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Background Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. Methods All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (January 2008 to June 2018). Baseline and on-treatment data were collected. Results Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor [mTORi], 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% confidence Interval [CI], 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95% CI, 8-27); 5-year OS was 18% (95% CI, 4%-32%). Baseline predictors of OS were SOR+mTORi (hazard ratio [HR], 0.4; 95% CI, 0.2-0.9; P = 0.04), previous curative treatments (HR, 0.3; 95% CI, 0.2-0.7; P = 0.003) and alpha-fetoprotein > 100 ng/mL (HR, 2.5; 95% CI, 1.1-5.0, P = 0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR, 0.4; 95% CI 0.2-1.0; P = 0.04). Conclusions Early and combined treatment with SOR and mTORi resulted in a favorable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS.

Background and aim Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared to best supportive care (BSC) in LT-patients after sorafenib discontinuation. Methods This observational multicenter retrospective study included LT-patients with HCC-recurrence who discontinued first-line sorafenib. Group-1 was constituted by regorafenib-treated patients, while control group was selected among patients treated with best supportive care (BSC) due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group-2). Primary endpoint was overall survival (OS) of group-1 compared to group-2. Secondary endpoints were safety and OS of sequential treatment sorafenib+regorafenib/BSC. Results Among 132 LT-patients who discontinued sorafenib included in the study, 81 patients were sorafenib-tolerant: 36 received regorafenib (group-1) and 45 (group-2) received BSC. Overall, 24 (67%) patients died in group-1 and 40 (89%) in group-2: the median OS was significantly longer in group-1 than in group-2 (13.1 vs 5.5 months; p=0.002). Regorafenib treatment was an independent predictor of reduced mortality (HR 0.37, 95%CI 0.16-0.89, p=0.02). Median treatment duration with regorafenib was 7.0 (95%CI 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93%. The median OS calculated from sorafenib start was 28.8 months (95%CI: 17.6-40.1) in group-1 vs 15.3 months (95%CI: 8.8-21.7) in group-2 (p=0.002). Conclusions Regorafenib is an effective second-line treatment after sorafenib in patients with HCC-recurrence after LT.

Introduction: The quantitative determination of urinary Cystatin C (cyst-C) associated with the qualitative analysis of its polymorphisms is an excellent method for early identification of newborns predisposed to renal function impairment. PETIA, PENIA and EIA are the immunometric methods used for the quantitative determination of cyst-C inhuman biologic fluid but they have limitations and do not allow qualitative analysis. The present study is a validation of Immunoblot SDS-PAGE for the qualitative and quantitative analysis of urinary cyst-C. Methods: Urine was collected from neonates in the nursey at S. Maria della Misericordia Hospital. Urinary cyst-C was investigated by the immunoblot SDS-PAGE and by reading of optical density. Results: The qualitative analysis showed two different molecular forms: A reactivity at about 70 KDa in all samples and a reactivity at 13 KDa in a limited number of samples. This analysis allows the correlation of the polymorphisms of cyst-C with specific alterations of renal function in newborns. The quantitative analysis is specific, sensitive and accurate. In fact the coefficient of variation for assay precision was 10% and for assay accuracy was ± 10%, the detection limit was 0.009 ng/ µL and the calibration line has satisfactory linearity (range 0.02-0.3 ng/µL). The stability of urinary cyst-C was acceptable, even without the use of protease inhibitors, as long as the assay was performed on freshly recruited urine or immediately after thawing the samples, which had been stored for up to six months. Conclusion: Immunoblot SDS-PAGE analysis is a valid method of obtaining a qualitative and quantitative analysis of urinary cyst-C. This method presents unique information about a previously unknown 70 KDa cyst-C form. The assay may offer potential diagnostic information not available with immunometric method.

On behalf of MAST4HEALTH consortium: et al., [Scope]: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with poor therapeutic strategies. Mastiha possesses antioxidant/anti-inflammatory and lipid-lowering properties. The authors investigate the effectiveness of Mastiha as a nonpharmacological intervention in NAFLD., [Methods and Results]: Ninety-eight patients with NAFLD in three countries (Greece, Italy, Serbia) are randomly allocated to either Mastiha or Placebo for 6 months, as part of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The authors assess NAFLD severity via magnetic resonance imaging (MRI) scanning and LiverMultiScan technique and evaluate the effectiveness of Mastiha through medical, anthropometric, biochemical, metabolomic, and microbiota assessment. Mastiha is not superior to Placebo on changes in iron-corrected T1 (cT1) and Liver Inflammation Fibrosis score (LIF) in entire patient population; however, after BMI stratification (BMI ≤ 35 kg m-2 and BMI > 35 kg m-2), severely obese patients show an improvement in cT1 and LIF in Mastiha versus Placebo. Mastiha increases dissimilarity of gut microbiota, as shown by the Bray-Curtis index, downregulates Flavonifractor, a known inflammatory taxon and decreases Lysophosphatidylcholines-(LysoPC) 18:1, Lysophosphatidylethanolamines-(LysoPE) 18:1, and cholic acid compared to Placebo., [Conclusion]: Mastiha supplementation improves microbiota dysbiosis and lipid metabolite levels in patients with NAFLD, although it reduces parameters of liver inflammation/fibrosis only in severely obese patients., This project was funded by the European Union’s Horizon 2020 researchand innovation program MAST4HEALTH under the Marie Skłodowska-Curie grant agreement no. 691042.

Introduction The quantitative determination of urinary Cystatin C (cyst-C) associated with the qualitative analysis of its polymorphisms is an excellent method for early identification of newborns predisposed to renal function impairment. PETIA, PENIA and EIA are the immunometric methods used for the quantitative determination of cyst-C in human biologic fluid but they have limitations and do not allow qualitative analysis. The present study is a validation of Immunoblot SDS-PAGE for the qualitative and quantitative analysis of urinary cyst-C. Methods Urine was collected from neonates in the nursey at S. Maria della Misericordia Hospital. Urinary cyst-C was investigated by the immunoblot SDS-PAGE and by reading of optical density. Results The qualitative analysis showed two different molecular forms: a reactivity at about 70 KDa in all samples and a reactivity at 13 KDa in a limited number of samples. This analysis allows the correlation of the polymorphisms of cyst-C with specific alterations of renal function in newborns. The quantitative analysis is specific, sensitive and accurate. In fact the coefficient of variation for assay precision was 10% and for assay accuracy was ±10%, the detection limit was 0.009 ng/ µL and the calibration line has satisfactory linearity (range 0.02–0.3 ng/ µL). The stability of urinary cyst-C was acceptable, even without the use of protease inhibitors, as long as the assay was performed on freshly recruited urine or immediately after thawing the samples, which had been stored for up to six months. Conclusion Immunoblot SDS-PAGE analysis is a valid method of obtaining a qualitative and quantitative analysis of urinary cyst-C. This method presents unique information about a previously unknown 70 KDa cyst-C form. The assay may offer potential diagnostic information not available with immunometric method.

Background & Aims: The ANSWER study reported that long-term albumin administration in patients with cirrhosis and uncomplicated ascites improves survival. During treatment, serum albumin increased within a month and remained stable thereafter. In this post hoc analysis, we aimed to determine whether on-treatment serum albumin levels could guide therapy. Methods: Logistic regression was used to assess the association between baseline serum albumin and mortality, as well as to determine on-treatment factors associated with mortality and to predict the achievement of a given on-treatment serum albumin level. Survival was assessed by Kaplan-Meier estimates and second-order polynomial regression. Patients whose on-treatment serum albumin remained below normal were compared with a subset of patients from the control arm matched by principal score. Results: Baseline serum albumin was closely associated with 18-month mortality in untreated patients; albumin treatment almost effaced this relationship. On-treatment serum albumin and MELD-Na at month 1 were the sole independent variables associated with mortality. Second-order polynomial regression revealed that survival improved in parallel with increased 1-month on-treatment serum albumin. Kaplan-Meier estimations showed that any value of 1-month on-treatment serum albumin (0.1 g/dl intervals) in the range 2.5–4.5 g/dl discriminated patient survival. In the normal range of serum albumin, the best discriminant value was 4.0 g/dl. Compared to untreated patients, survival even improved in patients whose on-treatment serum albumin remained below normal. Conclusion: Baseline serum albumin per se should not guide the decision to start albumin therapy. Conversely, 1-month on-treatment serum albumin levels are strongly associated with outcomes and could guide the use of albumin – 4.0 g/dl being the target threshold. However, even patients whose serum albumin remains below normal benefit from long-term albumin administration. Lay summary: The ANSWER study has shown that long-term albumin administration improves survival and prevents the occurrence of major complications in patients with cirrhosis and ascites. This study shows that the achievement of these beneficial effects is related to a significant increase in serum albumin concentration. Even though the best results follow the achievement of a serum albumin concentration of 4 g/dl, a survival benefit is also achieved in patients who fail to normalise serum albumin.

Aldehyde oxidase (AOX) is a molibdo-flavoenzyme that has raised great interest in recent years, since its contribution in xenobiotic metabolism has not always been identified before clinical trials, with consequent negative effects on the fate of new potential drugs. The fundamental role of AOX in metabolizing xenobiotics is also due to the attempt of medicinal chemists to stabilize candidates toward cytochrome P450 activity, which increases the risk for new compounds to be susceptible to AOX nucleophile attack. Therefore, novel strategies to predict the potential liability of new entities toward the AOX enzyme are urgently needed to increase effectiveness, reduce costs, and prioritize experimental studies. In the present work, we present the most up-to-date computational method to predict liability toward human AOX (hAOX), for applications in drug design and pharmacokinetic optimization. The method was developed using a large data set of homogeneous experimental data, which is also disclosed as Supporting Information .

s / Digestive and Liver Disease 47S (2015) e1–e18 e7 (months; 95% CI): CPT 0 62 (52.9–71.1), A 44 (41.6–46.4), B 22 (19.7–24.3), C 9 (6.6–11.3), p

Objective: Peripheral cholangiocarcinoma may be more frequent than expected, and is usually asymptomatic until it is well advanced. Our purpose was to assess the accuracy of ultrasound in differential diagnosis. Methods: We compared the sonographic findings of ten consecutive patients with histologically proven peripheral cholangiocarcinoma with those obtained in 26 consecutive patients with hepatocarcinoma detected in the same period. In every patient we performed an ultrasound-guided biopsy with a fine (22 gauge) cutting needle. Results: In all patients with a final diagnosis of peripheral cholangiocarcinoma, the ultrasound scan disclosed multiple well-defined nodules with a hypoechoic or target pattern. Two patients had dilated intrahepatic bile ducts and suspected infiltration of the common duct. No patient had ascites. Only minimal alterations in laboratory examinations were found. Ultrasound-guided fine cutting needle biopsy yielded diagnostic material and allowed the definitive differential diagnosis. Conclusion: Peripheral cholangiocarcinoma even in Western countries may represent a significant proportion of all primary liver cancers. Due to non-specific symptomatology only intractable and far advanced cases were detected by means of sonography. Ultrasound findings did not differ from those found in cases of metastases from extrahepatic adenocarcinomas or hepatocarcinoma with multinodular pattern (10/26 in our series).