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Introduction Enhanced recovery after surgery (ERAS) has been shown to facilitate discharge, decrease length of stay, improve outcomes and reduce costs. We used this concept to design a comprehensive fast-track pathway (OR-to-discharge) before starting our liver transplant activity and then applied this protocol prospectively to every patient undergoing liver transplantation at our institution, monitoring the results periodically. We now report our first six years results. Patients and methods Prospective cohort study of all the liver transplants performed at our institution for the first six years. Balanced general anesthesia, fluid restriction, thromboelastometry, inferior vena cava preservation and temporary portocaval shunt were strategies common to all cases. Standard immunosuppression administered included steroids, tacrolimus (delayed in the setting of renal impairment, with basiliximab induction added) and mycophenolate mofetil. Tacrolimus dosing was adjusted using a Bayesian estimation methodology. Oral intake and ambulation were started early. Results A total of 240 transplants were performed in 236 patients (191♂/45♀) over 74 months, mean age 56.3±9.6 years, raw MELD score 15.5±7.7. Predominant etiologies were alcohol (n = 136) and HCV (n = 82), with hepatocellular carcinoma present in 129 (54.7%). Nine patients received combined liver and kidney transplants. The mean operating time was 315±64 min with cold ischemia times of 279±88 min. Thirty-one patients (13.1%) were transfused in the OR (2.4±1.2 units of PRBC). Extubation was immediate (p=0.015) in the fast-track group. Patient survival was 86.8% at 1 year and 78.6% at five years. Conclusion Fast-Tracking of Liver Transplant patients is feasible and can be applied as the standard of care

Background & Aims: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population. Methods: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded. Results: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4months (interquartile ranges [IQR], 0.8-3.8), 10.8months (IQR, 4.5-16.9), and 17.5months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE. Conclusions: The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.

Resumen A pesar del consenso universal sobre la necesidad de administrar profilaxis para evitar la recurrencia de la hepatitis B despues del trasplante hepatico (TH), no existen hasta el momento unas recomendaciones nacionales sobre las pautas concretas para la profilaxis y el tratamiento de la infeccion por el virus de la hepatitis B (VHB) en el TH. El objetivo de la VII Reunion de consenso organizada por la Sociedad Espanola de Trasplante Hepatico (SETH) fue unificar criterios y protocolos clinicos entre todas unidades de TH en Espana, sobre como prevenir y tratar la reinfeccion por el VHB despues del TH. La evidencia y las recomendaciones de este documento se han llevado a cabo acuerdo con el sistema Grading of Recommendations Assessment Development and Evaluation (GRADE). En el presente documento se describen las recomendaciones y su grado de evidencia para: la definicion de la recurrencia del VHB post-TH y sus factores de riesgo, la monitorizacion y la profilaxis de la recurrencia del VHB tras el TH en sus diversas etapas, el tratamiento de la hepatitis B antes y despues del TH, y la profilaxis de la infeccion por VHB los receptores de TH con donantes anti-HBc positivo.

De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society-Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk factors, management, and survival after DNMs. Recommendations for screening and surveillance for specific tumors, as well as immunosuppression and cancer-specific management in patients with DNM, are summarized.

Long-term humoral immunity and its protective role in liver transplantation (LT) patients have not been elucidated. We performed a prospective multicenter study to assess the persistence of immunoglobulin G (IgG) antibodies in LT recipients 12 months after coronavirus disease 2019 (COVID-19). A total of 65 LT recipients were matched with 65 nontransplanted patients by a propensity score including variables with recognized impact on COVID-19. LT recipients showed a lower prevalence of anti-nucleocapsid (27.7% versus 49.2%; P = 0.02) and anti-spike IgG antibodies (88.2% versus 100.0%; P = 0.02) at 12 months. Lower index values of anti-nucleocapsid IgG antibodies were also observed in transplantation patients 1 year after COVID-19 (median, 0.49 [interquartile range, 0.15-1.40] versus 1.36 [interquartile range, 0.53-2.91]; P

[Background & Aims] The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic., [Methods] An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave., [Results] Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37)., [Conclusions] The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making., [Lay summary] The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes.

Background Hepatocellular carcinoma (HCC) appears in most of cases in patients with advanced liver disease and is currently the primary cause of death in this population. Surveillance of HCC has been proposed and recommended in clinical guidelines to obtain earlier diagnosis, but it is still controversial and is not accepted worldwide. Aim To review the actual evidence to support the surveillance programs in patients with cirrhosis as well as the diagnosis procedure. Methods Systematic review of recent literature of surveillance (tools, interval, cost-benefit, target population) and the role of imaging diagnosis (radiological non-invasive diagnosis, optimal modality and agents) of HCC. Results The benefits of surveillance of HCC, mainly with ultrasonography, have been assessed in several prospective and retrospective analysis, although the percentage of patients diagnosed in surveillance programs is still low. Surveillance of HCC permits diagnosis in early stages allows better access to curative treatment and increases life expectancy in patients with cirrhosis. HCC is a tumor with special radiological characteristics in computed tomography and magnetic resonance imaging, which allows highly accurate diagnosis without routine biopsy confirmation. The actual recommendation is to perform biopsy only in indeterminate nodules. Conclusion The evidence supports the recommendation of performing surveillance of HCC in patients with cirrhosis susceptible of treatment, using ultrasonography every 6 mo. The diagnosis evaluation of HCC can be established based on noninvasive imaging criteria in patients with cirrhosis.

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case-control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17-83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03-1.36), and therapy with renin-angiotensin-aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47-34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.

Background & aims Few studies have fully applied an enhanced recovery after surgery (ERAS) protocol to liver transplantation (LT). Our aim was to assess the effects of a comprehensive ERAS protocol in our cohort of low- and medium-risk LT patients. Methods The ERAS protocol included pre-, intra-, and post-operative steps. During the five-year study period, 181 LT were performed in our institution. Two cohorts were identified: low risk patients (n = 101) had a laboratory model for end-stage liver disease (MELD) score of 20 points or less at the time of LT, received a liver from a donor after brain death, and had a balance of risk score of 9 points or less; medium-risk patients (n = 15) had identical characteristics except for a higher MELD score (21–30 points). In addition, we analyzed the remaining patients (n = 65) who were transplanted over the same study period separately using the ERAS protocol. Results The low-risk cohort showed a low need for packed red blood cells transfusion (median: 0 units) and renal replacement therapy (1%), as well as a short length of stay both in the intensive care unit (13 h) and in the hospital (4 days); morbidity during one-year follow-up, and probability of surviving to one year (89.30%) and five years (76.99%) were in line with well-established reference data. Similar findings were observed in the medium-risk cohort. Conclusions This single-center prospective observational cohort study provides evidence that ERAS is feasible and safe for low- and medium-risk LT.

Liver transplantation (LT) is one of the most complex surgical procedures. Enhanced recovery after surgery (ERAS) aims to reduce the risk of postoperative complications. When patients achieve all desirable outcomes after a procedure, they are considered to have experienced a textbook outcome (TO).Two cohorts of patients undergoing low (n = 101) or medium risk (n = 15) LT were identified. The remaining patients (n = 65) were grouped separately. The ERAS protocol included pre-, intra-, and post-operative steps. TO was defined as the absence of complications, prolonged length of hospital stays, readmission and mortality during the first 90 days.One third of patients who underwent ERAS after LT experienced a TO. On multivariable analysis, age (OR, 1.05 [95% CI, 1.01-1.09]; P = .02), and having hepatocellular carcinoma (OR, 2.83 [95% CI, 1.37-6.03]; P = .005) were individually associated with a greater probability of achieving a TO. Belonging to the cohorts of medium risk or outside the selection criteria was associated with a lower probability of achieving a TO (OR, 0.46 [96% CI, 0.22-0.93]; P = .03). Patients less likely to experience TO required more hospital resources. Patients who achieved TO were more likely to remain free of chronic kidney disease (achieved TO, 83.8% [82.7-85.6]; failed TO, 67.9% [66.9-70.2]; P .05). Tacrolimus dose and trough levels were similar.A novel finding of our study is that short and medium-term kidney function is better preserved in patients who experience a TO. Better kidney function of patients who achieve TO is not due to lower tacrolimus dosage.

Background In patients with cirrhosis, beta-adrenoceptors expressed on peripheral blood mononuclear cells have a reduced response to catecholamine stimulation. This study aimed to determine if chronic treatment with beta-blockers influences these changes. Methods Blood samples were collected from patients with cirrhosis treated in outpatient clinics. Differences in cyclic AMP production before and after stimulation of mononuclear cells with epinephrine and/orN-Formylmethionine-leucyl-phenylalanine (fMLP) was used as a marker of beta-adrenoceptors activity in patients treated (N = 19) versus not treated (N = 55) with beta-blockers. In addition, we studied the gene expression of different types of adrenoceptors and possible associations with the activity of beta-adrenoceptors, the serum concentrations of catecholamines and cytokines, and the presence of bacterial antigens such as DNA or gram-negative bacterial endotoxin in patients' blood. Results The increase in intracellular cAMP concentrations after stimulation of adrenergic receptors with epinephrine was significantly higher in samples from patients treated with beta-blockers. Older patients showed lower responses to epinephrine stimulus, while the response increased linearly with the duration of the beta-blocker treatment. mRNA expression levels of adrenoceptors beta 1, beta 2, beta 3 and alpha 1-A, B and D showed no significant differences according to treatment with beta-blockers. Neither serum cytokines nor catecholamines levels were significantly associated with the intracellular production of cAMP after adrenergic stimulation. Conclusion Chronic treatment with beta-blockers in patients with cirrhosis enables beta-adrenoceptors to respond to catecholamine stimulation irrespective of the degree of systemic adrenergic or immune activations of the patient at the time of sampling. [GRAPHICS] .

Background & Aims The incidence and outcomes of coronavirus disease 2019 (Covid-19) in immunocompromised patients are a matter of debate. Methods Prospective nationwide study including a consecutive cohort of liver transplant patients with Covid-19 recruited during the Spanish outbreak from February 28th to April 7th, 2020. The primary outcome was severe Covid-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardized incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe Covid-19 among hospitalized patients were analyzed using multivariate Cox regression. Results A total of 111 liver transplant patients were diagnosed with Covid-19 (SIR=191.2 [95%CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. Twelve patients were admitted to the ICU (10.8%). The mortality rate was 18%, being lower compared to the matched general population (SMR=95.5 [95%CI 94.2-96.8]). Thirty-five patients (31.5%) met criteria of severe Covid-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe Covid-19 (RR=3.94; 95%CI 1.59-9.74; p=0.003), particularly at doses higher than 1,000 mg/day (p=0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit. Conclusions Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring Covid-19 but their mortality rates are lower than matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe Covid-19. However, complete immunosuppression withdrawal should be discouraged., Graphical abstract, HIGHLIGHTS • The incidence of Covid-19 is increased in liver transplant patients. • Mortality rates are lower than those observed in matched general population. • Immunosuppression withdrawal may not be justified. • Mycophenolate may increase the risk of severe Covid-19 in a dose dependent-manner. • Calcineurin inhibitors and everolimus are not deleterious for Covid-19., In liver transplant patients, chronic immunosuppression increases the risk of acquiring Covid-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalized patients.

Background & Aims The use of non‐selective beta‐blockers has been associated with lower rates of infection and reduced infection‐associated morbidity in patients with cirrhosis. However, it is unknown if these drugs modify the systemic inflammatory response to circulating bacterial DNA. Methods Sixty‐three patients with cirrhosis were included during an episode of decompensation by ascites. Thirty of those patients were on beta‐blockers. Blood samples were obtained after each patient had been in the supine position for at least 30 minutes in a quiet atmosphere. Bacterial DNA, serum cytokines, nitric oxide, and LPS were determined. Phagocytic and oxidative burst activities were determined in polymorphonuclear cells from the patients. Results The detection rate of bacterial DNA in the blood was the same (33%) for patients not treated and treated with non‐selective beta‐blockers. Patients naive to non‐selective beta‐blockers showed significantly higher serum levels of IL6, IFN‐gamma and IL10 in response to the presence of bacterial DNA. Patients treated with non‐selective beta‐blockers showed higher basal inflammatory activity that did not change with the presence of bacterial DNA. Monocytes and granulocytes from patients treated with non‐selective beta‐blockers showed a significantly increased phagocytic capacity in the presence of bacterial DNA. Conclusions In patients with cirrhosis, chronic treatment with beta‐blockers is associated with a higher unstimulated production of serum cytokines and an increased phagocytic activity in the presence of bacterial DNA.

Introduction: The appropriate selection of hepatocellular carcinoma (HCC) patients who are eligible for transarterial chemoembolization (TACE) remains a challenge. The ART score has recently been proposed as a method of identifying patients who are eligible or not for a second TACE procedure. Objective: To assess the validity of the Assessment for Retreatment with TACE (ART) score in a cohort of patients treated with drug-eluting bead TACE (DEB-TACE). Secondary objective: to identify clinical determinants associated with overall survival (OS). Method: A retrospective, multicentre study conducted in Spain in patients with HCC having undergone two or more DEB-TACE procedures between January 2009 and December 2014. The clinical characteristics and OS from the day before the second DEB-TACE of patients with a high ART score (ART >= 2.5) and a low ART score (ART 0-1) were compared. Risk factors for mortality were identified using Cox's proportional hazards model. Results: Of the 102 patients included, 51 scored 0-1.5 and 51 scored >= 2.5. Hepatitis C was more frequent in patients scoring >= 2.5. Median OS from the day before the second DEB-TACE was 21 months (95% CI, 15-28) in the group scoring 0-1.5, and 17 months (95% CI, 10-25) in the group scoring >= 2.5 (P=0.3562). Platelet count and tumour size, but not the ART score, were independent baseline predictors of OS. Conclusions: The ART score is not suitable for guiding DEB-TACE retreatment according to Spanish clinical practice standards. (C) 2017 Elsevier Espana, S.L.U., AEEH y AEG. All rights reserved.

Resumen Antecedentes y objetivo En 2010 publicamos que en Espana el 53% de los carcinomas hepatocelulares (CHC) se diagnostican fuera de programas de cribado, lo que conlleva una menor supervivencia. El objetivo del presente estudio es evaluar la situacion actual y las causas del diagnostico fuera de cribado. Material y metodos Registro prospectivo entre el 1 de octubre de 2014 y el 31 de enero de 2015 en 73 centros asistenciales espanoles de segundo/tercer nivel. Se registraron las caracteristicas basales y el primer tratamiento de los tumores primarios hepaticos incidentales de ese periodo. Resultados Se incluyeron 720 pacientes: CHC (n = 686), colangiocarcinoma intrahepatico (n = 29), hepatocolangiocarcinoma (n = 2), otros (n = 3). Los pacientes con CHC fueron varones en el 82% de los casos; media de 67 anos; cirrosis en el 87%; etiologia: alcohol 35%, VHC 30%, alcohol y VHC 15%, enfermedad hepatica por deposito de grasa 6%; estadio tumoral: BCLC-0 11%, A 43%, B 19%, C 16% y D 11%; tratamiento inicial: quimioembolizacion transarterial (23%), ablacion percutanea (22%), tratamiento sintomatico (20%), reseccion (11%), sorafenib (11%). Se diagnosticaron fuera de cribado 356 pacientes (53%). Los motivos principales fueron la ausencia de diagnostico previo de hepatopatia (76%) y la mala adherencia al cribado (18%). Estos pacientes eran predominantemente varones (p Conclusiones En Espana, la principal causa del diagnostico de CHC fuera del cribado es la ausencia de diagnostico previo de enfermedad hepatica, principalmente en varones con consumo de alcohol. La deteccion de hepatopatia en poblacion asintomatica y la mejora de la adherencia al cribado son los principales aspectos para mejorar la deteccion precoz.

Bacterial (bact)DNA is an immunogenic product that frequently translocates into the blood in cirrhosis. We evaluated bactDNA clearance in patients undergoing liver transplantation (LT) and its association with inflammation and clinically relevant complications. We prospectively included patients consecutively admitted for LT in a one-year follow-up study. We evaluated bactDNA before and during the first month after LT, quantifying cytokine response at 30 days. One hundred patients were included. BactDNA was present in the blood of twenty-six patients undergoing LT. Twenty-four of these showed bactDNA in the portal vein, matching peripheral blood-identified bactDNA in 18 cases. Thirty-four patients showed bactDNA in blood during the first month after LT. Median TNF-α and IL-6 levels one month after LT were significantly increased in patients with versus without bactDNA. Serum TNF-α at baseline was an independent risk factor for bactDNA translocation during the first month after LT in the multivariate analysis (Odds ratio (OR) 1.14 [1.04 to 1.29], P = 0.015). One-year readmission was independently associated with the presence of bactDNA during the first month after LT (Hazard ratio (HR) 2.75 [1.39 to 5.45], P = 0.004). The presence of bactDNA in the blood of LT recipients was not shown to have any impact on complications such as death, graft rejection, bacterial or CMV infections. The rate of bactDNA translocation persists during the first month after LT and contributes to sustained inflammation. This is associated with an increased rate of readmissions in the one-year clinical outcome after LT.

INTRODUCTION Patients with cirrhosis by hepatitis C virus infection treated with β-blockers (BB) have been shown to have a reduced incidence of hepatocellular carcinoma (HCC). Also, an association between propranolol therapy and lower incidence of other tumors has been described. AIM To analyze the incidence of HCC according to BB treatment in cirrhosis of any cause. PATIENTS AND METHODS Cirrhotic patients included in the program for early detection of HCC were followed. Patients' data were prospectively registered, including transplantation and death. Patients were classified as chronically taken or not BB and the proportions of patients who remained free of tumor from the diagnosis of cirrhosis until the end of follow-up were compared using Kaplan-Meier analysis and the Breslow test. RESULTS A total of 173 patients (73 treated and 100 untreated BB) were followed. The median duration of follow-up was 11 years. There were no differences between both groups in the overall survival, number of deaths, or liver transplant.Overall, 28 patients developed HCC during the follow-up, 20 patients who were untreated and eight patients treated with BB. The cumulative proportion of cases of HCC between untreated and treated with BB from the diagnosis of cirrhosis was statistically significant (6 vs. 3%, at 5 years; 19 vs. 6% at 10 years; 24 vs. 16% at 15 years; P=0.048). Multivariate analyses showed BB intake as the only significant variable associated with the development of HCC. CONCLUSION Cirrhotic patients treated with BB have a lower cumulative probability of developing HCC during the 10 years after the diagnosis of cirrhosis.

Background & aims Patients with decompensated cirrhosis show a marked innate immune response that shows a wide variability. The reasons for this fact have not been previously evaluated. This investigation was undertaken to study factors influencing the immune response intensity in both serum and ascitic fluid in patients with cirrhosis and ascites with presence of bactDNA. Methods 77 patients with cirrhosis and presence of bactDNA fragments in blood and ascitic fluid were included. Identification of bactDNA was evaluated by 16SrRNA gene PCR followed by nucleotide sequencing and by species-specific PCR. Concentration of amplified bacterial-DNA, bacteria identification, LPS, TNF-alpha, IFN-gamma, Interleukin 12 and nitric oxide in serum and ascitic fluid were evaluated as factors related to intensity of the immune response. Results Serum and AF levels of bactDNA, TNF-α, IFN-γ and nitric oxide concentration were higher in patients with presence of bactDNA from gram negative bacteria. Serum TNF-α levels showed a significant correlation with concentrations of bactDNA (r = 0.88; P = 0.001) and LPS (r = 0.28; P = 0.016). Serum nitric oxide levels were also significantly correlated with concentrations of bactDNA (r = 0.761; P = 0.001) but not with LPS levels. Levels of INF-γ and IL-12 were not significantly correlated with either bactDNA nor LPS levels. Plasmatic concentration of bactDNA was the most accurately correlated factor with the inflammatory response (ancova model included only levels of bactDNA (r(2) = 0.87, P = 0.047 for TNF-α; r(2) = 0.45, P = 0.03 for NOx). Conclusions Bacterial-DNA concentration is the most influencing variable associated with serum TNF-α and nitric oxide response.

Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation. To this end, a phenotypic screen was performed using poly I:C / IL-4 stimulated NHBE cells interrogated with a 44,974 compound library. As a result, 85 hits which downregulated TSLP protein and mRNA levels were identified and a representative subset of 7 hits was selected for further characterization. These molecules inhibited the activity of several members of the MAPK, PI3K and tyrosine kinase families and some of them have been reported as modulators of cellular phenotypic endpoints like cell-cell contacts, microtubule polymerization and caspase activation. Characterization of the biological profile of the hits suggested that mTOR could be a key activity involved in the regulation of TSLP production in NHBE cells. Among other targeted kinases, inhibition of p38 MAPK and JAK kinases showed different degrees of correlation with TSLP downregulation, while Syk kinase did not seem to be related. Overall, inhibition of TSLP production by the selected hits, rather than resulting from inhibition of single isolated targets, appeared to be due to a combination of activities with different levels of relevance. Finally, a hit expansion exercise yielded additional active compounds that could be amenable to further optimization, providing an opportunity to dissociate TSLP inhibition from other non-desired activities. This study illustrates the potential of phenotypic drug discovery to complement target based approaches by providing new chemistry and biology leads.

[Abstract] Background and Aims. Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real‐world clinical practice, showed high rates of sustained virological response (SVR) in non‐cirrhotic genotype (GT)‐1 and GT‐4 patients. These results were slightly lower in cirrhotic patients. We investigated real‐life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. Methods. This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV‐GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January‐2014 and December‐2015. Demographic, clinical, virological and safety data were analysed. Results. Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109/L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%‐91.9%) than patients with less advanced liver disease (93.8%‐95.9%, P

Background & Aims Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients. Methods Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain. Results In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p =0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT. Conclusions Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need. Lay summary Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need.

Background & Aims Direct-acting antiviral agents (DAA) combining daclatasvir (DCV) have reported good outcomes in the recurrence of hepatitis C virus (HCV) infection after liver transplant (LT). However, its effect on the severe recurrence and the risk of death remains controversial. We evaluated the efficacy, predictors of survival, and safety of DAC-based regimens in a large real-world cohort. Methods A total of 331 patients received DCV-based therapy. Duration of therapy and ribavirin use were at the investigator's discretion. The primary endpoint was sustained virological response (SVR) at week 12. A multivariate analysis of predictive factors of mortality was performed. Results Intention-to-treat (ITT) and per-protocol SVR were 93.05% and 96.9%. ITT-SVR was lower in cirrhosis (n=163) (96.4% vs. 89.6% p=0.017); the SVR in genotype 3 (n=91) was similar, even in advanced fibrosis (96.7% vs. 88%, p=0.2). Ten patients (3%) experienced virological failure. Therapy was stopped in 18 patients (5.44%), and ten died during treatment. A total of 22 patients (6.6%) died. Albumin (HR= 0.376; 95%CI 0.155-0.910) and baseline MELD (HR=1.137; 95%CI: 1.061-1.218) were predictors of death. Conclusion DCV-based DAA treatment is efficacious and safe in patients with HCV infection after LT. Baseline MELD score and serum albumin are predictors of survival irrespective of viral response. This article is protected by copyright. All rights reserved.

Background Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of 2nd-generation direct-acting antivirals (DAAs), and more data are needed to help guide treatment decisions. We still have even fewer data concerning liver transplant patients. Simeprevir (SIM) and sofosbuvir (SOF) combination is useful to treat this genotype. The aim of this study was to know the efficacy and safety of the combination SIM + SOF ± ribavirin (RBV) in a group of liver transplant patients with HCV genotype 4 infection in Spain in real life. Methods This was a multicenter retrospective study, including 28 HCV genotype 4 patients from 11 liver transplant centers who were treated with SIM + SOF ± RBV. We included in the analysis demographic, clinical, and virologic data and details of serious adverse events (SAEs), including mortality rate 6 months after treatment. Results All patients were male, mean age 52 ± 9.43 years, and 50% were IL28B CT and 37.5% TT; 46.42% of them were pretreated and 76.9 were null responders. Fibrosis stage 4 was found in 38.7% of patients; in 67.8% of those cases the diagnosis of fibrosis was made with the use of Fibroscan, in 21.4% by liver biopsy. The average Fibroscan was 13.86 KPa. The average Model for End-Stage Liver Disease (MELD) score of cirrhotic patients was 10.9 and the Child-Pugh score was A in 70%, B in 20%, and C in 10%. We included RBV in 75% of patients, and treatment duration was 12 weeks in all patients. The sustained virologic response at week 12 (SVR12) was 95.23%. There were no discontinuations due to SAEs, but the mortality rate at 6 months after treatment was 7.14%. All deceased patients were cirrhotic, Child C, and with an average MELD score of 20. Conclusions The combination SIM + SOF ± RBV to treat HCV genotype 4 in liver transplant patients is an option with high rates of SVR12 and very safe, similarly to genotype 1. There was no treatment-related mortality, but when it is administered in advanced stages of fibrosis it may not be enough to prevent mortality associated with cirrhotic hepatitis C recurrence after transplantation.

Presentation Poster

Patients with cirrhosis receiving norfloxacin show a restored inflammatory balance that likely prevents clinical complications derived from an excessive proinflammatory response to bacterial product challenges. This study sought to investigate associated inflammatory control mechanisms established in patients with cirrhosis receiving norfloxacin. A total of 62 patients with cirrhosis and ascites in different clinical conditions were considered. Blood samples were collected and intracellular and serum norfloxacin were measured. Inflammatory mediators were evaluated at messenger RNA and protein levels. Neutrophils from all patients were cultured with lipopolysaccharide (LPS) and anti–interleukin-10 (anti–IL-10) monoclonal antibody in different conditions. IL-10 and heme oxygenase-1 (HO-1) were up-regulated in patients receiving norfloxacin and correlated with norfloxacin in a concentration-dependent manner, whereas proinflammatory inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor-κB behaved inversely. Higher IL-10 levels correlated with lower white blood cell count and higher mean arterial pressure. No correlations were found between IL-10 and disease clinical scores or liver function markers in blood. Neutrophilic in vitro assays showed that the effect of LPS on proinflammatory mediator levels in the presence of norfloxacin was abrogated by significantly increasing IL-10 and HO-1 expression. After stimulation with LPS plus anti–IL-10, proinflammatory mediators were dramatically increased in patients receiving norfloxacin, and increasing intracellular norfloxacin concentrations did not decrease the expression levels of these proinflammatory molecules. Unblocking IL-10 restored proinflammatory mediator and HO-1 expression to previously observed levels in response to LPS stimulation. Conclusion: Although the described association does not necessarily mean causality, an IL-10–mediated HO-1–induced anti-inflammatory mechanism is present in patients with cirrhosis receiving norfloxacin, that is directly associated with cell-modulating events in these patients. (HEPATOLOGY 2011;)

Resumen Fundamento y objetivo El carcinoma hepatocelular (CHC) es la principal causa de muerte en pacientes con cirrosis, y su situacion actual en Espana no es bien conocida. Por esto, se ha creado un registro nacional para evaluar las caracteristicas de los pacientes con CHC de novo. Pacientes y metodo Entre el 1 de octubre de 2008 y el 31 de enero de 2009, 62 centros de referencia registraron las caracteristicas demograficas, clinicas y tumorales, la primera opcion de tratamiento y la elegibilidad para el trasplante ortotopico hepatico (TOH) de los CHC diagnosticados en este tiempo. Resultados Se contabilizaron 705 casos nuevos de CHC, un 78% en varones; la edad media era de 65 anos y un 89% eran cirroticos (el 58% con Child-Pugh clase A, el 42% estaban infectados por el virus de la hepatitis C, el 30% consumia alcohol). Solo 334 casos (47%) se diagnosticaron mediante cribado. El tamano del nodulo principal y el estadio Barcelona Clinic Liver Cancer fueron significativamente menores en el grupo de cribado que en el resto (p 75 anos) (p=0,171). La quimioembolizacion fue el tratamiento mas indicado: en tumores iniciales (46,4%), en tumores mayores de 5 cm (15,7%), en multifocales (37,9%) y como puente al TOH (33%). Conclusion La mayoria de los CHC en Espana se diagnostican fuera de los programas de deteccion precoz y esto limita la posibilidad de aplicacion de tratamientos con intencion curativa.

Aliment Pharmacol Ther 31, 1337–1345 Summary Background Drug-induced liver injury (DILI) profile in most drugs’ available information is based on both the incidence of alanine aminotansferase (ALT) elevations in clinical trials and published case reports. Aim To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting. Methods Hepatotoxic drugs were identified from product labelling and classified in high-medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (≥3 × ULN) for drug (ID) and placebo (IC) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE. Results The median IC was 10/1000. The high-medium-risk drugs’ median ID was significantly higher compared with low-risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi-squared test, absolute difference and odds ratio comparing ID and IC identified 35%, 51% and 77% of high-medium-risk drugs respectively. Less number of case reports were associated with low- than high-medium-risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (ID vs. IC) was the strongest predictor of published DILI case reports. Conclusion A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.