Incidence Rate Of Hepatocellular Carcinoma Research Articles

Interferon Gamma-Induced Interferon Regulatory Factor 1 Activates Transcription of HHLA2 and Induces Immune Escape of Hepatocellular Carcinoma Cells.

Immunosuppression developed by cancer cells remains a leading cause of treating failure of immunotherapies. This study aimed to explore the function of human endogenous retrovirus-H long terminal repeat-associating 2 (HHLA2), an immune checkpoint molecule from the B7 family, in the immune escape in hepatocellular carcinoma (HCC). Mouse models with primary HCC or with xenograft tumors were established. The portion of tumor-associated macrophages (TAMs) and the level of PD-L1 in the tumor tissues were examined. THP-1 cells were treated with PMA to obtain a macrophage-like phenotype. The PMA-treated THP-1 cells were co-cultured with the HCC cells in Transwell chambers to examine the function of HHLA2 in chemotactic migration and polarization of macrophages. HHLA2 expression was correlated with infiltration of immune cells, especially macrophages, and was linked to poor prognosis of patients with HCC. HHLA2 knockdown reduced incidence rate of primary HCC in mice. It also reduced tumor metastasis, the portion of M2 macrophages, and the expression of PD-L1 in primary and xenograft tumors. In vitro, HHLA2 upregulation increased expression of PD-L1 in HCC cells indirectly by inducing M2 polarization and chemotactic migration of macrophages. Interferon gamma (IFNG) enhanced expression of interferon regulatory factor 1 (IFR1) in HCC cells, and IFR1 bound to the promoter region of HHLA2 to activate HHLA2 expression. This study suggested that the IFNG/IFR1/HHLA2 axis in HCC induces M2 polarization and chemotactic migration of macrophages, which leads to immune escape and development of HCC.

Sex and regional disparities in incidence of hepatocellular carcinoma in autoimmune hepatitis: a systematic review and meta-analysis.

Recent studies have identified an increased risk of hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH). Sex and regional disparities in incidence of HCC in AIH continue to be reported worldwide. Nevertheless, the magnitude of this gap remains unknown. We searched several databases including PubMed, Embase, Web of Science, Cochrane Library, Wanfang Data, CNKI and SinoMed. Incidence rates of HCC in AIH were combined and analyzed following the EBayes method. Incidence rate ratios were pooled to assess the sex differences. The impact of population difference, sex, age, cirrhotic condition was further analyzed with subgroup analysis and linear regression analysis. 39 studies meeting our eligibility criteria were chosen for the analysis. The pooled incidence rate of HCC in AIH was 3.54 per 1000 person years (95% CI 2.76-4.55). Pooled IRR for the risk of HCC in male AIH patients compared to female was 2.16 (95% CI 1.25-3.75), with mild heterogeneity among studies. The pooled HCC incidence rate in AIH by continents was as follows: Europe 2.37 per 1000 person-years (95% CI 1.45-3.88), Asia 6.18 per 1000 person-years (95%CI 5.51-6.93), North America 2.97 per 1000 person-years (95%CI 2.40-3.68), Oceania 2.60 (95%CI 0.54-7.58). The pooled HCC incidence rate in AIH-related cirrhosis by continent was as follows: Europe 6.35 per 1000 person-years (95%CI 3.94-10.22), Asia 17.02 per 1000 person-years (95%CI 11.18-25.91), North America 10.89 per 1000 person-years (95%CI 6.69-17.74). A higher HCC incidence in AIH was observed among male and in Asian populations. Cirrhosis status at AIH diagnosis is significantly associated with an increased incidence rate for HCC, and routine HCC surveillance is recommended for patients with AIH cirrhosis, especially for those in Asia.

O-15 ABSENCE OF DISEASE REMISSION AS A RISK FACTOR FOR HEPATOCELLULAR CARCINOMA IN PATIENTS WITH AUTOIMMUNE HEPATITIS

Hepatocellular carcinoma (HCC) occurrence is rare in autoimmune hepatitis (AIH) and data about its characteristics are still scarce. The aims of this study were to describe HCC prevalence and risks factors in AIH patients in a tertiary referral hospital. Retrospective cohort of AIH patients followed from 2003 to 2019. The hazard ratios (HR) and their respective 95% confidence intervals (95%CI) were estimated using simple Cox regression. A multivariate regression model was fitted using relevant covariates for HCC occurrence. Among 355 AIH patients, 84.5% were female, 85% AIH-1, 65% with cirrhosis and mean age at AIH diagnosis of 27±18yr. Sixteen cases of HCC were diagnosed (4.5%), all of them in cirrhotic patients, 81.3% female, mean age of 49±20yr, 83% overweight (BMI 34±5kg/m 2 ) and 3 with associated steatohepatitis. The pooled incidence rate for HCC was 3.2 per 100 patient-years. The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 4.5 per 100 patient-years. The median time between AIH diagnosis and HCC was 9 years (1-42). At univariate analysis the factors associated with HCC risk were age at diagnosis of AIH (HR,1.05; 95%CI,1.02-1.08; p<0.001), platelet count <100 × 10 6 /mm 3 (HR,4.77; 95%CI, 1.73-13.17; p=0.003), presence of portal hypertension (HR,2.72; 95%CI,0.79-9.29; p=0.001), diabetes (HR,3.89; 95%CI,1.18-12.7; p=0.025) and disease remission at any time of follow up (HR,0.14; 95%CI,0.05-0.41; p<0.001). At multivariate analysis the factors associated with HCC risk were age at diagnosis (HR,1.05; 95%CI,1.027-1.083; p<0.001) and portal hypertension (HR,4.88; 95%CI,1.49-15.92; p=0.009). The occurrence of disease (AIH) remission during follow up was associated with lower risk of HCC (HR,0.128; 95%CI,0.043-0.38; p<0.001). The prevalence of HCC in this cohort was 4.5%. Advanced age at diagnosis, diabetes, platelet count <100 × 10 6 /mm 3 , presence of portal hypertension and absence of disease remission during treatment were associated with greater risk of HCC.

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n=5474, 58.9%) with a mean age of 47.5years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n=1595) and 13.2% (n=1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n=1740). During follow-up (median: 60.0months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p<.001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.

Follow-Up of Patients Who Achieved Sustained Virologic Response after Interferon-Free Treatment against Hepatitis C Virus: Focus on Older Patients.

Background and Objectives: Direct-acting antiviral agents (DAAs) have improved sustained virologic response (SVR) rates in patients with chronic hepatitis C virus (HCV) infection. Our aim was to elucidate the occurrence of hepatocellular carcinoma (HCC) and to compare the outcomes of patients aged 75 years or older (older group) with those of patients younger than 75 years (younger group) after SVR. Materials and Methods: Among 441 patients treated with interferon-free DAA combinations, a total of 409 SVR patients were analyzed. We compared the two age groups in terms of HCC incidence and mortality rates. Results: Older and younger groups consisted of 68 and 341 patients, respectively. Occurrence of HCC after SVR did not differ between the two groups of patients with a history of HCC. Occurrence of HCC after SVR was observed more in younger patients without a history of HCC (p < 0.01). Although older patients without a history of HCC had a higher mortality rate (p < 0.01), their causes of death were not associated with liver diseases. Among younger patients without a history of HCC, none died. Conclusions: After SVR, liver disease may not be a prognostic factor in older HCV patients without a history of HCC.

Racial Differences in Hepatocellular Carcinoma Incidence and Risk Factors among a Low Socioeconomic Population.

Simple SummaryLiver cancer incidence in the United States is higher among African Americans compared to White Americans. The determinants of racial disparities in liver cancer incidence are not clear. Using data from White and African Americans from low socioeconomic backgrounds, we compared the prevalence of known liver cancer risk factors by race and assessed factors associated with liver cancer incidence. Understanding liver cancer risk differences can assist prevention strategies that target people at high risk, potentially based on risk factors that differ by race.The purpose of this study was to examine differences in risk factors associated with hepatocellular carcinoma (HCC) among White and African Americans from low socioeconomic backgrounds in the Southern Community Cohort Study (SCCS). The SCCS is a prospective cohort study with participants from the southeastern US. HCC incidence rates were calculated. Multivariable Cox regression was used to calculate HCC-adjusted hazard ratios (aHR) associated with known baseline HCC risk factors for White and African Americans, separately. There were 294 incident HCC. The incidence rate ratio for HCC was higher (IRR = 1.4, 95%CI: 1.1–1.9) in African Americans compared to White Americans. White Americans saw a stronger association between self-reported hepatitis C virus (aHR = 19.24, 95%CI: 10.58–35.00) and diabetes (aHR = 3.55, 95%CI: 1.96–6.43) for the development of HCC compared to African Americans (aHR = 7.73, 95%CI: 5.71–10.47 and aHR = 1.48, 95%CI: 1.06–2.06, respectively) even though the prevalence of these risk factors was similar between races. Smoking (aHR = 2.91, 95%CI: 1.87–4.52) and heavy alcohol consumption (aHR = 1.59, 95%CI: 1.19–2.11) were significantly associated with HCC risk among African Americans only. In this large prospective cohort, we observed racial differences in HCC incidence and risk factors associated with HCC among White and African Americans.

Meta-analysis of the effects of statins on the risk of chronic liver disease and hepatocellular carcinoma

Objective: To evaluate the relationship between the application of statins and the risk of hepatocellular carcinoma in patients with chronic liver disease. Methods: PubMed, the Cochrane Library, EMBASE, Web of science, WeiPu, Wanfang Med online, and China National Knowledge Infrastructure database were searched. The literatures about statins and the risk of hepatocellular carcinoma in patients with chronic liver disease were collected, with a search deadline of February 2020. Two researchers independently conducted literature screening, data extraction, quality evaluation and proofreading. RevMan5.3 software was used for data analysis. The I2 combined with χ (2) test was used to evaluate the heterogeneity. Funnel plots were used to evaluate the publication bias of the included literature. Results: A total of 12 articles were included. Statins application had significantly reduced the risk of hepatocellular carcinoma in patients with chronic liver disease (OR = 0.50, 95% CI: 0.43~0.58, P < 0.01). Subgroup analysis showed that statins had reduced the incidence rate of hepatocellular carcinoma in patients with chronic hepatitis B (OR = 0.56, 95% CI: 0.47~0.66, P < 0.01) and chronic hepatitis C (OR = 0.56, 95% CI: 0.45~0.71, P < 0.01). Lipophilic statins had significantly reduced the risk of chronic liver disease development to hepatocellular carcinoma (OR = 0.48, 95% CI: 0.39~0.59, P < 0.01), but hydrophilic statins did not reduce the incidence rate of chronic liver disease development to hepatocellular carcinoma, and the difference was not statistically significant (OR = 0.64, 95% CI: 0.36~1.14, P = 0.13). Conclusion: Statins can effectively reduce the risk of hepatocellular carcinoma development in patients with chronic liver disease, including chronic hepatitis B and C. Among them, the lipophilic statins have a significant preventive effect on the development of chronic liver disease to hepatocellular carcinoma, but hydrophilic statins have no obvious effect.

Efficacy of entecavir versus tenofovir in preventing hepatocellular carcinoma in patients with chronic hepatitis B with maintained virologic response.

Several studies suggested that efficacy of tenofovir in reducing the risk of the development of hepatocellular carcinoma (HCC) might be better than that of entecavir. It remains unknown whether a change in therapy can further reduce the risk of HCC in patients receiving entecavir therapy and achieved goal of antiviral therapy, a maintained undetectable hepatitis B virus (HBV) DNA level in the serum. A total of 1336 treatment-naïve chronic HBV mono-infected adult patients, who started entecavir or tenofovir treatment and achieved a maintained virologic response during follow-up were analysed. During a median 4.4years of follow-up (range, 1.0-7.4years) after achieving virologic response, 99 patients developed HCC. The 5-year cumulative HCC incidence rate was 7.3% and 6.3% for the entecavir and tenofovir groups, respectively, with similar risk of HCC between the two groups (adjusted HR, 0.82; 95% CI, 0.52-1.29; p=0.3). The risk of HCC was similar in the propensity score-matched cohort (HR, 1.02; 95% CI, 0.68-1.52; p=0.94) and inverse probability treatment weighting analysis (HR, 1.11; 95% CI, 0.74-1.66; p=0.62). In the subgroup analysis, HCC risk was similar between the two drugs in both patients with and without cirrhosis. In patients showing maintained virologic response, no difference in the risk of HCC between entecavir and tenofovir was observed. This indicates entecavir might be as effective as tenofovir in the prevention of HCC among those patients and suggest that a change in therapy in anticipation of further reducing the risk of HCC might not be necessary for patients receiving entecavir and showing virologic response.

Controlled attenuation parameter value and the risk of hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy.

Controlled attenuation parameter (CAP) can evaluate hepatic steatosis in patients with chronic hepatitis B (CHB). However, prognostic implications of CAP value remain unclear. We evaluated the association between CAP and the risk of hepatocellular carcinoma (HCC) in patients with CHB under antiviral therapy and maintained virologic response. A total of 1823 CHB patients who were taking nucleos(t)ide analogue and showing suppressed hepatitis B virus replication were analyzed. The primary outcome was incident HCC during follow-up. Patients were grouped into those with and without advanced chronic liver disease (ACLD) (liver stiffness measurement cutoff: 10kPa), and those with and without hepatic steatosis (CAP cutoff: 222dB/m). During 6.4years of follow-up, 127 patients (7.0%) newly developed HCC. Among patients with ACLD (n = 382), the cumulative HCC incidence rate was lower for those with CAP ≥ 222 (11.0% at 5years) than those with CAP < 222 (24.0% at 5years, p = 0.002), and was an independent factor associated with HCC. When CAP value was further stratified, the cumulative HCC incidence rate decreased in dose-dependent manner according to an increase in CAP value (24.0%, 13.9%, 12.8% and 6.0% at 5years for those with CAP < 222, 222-246, 247-273 and ≥ 274, respectively). Among patients without ACLD (n = 1441), there was no significance difference in HCC risk according to CAP value (HCC incidence rate: 3.3% and 4.0% at 5years for those with CAP < 222 and CAP ≥ 222, p = 0.20). Among CHB patients under antiviral therapy showing suppressed HBV replication, low CAP value predicted higher risk for HCC among ACLD patients, indicating that CAP value has a prognostic implication in this population.

Association of Physical Activity with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B.

Simple SummaryAlthough viral replication in patients with a chronic hepatitis B (CHB) infection is effectively suppressed by potent antiviral therapy such as entecavir or tenofovir, the risk of hepatocellular carcinoma (HCC) development in CHB patients cannot be totally eliminated. Thus, control of modifiable risk factors for HCC development such as lifestyle modification is important to minimize the HCC risk. In this study, we analyzed a nationwide population-based cohort to evaluate whether there is a significant association between physical activity and development of HCC in CHB patients treated with entecavir or tenofovir. Results in this study suggest that physical activity was significantly associated with a lower risk of HCC development in CHB patients treated with potent antiviral therapy. Increasing physical activity can have beneficial outcomes on HCC development in CHB patients treated with entecavir or tenofovir.Background and Aims: In the general population, previous studies reported that physical activity was associated with risk of hepatocellular carcinoma (HCC) development. However, it is unclear whether physical activity is associated with risk of HCC development in patients with chronic hepatitis B (CHB). We aimed to elucidate the association between physical activity and risk of HCC development in CHB patients. Methods: This nationwide cohort study involved treatment-naive patients with CHB (n = 9727) who started treatment with entecavir or tenofovir and answered self-reported questionnaires between January 2012 and December 2017, using data from the Korean National Health Insurance Service database. The primary endpoint was development of HCC. Multivariable Cox regression and competing risk analyses were used. Results: During a median follow-up of 3.1 years, cumulative HCC incidence rates were 8.3%. There was an inverse association between physical activity and the risk of HCC (p < 0.001). Patients with 1000–1500 metabolic equivalent task (MET)-min/week, compared to those without physical activity, showed a significantly lower risk of HCC in both patients without cirrhosis (adjusted hazard ratio [aHR] 0.66, p = 0.02) and patients with cirrhosis (aHR 0.61, p = 0.02). In patients who were younger (<60), male, without diabetes, and with high BMI, amounts of physical activity of 1000–1500 MET-min/week showed an inverse association with the risk of HCC (aHR 0.65, 0.63, 0.65, and 0.64, respectively, all p < 0.05). Conclusion: Physical activity was significantly associated with a low risk of HCC in CHB patients treated with entecavir or tenofovir.

Abstract 748: Conjugated primary bile acids as a biomarker for hepatocellular carcinoma risk in two prospective cohorts

Abstract Background: Incidence rates of hepatocellular carcinoma (HCC) has been increasing for several decades in the U.S. Non-alcoholic liver disease (NAFLD) increasingly plays a role in the rising rate of HCC. Experimental data have shown that bile acids, which play key roles in the host-gut microbiota co-metabolism, contribute to the development of NAFLD and HCC. We propose to comprehensively examine the associations of bile acids with risk of HCC in two cohorts. Methods: Thirty-five bile acids were quantified using the state-of-the-art ultraperformance liquid chromatography triple-quadrupole mass spectrometry assays in serum samples collected, on average, five years prior to diagnosis of 197 HCC and the same number of individually matched controls from the Singapore Chinese Health Study and the Shanghai Cohort Study. Conditional logistic regression was used to assess the associations for major bile acids and their conjugates, and bile acid ratios with the risk of HCC. Results: Total primary bile acids were significantly elevated whereas the ratio of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls in both cohorts (P's ≤ 0.001). Doubling of tauro- vs. glyco-conjugates of all bile acids, primary bile acids, and specifically chenodeoycholic acid resulted in an increase in HCC risk of 44, 48, and 34% (P = 0.004, &amp;lt;0.001, 0.001) respectively after adjustment for potential confounders. Conclusion: Primary bile acids, especially tauro-conjugated bile acids were strongly associated with increased risk of HCC risk whereas the secondary vs. primary bile acids ratios were associated with decreased risk of HCC. Citation Format: Claire Elizabeth Thomas, Hung Luu, Renwei Wang, Guoxiang Xie, Jennifer Adams-Haduch, Aizhen Jin, Woon-Puay Koh, Wei Jia, Jaideep Behari, Jian-Min Yuan. Conjugated primary bile acids as a biomarker for hepatocellular carcinoma risk in two prospective cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 748.

Systemic Treatment for Older Patients with Unresectable Hepatocellular Carcinoma.

The incidence rate of hepatocellular carcinoma is growing and age at diagnosis is increasing; however, despite the unprecedented wealth of therapeutic options for advanced HCC, its optimal management in some categories, such as older adults, is yet to be defined. Even though age is not an exclusion criterion per se, most of the landmark trials enrolled a limited number of senior patients, raising some concerns on the potential benefit of active treatments in this group. The identification of more vulnerable patients remains a crucial issue in clinical practice. In fact, the suitability assessment for systemic therapy through performance status metrics might underestimate or conversely overestimate the fitness of older patients, failing to detect other relevant impairments. Thus, the assessment of frailty through geriatric screening scales is largely necessary. In addition, most of the available data relate to the use of sorafenib, while very little is known about the most recent therapeutic agents. Age subgroup analyses provided by many of the pivotal trials did not find significant efficacy or safety differences across ages; however, the most widely used cut-off age of 65 years may not be very informative for the current older population. Regarding immunotherapy, the clinical benefit reported with immune checkpoint inhibitors reassures their safe use in senior patients and supports further investigations to assess their efficacy in this population.

Hepatitis B core-related antigen predicts disease progression and hepatocellular carcinoma in hepatitis B e antigen-negative chronic hepatitis B patients.

The serum hepatitis B core-related antigen (HBcrAg) is considered a surrogate marker of the amount and activity of intrahepatic covalently closed circular DNA. This study aims to investigate the virological characteristics of HBcrAg in chronic hepatitis B (CHB) patients and to reveal the hepatocellular carcinoma (HCC) risk factors of hepatitis B e antigen (HBeAg)-negative patients. Hepatitis B core-related antigen was measured in 245 naive CHB patients before receiving nucleoside/nucleotide analog (NA) therapy. All patients were receiving NA (entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide) continuously for more than 1year until the end of follow-up, and they did not have a history of HCC. Hepatitis B viral status was compared between 106 HBeAg-positive and 139 HBeAg-negative patients. Median HBcrAg levels were significantly higher in HBeAg-positive patients than in HBeAg-negative patients (>6.8 vs 3.7log U/mL, P<0.01). In HBeAg-negative patients, higher HBcrAg levels were associated with cirrhosis (119 chronic hepatitis/20 cirrhosis=3.5/4.7log U/mL, P=0.03) and higher serum hepatitis B virus DNA. During a median follow-up of 5.28 (1.03-12.0) years, the 5-year cumulative HCC incidence rate was 5.4% in the HBeAg-negative cohort. In the multivariate Cox regression analysis, higher HBcrAg levels at 1year were independent predictive factors for HCC development in HBeAg-negative patients who received NA therapy (cutoff value, 4.1log U/mL; hazard ratio, 6.749; 95% confidence interval, 1.334-34.15, P<0.01) and even in non-cirrhosis patients. Hepatitis B core-related antigen was useful for understanding disease progression in CHB patients and for stratifying the risk for carcinogenesis in HBeAg-negative patients receiving NA therapy.

State-Level HCC Incidence and Association With Obesity and Physical Activity in the United States.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with a disproportionate impact on racial/ethnic minority groups. However, state-level variation in racial/ethnic disparities and temporal trends of HCC incidence remain unknown. Therefore, we aimed to characterize (1) state-level racial/ethnic disparity in HCC incidence, (2) state-level temporal changes in HCC incidence, and (3) the ecological correlation between HCC incidence and obesity/physical activity levels in the USA. Trends in HCC incidence between 2001 and 2017 were calculated using data from the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology and End Results, and annual percent change in rates were calculated. State-level percent of obesity and level of physical activity were obtained from the Centers for Disease Control and Prevention, and the correlation among obesity, physical activity, and state-specific average annual percent change was tested by Pearson correlation coefficient. There were striking state-level racial/ethnic disparities in HCC incidence; incidence rate ratios ranged between 6.3 and 0.9 in Blacks, 6.1 and 1.7 in Asians/Pacific Islanders, 3.8 and 0.9 in Hispanics, and 6.0 and 0.9 in American Indians/Alaska Natives (compared with Whites as reference). Despite overall decreasing HCC incidence rates after 2015, HCC incidence continued increasing in 26 states over recent years. HCC incidence trends had a moderate correlation with state-level obesity (r=0.45, P<0.001) and a moderate inverse correlation with state-level physical activity (r=-0.40, P=0.004). There is wide state-level variation in racial/ethnic disparity of HCC incidence. There are also disparate incidence trends across states, with HCC incidence continuing to increase in over half of the states. Regional obesity and lack of physical activity have moderate correlations with HCC incidence trends, suggesting that interventions targeting these factors may help curb rising HCC incidence.

Association of liver stiffness and steatosis with hepatocellular carcinoma development in patients with hepatitisC virus infection who received direct-acting antiviral therapy and achieved sustained virological response.

The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with chronic hepatitisC virus who receive direct-acting antiviral therapy and achieve sustained virological response. This study investigated two risk factors for HCC in these patients; specifically, hepatic fibrosis and steatosis. A total of 355 patients in whom hepatitisC virus was eradicated by direct-acting antiviral were evaluated. Fibrosis and steatosis were assessed using transient elastography (TE) and the controlled attenuation parameter (CAP). Inverse probability weighting was applied to patient age, sex, albumin-bilirubin, α-fetoprotein, history of HCC, TE, or CAP. The 12-, 24-, and 36-month cumulative incidence rates of HCC were 0.9%, 2.4%, and 4.1%, respectively. Univariate analysis with the Cox proportional hazards model showed that whereas a high TE value (≥10kPa) was significantly associated with HCC development (HR 7.861, 95% CI 2.126-29.070; p=0.002), CAP was not. Additionally, univariate analysis with the Cox proportional hazards model adjusted by inverse probability weighting showed that a high TE value was significantly associated with HCC development (HR 3.980, 95% CI, 1.036-15.290; p=0.044), whereas CAP was not. The cumulative inverse probability weighting-adjusted incidence of HCC rates at 12, 24, and 36months were 0.0%, 0.5%, and 1.7%, respectively, in patients with a low TE value, and 2.5%, 5.1%, and 7.6%, respectively, in those with a high TE value. A high TE value was a risk factor for HCC in hepatitisC virus patients who received direct-acting antiviral therapy and achieved sustained virological response.

Comparison of Hepatocellular Carcinoma in Hispanic and Non-Hispanic Patients.

Background: Hepatocellular carcinoma (HCC) is the fastest growing cancer in the United States. Studies have shown that compared to Blacks and non-Hispanic Whites, Hispanics have a higher HCC incidence and mortality rate. Most studies investigating HCC in Hispanics have been conducted utilizing data largely from the Western and Southern United States. These findings may, however, not be highly representative of Hispanics in the Northeast, given the nonhomogenous distribution and diversity of Hispanics across the United States.Methods: Some 148 HCC patients diagnosed between 1996 and 2012 were identified from a tertiary center in the northeastern United States. Hispanic patients were randomly matched to non-Hispanic White patients by year of diagnosis. Patient characteristics, HCC risk factors, treatment, and outcome were recorded. A Kaplan-Meier (KM) plot with log-rank tests was used for survival analysis.Results: Compared to non-Hispanic White patients (n=89), Hispanic HCC patients (n=59) were more likely to have chronic hepatitis C infection (69.5% vs. 38.2%, p < 0.01), alcoholic liver disease (37.3% vs. 21.4%, p = 0.04) and were less likely to have chronic hepatitis B infection (6.8% vs. 24.7%, p = 0.01), and private insurance (37.3% vs. 57.3%, p = 0.02). Hispanics were more likely to be diagnosed with an earlier stage disease (Barcelona Clinic Liver Cancer, BCLC stages A and B) compared to non-Hispanic patients (71.7% vs. 36.8%, p < 0.01) and were more likely to receive locoregional treatment. Although Hispanics trended towards improved overall survival, this finding did not hold when stratified by the BCLC stage.Conclusion: Risk factors for HCC in the northeastern Hispanic population are like those found among Hispanics in other US regions. Other research suggests Hispanics are at increased risk for hepatic injury and HCC. However, HCC in this northeastern Hispanic population appears to be less aggressive (earlier stage and trend towards better overall survival) than non-Hispanics. Further research may be needed to identify potential differences by ethnic group for HCC risk factors, presentation, and outcomes.

Risk analysis for hepatocellular carcinoma in patients with chronic hepatitis B-associated cirrhosis complicated by type 2 diabetes mellitus: a 5-year prospective cohort study

To elucidate the risk and synergistic factors of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B-associated cirrhosis (CHB-Cir) complicated by type 2 diabetes (T2DM). The patients with CHB-Cir who were followed up in Hepatology Center of Nanfang Hospital from June 2010 to June 2019 were divided based on their T2DM status into two cohorts matched for gender, age, HBeAg status and HBV DNA load: CHB-Cir with T2DM group (observation group) and CHB-Cir without T2DM group (control group). All the patients were followed up at a 6-month interval, and the cases with complete clinical data and follow-up data for more than 2 years were included in the analysis. Kaplan- Meier method was used to compare the cumulative incidence of HCC between the two groups. A Cox proportional hazard regression model was used to analyze the relationship between T2DM and the risk of HCC in these patients. A total of 467 patients with a mean follow-up time of 4.4±1.62 years were included in the analysis, including 203 in the observation group and 264 in the control group. Sixty-nine and forty-eight new HCC cases occurred in the observation group and control group, respectively, showing a significantly higher incidence rate of HCC in the observation group (P < 0.001). The cumulative incidence of HCC in the observation group was significantly higher than that in the control group (P < 0.001), with a relative risk of 2.096 (P < 0.01). After adjustment for age (≥40 years), family history of liver cancer, previous antiviral therapy, elevated cholesterol and elevated LDL cholesterol, T2DM remained an independent risk factor for HCC in CHB-Cir patients (P=0.000). T2DM is an independent risk factor for HCC, and the risk of HCC increases by more than two folds in CHB-Cir patients complicated by T2DM, suggesting the clinical significance of early interventions of diabetes to reduce the risk of HCC in CHB-Cir patients.

Prediction of Hepatocellular Carcinoma by On-Therapy Response of Noninvasive Fibrosis Markers in Chronic Hepatitis B.

Antiviral therapy improves hepatic fibrosis and reduces hepatocellular carcinoma (HCC) incidence. This study aimed to evaluate whether on-therapy changes in scores for fibrosis index based on 4 factors and aspartate aminotransferase-to-platelet ratio index are associated with HCC development and establish an HCC risk score model incorporating noninvasive fibrosis marker (NFM) response. This multicenter study recruited 5,147 patients with chronic hepatitis B (4,028 for derivation cohort and 1,119 for validation cohort) who were given entecavir/tenofovir for >12 months between 2007 and 2018. A risk prediction model for HCC was developed using predictors based on multivariable Cox models, and bootstrapping was performed for validation. The 10-year cumulative HCC incidence rates were 12.6% and 13.7% in the derivation and validation cohorts, respectively. The risk of HCC significantly differed with early NFM response, with a marked reduction in HCC risk in patients achieving a significant decrease in NFM by 12 months (P < 0.001). NFM response, sex, age, and cirrhosis were independently predictive of HCC. We developed the Fibrosis marker response, Sex, Age, and Cirrhosis (FSAC) score based on regression coefficients of each variable. For the 10-year prediction of HCC, FSAC showed higher C-index values than PAGE-B, modified PAGE-B, CU-HCC, and REACH-B (0.84 vs 0.77, 0.80, 0.77, and 0.67, respectively; all P < 0.005). The predictive performance of FSAC was corroborated in the validation cohort, with higher C-index than other models (all P < 0.050). On-therapy changes in NFM are an independent indicator of HCC risk. FSAC incorporating NFM response is a reliable risk score for risk estimation for HCC with better performance than other models.

International Liver Cancer Association (ILCA) White Paper on Biomarker Development for Hepatocellular Carcinoma

International Liver Cancer Association (ILCA) White Paper on Biomarker Development for Hepatocellular Carcinoma

Long-term effectiveness of population-wide multifaceted interventions for hepatocellular carcinoma in Taiwan

Taiwan has launched a series of population-wide interventions to prevent hepatocellular carcinoma (HCC) related to hepatitis B and C virus infection since 1984. We took this opportunity to investigate the impact of each intervention on the incidence and case-fatality rate of HCC, and assessed their relative contributions to the overall reduction in mortality during this period. Population-based registry data on HCC mortality and incidence from individuals aged 0 to 84 years between 1979 and 2016 were collected before (Period 1) and after universal hepatitis B vaccination from 1984 (Period 2), universal health care from 1995 (Period 3), and viral hepatitis therapy from 2003 (Period 4). A Bayesian Poisson regression model was used for mortality decomposition analysis to estimate the respective contributions of these interventions to the reduction in age-specific incidence and case-fatality rates. Mortality declined substantially in children, young- and middle-aged groups, but only slightly decreased in the elderly group. The declining trends in mortality were in part explained by incidence reduction and in part by a remarkable decline in case-fatality rate attributed to universal health care. Hepatitis B vaccination led to a 35.9% (26.8% to 44.4%) reduction in incidence for individuals aged 30 years or below, whereas antiviral therapy reduced the incidence of HCC by 14.9% (11.8% to 17.9%) and 15.4% (14.1% to 16.6%) for individuals aged 30-49 years and 50-69 years, respectively. Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups. Since 1984, a series of population-wide interventions have been launched in Taiwan to prevent viral hepatitis-related hepatocellular carcinoma, including a universal hepatitis B vaccination program (from 1984), universal health care (from 1995), and a national viral hepatitis therapy program (from 2004). Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups.