High Risk Of Developing Hepatocellular Carcinoma Research Articles

Hepatocellular carcinoma surveillance in cirrhotic patients: Beyond guidelines

Hepatocellular carcinoma (HCC) surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival. HCC surveillance is a complex process, with failure at any step in the process contributing to a gap between its efficacy and effectiveness. Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance, but it has limited sensitivity in early disease and may be inadequate in certain individuals. HCC surveillance implementation can be affected by either provider or patient-related factors. Proper screening for HCC is a continuum of services, extending from initial patient screening, diagnosis, treatment and ultimately surveillance. As one may expect, there are numerous chances for failure in the delivery of cancer screening care. When considering the risk versus benefits of HCC surveillance, we must consider the possible harm to the patient. Such concerns include false-positive testing resulting in unnecessary and risk-associated procedures such as liver biopsy, overdiagnosis of HCC among patients with cirrhosis, as well as false-negative investigations resulting in delayed diagnosis of HCC. The development of tools to enhance our ability in optimizing available surveillance is likely to improve the prognosis of patients with HCC. This review article will provide a comprehensive overview of the rationale behind current HCC surveillance guidelines, their utilisation, effectiveness, limitations, benefits, and harms as well as methods to improve the outcome of HCC surveillance.

CAGE-B and SAGE-B models better predict the hepatitis B virus-related hepatocellular carcinoma after 5-year of entecavir treatment than PAGE-B.

The PAGE-B model consists of variables at the initiation of antiviral therapy (AVT), whereas the SAGE-B and CAGE-B models consist of variables after 5 years of AVT. We compared the predictive accuracy of three risk prediction models for hepatocellular carcinoma (HCC) development after 5 years of AVT in patients with chronic hepatitis B (CHB). A total of 1,335 patients who initiated entecavir (ETV) treatment between 2006 and 2011 and were followed up for more than 5 years were enrolled in the stduy. At ETV initiation, the median age of the patients was 49 years and the median of the PAGE-B model was 14. After 5 years of ETV treatment, the median SAGE-B and CAGE-B values were 6 and 6, respectively. During the study period, 93 (7.0%) patients developed HCC after 5-year treatment. In multivariate analysis, PAGE-B (hazard ratio [HR], 1.151; 95% confidence interval [CI], 1.087-1.219), SAGE-B (HR, 1.340; 95% CI, 1.228-1.463), and CAGE-B (HR, 1.327; 95% CI, 1.223-1.440) models independently predicted HCC development after 5 years of treatment (all P<0.001). The high-risk groups of the three risk prediction models showed a significantly higher risk of HCC development compared to the medium- and low-risk groups (all P<0.05). The areas under the receiver operating characteristic curves of the SAGE-B (0.772-0.844) and CAGE-B (0.785-0.838) models were significantly higher than those of the PAGE-B model (0.696-0.745) in predicting HCC development after 5 years of treatment (all P<0.05). The SAGE-B and CAGE-B models might be better than the PAGE-B model in predicting HCC development after 5 years of ETV treatment in patients with CHB.

Should we undertake surveillance for HCC in patients with MAFLD?

Over the last decade, metabolic-associated fatty liver disease (MAFLD) has become an important public health issue worldwide. In many countries, MAFLD has become the most common cause of chronic liver disease. On the contrary, hepatocellular carcinoma (HCC) mortality is rising. Liver tumors have become the third cause of cancer mortality worldwide. HCC is the most frequent liver tumor. While the burden of HCC related to viral hepatitis is declining, the prevalence of MAFLD-related HCC is rising rapidly. Classical screening criteria for HCC consider cirrhotic, advanced fibrosis, and viral hepatitis patients. Metabolic syndrome with liver involvement or MAFLD is associated with a higher risk of HCC development, even in the absence of cirrhosis. The question about the cost effectiveness of surveillance for HCC in MAFLD is yet not fully answered. There are no guidelines that address the question of when to start or how to define the population who can benefit of surveillance for HCC in MAFLD patients. This review aims to revise the evidence of HCC development in MAFLD. It hopes to be a step closer to defining screening criteria for HCC in MAFLD.

Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan

Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy. Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases. Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications. Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR. The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.

Older Age and High α-Fetoprotein Predict Higher Risk of Hepatocellular Carcinoma in Chronic Hepatitis-B-Related Cirrhotic Patients Receiving Long-Term Nucleos(t)ide Analogue Therapy.

Background: Nucleos(t)ide analogues (NUCs) were proved to reduce hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients, but data were limited on their efficacy in cirrhotic CHB patients. Methods: A total of 447 cirrhotic CHB patients treated with tenofovir/entecavir were retrospectively analyzed and divided into HCC (n = 48) and non-HCC (n = 399) groups. The median follow-up period was 62.1 months. Results: A total of 48 patients (10.7%) developed HCC during surveillance. The annual incidence rate of HCC was 2.04 per 100 person-years. The cumulative incidence of HCC was 0.9%, 9.8%, and 22.1% at 1, 5, and 10 years, respectively. Significant predictors for HCC identified using a multiple Cox regression analysis were age ≥50 years (hazard ratio (HR): 2.34) and α-fetoprotein (AFP) ≥8 ng/mL (HR: 2.05). The incidence rate of HCC was 8.67-fold higher in patients with age ≥50 years and AFP ≥8 ng/mL (3.14 per 100 person-years) than those with age <50 years and AFP <8 ng/mL (0.36 per 100 person-years). Conclusions: Cirrhotic CHB patients with age <50 years and AFP <8 ng/mL had the lowest annual incidence of HCC. However, those with age ≥50 years or/and AFP ≥8 ng/mL had a significantly higher risk for HCC development and warrant a careful surveillance schedule.

Combined ultrasound and magnetic resonance elastography predict hepatocellular carcinoma after hepatitis C virus eradication.

Elastography is an established, noninvasive method for measuring liver stiffness using to 2-D shear-wave elastography (2D-SWE) or magnetic resonance elastography (MRE). The aim of this study was to determine the usefulness of combined measurement using 2D-SWE and MRE to stratify the risk of developing hepatocellular carcinoma (HCC) in patients who achieved hepatitis C virus eradication. Five hundred and twenty-five patients who underwent 2D-SWE and MRE before antiviral therapy and who achieved eradication were enrolled. The optimal 2D-SWE and MRE cutoff values were determined using time-dependent receiver operating characteristic (ROC) curves for predicting HCC development. Inverse probability of treatment weighting (IPTW) and a Cox proportional hazards model were used to adjust the cumulative incidence rate of HCC development for potential imbalances. Time-dependent ROC analysis showed that the optimal cut-off values of 2D-SWE and MRE for predicting HCC development were 11.7 and 4.5kPa, respectively. The IPTW-adjusted cumulative incidence rate of HCC development in patients with both an 2D-SWE value≥11.7kPa and an MRE value≥4.5kPa had a higher hazard ratio (28.080; 95% confidence interval, 5.527-132.600; p<0.001) than those with either an 2D-SWE value<11.7kPa or an MRE value<4.5kPa. The combined measurement of 2D-SWE and MRE was very effective for identifying patients at high risk of HCC development. US-based elastography should be performed first, and if the 2D-SWE value is high, MRE should then be carried out to confirm the degree of liver stiffness.

Approaches for Detection of Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins and Their Application in Prediction of Higher Risk of Hepatocellular Carcinoma Development and Recurrence.

Hepatocellular carcinoma (HCC) is among the most common and lethal human cancers worldwide and is closely associated with chronic hepatitis B virus (HBV) infection. Pre-S deleted proteins are naturally occurring mutant forms of HBV large surface proteins that are expressed by HBV surface genes harboring deletion mutations over the pre-S gene segments. It has been well demonstrated that HBV pre-S deleted proteins function as important oncoproteins, which promote malignant phenotypes of hepatocytes through the activation of multiple oncogenic signaling pathways and result in HCC formation. The oncogenic signaling pathways activated by pre-S deleted proteins have been verified as potential therapeutic targets for the prevention of HCC development. Moreover, the presence of pre-S gene deletions and the expression of pre-S deleted proteins in the blood and liver tissues of HBV-infected patients have been evaluated as valuable biomarkers for predicting a higher risk of HCC development and recurrence after curative surgical resection. Therefore, the precise detection of pre-S gene deletions and pre-S deleted proteins holds great promise as regards identifying the patients at higher risk of HCC development and recurrence, thus aiding in more timely and better treatments to improve their survival. This review summarizes the major approaches used for the detection of pre-S gene deletions and pre-S deleted proteins, including the approaches based on Sanger DNA sequencing, pre-S gene chips, next-generation sequencing and immunohistochemistry staining, and it highlights their important applications in the prediction of higher risks of HCC development and recurrence.

Hepatocellular carcinoma surveillance: current practice and future directions.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer incidence and mortality worldwide. Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival. Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance, but it has limited sensitivity in early disease and may be inadequate in certain individuals. This review article will provide a comprehensive overview of the current landscape of HCC surveillance, including the rationale and indications for HCC surveillance, standard methods for HCC surveillance, and their strengths/limitations. Alternative surveillance methods such as the role of cross-sectional imaging, emerging circulating biomarkers, as well as the problem of under-utilization of HCC surveillance and surveillance-related harms will also be discussed in this review.

Tolloid-like 1 gene variant rs17047200, pretreatment FIB-4, ALBI and PALBI scores as predictors of hepatocellular carcinoma occurrence after directly acting antivirals.

Identifying persons at increased risk of developing hepatocellular carcinoma (HCC) after exposure to directly acting antivirals (DAAs) is of utmost importance. Our aim was to identify the predictors of de novo HCC occurrence among cirrhotic patients after hepatitis C virus (HCV) treatment using DAAs. 529 cirrhotic patients who initiated treatment for HCV using DAAs were followed up for 2 years from the end of treatment for development of HCC. Pretreatment clinical and laboratory data were assessed as possible predictors for HCC occurrence. Genotyping for tolloid-like 1 gene (TLL1) variant rs17047200 was assessed in all patients who developed HCC and in the matched control group. Pretreatment bilirubin, FIB-4 and platelet-albumin-bilirubin (PALBI) scores were significantly higher among those who developed HCC than those who did not develop HCC during the 2-year follow-up period while hemoglobin level was significantly lower. ROC curve analysis revealed that at a cut-off ≥ 3.07, pretreatment FIB-4 had a sensitivity of 76.5%, and negative predictive value (NPV) of 92%. At a cut-off ≥ -2.5, pretreatment PALBI score had a sensitivity of 82.4%, and NPV of 93.2%. Regarding genotyping for TLL1 rs17047200 there were no statistically significant differences between those who developed HCC during follow-up and the matched control group. TLL1 rs17047200 genotyping is not helpful in predicting HCC occurrence after DAAs. On the other hand, lower pretreatment hemoglobin level and higher pretreatment bilirubin, FIB-4 and PALBI scores are associated with higher risk of HCC development after DAAs.

Risk of hepatocellular carcinoma in hepatitis B and D virus co-infected patients: A systematic review and meta-analysis of longitudinal studies.

Hepatitis D virus (HDV) infection causes a severe chronic viral hepatitis with accelerated development of liver cirrhosis and decompensation, but whether it further increases the risk of hepatocellular carcinoma (HCC) is unclear. We performed a comprehensive systematic review of the published literature and meta-analysis to assess the risk of HCC in HDV and hepatitis B virus (HBV) co-infected, compared to HBV mono-infected patients. The study was conducted per a priori defined protocol, including only longitudinal studies, thus excluding cross-sectional studies. Random-effects models were used to determine aggregate effect sizes (ES) with 95% confidence intervals (CI). Meta-regression was used to examine the associations among study level characteristics. Twelve cohort studies comprising a total of 6099 HBV/HDV co-infected and 57,620 chronic HBV mono-infected patients were analysed. The overall pooled ES showed that HBV/HDV co-infected patients were at 2-fold increased risk of HCC compared to HBV mono-infected patients (ES=2.12, 95% CI 1.14-3.95, I2 =72%, N=12). A six-fold significant increased risk of HCC was noted among HIV/HBV/HDV triple-infected, compared to HIV/HBV co-infected patients. The magnitude of ES did not differ significantly after adjustment for study design and quality, publication year and follow-up duration in univariable meta-regression analysis. This systematic review and meta-analysis shows that infection with HDV is associated with a 2-fold higher risk of HCC development compared to HBV mono-infection. HCC surveillance strategies taking this increased risk into account, and new treatment options against HDV, are warranted.

Prediction of hepatocellular carcinoma using fibro markers in Egyptian patients with chronic liver disease

Objective The aim was to evaluate inflammatory and fibrosis markers as predictors for hepatocellular carcinoma (HCC) development among patients with chronic liver disease (CLD). Background Progression of liver fibrosis in chronic hepatitis C is closely associated with the high risk of HCC development. Patients and methods This study was conducted on 100 patients suffering from liver cirrhosis as group A and 100 patients suffering from liver cirrhosis with HCC as group B from January 2018 to April 2019. Diagnosis of CLD was based on clinical, laboratory, and imaging evidence of CLD with and without hepatic decompensation or portal hypertension. Results Child–Pugh C patients was significantly more prevalent in HCC (37 vs 10% in liver cirrhosis cases). Serum hemoglobin, albumin, and leukocytic count were significantly lower in HCC cases. Also, α-fetoprotein, bilirubin international normalized ratio, and blood urea were highly significantly higher in the HCC group than the non-HCC group. King's score, fibro-quotient (Fibro Q), and FIB-4 scores were significantly higher in HCC than in cirrhotic cases, while blood red cells and Fibro-α scores were highly significantly higher in group B than in group A. Conclusion Our findings have shown the possibility to predict HCC development in Egyptian patients suffering from chronic hepatitis C by using noninvasive scores, (Fibro markers) as they performed well, cheap, and easy to perform.

Natural History and Hepatocellular Carcinoma Risk in Untreated Chronic Hepatitis B Patients With Indeterminate Phase

Many patients with chronic hepatitis B (CHB) may not conform to any of the defined phases and hence are classified as indeterminate. We aimed to characterize the baseline prevalence of indeterminate patients and their natural history, phase transition, and hepatocellular carcinoma (HCC) risk. This was a retrospective cohort study of 3366 adult untreated noncirrhotic CHB patients seen at 5 US clinics and 7 Taiwanese townships who had at least 1 year of serial laboratory data before enrollment with a mean follow-up period of 12.5 years. Patients' clinical phases were determined at baseline and through serial data during follow-up evaluation, based on the American Association for the Study of Liver Diseases 2018 guidance. At baseline, 1303 (38.7%) patients were in the indeterminate phase. By up to year 10 of follow-up evaluation, 686 patients (52.7%) remained indeterminate, while 283 patients (21.7%) became immune active. Compared with patients who remained inactive, patients who remained indeterminate had a higher 10-year cumulative HCC incidence (4.6% vs 0.5%; P < .0001) and adjusted hazard ratio for HCC of 14.1 (P= .03). Among patients who remained indeterminate, age 45 years and older (adjusted hazard ratio, 18.4; P= .005) was associated independently with HCC development. Nearly 40% of patients had indeterminate CHB phase. Of these, half remained indeterminate and one-fifth transitioned to the immune active phase. HCC risk in persistently indeterminate CHB was 14 times higher than inactive CHB. Among persistently indeterminate CHB patients, age 45 years and older was associated with an 18 times higher risk for HCC development. Further studies are needed to evaluate the potential benefit of antiviral therapy for indeterminate patients, especially in the older subgroup.

Change in γ-glutamyl transpeptidase activity as a useful tool in identifying a group of patients with elevated risk of hepatocellular carcinoma development after DAA treatment of chronic hepatitis C.

Aim of the studyHepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) incidence will be diminishing due to use of direct acting antiviral agents (DAA), but there is still constant risk for HCC development. Elevated serum g-glutamyl transpeptidase (GGT) activity is associated with increased risk of liver cancer. In our study we tried to determine whether change in GGT activity may be useful in identifying patients with elevated risk of HCC development after DAA treatment.Material and methodsThe study population consisted of 111 patients with chronic hepatitis C (CHC) treated with DAA. Laboratory tests [alanine aminotransferase (ALT), GGT, a-fetoprotein (AFP)] and liver stiffness measurement (using FibroScan) were performed at the beginning and at the end of therapy.ResultsPre-treatment ALT activity, GGT activity and AFP concentration in patients with CHC were directly associated with the stage of liver fibrosis. Elimination of HCV after DAA treatment caused significant reduction in serum GGT activity and was not associated with pre-treatment liver fibrosis. AFP concentration was significantly lower after treatment. It was observed regardless of pre-treatment AFP concentration, but the largest reduction was demonstrated in the group of patients with advanced fibrosis. In multivariate analysis there was no significant difference in GGT activity after treatment only in patients with pre-treatment normal AFP concentration and advanced liver fibrosis.ConclusionsPatients who after achieving a sustained virological response (SVR) did not lower both AFP concentration and GGT activity may have higher risk of HCC development. Special monitoring may be required in patients with advanced liver fibrosis and normal AFP concentration before treatment.

Alpha-Fetoprotein, Protein Induced by Vitamin K Absence or Antagonist II and Glypican-3 for the Detection and Prediction of Hepatocellular Carcinoma in Patients with Cirrhosis of Viral Etiology.

Simple SummaryCirculating biomarkers for the early detection and prediction of hepatocellular carcinoma development are an unmet need. In the present study, we observed that serum values of three biomarkers (namely AFP, PIVKA-II and GPC-3) were significantly different between patients with cirrhosis and those with hepatocellular carcinoma; the best accuracy for the detection of tumors was achieved by a combination of AFP + PIVKA-II. However, PIVKA-II resulted as the only biomarker able to identify patients with cirrhosis at increased risk of hepatocellular carcinoma development. The measurement of PIVKA-II in patients with cirrhosis at risk of tumor development may be useful to tailor personalized surveillance strategies and thus to improve patients’ survival.International guidelines recommend the use of ultrasound as a surveillance tool for hepatocellular carcinoma (HCC) in patients with cirrhosis, while the role of serum biomarkers is still debated. We investigated serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II) and glypican-3 (GPC-3) diagnostic accuracy for HCC detection and prediction in patients with liver cirrhosis of viral etiology under surveillance. A total of 349 patients (200 cirrhosis and 149 HCC) were enrolled. The 200 patients with cirrhosis consisted of 114 patients still HCC-free after 36 months of follow-up and 86 patients that developed HCC after 13.8 (11.0–19.8) months. AFP, PIVKA-II and GPC-3 were measured in serum samples collected at tumor diagnosis in the 149 patients with HCC, and at the beginning of follow-up in the 200 patients with cirrhosis. The higher performance for HCC detection was observed for PIVKA-II (area under the curve (AUC) = 0.790), followed by AFP (AUC = 0.737) and GPC-3 (AUC = 0.637); the combination of AFP + PIVKA-II improved the diagnostic accuracy to AUC = 0.822. Serum PIVKA-II values, but not AFP and GPC-3, were significantly higher in the 86 cirrhotics that developed HCC compared with the 114 cirrhotics still HCC-free after 36 months of follow-up (p = 0.020). PIVKA-II ≥ 55 mAU/mL allowed to identify patients with cirrhosis at higher risk of HCC development (Log-rank test, p < 0.001; adjusted Hazard Ratio = 1.99, p = 0.001). In conclusion, the measurement of PIVKA-II in patients with cirrhosis may be useful to tailor personalized surveillance strategies.

Hepatitis B Virus Pre-S Mutants as Biomarkers and Targets for the Development and Recurrence of Hepatocellular Carcinoma.

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), the leading cause of cancer-related death worldwide. Despite progress in the prevention and therapy of HCC, high incidence and recurrence rates of HCC remain big threats, resulting in poor patient survival. Effective biomarkers and targets of HCC are therefore urgently needed for better management and to improve patient outcomes. Pre-S mutants have been well demonstrated as HBV oncoproteins that play important roles in HCC development through activation of multiple oncogenic signal pathways in hepatocytes, in vitro and in vivo. The presence of pre-S mutants in patients with chronic HBV infection and HBV-related HCC has been associated with a significantly higher risk of HCC development and recurrence after curative surgical resection, respectively. In this review, we summarize the roles of pre-S mutants as biomarkers for predicting HBV-related HCC development and recurrence, and highlight the pre-S mutants-activated oncogenic signal pathways as potential targets for preventing HBV-related HCC development.

Abstract 1050: Serum interleukin-27 serves as an early biomarker predicting development of hepatocellular carcinoma (HCC) in two large prospective cohorts

Abstract Background: Interleukin-27 (IL-27), which consists of p28 and Epstein-Barr virus induced gene 3 (EBI3) subunits, is a heterodimeric member of the IL-12/IL-23 cytokine family. Overexpression of IL-27 increases T cell expression of inhibitory receptors including PD-1, LAG3, TIGIT, and TIM3 that could limit intensity and duration of T cell responses to infection and cancer. IL-27 is overexpressed in HCC. The purpose of the study was to examine the role of IL-27 in the development of HCC in humans. Methods: Two parallel studies were conducted. The discovery study included 100 HCC cases and 100 individually matched controls from the Singapore Chinese Health Study, which enrolled 32,000 participants with blood samples free of cancer at entry into the study and subsequently followed up for &amp;gt;15 years. The validation study also included 100 HCC cases and 100 matched controls from the Shanghai Cohort Study, a prospective cohort of 18,000 participants who were free of cancer at entry and similarly followed up for &amp;gt;20 years. Human IL-27 protein was quantified in sera that were collected, on average, 4.5 year prior to the diagnosis of HCC. Conditional logistic regression method was used to estimate odds ratio (OR) and 95% confidence interval (CI) of HCC for higher tertiles of IL-27 with adjustment for hepatitis B surface antigen (HBsAg), alcohol intake, body mass index and cigarette smoking. The Cancer Genome Atlas (TCGA) data were analyzed for the IL-27 gene expression in liver and other cancers. Results: Serum IL-27 levels were significantly higher in persons who subsequently developed HCC than controls who remained free of HCC in both studies. In the discovery study, persons in the 2nd (1.39-1.95 ng/mL) and 3rd tertile of IL-27 (&amp;gt;1.95 ng/ml) had 9.3 (95% CI = 1.07-80.36) and 51.7 (95% CI = 5.1-527.8) times the risk of developing HCC, respectively, compared with the lowest IL-27 (&amp;lt;1.39 ng/ml). These novel results were confirmed in the validation study; the corresponding ORs (95% CIs) for HCC were 4.9 (1.2-19.6) and 16.3 (3.5-77.4) (both Ptrend &amp;lt; 0.001). When IL-27 and HBsAg were jointly analyzed, the OR (95% CI) of HCC was 24.73 (3.23-189.09) for lowest IL-27 &amp; positive HBsAg, 45.52 (8.71-237.91) for highest IL-27 &amp; negative HBsAg, and 265.19 (40.69-1728.45) for highest IL-27 &amp; positive HBsAg, compared with lowest IL-27 &amp; negative HBsAg. The TCGA analysis revealed that the IL-27 mRNA levels in primary liver cancer was at least 20 times higher than that of any other cancer. Conclusion: Higher serum levels of IL-27 are associated with significantly higher risk of HCC development. Implications: IL-27 can be further developed as a biomarker for identification of individuals at high risk for HCC and for diagnosis of HCC at an early stage, enabling more frequent surveillance. Anti-IL-27 agents may be developed for primary prevention of HCC. The blockade of IL-27 alone or in combination with other anti-immunosuppressive agents such as anti-PD1, anti-PD-L1, IL-2 and anti-LAG3 may represent novel immunotherapy strategies for HCC. Citation Format: Jian-Min Yuan, Wang Yue, Renwei Wang, Jennifer Admas-Haduch, Woon-Puay Koh, Yu-Tang Gao, Michael T. Lotze. Serum interleukin-27 serves as an early biomarker predicting development of hepatocellular carcinoma (HCC) in two large prospective cohorts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1050.

Hypovascular tumors developed into hepatocellular carcinoma at a high rate despite the elimination of hepatitis C virus by direct-acting antivirals.

Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) exert high anti-HCV activity and are expected to show anti-inflammatory effects associated with HCV elimination. Furthermore, hepatocellular carcinoma (HCC) is known to dedifferentiate from hypovascular tumors, such as dysplastic nodules or well-differentiated HCC, to hypervascular tumors. We therefore explored whether or not DAAs can suppress the growth and hypervascularization of hypovascular tumors. We enrolled 481 patients with HCV genotype 1 infection who were treated with Daclatasvir and Asunaprevir therapy. Of these, 29 patients had 33 hypovascular tumors, which were confirmed by contrast-enhanced MRI or CT before therapy. We prospectively analyzed the cumulative incidence of HCC, i.e. the growth or hypervascularization of hypovascular tumors, and compared the HCC development rates between patients with hypovascular tumors and those without any tumors. The mean size of the hypovascular tumors was 11.3 mm. Twenty seven of 29 patients who achieved an SVR had 31 nodules, 19 of 31 nodules (61.3%) showed tumor growth or hypervascularization, and 12 (38.7%) nodules showed no change or improvement. The cumulative incidence rates of tumor growth or hypervascularization were 19.4% at 1 year, 36.0% at 2 years, 56.6% at 3 years, and 65.3% at 4 years. Among the patients who achieved a sustained virologic response, the cumulative HCC development rates of patients with hypovascular tumors was significantly higher than in those without any tumors. A Cox proportional hazard analysis showed that a history of HCC therapy, the presence of a hypovascular tumor, and AFP >4.6 ng/mL at the end of treatment were independent risk factors for HCC development. Hypovascular tumors developed into HCC at a high rate despite the elimination of HCV by DAAs. As patients with hypovascular tumors were shown to have a high risk of HCC development, they should undergo strict HCC surveillance.

Detectable HBV DNA during nucleos(t)ide analogues stratifies predictive hepatocellular carcinoma risk score

Nucleos(t)ide analogs (NA) suppress hepatitis B virus (HBV) replication and reduce the risk of hepatocellular carcinoma (HCC). However, NA cannot suppress carcinogenesis completely in patients with chronic hepatitis B. The aims of this study were to identify risk factors for HCC and develop a refined carcinogenesis prediction model. Patients receiving NA therapy (n = 1,183) were recruited retrospectively from the 16 hospitals. All patients had been receiving NA continuously for more than 1 year until the end of the follow-up. During a median follow-up of 4.9 (1.0–12.9) years, 52 (4.4%) patients developed HCC. A multivariate analysis revealed that male gender, older age, lower platelet counts at the baseline, and detectable HBV DNA during NA therapy were independent predictive factors of HCC development. The PAGE-B score was calculated by using these factors. 240 (20.3%), 661 (55.9%), and 282 (23.8%) patients were classified into low-, intermediate-, and high-risk groups, respectively. In the intermediate- and high-risk group, detectable HBV DNA was significantly associated with a higher risk of HCC development compared with continuously undetectable HBV DNA, respectively (HR 3.338; 95% CI 1.045–10.66/HR 3.191; 95% CI 1.543–6.597). PAGE-B–DNA, which is the combined PAGE-B and HBV DNA status, was valuable for a more refined stratification of PAGE-B.

A Comparison of Biannual Two-Phase Low-Dose Liver CT and US for HCC Surveillance in a Group at High Risk of HCC Development

Background and Aims: Biannual ultrasonography (US) is a current recommendation for hepatocellular carcinoma (HCC) surveillance in a high-risk group. The sensitivity of US, however, has been low in patients with a high risk of developing HCC. We aimed to compare sensitivity for HCC of biannual US and two-phase low-dose computed tomography (LDCT) in patients with a high risk of HCC. Methods: In this prospective single-arm study, participants with an annual risk of HCC greater than 5% (based on a risk index of ≥2.33) and who did not have a history of HCC were enrolled from November 2014 to July 2016. Participants underwent paired biannual US and two-phase LDCT 1–3 times. Two-phase LDCT included arterial and 3-min delayed phases. The sensitivity, specificity, and positive predictive value of HCC detection using US and two-phase LDCT were compared using a composite algorithm as a standard of reference. Results: Of the 139 enrolled participants, 137 underwent both the biannual US and two-phase LDCT at least once and had follow-up images. Among them, 27 cases of HCC (mean size: 14 ± 4 mm) developed in 24 participants over 1.5 years. Two-phase LDCT showed a significantly higher sensitivity (83.3% [20/24] vs. 29.2% [7/24], p < 0.001) and specificity (95.6% [108/113] vs. 87.7% [99/113], p =0.03) than US. A false-positive result was reported in 14 participants at US and 5 participants at two-phase LDCT, resulting in a significantly higher positive predictive value of two-phase LDCT (33.3% [7/21] vs. 80% [20/25], p < 0.001). Conclusions: Patients with a risk index ≥2.33 showed a high annual incidence of HCC development in our study, and two-phase LDCT showed significantly higher sensitivity and specificity for HCC detection than US.

Coexistence of low levels of HBsAg and high levels of anti-HBs may increase risk of hepatocellular carcinoma in chronic hepatitis B patients with high HBV load

ObjectiveThe clinical significance of coexistence of HBsAg/anti-HBs in chronic hepatitis B (CHB) patients remains controversial. This study was aimed to assess the association of this serological pattern with hepatocellular carcinoma (HCC) in patients with CHB. MethodsIn this cross-section study, 206 CHB patients with coexistence of HBsAg/anti-HBs and 206 CHB patients with HBsAg alone were included to evaluate the risk of HCC development by logistic regression analysis. In addition, a retrospective cohort of 260 patients with CHB was recruited to estimate the cumulative incidence of HCC by Kaplan–Meier analysis. ResultsThe serological pattern of coexistence of HBsAg/anti-HBs, with high levels of (“High”) HBsAg/low levels of (“Low”) anti-HBs, were considered as independent risk factors for HCC. In particular, patients with “High” HBsAg/“High” anti-HBs [odds ratio (OR), 4.295; 95% confidence interval (CI), 1.104–16.699; p = 0.035] and “Low” HBsAg/ “High” anti-HBs (OR, 3.207; 95%CI, 1.299–7.919; p = 0.012) exhibited significantly higher risk for HCC development. However, only “Low” HBsAg /“High” anti-HBs might increase risk of HCC in CHB patients with high HBV load (logrank p < 0.001) in our cohort study. ConclusionThe coexistence of “Low” HBsAg /“High” anti-HBs might increase the risk of HCC development in CHB patients with high HBV load, which reflected that the long-term interaction between immune response and virus might lead to the development of HCC. The identification of the patients with poor prognosis will help clinicians to refine the therapeutic decisions and individualize follow-up strategies.