCC (control subjects). RESULTS: In the cohort study, HBV carriers with a family history of HCC had a multivariate-adjusted rate ratio for HCC of 2.41 (95% confidence interval [CI] = 1.47-3.95) compared with HBV carriers without a family history of HCC. For carriers with two or more affected relatives, the ratio increased to 5.55 (95% CI = 2.02-15.26). Cumulative HCC risk by age 70 years was 235.6 per 1000 (95% CI = 95. 3-375.9 per 1000) for HBV carriers with family history compared with 88.9 per 1000 (95% CI = 67.9-109.9 per 1000) for those without. In the case-control family study, first-degree relatives of case subjects were more likely to have HCC (age-sex-adjusted odds ratio [OR] = 2.57; 95% CI = 2.03-3.25) than first-degree relatives of control subjects. The excess risk of HCC among relatives was particularly evident in siblings (sisters-age-adjusted OR = 4.55 [95% CI = 2.22-9.31]; brothers-age-adjusted OR = 3.73 [95% CI = 2. 64-5.27]), but it was also observed in parents. The cumulative risk of HCC to age 80 years was 83.0 per 1000 among relatives of case subjects and 42.0 per 1000 among relatives of control subjects. Among relatives of case subjects, the cumulative risk of HCC was greater if the case subjects were diagnosed before age 50 years (two-sided P =.047). Liver cirrhosis was 2.29 (95% CI = 1.68-3.11) times more frequent in relatives of case subjects than in relatives of control subjects. CONCLUSIONS: First-degree relatives of patients with HBV-related HCC appear to be at increased risk of HCC and should be considered in the formulation of HCC-screening programs.     

Microvesicle microRNA profiles and functional roles between chronic hepatitis B and hepatocellular carcinoma

Objectives

Hepatocellular carcinoma (HCC) is an inflammation-related malignancy and chronic hepatitis B (CHB) predisposes to HCC. Microvesicles (MVs) transfer various bioactive molecules including microRNA (miRNA) between cells and exert biological functions. The purpose of this study was to detect CHB-MV and HCC-MV miRNAs and analyze the expression profiles and functional roles between CHB and HCC.

Methods

We examined MV miRNA profiles of CHB and HCC using miRNA microarrays. TargetScan, PicTar and miRanda were exerted to predict target genes regulating these differentially expressed miRNAs.

Results

A total of 272 and 242 aberrant fluctuation miRNAs were identified in CHB-MVs and HCC-MVs, respectively. Among them, there were 53 miRNAs co-expressing both in CHB-MVs and HCC-MVs. These miRNAs affected cellular apoptosis, proliferation and molecular signaling pathways. Among them, 25 co-expressed MV miRNAs targeted 21 inflammatory factors and these miRNAs may be a tight linkage between CHB and HCC. Interestingly, there were 14 co-expressed MV miRNAs targeting 17 oncogenes and 7 miRNAs targeting 9 tumor suppressors in the study. In addition, MVs were enriched with maladjusted miRNAs regulating zinc finger proteins and chromosome open reading frame. Those MV miRNAs may play roles in CHB developing to HCC.

Conclusions

We demonstrated that CHB and HCC displayed aberrantly co-expressed MV miRNA profiles for the first time, which may have a link between CHB and HCC. Those MV miRNAs may serve as early biomarkers for HCC and may aid to promote CHB developing to HCC.     

High serum interleukin‐6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B

Increased interleukin‐6 (IL‐6) production is implicated in the pathogenesis of hepatocellular carcinoma (HCC) in animal models. Although previous studies showed that HCC patients had higher serum IL‐6 level at the time of diagnosis, it is unclear if the cytokine contributes to the development of HCC or is just a reaction to cancer. To address this question, we performed a nested case‐control study. Consecutive chronic hepatitis B patients were recruited from 1997 to 2000 and followed till 2008. Profiling of 27 cytokines, chemokines and growth factors was performed at baseline, date of peak alanine aminotransferase (ALT) level and the last visit. Thirty‐seven patients developed HCC at a median follow‐up of 62 months (interquartile range: 41–110). Serum IL‐6 was higher in patients with HCC than controls both during peak ALT and at the last visit (both p = 0.02). Patients with IL‐6 above 7 pg/ml during peak ALT had increased risk of HCC or death (adjusted hazard ratio 3.0; 95% confidence interval 1.2, 7.8; p = 0.02). The sensitivity, specificity, positive and negative predictive values of this cutoff to predict future HCC development were 70%, 73%, 72% and 71%, respectively. Combination of IL‐6 and AFP improved the sensitivity in diagnosing HCC or predicting future HCC development. In conclusion, high serum IL‐6 level predates the development of HCC in chronic hepatitis B patients, and has moderate accuracy in predicting future cancer. This may assist clinicians in selecting high‐risk patients for HCC surveillance program. © 2009 UICC     

P48 is a predictive marker for outcome of postoperative interferon-alpha treatment in patients with hepatitis B virus infection-related hepatocellular carcinoma

BACKGROUND: Postoperative interferon-alpha (IFN-alpha) therapy improved survival in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The identification of predictive markers of outcome will help to select patients who are most likely to benefit from treatment. METHODS: An immunohistochemical study of P48 was performed on specimens that were collected from patients in a randomized trial who received postoperative IFN-alpha therapy (Group 1; n = 80 patients) and who did not receive postoperative IFN-alpha therapy (Group 2; n = 75 patients). Positive P48 expression was graded as >/=20% positive cells in 1 sample. RESULTS: Eighty-one patients were positive for P48, and 74 patients were negative for P48. The clinicopathologic data were comparable between patients with P48-negative and P48-positive staining. Disease-free survival (DFS) and overall survival (OS) in P48-positive patients were better than that in P48-negative patients in Group 1 (DFS, P = .036; OS, P = .014), however, DFS and OS did not differ between patients with positive and negative P48 in Group 2. OS in P48-positive patients from Group 1 was better than that in patients with P48-positive patients from Group 2 (OS, P = .001) but did not differ when P48 was negative. In Group 1, the risk factors for DFS were cirrhosis and P48 staining, and the risk factors for OS were tumor differentiation and P48 staining. Receiver operating curve analysis indicated that, in the first 2 years of DFS, combined cirrhosis and P48 had good predictive accuracy; and, in the first 4 years of OS, combined tumor differentiation and P48 had good predictive accuracy. CONCLUSIONS: P48 was useful as a predictive marker of outcome after postoperative IFN-alpha treatment in patients with HBV-related HCC.     

Relationship between chronic viral hepatitis and hepatocellular carcinoma

Recent years have seen a correlation between the rise in morbidity and lethality from chronic viral hepatitis and that of hepatocellular carcinoma. Present-day methods of hepatotropic viruses (HBV and HCV) identification point to a growing role of chronic viral hepatitis in etiology of cirrhosis which gives rise to hepatocellular cancers. A study of 49 cases based on sectional material established hepatocellular carcinoma development in smoldering chronic viral hepatitis caused by B or C virus or their combination. An immunohistochemical investigation (29) identified differences in hepatitis B and C virus antigen expression in tumor and adjacent hepatic tissue.     

Recent advances in hepatitis B viruses and hepatocellular carcinoma

The data reviewed at this meeting reinforce the notion that HBV may contribute to the development of liver cancer through a variety of mechanisms, including activation of oncogenes (c-myc and N-myc) by insertional mutagenesis, expression of viral proteins (X and pre-S2/S) that function as trans-activators and possibly oncoproteins, and introduction of chromosomal defects through enzymatically mediated integration into the host genome. Not all of these mechanisms appear to be active in every tumor, however. Thus, future work will be aimed at characterizing each mechanism in more detail and determining its relative importance in the carcinogenic process.