High Incidence Of Hepatocellular Carcinoma Research Articles

Profile of hepatocellular carcinoma in the Republic of Moldova: first-hand information on the presentation, distribution and etiologies.

Moldova is the European country with the highest incidence of hepatocellular carcinoma (HCC) in both sexes. There is, however, no data comprehensively describing the presentation and the risk factors of HCC in the country. We decided to analyze cases of HCC recently received in a tertiary healthcare Institution from Chisinau, the Moldovian capital. A series of 148 primary liver tumors including 139 cases of HCC were retrospectively analyzed for demographic features, serological and biochemical data, and clinical presentation. The mean age of patients was 59 ± 10 years (range: 19-66) with a M:F sex ratio of 1.9. Tumors appeared on full-blown liver cirrhosis in 83% of cases and were composed of multiple nodules at diagnosis in 36% of patients. Serum Alpha-fetoprotein was exceeding 10ng/mL in 76% of cases. Liver tumor and hepatitis were co-discovered in 34% of cases. More than 81% of hepatocellular carcinomas were associated with at least one hepatitis virus. Carriers of anti-hepatitis C virus were predominating (55% of cases) over patients seropositive for hepatitis B virus surface antigen (36%). Half of the latter were also infected with hepatitis Delta virus. In total, dual or triple infections were present in 24% and 7% of cases. The burden of infections with hepatitis viruses is particularly important in Moldova and corresponds to a situation commonly observed in countries of the Southern hemisphere. A pro-active policy of screening for persistent liver infection targeting population at risk of HCC (> 50 years) and coupled with the distribution of antivirals in positive cases should be rapidly implemented in Moldova to reduce incidence or primary liver cancer.

Magnetic Resonance Imaging Is Cost-Effective for Hepatocellular Carcinoma Surveillance in High-Risk Patients With Cirrhosis.

Ultrasonography (US) is generally recommended for the surveillance of hepatocellular carcinoma (HCC) in patients at risk. However, in patients with cirrhosis who have sufficiently high HCC incidence, surveillance using magnetic resonance imaging (MRI) with liver-specific contrast showed markedly higher sensitivity in detecting early-stage HCC than US. This study aimed to compare the cost-effectiveness of semiannual surveillance using MRI versus US in patients with compensated cirrhosis and to identify the population that would gain optimal cost-effectiveness through MRI surveillance. We designed a Markov model to compare the expected costs and quality-adjusted life-years (QALYs), between MRI and US, with a 20-year time horizon, from the health care system perspective. The starting age of the cohort was 50 years, and 71% had hepatitis B virus-associated cirrhosis. The cycle length was 6 months. Transition probabilities and costs were obtained mainly from a prospective cohort study (the PRIUS study, NCT01446666). Cost and effectiveness were discounted at 5%. An incremental cost-effectiveness ratio (ICER) was calculated and tested using sensitivity analyses. The cost-effectiveness analysis indicated that the use of MRI incurred $5,562 incremental costs, 0.384 incremental life-years (LYs), and 0.221 incremental QALYs compared to US. The annual HCC incidence was the most influential factor on the ICER. The ICERs were $14,474/LY and $25,202/QALY at an annual HCC incidence of 3%. When the HCC incidence rate was >1.81%, the ICER was below $50,000/QALY. With increased HCC incidence, MRI surveillance was acceptable as a cost-effective option, even with an increased MRI/US cost ratio. Conclusion: Semiannual surveillance using MRI with liver-specific contrast may be more cost-effective than US in patients with virus-associated compensated cirrhosis at sufficiently high HCC risk despite the higher test cost of MRI.

Real-world study on clinical outcomes of nucleos(t)ide analogues antiviral therapy in patients with chronic hepatitis B.

Nucleos(t)ide analogues (NAs) are widely used for antiviral therapy in patients with chronic hepatitis B (CHB), but real-world data on treatment patterns and long-term clinical outcomes are not always available. Using data from electronic medical records between January 2011 and December 2016 in Shanghai, China, we evaluated patient characteristics, treatment patterns and clinical outcomes in patients with CHB. There were 6688 patients in the study cohort. The incidences of cirrhosis and hepatocellular carcinoma (HCC) were 41.0‰ and 6.8‰ person-years, respectively. There were more cirrhosis and HCC cases among patients who had shorter NA treatment duration (<365 days), or who were less compliant (<80%). In addition, increased risk of cirrhosis and HCC was observed in patients who did not achieve hepatitis B surface antigen (HBsAg) loss/seroconversion. Moreover, patients with cirrhosis developed after antiviral treatments had a higher incidence of HCC (adjusted hazard ratio 15.86, 95% confidence interval 7.35-34.24). Good compliance with treatment and longer treatment duration significantly decreased the risk of developing cirrhosis and HCC. HBsAg loss seemed to be a protective factor for cirrhosis/HCC in NAs-treated patients with CHB, and cirrhosis was a confirmed risk factor for HCC development as expected.

Clinical Features Associated with Survival Outcome in African-American Patients with Hepatocellular Carcinoma.

African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades. HCC patients from three US medical centers were matched by year of diagnosis (1991-2016): AA (n = 578)/Caucasian (n = 578) and placed in one of two groups-HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted. Prior to 2010, there was no difference in survival between Caucasians and AA (p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26-2.43, p = 0.001) and child's class C (aHR 2.05, 95% CI: 1.23-3.41, p = 0.006) were the strongest predictors of mortality, while race was not. African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.

Suppression of Hepatic Bile Acid Synthesis by a non-tumorigenic FGF19 analogue Protects Mice from Fibrosis and Hepatocarcinogenesis

Critical regulation of bile acid (BA) pool size and composition occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by the combined actions of the nuclear Farnesoid X receptor (FXR) and the enterokine fibroblast growth factor 19 (FGF19) with the final aim of reducing hepatic BA synthesis in a negative feedback fashion. Disruption of BA homeostasis with increased hepatic BA toxic levels leads to higher incidence of hepatocellular carcinoma (HCC). While native FGF19 has anti-cholestatic and anti-fibrotic activity in the liver, it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity and maintain BA metabolic action. Here, using BA related Abcb4−/− and Fxr−/− mouse models of spontaneous hepatic fibrosis and HCC, we explored the role of a novel engineered variant of FGF19 protein, called FGF19-M52, which fully retains BA regulatory activity but is devoid of the pro-tumoral activity. Expression of the BA synthesis rate-limiting enzyme Cyp7a1 is reduced in FGF19-M52-treated mice compared to the GFP-treated control group with consequent reduction of BA pool and hepatic concentration. Treatment with the non-tumorigenic FGF19-M52 strongly protects Abcb4−/− and Fxr−/− mice from spontaneous hepatic fibrosis, cellular proliferation and HCC formation in terms of tumor number and size, with significant reduction of biochemical parameters of liver damage and reduced expression of several genes driving the proliferative and inflammatory hepatic scenario. Our data bona fide suggest the therapeutic potential of targeting the FXR-FGF19 axis to reduce hepatic BA synthesis in the control of BA-associated risk of fibrosis and hepatocarcinoma development.

Covering the Cover

Covering the Cover

Effects of Estrogen and Estrogen Receptors on Transcriptomes of HepG2 Cells: A Preliminary Study Using RNA Sequencing.

Men have a much higher incidence of hepatocellular carcinoma (HCC), the predominant form of liver cancer, than women, suggesting that estrogens play a protective role in liver cancer development and progression. To begin to understand the potential mechanisms of estrogens' inhibitory effects on HCC development, RNA sequencing was used to generate comprehensive global transcriptome profiles of the human HCC-derived HepG2 cell line following treatment of vehicle (control), estradiol (E2), estrogen receptor alpha- (ERα-) specific agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), or ERβ-specific agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) using a small set of cells. Gene ontology (GO) analysis identified increased expression of genes involved in the biological process (BP) of response to different stimuli and metabolic processes by E2 and ER agonists, which enhanced molecular function (MF) in various enzyme activities and chemical bindings. Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathway analysis indicated enhanced pathways associated with carbohydrate metabolism, complement and coagulation cascades, and HIF-1 signaling pathway by E2 and ER agonists. GO analysis also identified decreased expression of genes by E2, PPT, and DPN involved in BP related to the cell cycle and cell division, which reduced MF in activity of multiple enzymes and microtubule activity. KEGG analysis indicated that E2, PPT, and DPN suppressed pathways associated with the cell cycle; E2 and PPT suppressed pathways associated with chemical carcinogenesis and drug metabolism, and DPN suppressed DNA replication, recombination, and repair. Collectively, these differentially expressed genes across HepG2 cell transcriptome involving cellular and metabolic processes by E2 and ER agonists provided mechanistic insight into protective effects of estrogens in HCC development.

Effect of 5-aminolevulinic acid on the expression of carcinogenesis-related proteins in cultured primary hepatocytes.

Acute intermittent porphyria (AIP) is a heme pathway disorder caused by a decrease in the activity and synthesis of porphobilinogen deaminase. Thus, the first heme precursor 5-aminolevulinic acid (ALA) accumulates in the liver. Reactive oxygen species (ROS) resulting from ALA oxidation may be correlated to a higher incidence of hepatocellular carcinoma (HCC) in AIP patients. However, the molecular mechanisms of this relationship have not been thoroughly elucidated to date. In this study, we investigated the effect of increasing levels of ALA on the expression of proteins related to DNA repair, oxidative stress, apoptosis, proliferation and lipid metabolism. Primary rat hepatocytes were isolated by the collagenase perfusion method, lipoperoxidation was evaluated by a TBA fluorimetric assay and Western blotting was used to assess protein abundance. The data showed that ALA treatment promoted a dose-dependent increase of p53 expression, downregulation of Bcl-2, HMG-CoA reductase and OGG1 and an increase in lipoperoxidation. There was no alteration in the expression of the transcription factor NF-κB, catalase and superoxide dismutase. ALA oxidation products induced protein regulation patterns, suggesting the interconnection of cellular processes, such as the intrinsic pathway of apoptosis, redox homeostasis, cell proliferation, lipid metabolism and DNA repair. This study helps to elucidate the molecular mechanisms of hepatotoxicity mediated by ALA pro-oxidant effects and supports the hypothesis that ALA accumulation correlates with a higher incidence of hepatic carcinogenic events.

Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis

More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients' inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5-95.4), 80.3% (95% CI 76.9-83.9), and 3.2% (95% CI 1.6-4.8) respectively. This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%. Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening.

Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs

Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN). Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n= 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n= 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n= 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC. Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P= .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCCscreening than the other 2 groups (P= .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR0.89; 95% CI 0.46-1.73; P= .73). Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.

Prognostic value of heterogeneous ribonucleoprotein A1 expression and inflammatory indicators for patients with surgically resected hepatocellular carcinoma: Perspectives from a high occurrence area of hepatocellular carcinoma in China.

Heterogeneous ribonucleoproteinA1 (hnRNPA1) is a documented tumor biomarker known to be aberrantly expressed in a number of types of human cancer. However, to the best of our knowledge, its prognostic value for surgically resected HCC (RHCC) in the high incidence areas of China has not been described; the association between hnRNPA1 expression, pre-operative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) is also not understood. In the present study, hnRNPA1 expression was retrospectively measured in two independent cohorts of patients with hepatocellular carcinoma (HCC) who underwent surgery to remove the primary cancer at one center in Fujian, an area with a high incidence of HCC in China. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC) were used to quantify hnRNPA1 expression in RHCC tissues. The survival curves were plotted using the Kaplan-Meier method, and the prognostic significance of hnRNPA1, NLR and PLR was analyzed using the log-rank test. The relevant prognostic factors were identified by multivariate Cox regression analysis. RT-qPCR and western blotting revealed that hnRNPA1 was upregulated in HCC tissues (P<0.001), and particularly overexpressed in tumor tissues of patients with recurrent HCC (P<0.001) (cohort 1; 54 patients). Differential hnRNPA1 expression was measured in 426HCC tissues with IHC; 259 exhibited high hnRNPA1 expression and 167 exhibited low expression. High hnRNPA1 expression was significantly associated with Tumor-Node-Metastasis stage (P=0.024), tumor size (P=0.027), vascular invasion (P<0.001), Edmonson grade (P<0.001), pre-operative serum α-fetoprotein (AFP) (P<0.001), NLR (P<0.001) and PLR (P<0.001). In addition, multivariate Cox regression analysis confirmed that high hnRNPA1 expression was associated with relapse-free survival (RFS; HR, 0.685; 95% CI, 0.506–0.928; P=0.015) and overall survival (OS; HR, 0.629; 95% CI, 0.454–0.871; P=0.005). Multivariate analysis confirmed that higher pre-operative serum AFP had an unfavorable impact on RFS (HR, 1.350; 95% CI, 1.006–1.811; P=0.045) and OS (HR=1.564; 95% CI, 1.151–2.126; P=0.004), while higher pre-operative NLR had an unfavorable impact on OS (HR, 1.758; 95% CI, 1.161–2.661; P=0.008) (cohort 2;426 patients). The expression of hnRNPA1 was also positively correlated with NLR (Spearman's correlation; r=0.122, P=0.012) and PLR (Spearman's correlation; r=0.140, P=0.004). In conclusion, high hnRNPA1 expression was revealed as prognostic for poor survival in patients with RHCC, and detection of hnRNPA1 protein in tumor tissues demonstrated potential in estimating survival for patients with RHCC in areas with high incidence rates. Furthermore, the combination of high hnRNPA1 expression and pre-operative serum AFP levels (>400 µg) proved to be a good diagnostic and prognostic biomarker for this specific population of patients. Finally, a correlation may also exist between hnRNPA1 expression and other markers of systemic inflammation.

Abstract LB-387: In vivo study on the pathological role of microRNA 155 in liver malignancy

Abstract Growing body of evidence proposes that causative factor for liver damage, such as viral infection, inflammation, fatty liver and genotoxin, induces over-expression of microRNA-155 (miR-155), and increases the chance to develop hepatocellular carcinoma (HCC), where miR-155 is also found to be highly over-expressed. To understand the underlying mechanism how over-expression of miR-155 in liver induces pathologic changes linking early liver damage to malignant HCC development, we have generated conditional transgenic and knockout mice for hepatocyte-specific over-expression or deletion of miR-155 using Cre-LoxP technology. Although the miR-155 over-expressing Tg mice did not develop spontaneous HCC, they showed early inflammation in liver with elevated level of pro-inflammatory cytokines in both liver and serum through Caspase-I activation. Postnatal insulting by genotoxin, Diethylnitrosamine (DEN), has dramatically increased incidents of HCC in miR-155 Tg mice (82%) compared to wildtype mice (21%) by 9 months. Microarray analysis on whole mouse liver transcriptome has revealed that 294 genes were significantly up-regulated in the Tg mice while 147 genes were significantly down-regulated. Further pathway analysis showed that those affected genes mainly involve in acute-phase response, inflammatory response, fatty acid metabolic process, and cholesterol metabolic process, which coincides with our phenotypic observation. In addition, it was found that high incidence of HCC by DEN insult is consequence of impaired DNA damage repair and apoptosis pathways through downregulation of several genes including Foxo3a, Sirt1, C/EBP-beta and Smac by miR-155. Our in vivo study provides first insight of dysregulation of single microRNA can set forth liver damage to malignant HCC, which makes miR-155 a promising therapeutic target not only for HCC but also many type of liver damage-related liver diseases. Citation Format: Tae Jin Lee, Ji Young Yoo, Balveen Kaur, Carlo Croce. In vivo study on the pathological role of microRNA 155 in liver malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-387.

Long-Term Incidence of Liver Disease in the Diabetes Population in Israel

In light of the high variability in the literature on the burden of liver disease in relation to diabetes (DM), this study compared the incidence and risk of liver disease between patients with and without DM in a large population-based cohort. The study utilized the computerized database of a nationally representative payer-provider health fund in Israel. All members without cirrhosis, cancer, viral hepatitis or excess alcohol intake were followed from 2000 to 2017. Liver disease: Cirrhosis, liver transplant and hepatocellular carcinoma (HCC), were detected by coded diagnoses, procedures, and the national cancer registry. DM was defined by a previously validated registry. Age specific incidence density rates were calculated based on person years under observation. Risks of liver transplant, HCC and all-cause mortality in the cirrhotic diabetes patients were described using cox proportional hazards multivariate regression. The cohort included 1,083,4subjects with a mean follow-up of 15.1 years (SD=4.2), 2% with DM at index. A total of 2,511 incident cases of liver complications were observed. Higher incidence rates of cirrhosis were observed in patients with DM at index as compared with DM-free with rate ratios of 7.5 (95% CI: 6.5-8.7), 4.1 (3.8-4.4) and 2.3 (2.2-2.5) among patients aged &amp;lt;40, 40-60 and &amp;gt;60 years old respectively. DM was also associated with higher incidence of HCC (rate ratio 3.6 (95% CI: 3.2-4.1) and 1.7 (1.6-1.8) among ages 40-60 and &amp;gt;60 years old respectively) and liver transplant (rate ratio of 4.5 (3.3-6.2) and 1.6 (1.1-2.2) among ages 40-60 and &amp;gt;60 years old respectively). Among cirrhotic patients (n=1,527), those with DM had an adjusted HR=2.3 (95% CI: 1.2-4.5) for developing HCC, a HR=2.2 (0.9-5.3) for undergoing a liver transplant and a HR of 1.8 (1.5-2.3) for all-cause mortality as compared with DM-free, after controlling for age, BMI, sex and smoking. Diabetes is associated with higher incidence rates and higher risk of liver complications compared to those without diabetes. Disclosure I. Goldshtein: None. G. Fernandes: Employee; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; Janssen Research &amp; Development. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Spouse/Partner; Janssen Research &amp; Development. A. Karasik: Stock/Shareholder; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Merck &amp; Co., Inc., GlucoMe. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc.. G. Chodick: None.

The extent of liver injury determines hepatocyte fate toward senescence or cancer

It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.

Significance of Glypican-3 in Early Detection of Hepatocellular Carcinoma in Cirrhotic Patients

Egypt has high incidence of hepatocellular carcinoma (HCC). This is due to wide spread of hepatitis C virus (HCV) infection which is responsible for most of the cases of liver cirrhosis. The major diagnostic techniques for HCC include serum markers and various imaging modalities. Glypican 3 (GPC3) protein is highly expressed in HCC, but not in normal liver tissue. The significance of GPC3 as a predictor or diagnostic tool for human tumors other than HCC is unclear. To quantitatively assess the role of GPC3 in diagnosis of HCC in comparison to α-fetoprotein (AFP), ultrasonography (US), and computerized tomography (CT). This cross-sectional study enrolled 85 subjects: 40 cirrhotic patients with primary HCC, 30 cirrhotic patients without HCC, and 15 healthy individuals. All patients were recruited from the Gastroenterology and Tropical Departments and outpatient clinics of New Damietta Hospital during the period from November 2010 to August 2012. GPC3 is positive in some HCC patients with normal levels of AFP. AFP has lower sensitivity (67.5%) compared to higher sensitivity of GPC3 (82.5%), and near specificity (61.2%) to GPC3 (57.8%). The combined serum AFP and GPC3 significantly increased the sensitivity of HCC diagnosis. Although GPC3 is better than AFP in diagnosis of HCC, it still lacks the 100% sensitivity and specificity because some patients have negative or normal level of GPC3 (below the cutoff point 1.5ng/ml) despite being diagnosed by triphasic CT.

HEPATITIS DELTA

Objectives: The objective of this study is to prevalence of hepatitis delta inpatients with chronic hepatitis B infection. Study Design: Cross-sectional study. Period: Oneyear starting from February 2016 to January 2017. Setting: Patients OPD and admitted to Dowuniversity hospital and Zubaida Medical Center Karachi. Methods: Hepatitis B surface antigen(HbsAg) were analyzed for the presence or absence of Hepatitis D antibody (Anti HDV). 368patients with chronic hepatitis B were included to be part of this study. Patient’s age, duration ofillness and previous treatments were recorded. HBV and HDV virus presence was confirmed byusing Polymerase chain reaction (PCR). Results: Out of 368 patients with chronic HBV infection,291 (79.07%) were males and 77 (20.92%) were females. The male to female ratio was 3.7:1.Patients were aged between 35-60 years. 251 (68.2%) were positive for anti HDV. 211 of themwere males (84%) and 40 were females (15.9%). Conclusion: We have concluded that HDVinfection is associated with higher incidence of hepatocellular carcinoma in patients. Effectiveand early treatment of HDV can reduce the frequency of patients advancing to decompensatedchronic liver disease and hepatocellular carcinoma.

PREVALENCE OF HEPATITIS DELTA IN PATIENTS WITH CHRONIC HEPATITIS B INFECTION

Objectives: The objective of this study is to prevalence of hepatitis delta inpatients with chronic hepatitis B infection. Study Design: Cross-sectional study. Period: Oneyear starting from February 2016 to January 2017. Setting: Patients OPD and admitted to Dowuniversity hospital and Zubaida Medical Center Karachi. Methods: Hepatitis B surface antigen(HbsAg) were analyzed for the presence or absence of Hepatitis D antibody (Anti HDV). 368patients with chronic hepatitis B were included to be part of this study. Patient’s age, duration ofillness and previous treatments were recorded. HBV and HDV virus presence was confirmed byusing Polymerase chain reaction (PCR). Results: Out of 368 patients with chronic HBV infection,291 (79.07%) were males and 77 (20.92%) were females. The male to female ratio was 3.7:1.Patients were aged between 35-60 years. 251 (68.2%) were positive for anti HDV. 211 of themwere males (84%) and 40 were females (15.9%). Conclusion: We have concluded that HDVinfection is associated with higher incidence of hepatocellular carcinoma in patients. Effectiveand early treatment of HDV can reduce the frequency of patients advancing to decompensatedchronic liver disease and hepatocellular carcinoma.

De novo hepatocellular carcinoma occurrence in hepatitis C cirrhotics treated with direct-acting antiviral agents.

Aim:Recent studies raise concerns for higher incidence of hepatocellular carcinoma (HCC) after direct-acting antiviral therapy for hepatitis C virus (HCV).Methods:In this study, using analysis of liver imaging pre- and post-DAA treatment, we queried new occurrence or ‘de novo’ of HCC in patients with HCV-cirrhosis treated with DAAs. Of 150 patients who met study criteria, 7 (4.7%; 95% CI: 2.1–9.5%) patients developed de novo HCC which did not differ from historical rates of 3% (p = 0.22).Results:Notably, patients with decompensated cirrhosis had significantly higher rate of de novo HCC (9.3%; 95% CI: 3.12–22.2%; p = 0.04).Conclusion:Our data support the need for continued surveillance for HCC in HCV cirrhotics even after successful therapy.

The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: Role of the treatment regimen

Previous studies have reported a high frequency of hepatocellular carcinoma (HCC) occurrence in patients with advanced liver disease, after receipt of interferon (IFN)-free therapy for hepatitis C virus (HCV) infection. Our objective was to verify and account for this phenomenon using data from the Scottish HCV clinical database. We identified HCC-naïve individuals with liver cirrhosis receiving a course of antiviral therapy in Scotland from 1997-2016 resulting in a sustained virologic response. Patients were followed-up from their treatment start date to the earliest of: date of death, date of HCC occurrence, or 31 January 2017. We used Cox regression to compare the risk of HCC occurrence according to treatment regimen after adjusting for relevant co-factors (including: demographic factors; baseline liver disease stage; comorbidities/health behaviours, virology, and previous treatment experience). HCC occurrence was ascertained through both the HCV clinical database and medical chart review. For our main analysis, treatment regimen was defined as IFN-free vs. IFN-containing. A total of 857 patients met the study criteria, of whom 31.7% received an IFN-free regimen. Individuals receiving IFN-free therapy were more likely to be: older; of white ethnicity, Child-Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic; non-genotype 3; and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated with a significantly increased risk of HCC (HR: 2.48; p = 0.021). However, after multivariate adjustment for baseline factors, no significant risk attributable to IFN-free therapy persisted (aHR: 1.15, p = 0.744). These findings suggest that the higher incidence of HCC following sustained virologic response with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se. We examined the risk of liver cancer in 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer.

Prevalence of Aflatoxin-Associated TP53R249S Mutation in Hepatocellular Carcinoma in Hispanics in South Texas.

We aimed to determine whether aflatoxin dietary exposure plays a role in the high incidence of hepatocellular carcinoma (HCC) observed among Hispanics in South Texas. We measured TP53R249S somatic mutation, hallmark of aflatoxin etiology in HCC, using droplet digital PCR and RFLP. TP53R249S mutation was detected in 3 of 41 HCC tumors from Hispanics in South Texas (7.3%). We also measured TP53R249S mutation in plasma cell-free DNA (cfDNA) from 218 HCC patients and 96 Hispanic subjects with advanced fibrosis or cirrhosis, from South Texas. The mutation was detected only in Hispanic and Asian HCC patients, and patients harboring TP53R249S mutation were significantly younger and had a shorter overall survival. The mutation was not detected in any Hispanic subject with advanced fibrosis or cirrhosis. Genes involved in cell-cycle control of chromosomal replication and in BRCA1-dependent DNA damage response were enriched in HCCs with TP53R249S mutation. The E2F1 family members, E2F1 and E2F4, were identified as upstream regulators. TP53R249S mutation was detected in 5.7% to 7.3% of Hispanics with HCC in South Texas. This mutation was associated with a younger age and worse prognosis. TP53R249S was however not detected in Hispanics in South Texas with cirrhosis or advanced fibrosis. Aflatoxin exposure may contribute to a small number of HCCs in Hispanics in South Texas, but the detection of TP53R249S mutation in plasma cfDNA is not a promising biomarker of risk assessment for HCC in subjects with cirrhosis or advanced fibrosis in this population. Cancer Prev Res; 11(2); 103-12. ©2017 AACR.