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Background: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. Materials and methods: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. Results: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. Conclusions: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

This work investigates the effect of the anisotropy on the heat transfer properties of layered composite materials with discrete heat sources, that are used in the power electronics of hybrid-electric propulsion systems. An analytical method, based on closed-form expressions structured on Fourier expansion series, is proposed for the solution of the Laplace’s steady-state anisotropic heat equation. The physical presence of electrical components is replaced by externally applied power sources. The method provides an accurate prediction of the temperature distribution and of the heat transfer across perfect layer-to-layer adhesion or finite conductance interfaces; its use is therefore encouraged for the optimization of composite substrates. Code verification has been employed on test cases for which the analytical solution was available.

Background and aims: Non-invasive methods accurately estimating hepatic venous pressure gradient (HVPG) are un unmet clinical need. Preliminary data suggested that graph analysis of dynamic contrast enhanced ultrasonography (DCE-US) of the liver using a “connectome” approach allows assessment of the liver microcirculatory derangement and mirrors the severity of portal hypertension (Amat-Roldan et al. Radiology 2015). The EC-funded prospective CLEVER study (FP7-IAPP-GA-2013-612273-CLEVER) is aimed at developing a novel automatized software based on DCE-US able to improve prognostication in cirrhosis. First extended results were developed with a Siemens Acuson Sequoia in Barcelona, showing optimal correlation with HVPG. Here we report the adaptation of this CLEVER software to DCE-US videos acquired with ESAOTE MyLab equipments in Bologna to predict HVPG in a population of patients with F≥3 hepatopathy. Method: Ten seconds long videoclip(s) of the right liver lobe were recorded in each patient producing one cycle of microbubble disruption and reperfusion during SonoVue infusion. A total of 90 videos from randomly selected 47 patients were utilized to optimize the autoselection algorithm of the computer among 5models based on platelet count and spleen diameter. Results: Applicability: the CLEVER software was technically able to provide portal pressure estimations from DCE-US in 41/90 videos corresponding to 28/47 patients (59.6%). The Spearman coefficient of correlation between CLEVER values and HVPG was r = 0.585 ( p < 0.001). The CLEVER software was then tested in a separate validation set of 17 technically successful patients, showing a correlation r = 0.701 ( p < 0.002). Conclusion: We developed and validated the DCE-US based CLEVER software which allows an automatic and quantitative non-invasive estimation of portal pressure in patients with CLD. Larger set of patients with precise subgrouping will help improving the non-invasive predictability of portal pressure by DCE-US.

The implementation and the combination of advanced boundary conditions and subgrid scale models for Large Eddy Simulations are presented. The goal is to performreliable cold flow LES simulations in complex geometries, such as in the cylinders of internal combustion engines. The implementation of an inlet boundary condition for synthetic turbulence generation and of two subgrid scale models, the local Dynamic Smagorinsky and the Wall-Adapting Local Eddy-viscosity SGSmodel(WALE) is described. TheWALEmodel is based on the square of the velocity gradient tensor and it accounts for the effects of both the strain and the rotation rate of the smallest resolved turbulent fluctuations and it recovers the proper y3 near-wall scaling for the eddy viscosity without requiring dynamic pressure; hence, it is supposed to be a very reliable model for ICE simulation. Model validation has been performed separately on two steady state flow benches: a backward facing step geometry and a simple IC engine geometry with one axed central valve. A discussion on the completeness of the LES simulation (i.e. LES simulation quality) is given. © 2013, IFP Energies nouvelles.

The third part of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Guidelines on Interventional Ultrasound (INVUS) assesses the evidence for ultrasound-guided and assisted interventions in abdominal treatment procedures. Recommendations for clinical practice are presented covering indications, contraindications, and safe and effective performance of the broad variety of these techniques. In particular, drainage of abscesses and fluid collections, interventional tumor ablation techniques, interventional treatment of symptomatic cysts and echinococcosis, percutaneous transhepatic cholangiography and drainage, percutaneous gastrostomy, urinary bladder drainage, and nephrostomy are addressed (long version).

Summary Aim To evaluate the acute effect of treatment with the molecular adsorbent recirculating system (MARS) on splanchnic, renal and systemic haemodynamics in patients with end-stage cirrhosis. Methods Twelve patients with end-stage cirrhosis, undergoing MARS treatment, were enrolled. The following haemodynamic parameters were measured by means of Doppler ultrasonography and thoracic electrical bioimpedance, before and after each session: portal velocity, renal and splenic resistance indices, cardiac output, cardiac stroke volume, heart rate, mean arterial pressure, systemic vascular resistance. Results Median portal velocity increased significantly after treatment (23.7 vs. 20.3 cm/s, P

This is the first part of the Guidelines on Interventional Ultrasound of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and covers all general aspects of ultrasound-guided procedures (long version).

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

BACKGROUND: The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation. METHODS: Adult primary transplants performed with deceased heart-beating donors were included. Relevant information on donors and recipients, organ procurement and allocation were prospectively entered in an ad hoc database within the National Transplant Centre web-based Network. Data were blindly analysed by an independent Biostatistical Board. RESULTS: The study enrolled 1530 donor/recipient matches. Median donor age was 56 years. Female donors (n = 681, median 58, range 12-92 years) were older than males (n = 849, median 53, range 2-97 years, p < 0.0001). Donors older than 60 years were 42.2%, including 4.2% octogenarians. Brain death was due to non-traumatic causes in 1126 (73.6%) cases. Half of the donor population was overweight, 10.1% was obese and 7.6% diabetic. Hepatitis B core antibody (HBcAb) was present in 245 (16.0%) donors. The median Donor Risk Index (DRI) was 1.57 (>1.7 in 35.8%). The median cold ischaemia time was 7.3h (≥ 10 in 10.6%). Median age of recipients was 54 years, and 77.7% were males. Hepatocellular carcinoma (HCC) was the most frequent indication overall (44.4%), being a coindication in roughly 1/3 of cases, followed by viral cirrhosis without HCC (28.2%) and alcoholic cirrhosis without HCC (10.2%). Hepatitis C virus infection (with or without HCC) was the most frequent etiologic factor (45.9% of the whole population and 71.4% of viral-related cirrhosis), yet hepatitis B virus infection accounted for 28.6% of viral-related cirrhosis, and HBcAb positivity was found in 49.7% of recipients. The median Model for End Stage Liver Disease (MELD) at transplant was 12 in patients with HCC and 18 in those without. Multivariate analysis showed a slight but significant inverse association between DRI and MELD at transplant. CONCLUSIONS: The deceased donor population in Italy has a high-risk profile compared to other countries, mainly due to older donor age. Almost half of the grafts are transplanted in recipients with HCC. Higher risk donors tend to be preferentially allocated to recipients with HCC, who are usually less ill and older. No other relevant allocation strategy is currently adopted at national level.

In the last years the incidence of hepatocellular carcinoma (HCC) is rising in cirrhotic patients worldwide. Due the importance of early and definite diagnosis of HCC, any nodular lesion detected in patients with chronic liver disease should be considered as suspicious for HCC. The screening and surveillance programs in patients with liver diseases have increased the number of small HCC detected at an early stage, when the therapeutic options available are able to provide benefit. The introduction of new imaging techniques has improved the accuracy of characterizing these nodules. According to the EASL recommendations, contrast-enhanced computed tomography (CT), contrast enhanced ultrasound (US) and magnetic resonance (MR) with different MR-contrast agents are currently used to characterize liver lesions. Imaging guided biopsy is recommended for small nodules or in lesions without typical features (arterial hypervascularization) in at least two imaging techniques. Frequently the differential diagnosis of small nodules is complicated by discordant vascularity and recent studies have also demonstrated the presence of small hypovascular HCC at perfusional US and helical CT. At present, different treatment options can be offered to patients with diagnosis of small HCC at an early stage; percutaneous techniques, surgical resection and liver transplantation can provide benefit in properly selected patients. This review describes some critical points regarding the detection, diagnosis and therapeutic management of small nodules of HCC in cirrhotic patients.

Since the incidence of myocardial infarction and other cardiovascular ischaemic events is highest in early morning, on account of a relative hypercoagulable state occurring in this time period, an attempt was made to test whether reperfusion of the hepatic artery at this time of the day, at liver transplantation, produces an increased risk of early thrombosis.The records of 255 consecutive patients receiving a first transplant for chronic liver disease were retrospectively analysed. As possible risk factors, for early post-operative thrombosis (30 days from transplantation), several medical and surgical parameters were taken into consideration. Arterial reperfusion was considered to have taken place at a time of high coagulability when occurred between 6.00 a.m. and 10.00 a.m. on the basis of previous reports.Logistic regression identified donor age (OR for age60: P=0.017), bench reconstruction of the artery (OR: 5.06, P=0.013) and time of high coagulability at reperfusion (OR 2.93, P=0.087), as independently associated with early hepatic artery thrombosis.The present findings identified three independent predictors of early hepatic thrombosis, warranting stricter post-surgical follow-up of patients presenting such conditions. Interestingly, these factors are consistent with arterial reperfusion in the early morning being associated with an increased risk of early hepatic artery thrombosis, suggesting relative coagulative imbalances to provide a contribution in the pathogenesis of this severe complication of liver transplantation.

In early stage hepatocellular carcinoma (HCC), liver transplantation, surgical resection and percutaneous techniques are classified as radical treatments, and may be offered to about 25% of all patients with HCC evaluated in referral centres. The restricted inclusion criteria for surgical resection and the shortage of liver donors for transplantation have stimulated an increasing demand for minimally invasive treatments able to achieve effective and reproducible percutaneous tumour ablation, with less associated morbidity and lower cost than other interventions. Among percutaneous techniques, ethanol injection has proven to be highly effective in single HCC up to 3 cm, with a rate of complete response of 80%, being well tolerated and with a limited risk of minor complication. In larger and/or multinodular HCC the efficacy is reduced to 50% of complete response in nodules between 3 and 5 cm, and to lower rate in larger tumours. Alternative options to ethanol injection have been recently proposed, including radiofrequency, microwave and laser thermal ablation, aimed to extend the necrotic area thus improving the rate of complete response. To date, radiofrequency is the most used technique, with a reported rate of complete response of 90-98% in nodules smaller than 3 cm, and with the advantage of fewer sessions, otherwise counteracted by a higher rate of side-effects. Microwave and laser are promising technologies, but only few clinical data are available. Randomized controlled trials are needed in order to assess treatment response, long-term survival, rate of complication and cost-efficacy of newer technologies in comparison to ethanol injection.

In advanced hepatocellular carcinoma (HCC), allelic loss on chromosome 16q may occur. To better define the frequency of this alteration in small HCC and to more closely identify the affected region for further positional cloning of the putative tumor suppressor gene contained in this region, microsatellite polymorphism analysis was conducted on small, unifocal HCC, without signs of intrahepatic or systemic spread. We also tried to assess its possible correlation with hepatitis virus infections (HBV and HCV) and cellular proliferation rate. DNA from 35 small (4 cm), unifocal HCC and from the corresponding nontumorous surrounding tissue was analyzed by 10 sets of microsatellite polymorphic markers. Serologic markers for hepatitis virus B and C infections were investigated in all cases. AgNOR protein quantity was assessed by image analysis on cryostatic sections stained with silver. The percentage of tumours with allelic imbalance ranged from 11.1 to 37%. The minimal involved region was assessed at 16q24.3, corresponding to the D16S413 marker, which was also the most commonly affected locus (10 of 27 informative cases, 37%). Allelic imbalance on chromosome 16q was significantly associated with HBV infection: 8 of 10 cases showed an actual or previous HBV infection in the group showing allelic imbalance, versus 6 with a previous HBV infection out of 25 in the control group (P0.01). No difference was found as far as HCV infection is concerned. The mean (+/-SE) AgNOR protein value in six cases showing allelic imbalance was 8.36 +/- 1.2 microm2, compared to 6.45 +/- 0.68 microm2 in 13 cases retaining both the alleles at 16q but the difference proved not statistically significant. In conclusion, in this series of small, unifocal HCC the minimal region of allelic imbalance on 16q was restricted to 16q24.3. It was found to be associated with HBV infection but not with increased cellular proliferation rate.

A decrease in portal flow is an important pharmacological effect of drugs used for the prophylaxis of variceal bleeding.To assess the acute and chronic effects of propranolol, and the effect of the acute addition of isosorbide-5-mononitrate, on splanchnic circulation.Measurements of portal blood flow volume (PBFV) and of Doppler ultrasound pulsatility index of the superior mesenteric, femoral and interlobar renal arteries were performed in 10 cirrhotic patients with varices at baseline, 90 min after propranolol or placebo, after 30 days of chronic propranolol treatment and 45 min after the addition of isosorbide-5-mononitrate.The mean PBFV was significantly lower at all times than at baseline, with the greatest mean percentage decrease achieved after the addition of isosorbide-5-mononitrate (or = 20% in all patients). Acute changes, however, did not predict the chronic effects in many patients. Isosorbide-5-mononitrate significantly increased the mesenteric and femoral pulsatility indices, whereas no significant change was observed in the kidney.Propranolol significantly decreases PBFV, but chronic effects cannot be reliably predicted by the acute change. All patients achieved a decrease in PBFV ofor = 20% after the acute addition of isosorbide-5-mononitrate to chronic propranolol treatment.

In 153 consecutive patients with cirrhosis we assessed: (1) the prevalence of IgG to Helicobacter pylori and compared it with that found in 1010 blood donors resident in the same area; and (2) the relationships of IgG to Helicobacter pylori with clinical and endoscopic features and with the risk of peptic ulcer. The IgG to Helicobacter pylori prevalence of cirrhotics was significantly higher than in blood donors (76.5% vs 41.8%; P0.0005) and was not associated with sex, cirrhosis etiology, Child class, gammaglobulins and hypertensive gastropathy. In both groups, the prevalence of IgG to Helicobacter pylori was significantly higher in subjects over 40. Among patients with cirrhosis a significantly higher prevalence of Helicobacter pylori was found in patients with previous hospital admission (P = 0.02) and/or upper gastrointestinal endoscopy (P = 0.01) and patients with peptic ulcer (P = 0.0004). Multivariate analysis identified increasing age and male sex as risk factors for a positive Helicobacter pylori serology and no independent risk factors for peptic ulcer. The high prevalence of Helicobacter pylori-positive serology found in the present series is related to age and sex and might also be explained by previous hospital admissions and/or upper gastrointestinal endoscopy. Our results do not confirm the role of Helicobacter pylori as risk factor for peptic ulcer in patients with liver cirrhosis.

We investigated the cost-effectiveness of a screening program for the early diagnosis and treatment of hepatocellular carcinoma (HCC) in liver cirrhosis patients. An HCC screening program in liver cirrhosis patients should be carried out when the HCC makes a major cause of death and considering that: 1) the diagnostic techniques should be highly sensitive and specific; 2) the overall cost of the screening program should not be too high; 3) patient survival should be improved.March, 1989, to November 1991, 324 Italian patients with liver cirrhosis (201 men and 123 women) whose age ranged 18-83 years (mean +/- SD: 57.2 +/- 11.9) were submitted to US examinations and serum alpha-fetoprotein titration at six months' intervals.During the follow-up, 38 patients (11.7%) developed HCC, with 4.3% incidence per follow-up year. The Cox model identified serum alpha-fetoprotein, Child-Pugh classes B and C and the male gender as independent risk factors for developing HCC. Only 22 of 38 HCC patients (58%) were submitted to resection, orthotopic liver transplantation or local therapy. The 3-year survival of the 38 HCCs diagnosed during the follow-up is 37%. In all, 1800 US examinations and serum alpha-fetoprotein titrations were carried out during this screening program, costing 219,600 US dollars/patient. Each HCC treated successfully (stable disease at 12 months) was diagnosed at a cost of 24,400 US dollars.Screening all liver cirrhosis patients is a questionable approach because it is very expensive and its benefit in terms of patient survival is poor. More targeted screening programs with definite risk factors should be tested for cost-effectiveness.

It has been showed that peptic ulcer is more frequent in patients with liver cirrhosis, is associated with the severity of cirrhosis, and occurs without upper abdominal pain in up to 70% of patients and with complications in 29%. The aim of this study was to retrospectively assess the characteristics of peptic ulcer in a large series of patients with liver cirrhosis.In this retrospective study the consecutive records of 1,748 endoscopies, performed in patients with liver cirrhosis during a period of 14 years, were reviewed to evaluate the frequency and clinical characteristics of peptic ulcer.The ulcer prevalence was 6.3%, and 77.5% of the ulcers were asymptomatic. Complications from ulcer were present in 29% of all patients and in 32% of those who has the first diagnosis of ulcer during the study. Patients with asymptomatic ulcer had a more decompensated cirrhosis. After healing, 20%-25% of the recurrent ulcers had complications while patients were on standard maintenance treatment.This retrospective study confirms the high frequency of peptic ulcer in patients with liver cirrhosis. It also confirms that the peptic ulcer in these patients is very often asymptomatic and associated with concurrent complications, especially in those with more severe liver disease. The complication rate in recurrent ulcers was 20%-25%. However, due to the retrospective nature of this study, after ulcer healing the endoscopic follow-up was irregular. Regularly repeated endoscopy should be carried out in patients with liver cirrhosis and peptic ulcer to diagnose new and recurrent ulcers and to prevent related complications.

Background Few data exist on real-life adherence to international guidelines for the treatment of hepatocellular carcinoma. We analysed the rate of adherence to American Association for the Study of Liver Diseases guidelines, to identify reasons for discrepancy with treatments performed in our centre. Methods 227 consecutive cirrhotics with a first hepatocellular carcinoma diagnosis (2005–2010) were retrospectively evaluated and stratified based on Barcelona Clinic Liver Cancer system: 126 early, 50 intermediate, 40 advanced, and 11 end stage. Results Early hepatocellular carcinomas were theoretically eligible for resection ( n = 27), liver transplantation ( n = 36), and percutaneous treatment ( n = 63). In practice, 15/27 (55.5%), 31/36 (86.1%), and 22/63 (34.9%) respectively were treated as recommended. Reasons for discrepancy were age/comorbidity, tumour location, ultrasound visibility, surgical contraindications. Transarterial chemoembolisation was performed in 25/126 early hepatocellular carcinomas (19.8%), resection in 11/63 early hepatocellular carcinomas eligible for percutaneous treatment (17.5%). Transarterial chemoembolisation was excluded in 16/50 intermediate hepatocellular carcinomas (32%). Resection or transarterial chemoembolisation was performed in 6/40 advanced hepatocellular carcinomas (15%). Conclusion Overall, 60% of patients were treated according to American Association for the Study of Liver Diseases guidelines. Approximately 28% of hepatocellular carcinomas were “under-treated” and 7% treated more aggressively than recommended. Peculiarities of individual patients can lead the multidisciplinary team to personalise real-life treatments.

Background and aims the Barcelona Clinic Liver Cancer intermediate stage (BCLC-B) of hepatocellular carcinoma (HCC) includes extremely heterogeneous patients in terms of tumor burden and liver function. Transarterial-chemoembolization (TACE) is the first-line treatment for these patients although it may be risky/useless for someone, while others could undergo curative treatments. This study assesses the treatment type performed in a large cohort of BCLC-B patients and its outcome. Methods retrospective analysis of 485 consecutive BCLC-B patients from the ITA.LI.CA database diagnosed with naive HCC after 1999. Patients were stratified by treatment. Results 29 patients (6%) were lost to follow-up before receiving treatment. Treatment distribution was: TACE (233, 51.1%), curative treatments (145 patients, 31.8%), sorafenib (18, 3.9%), other (39, 8.5%), best supportive care (BSC) (21, 4.6%). Median survival (95% CI) was 45 months (37.4-52.7) for curative treatments, 30 (24.7-35.3) for TACE, 14 (10.5-17.5) for sorafenib, 14 (5.2-22.7) for other treatments and 10 (6.0-14.2) for BSC (p