The CC5 and CXC3 chemokines (CK) pathways are involved in the pathogenesis and outcome of several disease states, including chronic hepatitis C (CHC). The kinetics of Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) (CCL5) and IP-10 (CXCL10) during direct-acting antivirals (DAA) treatment was retrospectively analyzed in 18 liver transplant recipients (LT-R) compared with 20 patients with CHC and 49 healthy controls (HC). CK levels were determined at baseline, week 4, end of treatment, 24 weeks post-treatment (sustained virological response [SVR]), and later-on during follow-up (FU), 12 and 24 months post-DAA. At baseline, median RANTES levels were higher in HC than in both LT-R (p > 0.01) and CHC (p > 0.01), whereas IP-10 levels were higher in LT-R and CHC than in HC (p > 0.05 and p = 0.01), respectively. Mean RANTES values increased during DAA therapy to peak at SVR and FU with significantly higher levels than at baseline in LT-R (p < 0.01) and in CHC, but only at FU (p < 0.003). A subsequent return to baseline or lower levels was observed at extended FU. On the contrary, IP-10 values showed a significant decrease from baseline to SVR and FU in both LT-R (p < 0.03) and CHC (p < 0.01). RANTES profiles during the first 4 weeks of DAA treatment showed an increase or decrease from baseline according to baseline RANTES levels. CCR5 genotyping in LT-R showed the presence of 1 homozygous Δ32/Δ32 and 2 heterozygous WT/Δ32 haplotypes with a prevalence of 5.5% and 11.1%, respectively. In conclusion, although IP-10 showed the expected kinetics, the CC5 pathway appears extensively altered during CHC infection: monitoring these patients may be indicated as they may be at risk of other infections or immune-mediated disorders.

“HER2 signaling enhances 5′UTR‐mediated translation of c‐Myc mRNA”, J. Cell. Physiol. 200: 82–88, 2004, by Enrico Galmozzi, Patrizia Casalini, Marilena Valeria Iorio, Barbara Casati, Clelia Olgiati, and Sylvie Ménard. The editors of the Journal of Cellular Physiology and the Wiley Periodicals LLC agree to publish an Expression of Concern regarding the above article, published online on 23 January 2004, in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/jcp.20012).

Background and Aims Genetic factors and steatosis predispose to hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus; however, their impact in patients with cirrhosis cured by direct‐acting antivirals (DAAs) is still undefined. We assessed the association between a genetic risk score (GRS) of hepatic fat accumulation, combining variants in PNPLA3 (patatin‐like phospholipase domain containing 3), MBOAT7 (membrane bound O‐acyltransferase domain containing 7), TM6SF2 (transmembrane 6 superfamily member 2), GCKR (glucokinase regulator), and HCC in patients treated with DAAs. Approach and Results We considered 509 consecutive patients with HCV cirrhosis (defined histologically or when liver stiffness ≥12 kPa) treated with DAAs. HCC was diagnosed according to international recommendations. GRS was calculated from the weighted impact of single variants on hepatic fat content quantified by H1 spectrometry in the general population (Dallas Heart Study). During a median follow‐up of 43 (3‐57) months after DAA start, 36 of 452 (8%) patients developed de novo HCC, 4‐year cumulative probability being 9% (95% confidence interval 7%‐12%). Male sex (hazard ratio [HR] 2.54, P = 0.02), diabetes (HR 2.39, P = 0.01), albumin (HR 0.35, P = 0.001), and GRS score >0.597 (HR 2.30, P = 0.04) were independent predictors of de novo HCC. In contrast, single genetic risk variants were not useful in stratifying HCC risk. The proportion of patients who developed HCC according to the combination of the independent risk factors ranged from 11% to 67%. HCC recurred in 28 of 57 (49%) patients with previous history; diabetes and ethnicity were the only independent predictors of HCC recurrence. Conclusions In a large cohort of DAA‐treated patients with cirrhotic HCV, GRS was associated with de novo HCC independently of classical risk factors, including liver disease severity. These data suggest that hepatic fat (i.e., lipotoxicity) promotes HCC in this setting and may represent a target for chemoprevention. Combination of clinical and genetic predictors may improve HCC risk stratification.

Introduction Signal transducers and activators of transcription (STAT4), Epidermal Growth Factor 1 (EGF1), Tolloid like 1 gene (TLL1), Myeloid-epithelial-reproductive tyrosine kinase (MERTK) and for domain II (MERTK2), Patatin-like phospholipase-3 gene (PNPLA3) and Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) genetic variants have been associated with the development of hepatocellular carcinoma (HCC) in Asian and Caucasian HBV patients.

Introduction: Recently, the single-nucleotide polymorphism (SNP) rs6834314 near to the 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) gene has been associated with NAFLD histology. Particularly, the minor G allele of the rs6834314 variant correlated with increased steatosis but decreased inflammation.

Background: Several single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotics, however their role in patients cured by direct-acting antivirals (DAA) is still undefined.

Tolloid-like 1 gene (TLL1) variant rs17047200 has been associated with hepatocellular carcinoma (HCC) in Japanese hepatitis C virus (HCV) patients with sustained virological response (SVR) to interferon or direct-acting antiviral (DAA)-based regimens. We investigated whether this holds true also in Caucasian cirrhotic patients cured by DAAs. Consecutive Caucasian HCV cirrhotics receiving DAA between December 2014 and December 2016 in a single centre were enrolled. Cirrhosis was defined histologically (METAVIR F4) or by liver stiffness measurement (LSM > 11.9 kPa). TLL1 rs17047200 was analysed by TaqMan SNP genotyping assay. 452 patients were enrolled: median age 63 (28-87) years, 58% males, 47% HCV-1b, LSM 19.1 (12.0-75.0) kPa and Fibrosis-4 (FIB-4) score 4.9 (0.3-46.0). 96% patients achieved an SVR. TLL1 genotype was AA in 329 (73%) and AT/TT in 123 (27%) (MAF = 0.14, HWE P > 0.05). Patients' clinical features were similar across TLL1 genotypes. After 33 (3-47) months from DAA start, 31 patients developed HCC, with a 3-year estimated cumulative probability being 7.5% (95% CI: 5%-10%). The cumulative incidence of HCC was 9% in TLL1 AA vs 7% in AT/TT patients (P = 0.55). Male sex (HR: 3.78, 95% CI: 1.4-10.1, P = 0.008), diabetes (HR: 3.5, 95% CI: 1.68-7.27, P = 0.001) and FIB-4 (HR: 1.09, 95% CI: 1.03-1.14, P = 0.001) were baseline-independent predictors of HCC. The incidence of HCC was not influenced by TLL1 genotypes even when considering an additional group of 348 noncirrhotic patients, being 2% in AA vs 1% AT/TT patients (P = 0.58). In a large cohort of Caucasian HCV cirrhotics treated with DAA, TLL1 variants do not predict HCC development.

Background and aim: Several single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotics, however their role in patients cured by direct-acting antivirals (DAA) is still undefined. We assessed the association between nine SNPs and HCC in a cohort of DAA-treated patients.

Male gender 1.12 (0.78-1.62) 0.54 1.18 (0.79-1.76) 0.41 Age 1.00 (0.99-1.02) 0.74 1.01 (0.99-1.02) 0.27 Arterial hypertension 1.02 (0.76-1.37) 0.91 1.08 (0.78-1.48) 0.63 INR 1.57 (1.00-2.46) 0.05 2.07 (1.26-3.39) 0.004 Bilirubin, mg/dL 1.53 (1.16-2.01) 0.003 1.27 (1.00-1.62) 0.049 Albumin, g/dL 0.71 (0.51-0.97 0.03 0.68 (0.48-0.95) 0.03 Ascites 1.52 (0.98-2.37) 0.06 1.35 (0.84-2.15) 0.21 Encefalopathy 2.07 (1.09-3.94) 1.65 (0.86-3.15) 0.13 AFP, ng/mL 0.99 (0.99-1.00) 0.53 0.99/0.99-1.00) 0.23 Varices (Y vs N) 1.56 (1.22-1.99)< 0.001 1.27 (0.92-1.74) 0.144 1.42 (1.02-1.95) 0.035 1.40 (1.01-195) 0.045 CPT (A vs B) 2.11 (1.35-3.30) 0.001 2.10 (1.06-4.16) 0.033 2.27 (1.27-4.00) 0.005 2.24 (1-13-4.41) 0.020 ECOG PS (0 vs 1) 1.81 (1.42-2.32)< 0.001 1.57 (1.07-2.32) 0.022 1.94 (1.40-2.68)< 0.001 2.51 (1.66-3.79)< 0.001 Macrovascular tumor invasion 0.94 (0.68-1.29) 0.69 1.35 (0.98-1.87) 0.068Metastases 1.15 (0.87-1.53) 0.33 0.97 (0.71-1.31) 0.83 eDAE 0.69 (0.451. 06) 0.09 0.61 (0.37-1.01) 0.05 0.57 (0.34-0.96) 0.036 0.62 (0.35-1.09) 0.097 eCardiovascular 1.62 (0.86-3.07) 0.14 1.44 (0.73-2.81) 0.29 eGastrointestinal 0.91 (0.43-1.93) 0.80 0.79 (0.33-1.94) 0.62 eFatigue 2.19 (0.30-15.7) 0.44 1.46 (1.08-1.98) 0.014 0.78 (0.52-1.16) 0.228 eWeight-loss 2.97 (0.93-9.43) 0.06 1.20 (0.74-1.82) 0.46 3.39 (1.07-10.7) 0.04 1.57 (0.97-2.53) 0.065 eRadiological

Introduction: Genetic variants of Signal transducers and activators of transcription (STAT4) are associated with greater fibrosis, while Epidermal Growth Factor 1 (EGF1), Myeloid-epithelial-reproductive tyrosine kinase (MERTK) and for domain II (MERTK2), Patatin-like phospholipase-3 gene (PNPLA3) and Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) to hepatocellular carcinoma (HCC) onset in untreated or IFN-treated Asian HBV patients. Aim was to assess their prediction for HCC in Caucasian HBV cirrhotics long-term treated by tenofovir or entecavir.

Background and aims: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (aHCC). It has recently emerged that the AGT-gene polymorphisms (SNPs) predict the early (<2 months) occurrence of dermatological adverse events (eDAEs) requiring dose-reduction, a predictor of overall survival (OS). We evaluated the predictive role of eDAE and AGT-gene SNPs for sorafenib in aHCC.

Background and aims: As HCC remains the leading complication in HBV compensated cirrhotics long-term TDF/ETV treated, we aimed to define baseline predictors of HCC, including the tolloid like 1 gene (TLL1) rs17047200 polymorphism which predicts HCC in HCV patients cured by IFN therapy.

Nonalcoholic fatty liver disease (NAFLD) consists of a spectrum of disorders characterized predominantly by hepatic steatosis in the absence of significant alcohol consumption, potentially evolving to nonalcoholic steatohepatitis (NASH), with increased hepatocellular injury and inflammation with or without fibrosis.

Background and aims: The 2017 EASL HBV CPG recommend switching TDF treated patients to TAF (NUC naïve or experienced) or ETV (only NUC naïve) if they have one of the following risk factors: (1) age >60 years, (2) bone disease [history of fragility fracture, osteoporosis, chronic use of steroids or medications that worsen BMD], and (3) renal alterations [eGFR <60 mL/min, albuminuria >30 mg/24 h or moderate dipstick proteinuria, low serum phosphate (<2.5 mg/dL), or hemodialysis]. We want to estimate the number of patients who could benefit from this switch in a cohort of TDF-treated patients.

Total or partial inactivation of the chemokine 5 (CC5) pathway, as caused by the CC5 receptor Δ32 deletion (CCR5Δ32), may result in a profound manipulation of immune surveillance with significant consequences on the course and response to therapy of diverse human infections, including HIV. It has been postulated that in chronic hepatitis C (CHC), such a deregulation of CC5 pathway may compromise T cell-dependent antiviral immune responses, which in turn may favor viral persistence. To test this hypothesis, we investigated a cohort of 100 patients with CHC in whom 12 heterozygous and 1 homozygous CCR5Δ32 mutations were detected compared to 8 and none in 98 healthy controls (13% vs. 8.2%, p = 0.36). As patients with and without CCR5Δ32 mutations were similar in terms of histological activity (p = 0.84) and fibrosis stage (p = 0.20) as well as CCR5 tissue expression, we reasonably exclude that this CCR5 mutation is significantly involved in the pathogenesis of CHC and may be a potential therapeutic target. However, deleted patients showed a significantly higher response to pegylated interferon-alfa (PEG-IFN), suggesting that a dormant immune system is more readily primed by immunostimulation.

Hepatitis delta virus (HDV) is a defective RNA virus that depends on the presence of hepatitis B virus (HBV) for the creation of new virions and propagation of the infection to hepatocytes. Chronic infection with HDV is usually associated with a worsening of HBV infection, leading more frequently to cirrhosis, increased risk of liver decompensation and hepatocellular carcinoma (HCC) occurrence. In spite of a progressive declining prevalence of both acute and chronic HDV infection observed over several years, mainly due to increased global health policies and mass vaccination against HBV, several European countries have more recently observed stable HDV prevalence mainly due to migrants from non-European countries. Persistent HDV replication has been widely demonstrated as associated with cirrhosis development and, as a consequence, development of liver decompensation and occurrence of HCC. Several treatment options have been attempted with poor results in terms of HDV eradication and improvement of long-term prognosis. A global effort is deemed urgent to enhance the models already existing as well as to learn more about HDV infection and correlated tumourigenesis mechanisms.