Higher Risk Of Hepatocellular Carcinoma Research Articles

International Multicenter Validation of GES Score for HCC Risk Stratification in Chronic Hepatitis C Patients

Background and Aims: We have recently demonstrated the ability of a simple predictive model (GES) score to determine the risk of hepatocellular carcinoma (HCC) after using direct-acting antivirals. However, our results were restricted to Egyptian patients with hepatitis C virus (HCV) genotype 4. Therefore, we studied a large, independent cohort of multiethnic populations through our international collaborative activity. Methods: Depending on their GES scores, patients are stratified into low risk (≤ 6/12.5), intermediate risk (> 6–7.5/12.5), and high risk (> 7.5/12.5) for HCC. A total of 12038 patients with chronic HCV were analyzed in this study, of whom 11202 were recruited from 54 centers in France, Japan, India, the U.S., and Spain, and the remaining 836 were selected from the Gilead-sponsored randomized controlled trial conducted across the U.S., Europe, Canada, and Australia. Descriptive statistics and survival analysis were performed using Kaplan–Meier and log-rank tests. The performance of the GES score was evaluated using Harrell’s C-index (HCI). Results : The GES score proved successful at stratifying all patients into 3 risk groups, namely low-risk, intermediate-risk, and high-risk. It also displayed significant predictive value for HCC development in all participants (P < 0 .0001), with HCI ranging from 0.55 to 0.76 among all cohorts after adjusting for HCV genotypes and patient ethnicities. Conclusion: The GES score can be used to stratify HCV patients into 3 categories of risk for HCC, namely low-risk, intermediate-risk, and high-risk, irrespective of their ethnicities or HCV genotypes. This international multicenter validation may allow the use of GES score in individualized HCC risk-based surveillance programs. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: The protocol was approved by the Institutional Research Board of each participating center, as per local regulations

Ectopic liver tissue (choristoma) on the gallbladder: A comprehensive literature review

BACKGROUNDLiver tissue situated outside the liver with a hepatic connection is usually called an accessory liver, and that without a connection to the mother liver, is called ectopic liver tissue. AIMTo identify studies in the literature on ectopic liver tissue located on the gallbladder surface or mesentery. METHODSWe present two patients and review published articles on ectopic liver tissue located on the gallbladder surface accessed via PubMed, MEDLINE, Google Scholar, and Google databases. Keywords used included accessory liver lobe, aberrant liver tissue, ectopic liver tissue, ectopic liver nodule, heterotopic liver tissue, hepatic choristoma, heterotopic liver tissue on the gallbladder, and ectopic liver tissue on the gallbladder. The search included articles published before June 2020 with no language restriction. Letters to the editor, case reports, review articles, original articles, and meeting presentations were included in the search. Articles or abstracts containing adequate information on age, sex, history of liver disease, preliminary diagnosis, radiologic tools, lesion size, surgical indication, surgical procedure, and histopathological features of ectopic liver tissue were included in the study.RESULTSA total of 72 articles involving 91 cases of ectopic liver tissue located on the gallbladder surface or mesentery were analyzed. Of these 91 patients, 62 were female and 25 were male (no gender available for 4 patients), and the age range was 5 d to 91 years. Forty-nine patients underwent surgery for chronic cholecystitis or cholelithiasis, and 14 patients underwent surgery for acute cholecystitis. The remaining 28 patients underwent laparotomy for other reasons. Cholecystectomy was laparoscopic in 69 patients and open in 11 patients. The remaining 19 patients underwent various other surgical procedures such as autopsy, liver transplantation, living donor hepatectomy, Whipple procedure, and liver segment V resection. Histopathologically, hepatocellular carcinoma was detected in the ectopic liver tissue of one patient. CONCLUSIONEctopic liver tissue is a rare developmental anomaly which is usually detected incidentally. Although most studies suggest that ectopic liver located outside the gallbladder has a high risk of hepatocellular carcinoma, this is not reflected in statistical analysis.

Incidence and Characteristic of Hepatocellular Carcinoma in Hepatitis B Related Cirrhosis

Background: Hepatocellular carcinoma (HCC) and liver decompensation are the serious complications of chronic hepatitis B (CHB) especially after development of cirrhosis. Current treatment of CHB is nucleos(t)ide analogues (NA). Objective: To evaluate the incidence and characteristic of HCC in patients with HBV cirrhosis as well as the rate of hepatic decompensation in NA treated CHB. Materials and Methods: A retrospective chart review of the patients with HBV associated cirrhosis who had attended Hepatitis Clinic, Siriraj Hospital between December 1, 2010 to December 31, 2011 was conducted. The hospital charts were reviewed to capture HBV related treatment, cirrhotic complication, occurrence, and characteristic of HCC. Results: There were 241 HBV related compensated cirrhosis enrolled in the study. Among these, 234 patients received NA treatment. There were 29 (12%) patients developed HCC during a median follow-up of 4.6 years and the incidence rates of HCC per 100 personyear was 2.6. There was no risk factor that predicted the occurrence of HCC, however, from multivariate analysis, older age, male gender, diabetes mellitus, HBeAg positive, alpha-fetoprotein (AFP) &gt;10 IU/mL and HBV DNA &gt;2,000 IU/ml at baseline trended to have a higher risk of HCC but did not reach statistical significance. Most HCCs found in the present study were asymptomatic and were found during surveillance and were single lesion located in the right lobe without portal involvement. Most of the HCC patients received potentially curative treatment (37.9%). Moreover, we found that the incidence of liver decompensation was 0.53 per 100 person-year. Two HCC patients died because of progressive liver disease. Conclusion: HCC is among the most serious complication of HBV related cirrhosis and occurred 2.6 per 100 person-year in the present study. It is unclear whether treatment would reduce HCC since most of the patients received treatment. Liver decompensation was found at 0.53 per 100 person-year which is lower than previous report. Keywords: Chronic hepatitis B, Hepatocellular carcinoma, Incidence, Liver decompensation, Hepatitis B treatment, Treatment

Low incidence of HCC in chronic hepatitis C patients with pretreatment liver stiffness measurements below 17.5 kilopascal who achieve SVR following DAAs

To evaluate the ability of pretreatment liver stiffness measurements (pLSM) to predict hepatocellular carcinoma (HCC), incident decompensation and all-cause mortality in chronic hepatitis C (CHC) patients who achieved sustained virological response (SVR) after treatment with direct-acting antivirals (DAAs). 773 CHC patients with SVR after DAA treatment and no prior liver complications were identified retrospectively. Optimized cut-off of 17.5 kPa for incident HCC was selected by maximum Youden's index. Patients were grouped by pLSM: <10 kPa [reference], 10-17.4 kPa and ≥17.5 kPa. Primary outcomes were incident hepatocellular carcinoma and secondary outcomes were incident decompensated cirrhosis and all-cause mortality, analyzed using cox-regression. Median follow-up was 36 months and 43.5% (336) had cirrhosis (LSM>12.5 kPa). The median pLSM was 11.6 kPa (IQR 6.7-17.8, range 2.5-75) and pLSM of <10 kPa, 10-17.4 kPa and 17.5-75 kPa was seen in 41.5%, 32.2% and 26.3%. During a median follow-up time of 36 months, 11 (1.4%) developed HCC, 14 (1.5%) developed decompensated cirrhosis, and 38 (4.9%) patients died. A pLSM of 17.5 kPa identified patients with a high risk of HCC with a negative predictive value of 98.9% and incidence rate of HCC in the 17.5-75 kPa group of 1.40/100 person years compared to 0.14/100 person years and 0.12/100 person years in the 10-17.4 kPa and <10 kPa groups, p<0.001. Pretreatment LSM predicts risk of HCC, decompensation and all-cause mortality in patients with SVR after DAA treatment. Patients with a pLSM <17.5 kPa and no other risk factors for chronic liver disease appear not to benefit from HCC surveillance for the first 3 years after treatment. Longer follow-up is needed to clarify if they can be safely excluded from post treatment HCC screening hereafter.

The association of leptin and adiponectin with hepatocellular carcinoma risk and prognosis: a combination of traditional, survival, and dose-response meta-analysis

BackgroundAn increasing number of studies have focused on the association between leptin, adiponectin levels and the risk as well as the prognosis of hepatocellular carcinoma. However, the reported results are conflicting.MethodsA meta-analysis was performed to assess the correlation between leptin, adiponectin levels and risk and prognosis of hepatocellular carcinoma (CRD42020195882). Through June 14, 2020, PubMed, Cochrane Library and EMBASE databases were searched, including references of qualifying articles. Titles, abstracts, and main texts were reviewed by at least 2 independent readers. Stata 16.0 was used to calculate statistical data.ResultsThirty studies were included in this meta-analysis and results showed that hepatocellular carcinoma group had significantly higher leptin levels than the cancer-free control group (SMD = 1.83, 95% CI (1.09, 2.58), P = 0.000), the healthy control group (SMD = 4.32, 95% CI (2.41, 6.24), P = 0.000) and the cirrhosis group (SMD = 1.85, 95% CI (0.70, 3.01), P = 0.002). Hepatocellular carcinoma group had significantly higher adiponectin levels than the healthy control group (SMD = 1.57, 95% CI (0.37, 2.76), P = 0.010), but no statistical difference compared with the cancer-free control group (SMD = 0.24, 95% CI (− 0.35, 0.82), P = 0.430) and the cirrhosis group (SMD = − 0.51, 95% CI (− 1.30, 0.29), P = 0.213). The leptin rs7799039 polymorphism was associated with increased risk of hepatocellular carcinoma (G vs A: OR = 1.28, 95% CI (1.10, 1.48), P = 0.002). There were linear relationships between adiponectin levels and the risk of hepatocellular carcinoma (OR = 1.066, 95% CI (1.03, 1.11), P = 0.001). In addition, the results showed that high/positive expression of adiponectin was significantly related to lower overall survival in hepatocellular carcinoma patients (HR = 1.70, 95% CI (1.22, 2.37), P = 0.002); however, there was no significantly association between the leptin levels and overall survival (HR = 0.92, 95% CI (0.53, 1.59), P = 0.766).ConclusionThe study shows that high leptin levels were associated with a higher risk of hepatocellular carcinoma. Adiponectin levels were proportional to hepatocellular carcinoma risk, and were related to the poor prognosis.

Metabolomics approach to understand the hepatitis C virus induced hepatocellular carcinoma using LC-ESI-MS/MS

Hepatocellular carcinoma (HCC) is a typical cancer that has region specified analysis with the incidence of hepatitis C virus (HCV) infection. This study was conducted to improve the understanding of metabolic alterations associated with HCV induced HCC which can open up new strategies to monitor the high risk of HCC. Samples of the subjects with HCV, HCV induced chronic liver disease (CLD), HCV induced HCC, and healthy controls (HS) were collected after complete blood count (CBC), hepatitis viral load, α-fetoprotein (AFP), liver function tests, and albumin. A total of 147 serum samples including HCC (n = 11), CLD (n = 24), HCV (n = 71), and HS (n = 41) were analyzed by LC-ESI-MS/MS. The 21 compounds were found to be responsible for group discrimination after the application of chemometric tools. N-fructosyl tyrosine and hydroxyindoleacetic acid showed an increase in level whereas L-aspartyl-L-phenylalanine and thyroxine showed a consistent decrease in the progression of HCV to HCC in comparison with HS indicating their importance for early detection. The biological pathways such as glycerophospholipid metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism and tryptophan metabolism showed alteration in some metabolites. The method was internally validated by ROC plot showing AUC value for HS, HCV, CLD, and HCC as 0.99, 1, 1, and 0.89, respectively; while 16 blind samples were also validated with 93% specificity. The untargeted metabolomics investigation of HCV, CLD, and HCC can help to understand the progression of HCV-induced HCC. It reveals significant differences in metabolites to predict prognostic and diagnostic markers.

Quality diet indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study.

There is limited research on the effect of dietary quality on hepatocellular carcinoma (HCC) risk in populations with relatively high risk of HCC. Using data from Singapore Chinese Health Study, a prospective cohort study, of 63 257 Chinese aged 45 to 74, we assessed four diet-quality index (DQI) scores: the Alternative Health Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI). We identified 561 incident HCC cases among the cohort participants after a mean of 17.6 years of follow-up. Cox proportional hazard regression model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for HCC in relation to these DQI scores. Unconditional logistic regression method was used to evaluate the associations between DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). High scores of AHEI-2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend < .05). Compared with the lowest quartile, HRs (95% CIs) of HCC for the highest quartile of AHEI-2010, aMED and DASH were 0.69 (0.53-0.89), 0.70 (0.52-0.95) and 0.67 (0.51-0.87), respectively. No significant association between HDI and HCC risk was observed. Among HBsAg-negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED (HRQ4vsQ1 = 0.46, 95% CI: 0.23-0.94, Ptrend = .10). These findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC.

Associations of general obesity and central obesity with the risk of hepatocellular carcinoma in a Korean population: A national population-based cohort study.

Numerous previous studies have shown an association between general obesity and hepatocellular carcinoma (HCC). However, relatively few reports on the association of central obesity and HCC are available in Asian populations. Therefore, we investigated the association between WC representing central obesity and the risk of HCC in addition to BMI representing general obesity and the risk of HCC in Korea. A total of 10 505 818 participants who received the National Health Insurance Service (NHIS) health checkups in 2009 were screened for study eligibility, and 26 979 cases of HCC occurred during the 7.3 years of mean follow-up. General obesity increased the risk of HCC with hazard ratios (HRs) of 1.14 (95% CI, 1.11-1.18) for BMI 25.0-<30.0 kg/m2 and 1.52 (95% CI, 1.43-1.61) for BMI ≥30 kg/m2 compared to those whose BMI is within the normal range. Central obesity was also associated with a higher risk of HCC. For the participants with a WC ≥105 cm in men and WC ≥100 cm in women, the risk of HCC was higher than that of the reference group (HR = 1.69, 95% CI, 1.54-1.85). The HRs were 1.13 (95% CI, 1.07-1.19) for nonobese participants with central obesity, and 1.34 (95% CI, 1.30-1.38) for obese participants with central obesity compared to those without both conditions. Our findings suggest that the risk of HCC increases even more when general obesity is combined with central obesity. Moreover, central obesity is associated with the risk of HCC, regardless of general obesity.

Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes.

The long-term risk of disease for patients with nonalcoholic fatty liver disease (NAFLD) in the absence of elevated enzymes is unclear. We conducted a retrospective cohort study using the Corporate Data Warehouse of the Veterans Health Administration. We classified patients into three groups: patients with steatosis/normal alanine aminotransferase (ALT), steatosis/elevated ALT, and no steatosis/normal ALT. We examined incidence rates for cirrhosis and hepatocellular carcinoma (HCC) and conducted cause-specific hazard models to evaluate the risk of cirrhosis and HCC. We identified 3,522 patients with steatosis/normal ALT, 15,419 patients with steatosis/elevated ALT, and 9,267 patients with no steatosis/normal ALT. The mean age in each group was 58.9, 54.7 and 59.3years, respectively; over 90% were men. Compared to patients with hepatic steatosis/normal ALT, those with steatosis/elevated ALT were younger and more likely to be obese (both P<0.01). In patients with steatosis/normal ALT, the incidence rates of cirrhosis and HCC were 1.22 (95% confidence interval [CI]: 0.83-1.74) and 0.20 (95% CI: 0.06-0.46) per 1,000 person-years, respectively; this was lower than in patients with steatosis/elevated ALT (cirrhosis: 3.85; 95% CI: 3.50-4.23, and HCC: 0.37; 95% CI: 0.26-0.49). Patients with steatosis/elevated ALT had a higher risk of developing cirrhosis (adjusted hazard ratio:3.37; 95% CI: 2.34-4.86; P<0.01) than patients with steatosis/normal ALT; they also had a higher risk of HCC, although it did not reach statistical significance (hazard ratio:2.07; 95% CI:0.82-5.28; P=0.13). The risk of cirrhosis and HCC in patients with steatosis/normal ALT and those without steatosis was not significantly different. Patients with hepatic steatosis with persistently normal ALT are at lower risk for cirrhosis compared to those with steatosis and elevated ALT and not different from the risk in a clinical cohort without hepatic steatosis.

Imaging Modalities for Hepatocellular Carcinoma Surveillance: Expanding Horizons beyond Ultrasound.

In Asian countries favoring loco-regional treatment such as surgical resection or ablation, very early-stage hepatocellular carcinoma (HCC) should be the main target for surveillance. Even though ultrasound (US) has been accepted as a primary imaging modality for HCC surveillance, its performance in detecting very early-stage HCCs is insufficient. Moreover, in more than 20% of patients at high risk for HCC, visualization of the liver on US may be limited owing to the advanced distortion and heterogeneity of the liver parenchyma. Recently revised HCC clinical guidelines allow the use of alternative surveillance tools including computed tomography or magnetic resonance imaging in patients with inadequate US exams. This paper summarizes the findings of recent studies using imaging modalities other than US as surveillance tools for HCC as well as strengths and limitations of these modalities.

CD44, IL-33, and ST2 Gene Polymorphisms on Hepatocellular Carcinoma Susceptibility in the Chinese Population.

The interleukin- (IL-) 33/ST2 axis plays a pivotal role in tumorigenesis through influencing cancer stemness and other mechanisms. CD44 is one of the critical markers of hepatocellular carcinoma (HCC) among the cancer stem cells (CSCs). There is still a lack of CD44 gene single-nucleotide polymorphisms (SNPs) combined with IL-33/ST2 pathway single-nucleotide polymorphisms in HCC susceptibility analysis literature, although CD44 and IL-33/ST2 have been reported separately in human cancers. This study is aimed at investigating the relationship between CD44, IL-33, and ST2 SNPs and HCC susceptibility and clinicopathological features. We analyzed 565 HCC patients and 561 healthy controls in the Chinese population. The genes for CD44rs187115A>G, IL-33 rs1929992A>G, and ST2 rs3821204G>C were typed using the SNaPshot method. We found that the distribution frequencies of CD44 and ST2 alleles and genotypes in both the HCC case group and the control group were statistically significant (p < 0.05). The results showed that individuals carrying at least one G allele of the CD44 rs187115 gene were at a higher risk than the AA genotype carriers (p = 0.007, odds ratio (OR) = 1.429, 95% confidence interval (CI): 1.102–1.854). Similarly, individuals with at least one C allele of ST2 rs3821204 had a higher risk of HCC than those with GG genes (p ≤ 0.001, OR = 1.647, 95% CI: 1.296-2.093). Combining the haplotype analysis of the 3 loci suggested that CD44 rs187115, IL-33 rs1929992, and ST2 rs3821204 are associated with the risk of HCC and could potentially serve as useful genetic markers for HCC in some populations of China.

Extended application of subtraction arterial phase imaging in LI-RADS version 2018: a strategy to improve the diagnostic performance for hepatocellular carcinoma on gadoxetate disodium-enhanced MRI.

This study aimed to assess the detection of hepatocellular carcinoma (HCC) utilizing subtraction AP (arterial phase) imaging only for T1 hyperintense observations compared with the detection of HCC on subtraction AP imaging that included T1 hyper-, iso-, and hypointense lesions on gadoxetate disodium-enhanced MRI. This retrospective study included 234 patients (311 observations including 239 HCCs) at high risk for HCC who underwent gadoxetate disodium-enhanced MRI with subtraction AP imaging between 2015 and 2017. Arterial phase hyperenhancement (APHE) was divided into two subtypes: conventional APHE, where subtraction AP imaging is used to detect APHE only for T1 hyperintense observations; and modified APHE, where subtraction AP imaging is applied to T1 hyper-, iso-, and hypointense lesions. Two readers independently reviewed all observations and the per-observation diagnostic performances were compared using McNemar's test. Modified nonrim APHE showed significantly higher sensitivity than conventional nonrim APHE (90.0% vs 82.8%; p < 0.001) for diagnosing HCC, without a significant difference in specificity (66.7% vs 68.1%; p > 0.999). The LR-5 category with modified nonrim APHE provided better sensitivity than the LR-5 with conventional nonrim APHE (70.3% vs 63.2%; p < 0.001), without a significant decrease in specificity (94.4% vs 95.8%; p > 0.999). Extended application of subtraction AP imaging for T1 hypo- or isointense observations on gadoxetate disodium-enhanced MRI can improve sensitivity in the diagnosis of HCC without a significant difference in specificity. • Modified nonrim arterial phase hyperenhancement (APHE), extended application of subtraction arterial phase imaging for T1 hypo- or isointense observation, outperforms conventional nonrim APHE. • The LR-5 category with modified nonrim APHE provided better sensitivity in diagnosing HCC than the LR-5 with conventional APHE, without a significant decrease in specificity.

Contrast-enhanced ultrasound LI-RADS 2017: comparison with CT/MRI LI-RADS.

To compare the classification based on contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) with that of contrast-enhanced CT and MRI (CECT/MRI) LI-RADS for liver nodules in patients at high risk of hepatocellular carcinoma. Two hundred thirty-nine patients with 273 nodules were enrolled in this retrospective study. Each nodule was categorized according to the CEUS LI-RADS version 2017 and CECT/MRI LI-RADS version 2017. The diagnostic performance of CEUS and CECT/MRI was compared. The reference standard was histopathology diagnosis. Inter-modality agreement was assessed with Cohen's kappa. The inter-modality agreement for CEUS LI-RADS and CECT/MRI LI-RADS was fair with a kappa value of 0.319 (p < 0.001). The positive predictive values (PPVs) of hepatocellular carcinoma (HCC) in LR-5, LR-4, and LR-3 were 98.3%, 60.0%, and 25.0% in CEUS, and 95.9%, 65.7%, and 48.1% in CECT/MRI, respectively. The sensitivities and specificities of LR-5 for diagnosing HCC were 75.6% and 93.8% in CEUS, and 83.6% and 83.3% in CECT/MRI, respectively. The positive predictive values of non-HCC malignancy in CEUS LR-M and CECT/MRI LR-M were 33.9% and 93.3%, respectively. The sensitivity, specificity, and accuracy for diagnosing non-HCC malignancy were 90.9%, 84.5%, and 85.0% in CEUS LR-M and 63.6%, 99.6%, and 96.7% in CECT/MRI LR-M, respectively. The inter-modality agreement of the LI-RADS category between CEUS and CECT/MRI is fair. The positive predictive values of HCCs in LR-5 of the CEUS and CECT/MRI LI-RADS are comparable. CECT/MRI LR-M has better diagnostic performance for non-HCC malignancy than CEUS LR-M. • The inter-modality agreement for the final LI-RADS category between CEUS and CECT/MRI is fair. • The LR-5 of CEUS and CECT/MRI LI-RADS corresponds to comparable positive predictive values (PPVs) of HCC. For LR-3 and LR-4 nodules categorized by CECT/MRI, CEUS examination should be performed, at least if they can be detected on plain ultrasound. • CECT/MRI LR-M has better diagnostic performance for non-HCC malignancy than CEUS LR-M. For LR-M nodules categorized by CEUS, re-evaluation by CECT/MRI is necessary.

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.

ABO blood group genotypes and risk of hepatocellular carcinoma in a cohort of Egyptian patients

BackgroundGenetic profiles of ABO blood group system was reported to have clinical importance in predisposition to certain malignancies. This study was attempted to investigate any possible association between ABO genotypes and the risk of developing hepatocellular carcinoma (HCC) and to determine the major ABO allele's frequencies in a cohort of Egyptian population. Subjects and methodsOne hundred patients (HCC group) and 100 healthy subjects (control group) were enrolled in this study. ABO Genotyping was done using Real-time PCR-melting curve analysis. ResultsEgyptians with BO genotype were 3.38 times more likely to develop HCC. This association was gender related and noted in hepatitis-free HCC cases. In elderly subjects HCC risk increased not only with BO genotype but also with AO and AB genotypes. In the healthy Egyptian sample, frequencies of the three major alleles (A, B and O) were 0.2917, 0.2083 and 0.5000 respectively. Frequencies of sub-alleles (A1, A2, B, O1 and O2) were 0.2500, 0.0417, 0.2083, 0.2917 and 0.2083 respectively. Serological and genotyping results showed a concordance rate of 97.9%. ConclusionBO genotype is associated with a higher risk for HCC in Egyptians independent of the established HCC risk factors. Egyptian ABO allele frequencies are closely linked to Iranian and Palestinian populations.

Fatty acid composition of the erythrocyte membrane and risk of hepatocellular carcinoma in cirrhotic patients.

Disturbances in fatty acid (FA) metabolism have been reported in cirrhosis, but the role of FAs in the development of hepatocellular carcinoma (HCC) is still unclear. Biomarkers are a promising means to explore the associations between exogenous intake or endogenous production of FAs and cancer risk. To estimate the relationship between fatty acid content in erythrocyte membranes and HCC risk in cirrhotic patients METHODS: The "CiRCE" case-control study recruited cirrhotic patients from six French hospitals between 2008 and 2012. Cases were cirrhotic patients with HCC (n = 349); controls were cirrhotic patients without HCC at inclusion (n = 550). FA composition of phospholipids in erythrocyte membranes was determined by high performance gas chromatography. Odds ratios for HCC risk according to FA concentrations were estimated with multivariable logistic regression. HCC patients were older and more often men (P < 0.001). In both groups, saturated FAs represented more than 39% of all FAs in erythrocyte membranes, mono-unsaturated FAs around 14%, and polyunsaturated FAs around 46%. High levels of C15:0 + C17:0, C20:1 n-9, C18:2 n-6 and C20:2 n-6 were associated with higher risk of HCC. The levels of C18:0 and C20:4 n-6 were lower in HCC cases than in controls. The FA composition of erythrocyte membranes differed according to the presence of HCC with higher levels of saturated FAs, linoleic and eicosadienoic acids, and lower levels of stearic and arachidonic acids. These alterations may reflect particular dietary patterns and/or altered FA metabolism. Further investigations are warranted.

Surveillance of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is sufficient epidemiological cohort data to recommend the surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommends that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) consider HCC surveillance. NITs include the fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US), which is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US, or if an US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, the lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and the protein induced by the absence of vitamin K or antagonist-II (PIVKA-II), can help identify a high risk of HCC in NAFLD patients. Innovative parameters, including a Mac-2 binding protein glycated isomer, type IV collagen 7S, free apoptosis inhibitor of the macrophage, and a combination of single nucleoside polymorphisms, are expected to be established. Considering the large size of the NAFLD population, optimal screening tests must meet several criteria, including high sensitivity, cost effectiveness, and availability.

Contrast-enhanced ultrasound liver imaging reporting and data system for diagnosing hepatocellular carcinoma: A meta-analysis.

Contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) is a comprehensive system for standardizing CEUS at high risk for hepatocellular carcinoma (HCC). We performed a meta-analysis to determine the diagnostic performance of the CEUS LR-5 for HCC and the pooled proportions of HCCs in each CEUS LI-RADS category. We searched multiple databases for studies reporting the diagnostic accuracy of the CEUS LI-RADS. Random-effects model was used to determine summary estimates of the diagnostic performance of CEUS LR-5 and the pooled proportions of HCCs in each CEUS LI-RADS category. Risk of bias and concerns regarding applicability were evaluated with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Eleven studies were included in the final analysis, which consisted of 5535 observations with 3983 HCCs. The pooled per-observation sensitivity and specificity of the CEUS LR-5 for diagnosing HCC were 69% (95% confidence interval [CI], 64%-73%) and 92% (95% CI, 83%-96%) respectively. The pooled proportions of HCCs were 0% (95% CI, 0-0%) for LR-1, 1% (95% CI, 0%-4%) for CEUS LR-2, 26% (95% CI, 14%-39%) for CEUS LR-3, 77% (95% CI, 68%-86%) for CEUS LR-4, 97% (95% CI, 95%-98%) for CEUS LR-5, 57% (95% CI, 44%-69%) for CEUS LR-M and 100% (95% CI, 93%-100%) for CEUS LR-5V or TIV. The CEUS LR-5 category showed moderate sensitivity and high specificity for diagnosing HCC. The proportion of HCCs was higher in the higher CEUS LI-RADS categories.

Contrast-Enhanced Ultrasound Algorithms (CEUS-LIRADS/ESCULAP) for the Noninvasive Diagnosis of Hepatocellular Carcinoma - A Prospective Multicenter DEGUM Study.

Background This prospective multicenter study funded by the DEGUM assesses the diagnostic accuracy of standardized contrast-enhanced ultrasound (CEUS) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients. Methods Patients at high risk for HCC with a histologically proven focal liver lesion on B-mode ultrasound were recruited prospectively in a multicenter approach. Clinical and imaging data were entered via online entry forms. The diagnostic accuracies for the noninvasive diagnosis of HCC were compared for the conventional interpretation of standardized CEUS at the time of the examination (= CEUS on-site) and the two CEUS algorithms ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) and CEUS LI-RADS (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System). Results 321 patients were recruited in 43 centers; 299 (93.1 %) had liver cirrhosis. The diagnosis according to histology was HCC in 256 cases, and intrahepatic cholangiocarcinoma (iCCA) in 23 cases. In the subgroup of cirrhotic patients (n = 299), the highest sensitivity for the diagnosis of HCC was achieved with the CEUS algorithm ESCULAP (94.2 %) and CEUS on-site (90.9 %). The lowest sensitivity was reached with the CEUS LI-RADS algorithm (64 %; p Conclusion This is the first multicenter, prospective comparison of standardized CEUS and the recently developed CEUS-based algorithms in histologically proven liver lesions in cirrhotic patients. Our results reaffirm the excellent diagnostic accuracy of CEUS for the noninvasive diagnosis of HCC in high-risk patients. However, on-site diagnosis by an experienced examiner achieves an almost equal diagnostic accuracy compared to CEUS-based diagnostic algorithms.

Chronic hepatitis B exhibited higher rate of hepatocellular carcinoma occurrence than hepatitis C in cirrhotic patients after effective antiviral treatment

Effective antiviral-therapy can reduce the risk of liver cirrhosis related hepatocellular carcinoma in patients with chronic hepatitis B and hepatitis C. Yet, the differenceof hepatocellular carcinoma development in chronic hepatitis B and hepatitis Cpatientswith cirrhosis after effective antiviral therapy treatment is unknown. In this study, We comprehensive explored the difference among them. 1363 patients with cirrhosis and hepatitis B virus treated with nucleos(t)ide analogues (NUCs) with completely suppressed virus, and patients with cirrhosis and hepatitis C virus treated with pegylated interferon (peg-IFN)/ribavirin (RBV) combination therapy who achieved sustained virologic response were enrolled. Total 261 developed hepatocellular carcinoma within a median follow-up of 4.25 years. Univariate analysis, patients developed hepatocellular carcinoma tended to be of older age, and had lower platelet counts, were chronic hepatitis B carriers, and had higher serum alfa-fetoprotein (AFP) (≥20ng/mL), FIB-4 index and APRI scores. Subsequent multivariate analysis revealed older age, lower platelet counts, high AFP levels andchronic hepatitis B carriers were independent risk factors of hepatocellular carcinoma. Our findings identify that chronic hepatitis B patients were with a higher risk of hepatocellular carcinoma compared to chronic hepatitis C patients after achieving virological response. Special attention should be paid to those patients.