Interleukin 28 polymorphisms and hepatocellular carcinoma development after direct acting antiviral therapy for chronihepatitis c

Background & Aims: Cirrhotic patients with hepatitis C virus (HCV) infection remain at risk of developing hepatocellular carcinoma (HCC) even after the sustained virologic response (SVR). We aimed to evaluate whether the IL28 (rs12979860) single nucleotide polymorphism (SNP) may constitute a predisposing genetic factor and to identify the SVR patients at risk of HCC. Methods: Two hundred patients undergoing DAAs treatment for chronic hepatitis C with advanced fibrosis (F3-F4) were consecutively enrolled. Besides normal routine laboratory testing for HCV, patients’ sera were evaluated also for retinol, retinol-binding protein 4 and the following SNPs: PNPLA3 (rs738409), TM6SF2 (rs58542926), MBOAT7 (rs641738), IL28B (rs12979860), TIMP-1 (rs4898), TIMP-2 (rs8179090), NF-kB promoter (rs28362491). Statistical analyses were conducted using Stata/SE 14.2 statistical software (Stata Corp, College Station, TX). Results: Almost all patients (197/200) obtained SVR24. Seventeen patients had a previous history of treated HCC before DAAs. Six patients developed HCC recurrence and five patients developed de novo HCC after a mean period of 18 months since EOT. All these patients had SVR. A significant association between IL28B – TT genotype and HCC development after DAAs therapy was observed (OR 4.728, CI 95% 1.222 – 18.297, p=0.024). Conclusion: IL28B rs12979860 polymorphism was significantly associated with HCC development after DAAs. Assessment of this SNP may better identify patients at risk of developing HCC after treatment. Further prospective studies are required to confirm these hypotheses

High Doses of Ursodeoxycholic Acid Up-Regulate the Expression of Placental Breast Cancer Resistance Protein in Patients Affected by Intrahepatic Cholestasis of Pregnancy

BACKGROUND: Ursodeoxycholic acid (UDCA) administration in intrahepatic cholestasis of pregnancy (ICP) induces bile acids (BA) efflux from the foetal compartment, but the molecular basis of this transplacental transport is only partially defined. AIM: To determine if placental breast cancer resistance protein (BCRP), able to transport BA, is regulated by UDCA in ICP. METHODS: 32 pregnant women with ICP (14 untreated, 34.9\ub15.17 years; 18 treated with UDCA--25 mg/Kg/day, 32.7\ub14.62 years,) and 12 healthy controls (33.4\ub13.32 years) agreed to participate in the study. Placentas were obtained at delivery and processed for membrane extraction. BCRP protein expression was evaluated by immunoblotting techniques and chemiluminescence quantified with a luminograph measuring emitted photons; mRNA expression with real time PCR. Statistical differences between groups were evaluated by ANOVA with Dunn's Multiple Comparison test. RESULTS: BCRP was expressed only on the apical membrane of the syncytiotrophoblast. A significant difference was observed among the three groups both for mRNA (ANOVA, p\u200a=\u200a0.0074) and protein (ANOVA, p<0.0001) expression. BCRP expression was similar in controls and in the untreated ICP group. UDCA induced a significant increase in placental BCRP mRNA and protein expression compared to controls (350.7\ub1106.3 vs 100\ub118.68% of controls, p<0.05 and 397.8\ub156.02 vs 100\ub111.44% of controls, p<0.001, respectively) and untreated ICP (90.29\ub117.59% of controls, p<0.05 and 155.0\ub113.87%, p<0.01). CONCLUSION: Our results confirm that BCRP is expressed only on the apical membrane of the syncytiotrophoblast and show that ICP treatment with high dose UDCA significantly upregulates placental BCRP expression favouring BA efflux from the foetal compartment

Size and location of spontaneous portosystemic shunts predict the risk of decompensation in cirrhotic patients

Background: The prognostic role of spontaneous portosystemic shunts (SPSS) has been poorly investigated. / Aims: To evaluate the impact of the presence of SPSS, as well as their characteristics, on the risk of decompensation. / Methods: This is a retrospective cohort study of 235 advanced chronic liver disease (ACLD) patients with available imaging examination, transient elastography, and upper endoscopy. ACLD was defined as liver stiffness measurement (LSM) >10 kPa. Competitive risk analyses were performed to identify the factors associated with the main outcome. / Results: SPSS were reported in 141 (60%) of the patients. Non-viral etiology was independently associated with SPSS presence [Odds-Ratio (OR): 2.743;95%-Interval-of-Confidence (IC):1.129–6.664]. During a follow-up of 37 (20–63) months, SPSS were found predictors of any decompensation type [Subhazard Ratio (SHR):2.264; 95%-IC:1.259–4.071], independently from a history of decompensation or high-risk-varices presence. The risk of complications was higher in patients with large (SHR: 3.775; 95%-IC: 2.016–7.070) and multiple (SHR:3.832; 95%-IC: 2.004–7.330) shunts, and in those with gastrorenal shunts (SHR:2.636; 95%-IC:1.521–4.569). / Conclusions: The presence, size, and number of SPSS predict not only the risk of hepatic encephalopathy but that of any type of decompensation across all stages of cirrhosis. Future studies should explore the possibility of treating shunts to prevent decompensation

A nomogram-based prognostic model for advanced hepatocellular carcinoma patients treated with sorafenib: A multicenter study

Among scores and staging systems used for HCC, none showed a good prognostic ability in patients with advanced HCC treated with Sorafenib. We aimed to evaluate predictive factors of overall survival (OS) and drug response in HCC patients undergoing Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort. Patients in the ITA.LI.CA database treated with Sorafenib and updated on 30 June 2019 were included. Demographic and clinical data before starting Sorafenib treatment were considered. For the evaluation of predictive factors for OS, a time-dependent Cox proportional hazard model was used. A total of 1107 patients were included in our analysis. The mean age was 64.3 years and 81.7% were male. Most patients were staged as BCLC B (205, 18.9%) or C (706, 65.1%). The median time of Sorafenib administration was 4 months (interquartile range (IQR) 2–12), and the median OS was 10 months (IQR: 4–20). A total of 263 patients (33.8%) out of 780 with available evaluation experienced objective tumoral response to Sorafenib. The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (hazard ratio (HR) 1.284), maximum tumoral diameter (HR 1.100), plasma total bilirubin (HR 1.119), aspartate amino transferase assessed as multiple of the upper normal value (HR 1.032), alpha-fetoprotein ≥200 ng/mL (HR 1.342), hemoglobin (HR 0.903) and platelet count (HR 1.002) were associated with OS at multivariate Cox regression analysis. Drug response was predicted by maximum tumoral diameter and platelet count. A novel prognostic nomogram for patients undergoing Sorafenib is hereby proposed. The novelty introduced is the comprehensive patient’s assessment using common markers of patient’s general status, liver damage and function and HCC biology. Further studies are required to test its accuracy and provide external validation

Transarterial Chemoembolization for Hepatocellular Carcinoma in Clinical Practice: Temporal Trends and Survival Outcomes of an Iterative Treatment

Background: Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy. Methods: Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment. Results: The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p &lt; 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p &lt; 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC). Conclusions: Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis

BIOCHRONOLOGY OF SELECTED MAMMALS, MOLLUSCS AND OSTRACODS FROM THE MIDDLE PLIOCENE TO THE LATE PLEISTOCENE IN ITALY. THE STATE OF THE ART

The Authors have elaborated four range charts of mammalian (large and micro), molluscs and fresh-water and brackish ostracodes faunas, for the selected Plio-Pleistocene fossiliferous localities of the Italy. A new Mammal Age (Aurelian) correlatable to late Middle and Late Pleistocene has been defined. Inside this age two Faunal Units (Torre in Pietra and Vitinia) have been defined as characteristic for Early and Middle Aurelian, while no gisements have been chosen for the late Aurelian. Biochronological units are calibrated on magnetostratigraphic and isotopic scales and by radiometric datings.&nbsp;&nbsp; &nbsp

BIOCHRONOLOGY OF SELECTED MAMMALS, MOLLUSCS AND OSTRACODS FROM THE MIDDLE PLIOCENE TO THE LATE PLEISTOCENE IN ITALY. THE STATE OF THE ART

The Authors have elaborated four range charts of mammalian (large and micro), molluscs and fresh-water and brackish ostracodes faunas, for the selected Plio-Pleistocene fossiliferous localities of the Italy. A new Mammal Age (Aurelian) correlatable to late Middle and Late Pleistocene has been defined. Inside this age two Faunal Units (Torre in Pietra and Vitinia) have been defined as characteristic for Early and Middle Aurelian, while no gisements have been chosen for the late Aurelian. Biochronological units are calibrated on magnetostratigraphic and isotopic scales and by radiometric datings.&nbsp;&nbsp; &nbsp

Clinical significance of pneumatosis intestinalis - correlation of MDCT-findings with treatment and outcome.

To evaluate the clinical significance of pneumatosis intestinalis (PI) including the influence on treatment and outcome. Two radiologists jointly reviewed MDCT-examinations of 149 consecutive emergency patients (53 women, mean age 64, range 21-95) with PI of the stomach (n = 4), small (n = 68) and/or large bowel (n = 96). PI extension, distribution and possibly associated porto-mesenteric venous gas (PMVG) were correlated with other MDCT-findings, risk factors, clinical management, laboratory, histopathology, final diagnosis and outcome. The most frequent cause of PI was intestinal ischemia (n = 80,53.7 %), followed by infection (n = 18,12.1 %), obstructive (n = 12,8.1 %) and non-obstructive (n = 10,6.7 %) bowel dilatation, unknown aetiologies (n = 8,5.4 %), drugs (n = 8,5.4 %), inflammation (n = 7,4.7 %), and others (n = 6,4 %). Neither PI distribution nor extension significantly correlated with underlying ischemia. Overall mortality was 41.6 % (n = 62), mostly related to intestinal ischemia (p = 0.003). Associated PMVG significantly correlated with underlying ischemia (p = 0.009), as did the anatomical distribution of PMVG (p = 0.015). Decreased mural contrast-enhancement was the only other MDCT-feature significantly associated with ischemia (p p &lt; 0.001). Elevated white blood count significantly correlated with ischemia (p = 0.03). In emergency patients, ischemia remains the most common aetiology of PI, showing the highest mortality. PI with associated PMVG is an alerting sign. PI together with decreased mural contrast-enhancement indicates underlying ischemia. • In emergency patients, PI may be caused by various disorders. • Intestinal ischemia remains the most common cause of PI in acute situations. • PI associated with decreased mural contrast-enhancement indicates acute intestinal ischemia. • PI associated with PMVG should alert the radiologist to possible underlying ischemia

Overview of prognostic systems for hepatocellular carcinoma and ITA.LI.CA external validation of MESH and CNLC classifications

Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described