High Hepatocellular Carcinoma Research Articles

The adverse characteristics of hepatocellular carcinoma in the non-cirrhotic liver disproportionately disadvantage Black patients.

Black patients have higher hepatocellular carcinoma (HCC)-related mortality than White patients and more often develop HCC in non-cirrhotic liver. HCC surveillance is primarily directed toward cirrhotic patients. We aimed to characterize HCC in non-cirrhotic patients and to identify factors associated with HCC beyond Milan criteria. Demographic, imaging, laboratory, and pathology data of HCC patients at our institution, 2003-2018, were reviewed, retrospectively. Race/ethnicity were self-reported. Cirrhosis was defined as a Fibrosis-4 score ≥3.25. Compared to 1146 cirrhotic patients, 411 non-cirrhotic patients had larger tumors (median 4.7 cm vs. 3.1 cm, p < 0.01) and were less likely to be within Milan criteria (42.6% vs. 57.7%, p < 0.01). Among non-cirrhotic patients, Black patients had larger tumors (4.9 cm vs. 4.3 cm, p < 0.01) and a higher percentage of poorly differentiated tumors (39.4% vs. 23.1%, p = 0.02). Among cirrhotic patients, Black patients had larger tumors (3.3 cm vs. 3.0 cm, p = 0.03) and were less likely to be within Milan criteria (52.3% vs. 83.2%, p < 0.01). In multivariable analysis, lack of commercial insurance (OR 1.45 [CI 95% 1.19-1.83], p < 0.01), male sex (OR 1.34 [CI 95% 1.05-1.70], p < 0.01), absence of cirrhosis (OR 1.58 [CI 95% 1.27-1.98], p < 0.01) and Black race/ethnicity (OR 1.34 [CI 95% 1.09-1.66], p = 0.01) were associated with HCC beyond Milan criteria. Black patients had lower survival rates than other patients (p < 0.01). Non-cirrhotic patients had more advanced HCC than cirrhotic patients. Black patients (with or without cirrhosis) had more advanced HCC than comparable non-Black patients and higher mortality rates. Improved access to healthcare (commercial insurance) may increase early diagnosis (within Milan criteria) and reduce disparities.

Risk thresholds for patients to switch between daily tablets and biweekly infusions in second-line treatment for advanced hepatocellular carcinoma: a patient preference study

BackgroundHistorically, high hepatocellular carcinoma (HCC)–related mortality has been, in part, due to lack of effective therapies; however, several systemic therapies have been recently approved for HCC treatment, including regorafenib and ramucirumab. These two treatments utilize different routes of administration (four daily tablets and biweekly intravenous infusions, respectively) and have different risks of adverse events (AEs). However, we lack data on patient preferences in balancing the route of administration and risk of AEs in patients with HCC. We aimed to determine patient preferences and trade-offs for second-line treatment in patients with HCC. MethodsPatients with advanced or metastatic HCC were recruited through their physicians for this study. Patient preferences were assessed by using a modified threshold technique (TT) design in which respondents were asked two direct-elicitation questions before (assuming same safety and efficacy and only varying mode of administration) and after (incorporating the safety profiles of ramucirumab and regorafenib) the TT series on seven risks of clinically relevant AEs.ResultsIn total, of the 157 patients recruited by their physicians, 150 were eligible and consented to participate. In the first elicitation question (assuming risk and efficacy were equivalent), 61.3% of patients preferred daily tablets. However, 76.7% of patients preferred the biweekly infusion when the safety profiles of the two available second-line therapies were included. The TT analysis confirmed that preferences for oral administration were not strong enough to balance out the risk of AEs that differentiate the two therapies.DiscussionWe found that when patients were asked to choose between a daily, oral medication and a biweekly IV medication for HCC, they were more likely to choose a daily, oral medication if efficacy and safety profiles were the same. However, when risks of AEs representing the safety profiles of two currently available second-line treatments were introduced in a second direct-elicitation question, respondents often selected an IV administration with a safety profile similar to ramucirumab, rather than oral tablets with a safety profile similar to regorafenib. Our findings indicate that the risk profile of a second-line treatment for HCC may be more important than the mode of administration to patients.

EALT-F: A New Non-Invasive Staging Method to Identify Medium to High-Risk Patients with HCC from Ultra-High HBV Viral Load Population - China, 2010-2023.

The objective of this study was to examine the clinical characteristics of individuals with ultra-high hepatitis B virus (HBV) viral load and develop a novel staging method for chronic hepatitis B (CHB) that can more effectively identify patients with medium to high hepatocellular carcinoma (HCC) risk. A total of 2,118 patients with HBV DNA >1×107 IU/mL who visited Peking University People's Hospital between January 2010 and March 2023 were enrolled retrospectively. Clinical data from the first visit were obtained and analyzed. The traditional phases and new 'eALT-F' stages were compared to evaluate the risk of HCC. In the overall patients, more than one-third of the patients were under 30 years old. Additionally, a small proportion of older people (>60 years) also had ultra-high HBV viral load (4.3%). 9.1% and 6.7% of individuals with ultra-high HBV viral load showed FIB-4>3.25 and aMAP≥50, respectively. In the traditional stages of CHB, which are based on HBeAg and alanine aminotransferase (ALT) [the upper limit of normal (ULN) ALT level at 40 IU/L for both men and women], regardless of phase, a certain proportion of patients were at risk of developing HCC (4.1%, 6.4%, 25.0%, and 20.3%). However, in the new 'eALT-F' stages, which are based on HBeAg, ALT (the ULN of ALT level at 30 IU/L for men and 19 IU/L for women), and/or FIB-4 levels (>1.45), aMAP≥50 was only observed in chronic hepatitis patients with positive or negative HBeAg (6.4% and 22.1%, respectively). The 'eALT-F' staging method, based on HBeAg, ALT (males: the ULN of ALT was 30 IU/L, females: 19 IU/L) and/or FIB-4 levels, was more effective in identifying medium to high-risk patients with HCC from patients with ultra-high HBV viral load than the traditional staging methods.

Neighborhood-Level Factors Contribute to Disparities in Hepatocellular Carcinoma Incidence in Texas

Background and AimsTexas has the highest hepatocellular carcinoma (HCC) incidence rates in the continental United States, but these rates vary by race-ethnicity. We examined racial-ethnic disparities through a geospatial analysis of the social determinants of health. MethodsUsing data from the Texas Cancer Registry, we assembled 11,547 HCC cases diagnosed between 2011 and 2015 into Texas’s census tracts geographic units. Twenty-nine neighborhood measures representing demographics and socioeconomic, and employment domains were retrieved from the U.S. Census Bureau. We performed a series of aspatial and spatially weighted regression models to identify neighborhood-level characteristics associated with HCC risk. ResultsWe found positive associations between HCC and proportion of population in census tracts that are Black or African American, Hispanic, over 60 years of age, in the construction industry, and in the service occupation but an inverse association with the proportion of population employed in the agricultural industry. The magnitude of these associations varied across Texas census tracts. ConclusionsWe found evidence that neighborhood-level factors are differentially associated with variations in HCC incidence across Texas. Our findings reinforce existing knowledge about HCC risk factors and expose others, including neighborhood-level employment status.

Virologic response maintenance and hepatocellular carcinoma in chronic hepatitis B patients treated with entecavir

ABSTRACT Introduction The treatment evidence for entecavir-treated chronic hepatitis B (CHB) patients without maintaining of virologic response (MVR, defined as persistent HBV DNA <20 IU/mL during therapy) remains uncertain. We aimed to determine the relationship between non-MVR and hepatocellular carcinoma (HCC) risk in entecavir-treated CHB patients. Methods A cohort of 1447 entecavir-treated CHB patients were enrolled. Multivariate and propensity score-based inverse probability weighting (IPW) model was performed to estimate the effect of MVR on HCC. Results During a median follow-up of 5 years, 214 (14.8%) patients occurred with non-MVR. Non-MVR patients had a higher risk of HCC [the IPW model: hazard ratio (HR) = 3.59, 95% confidence interval (CI): 2.23–5.75] than MVR patients, especially in those with cirrhosis (HR = 4.60, 95% CI: 2.81–7.56) and the high HCC score by the Chinese University of Hong Kong (HR = 4.35, 95% CI: 2.58–7.32). MVR patients with transient (HR = 4.72, 95% CI: 1.98–11.24) or persistent (HR = 12.16, 95% CI: 3.58–41.31) abnormal ALT after virologic response had higher HCC hazard. Conclusions Our study indicated an elevated HCC probability for entecavir-treated CHB patients with Non-MVR, especially for those with cirrhosis or a high predicted score at baseline. For MVR patients, the trajectories of ALT after virologic response suggested different HCC risks.

Relationship between cyanobacterial bloom impacted drinking water sources and hepatocellular carcinoma incidence rates

Freshwater cyanobacterial blooms have increased in geographic distribution and intensity in recent decades worldwide. Cyanotoxins produced by many of these blooms, such as microcystins, are observed to play a role in tumor promotion and have been associated with increased liver cancer rates at the population level. Exposure occurs primarily via contaminated water (ingestion, inhalation, dermal contact), either from treated drinking water or during recreation in impacted surface waters; additional sources of exposure include consumption of fresh produce grown in cyanotoxin-contaminated environments or through the consumption of seafood caught in bloom-impacted waters.The current ecological study investigates whether populations served by cyanobacterial bloom-impacted surface waters for their drinking water source have higher hepatocellular carcinoma (HCC) incidence rates than those served by non-impacted surface waters and groundwater. Census tract level cancer incidence in the state of Ohio, United States was modeled using a negative binomial generalized linear model, controlling for differences in demographic composition (e.g. age, race, and income) at the census tract level. Presence of cyanobacterial blooms in surface waters was estimated using satellite multi-spectral remote sensing and in situ public water system cyanotoxin monitoring data. Census tracts estimated to be served by bloom-impacted surface waters had 14.2% higher HCC incidence rates than those served by non-bloom-impacted surface waters (incidence rate ratio, IRR: 1.142; 95% CI: 1.037–1.257). Additionally, these bloom-impacted census tracts had a 17.4% higher HCC incidence rate as compared to those estimated to receive drinking water from a groundwater source (IRR: 1.174; 95% CI: 1.101–1.252). No statistical difference was found in HCC incidence rates when comparing areas presumed to be served by non-bloom-impacted surface waters and those presumed to be served by groundwater sources. An important consideration for environmental justice, areas estimated to be served by bloom-impacted surface waters had higher levels of poverty and included a higher percentage of racial and ethnic minority populations than areas served by groundwater. These findings support the need for additional in-depth research into the potential hepatic carcinogenicity and exposures of cyanotoxins in those areas where severe blooms are chronically observed.

AB068. P-39. Comparison of selective internal radiation therapy (SIRT) versus sorafenib in patients with locally advanced hepatocellular carcinoma in Mongolia: a subgroup analysis of SIRveNIB study

Background: Mongolia has one the highest hepatocellular carcinoma (HCC) incidence in the world due to widespread hepatitis B and C endemic along with high alcohol consumption rate. However, local data on optimal therapeutic regime for these patients is scarce. The objective of this study is to evaluate the efficacy of selective internal radiation therapy (SIRT) using SIR-Spheres yttrium-90 microspheres versus sorafenib in Mongolian patients with locally advanced HCC patients at Barcelona Clinic Liver Cancer (BCLC) stage B and C patients without extra-hepatic metastasis.

Interferon-based treatment is superior to nucleos(t)ide analog in reducing HBV-related hepatocellular carcinoma for chronic hepatitis B patients at high risk

ABSTRACTBackground: The effect of nucleos(t)ide analogs (NAs) versus interferon (IFN) on the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is controversial. We assessed whether antiviral strategy affected HCC development in CHB patients at different HCC risks.Methods: 1112 CHB patients with antiviral therapy were included in this retrospective study. Patients treated with NAs only were classified into NAs group (n = 682) while those received IFN treatment with or without NAs were defined as IFN group (n = 430). Propensity score matching (PSM) was applied to minimize baseline differences.Results: Totally, 31 patients developed HCC during follow-up (median 5.41 years). The cumulative HCC incidence at 10 years was significantly lower in the IFN group than NAs group (2.7% vs 8.0%, p < 0.001). Similar results were obtained in the PSM-cohort. Patients with IFN-based treatment were less likely to develop HCC than those with NAs (Hazard ratio = 0.15; 95% CI 0.04–0.66; p = 0.012). Subgroup analyses demonstrated that this superiority of IFN in reducing HCC development was obvious in patients at high- but not low-risk of HCC.Conclusions: Reduction of HCC development was more significant in CHB patients at higher HCC risk with IFN-based therapy than NAs treatment.

Abstract IA18: Liver cancer among minority populations in the United States

Abstract Liver cancer incidence, the dominant histology of which is hepatocellular carcinoma (HCC), has been increasing in the U.S. for more than three decades. In comparison with non-Hispanic whites, all other racial/ethnic groups have notably higher incidence rates. For many years, the highest HCC rates occurred among Asians/Pacific Islanders. Recently, however, rates among Asians/Pacific Islanders have declined while rates among all other racial/ethnic groups have increased. As a consequence of the divergent trends, Hispanics are poised to become the group with the highest liver-cancer incidence in the U.S. The group that has seen the greatest increase in rates in the past twenty years, however, is non-Hispanic blacks. By 2030, forecasting models suggest that Hispanics and non-Hispanic blacks will have the highest rates and Asians/Pacific Islanders will have the lowest rates. Among all racial/ethnic groups in the U.S., males have higher rates of liver cancer than females. The male:female ratio varies from a low of 2.5:1 among American Indians/Alaska Natives to a high of 4.1:1 among non-Hispanic blacks. Males also are diagnosed at a younger average age than females, with the least discrepancy in age occurring among non-Hispanic blacks (2.7 years) and the greatest discrepancy in age occurring among Asians/Pacific Islanders (5.9 years). A likely explanation for declining HCC rates among Asian/Pacific Islanders is a declining prevalence of hepatitis B virus (HBV) infection in the population. Likely explanations for the increasing HCC rates in other racial/groups are the high rate of hepatitis C virus (HCV) infection in prior years and the increased prevalence of obesity/diabetes in the population. An analysis of population-attributable risk among persons of ages 65 and older, however, found differences in attributable risk by racial ethnic group. Among non-Hispanic whites and Hispanics, the dominant risk factor was obesity/diabetes. In contrast, HCV infection was the dominant risk factor among non-Hispanic blacks and Asians/Pacific Islanders. These differences in key factors suggest that cancer prevention strategies should be tailored to each specific racial/ethnic group. Citation Format: Katherine A. McGlynn. Liver cancer among minority populations in the United States [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA18.

Differential Expression of MicroRNAs in Hepatitis C Virus-Mediated Liver Disease Between African Americans and Caucasians: Implications for Racial Health Disparities.

African Americans (AAs) have higher hepatocellular carcinoma (HCC) mortality rates than Caucasian Americans (CAs). Chronic hepatitis C virus (HCV) infection leads to cirrhosis and HCC. HCV infection is highly prevalent in the AA population compared to other racial groups. AAs are also less likely to naturally clear HCV, potentially contributing to higher prevalence of HCV. However, the explanation for this disparity is currently unknown. Circulating microRNAs (miRNAs) in the blood are emerging as biomarkers for pathological conditions. Expression analysis of miRNAs in major racial groups would be important for optimizing personalized treatment strategies. Here we assessed the differential expression of circulatory miRNAs from HCV-infected AA and CA patients. We identified increased expression of miR-146a, miR-150, and miR-155 in HCV-infected AA patient sera compared to that of CA. Further analysis demonstrated that these miRNAs were significantly elevated in AA patients diagnosed with HCV-mediated HCC. Higher expression of miR-150 was also noted in cirrhosis and HCC in AA patients, which may serve as a predictor of liver disease progression in this population. The differential expression of miRNAs suggests that these miRNAs and their target genes could be useful to gain further mechanistic insight of racial disparity associated with HCV-mediated pathogenesis.

Diabetes Mellitus Increases Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients: A Systematic Review.

Rising rates of obesity, diabetes mellitus (DM), and nonalcoholic fatty liver disease (NAFLD) among chronic hepatitis C (HCV) patients may contribute to higher hepatocellular carcinoma (HCC) risk. To perform a systematic review evaluating the impact of DM, body mass index (BMI), or steatosis on HCC risk among chronic HCV patients. A structured keyword search of PubMed from January 1, 2001, to July 1, 2014, was performed to identify original articles evaluating the association of DM, BMI, or steatosis with HCC among adults with chronic HCV. Studies involving HCV patients co-infected with human immunodeficiency virus, hepatitis B virus, or other chronic liver diseases with the exception of NAFLD were excluded. Quality assessment utilized the Newcastle-Ottawa scale. Nine studies (seven cohorts, two case-controls) met inclusion criteria for the final analysis. Five of seven studies analyzing DM demonstrated significantly increased HCC risk associated with concurrent DM with effect sizes ranging from HR 1.73 (95 % CI 1.30-2.30) to RR 3.52 (95 % CI 1.29-9.24). One of three studies analyzing BMI demonstrated a significant association with HCC risk (BMI ≥ 30.0 vs. BMI < 23: RR 4.13, 95 % CI 1.38-12.40). Two of the three studies analyzing steatosis demonstrated significantly higher risk of HCC associated with steatosis ranging from RR 2.81 (95 % CI 1.49-4.41) to OR 6.39 (95 % CI 1.04-39.35). Concurrent DM is associated with increased HCC risk among chronic HCV patients. BMI and steatosis may also increase HCC risk, but the limitations of the current studies do not allow us to draw strong conclusions.

952 Age-Specific Disparities in Hepatocellular Carcinoma (HCC) Outcomes: Older Patients With HCC Have Lower Rates of HCC Treatment and Lower Overall Survival Despite Earlier Staged Disease at Presentation

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths in the U.S. The aging population coupled with the rising incidence of HCC will result in an emerging cohort of older patients with HCC needing treatment. Understanding the agespecific epidemiology and long term outcomes among HCC patients will help guide effective management among this cohort. Our study aims to evaluate age-specific HCC incidence, burden of disease, treatment rates, and overall survival outcomes. Methods: We retrospectively evaluated all U.S. adults with HCC using population-based cancer registry data from the 2003 2011 Surveillance, Epidemiology, and End Results database. Age-specific analyses utilized four age groups ( 70 years old). Age-specific disparities in stage of disease at presentation and HCC treatment were evaluated using multivariate logistic regression models. Age-specific disparities in overall survival were calculated using Kaplan Meier methods and multivariate Cox proportional hazards models (adjusted for age, sex, race/ethnicity, stage of disease, year of diagnosis, and treatment received). Results: Overall, the highest HCC incidence was seen among patients > 70 years old, nearly double that of patients 50-59 years old (28.4 vs. 16.2 per 100,000/year, p 70 years old: 28.4 per 100,000/year in men vs. 18.0 per 100,000/year in women, p 70 years old were significantly more likely to have localized disease at time of diagnosis (OR, 0.87; 95% CI, 0.79-0.96, p=0.01). Older age was also associated with significantly lower rates of receiving HCC treatment. Even after adjusting for stage of disease, patients > 70 years old were significantly less likely to receive any HCC treatment compared to patients 70 years old had significantly lower 5-year survival (HR, 1.22; 95% CI, 1.14-1.31, p 70 years old were more likely to have localized disease at presentation, but significantly less likely to receive any HCC treatment, and thus had significantly lower overall survival. Understanding age-specific disparities in HCC epidemiology and outcomes will be especially important given the increasing age of HCC patients in the U.S.

Risk stratification of HBV infection in Asia-Pacific region

Hepatitis B virus (HBV) infection is the major etiology of chronic liver disease worldwide and thus a global health problem, especially in Asia-Pacific region. The long-term outcomes of Asian HBV carriers vary widely; however, a significant proportion of them will finally develop end-stage liver disease. Over the past decade, several host and HBV factors predictive of clinical outcomes in Asian HBV carriers have been identified. The community-based REVEAL-HBV study illustrated the strong association between HBV-DNA level at study entry and risk of HCC over time, and male gender, older age, high serum alanine aminotransferase (ALT) level, positive HBeAg, higher HBV-DNA level, HBV genotype C infection and core promoter mutation are independently associated with a higher hepatocellular carcinoma (HCC) risk. Another hospital-based ERADICATE-B cohort further validated the HCC risk started to increase when HBV-DNA level was higher than 2,000 IU/mL. Of particular note, in patients with low viral load (HBV-DNA level <2,000 IU/mL), HBsAg level ≥1,000 IU/mL was a new independent risk factor for HCC. With the results from REVEAL-HBV study, a risk calculator for predicting HCC in adult non-cirrhotic patients has been developed and validated by independent international cohorts (REACH-B). With the combination of HBV-DNA, HBsAg, and ALT levels, ERADICATE-B study proposed an algorithm to predict disease progression and categorize risk levels of HCC as well as corresponding management in Asian HBV carriers. The introduction of transient elastography may further enhance the predictive power. In conclusion, HBsAg level can complement HBV-DNA level for the risk stratification of disease progression in Asian adult patients with chronic HBV infection.

Genetic variation near interleukin 28B and the risk of hepatocellular carcinoma in patients with chronic hepatitis C

We aimed to clarify the association between single nucleotide polymorphism (SNP) located near interleukin 28B and hepatocellular carcinoma (HCC). A cohort comprising 792 patients treated with interferon for chronic hepatitis C was investigated. SNPs at rs8099917 and rs12979860 were determined. Cumulative incidence and HCC risk were analyzed by Kaplan-Meier and Cox proportional hazard analyses for a mean follow-up period of 4.9 years. Fibrosis progression rate (FPR) was determined in these patients with a known time of infection (n = 294). Cumulative HCC incidence was significantly higher in rs8099917 nonTT (minor homozygote or heterozygote) patients than in rs8099917 TT (major homozygote) patients (20.8 vs. 10.5% over 10 years, logrank test, p = 0.002). This difference was notable in patients infected with genotype 1 and those treated with pegylated interferon and ribavirin. Among nonSVRs, interferon had a limited effect in suppressing alanine aminotransferase (ALT) and/or α-fetoprotein (AFP) levels in nonTT patients. The suppression of these values after interferon therapy was associated with a lower incidence of HCC. FPR were similar in TT and nonTT patients. rs8099917 nonTT is related to higher HCC development in patients with HCV genotype 1 and those treated with pegylated interferon and ribavirin. Higher HCC incidence observed in nonTT patients partly results from the limited suppression of ALT and/or AFP by interferon in these patients.

The Molecular Pathology and Clinical Impact of HBV Genetic Variability

According to the World Health Organization, about 2 billion persons worldwide have been infected with hepatitis B virus (HBV). More than 350 million are chronically infected worldwide with a high risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) (representing 1 million deaths per year). The epidemiology of HCC is peculiar with both geographic and temporal patterns of incidence paralleling exposure to viral etiologic factors. The highest HCC incidence rates are areas endemic for chronic infection with hepatitis B virus (Asia and Africa). Based on sequence divergence in the entire genome of >8%, HBV genomes have been classified into eight groups designated from A to H. The genotypes of HBV have distinct geographical distributions. Although preliminary clinical studies seem to indicate that there is an association between HBV genotype and natural history of infection and/or response to antiviral therapy, further evaluations on larger collectives of patients are necessary to give a clearer picture of the subject. The first paper of this special issue addresses the aetiology and picture of CTNNB1 and TP53 mutations in Thailand patients with HCC and provides a detailed study of the situation in an Asian country. The second paper presents the study on the etiology and viral genotypes in Colombia; these data are not common with South America. The two subsequent papers address the question of HBV variability and HCC in two different countries and continents. Indeed, the third paper is on TP53 mutations and HBx gene of hepatitis B virus status in HCC in Iran. It is bringing interesting discussion about the potential link between HBV genotypes and TP53 mutation R249S. The fourth paper of this special issue presents a fully picture of viral hepatitis viruses and TP53 mutations in HCC from Columbia. The fifth paper describes the evolution of HBV “quasispecies” in a chronic HBV chronic carrier over a 2-year period. The final paper of this special issue proposes an original study on the importance of HBV variability on RNAi strategies. Isabelle Chemin Helene Norder Patrick Soussan Runu Chakravarty

Significance of hepatitis B virus genotypes and mutations in the development of hepatocellular carcinoma in Asia

AbstractAdvances in molecular biology technology in the last two decades have allowed detailed study of the viral mutations and genomic heterogeneity of hepatitis B virus (HBV). The first mutant discovered was precore stop codon mutation. It was reported in HBeAg‐negative patients and initially thought to associate with fulminant hepatitis. Subsequent studies have suggested that it is merely one of the mechanisms of losing HBeAg by the virus. Another mutation that can downregulate the production of HBeAg is the basal core promoter mutation, which is located in the X gene upstream of the precore region. Based on the configuration of codon 15 and the stability of the epsilon of the precore region, these two mutants will be differentially selected during the course of HBeAg seroconversion. The most common HBV genotypes in South‐East Asia are genotype B and C HBV. The higher hepatocellular carcinoma (HCC) risk of genotype C HBV has been confirmed by longitudinal studies in Hong Kong and Taiwan. One possible carcinogenic mechanism is its association with basal core promoter mutation, which has also been found to be a risk factor of HCC. Within genotype C HBV, subgenotype Cs is predominant in South‐East Asia and subgenotype Ce is predominant in East Asia. Subgenotype Ce HBV has been found to have the highest risk of HCC as compared with subgenotype Cs or genotype B HBV. The understanding of the carcinogenic mechanisms of these HBV strains may shed light into future therapeutics in the prevention and treatment of HBV‐related HCC.

Editorial foreword special issue “Hepatocellular Carcinoma – A Worldwide Translational Approach”

abstract 2009 Elsevier Ireland Ltd. All rights reserved. Primary human liver cancer, of which hepatocellularcarcinoma (HCC) is the predominant type, is a major causeof cancer death worldwide, accounting for almost 600,000deaths per year. Because of poor curability, the number ofHCC deaths occurring each year is roughly equivalent tothe number of new cases. The global epidemiology ofHCC is striking, with both geographic and temporal pat-terns of incidence paralleling exposure to viral etiologicfactors. The highest HCC incidence rates occur in sub-Sah-aran Africa and parts of Asia, areas endemic for chronicinfection with hepatitis B virus. However, liver carcinogen-esis is much more complex than simply reflecting the pres-ence or absence of an antecedent viral infection. Givenchronic hepatitis B or C viruses (HBV, HCV) infection, thereare marked geographical differences in risk for HCC whichremain largely unexplained, the other known causes,including aflatoxin exposure, tobacco smoking, alcoholdrinking, and diabetes, explaining only a relatively smallproportion of cases. Moreover, there is significant variationin the pathological and natural history of the disease. Thepathways by which HCC develop are heterogeneous andinfluenced by a variety of environmental and host factors.This special issue of Cancer Letters dedicated to HCC in-cludes contributions that address the critical research is-sues of this disease from etiology and molecularepidemiology, mechanisms and viruses, and molecular car-cinogenesis, to preclinical models and therapeutic ap-proaches and biomarkers. The reviews were preparedfollowing the meeting ‘‘Hepatocellular carcinoma – AWorldwide Translational Approach” which took place atthe International Agency for Research on Cancer, Lyon,France on July 9–10, 2007.Chronic infection with hepatitis B or C viruses havebeen recognized as human liver carcinogens with the pro-portion of HCC attributable to virally induced chronic hep-atitis being close to 85% in most populations. An efficientHBV vaccine is available since the early eighties and hasbeen used since for universal infant vaccination in severalregions of high endemicity, here Plymoth et al. reviewuniversal vaccination programmes and designed field effi-cacy trials. Epidemiological studies on the seroprevalence

Risk of Hepatocellular Carcinoma Across a Biological Gradient of Serum Hepatitis B Virus DNA Level

Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B. To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma. Prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992. Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems. There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41,779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100,000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100,000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P<.001) after adjustment for sex, age, cigarette smoking, alcohol consumption, serostatus for the hepatitis B e antigen (HBeAg), serum alanine aminotransferase level, and liver cirrhosis at study entry. The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry. Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk. Elevated serum HBV DNA level (> or =10,000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.