Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation

Liver transplantation (LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma (HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to 85%of 3- to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma- carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation. These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumora

Coronavirus disease 2019 (COVID-19) in solid organ transplant recipients: A case-control study

Background: Material/Methods: Results: Conclusions: It is unclear whether solid organ transplant (SOT) patients have more severe coronavirus disease 2019 (COVID-19) and worse outcome than the general population. We conducted a case-control study on 32 SOT recipients and 84 non-SOT controls matched for age and sex admitted for confirmed COVID-19. The primary endpoint was in-hospital all-cause mortality rate. Secondary endpoints included severe acute respiratory distress syndrome (ARDS), use of high-flow oxygen therapy, and length of hospital stay. The median (IQR) Charlson comorbidity index (CCI) at admission was significantly higher in SOT recipients (6 (3-8) vs 3 (2-4); P<0.01). Fever was less frequent in SOT recipients (78% vs 94%, P=0.01). SOT recipients had a higher median SaO2/FiO2 at admission (452 [443-462] vs 443 [419-452], P<0.01) and reached the worst SaO2/FiO2 value later during hospitalization 15 (10-21) vs 11 (9-14) days, P=0.01). Both groups had a similar severe ARDS rate during hospitalization (33% vs 28%) (p=0.59). There were no significant differences during hospitalization in terms of highest level of respiratory support needed, or length of hospital stay: 8.5 (5.5-21) vs 11.5 (6.5-16.5) days; P=0.34) in SOT recipients when compared to controls. In-hospital all-cause mortality rates were significantly higher in SOT recipients (21.9% vs 4.7%, P<0.01; OR 1.08; 95% CI 0.10-10.98), but among patients who died, median CCI was similar between groups (8 [6-8] vs 7 [6-8]). In our experience, hospitalized SOT recipients for COVID-19 had higher in-hospital mortality compared to nonSOT patients, probably due to the greater number of underlying comorbidities, and not directly related to chronic immunosuppression

Mast cell-mediated splanchnic cholestatic inflammation

Introduction Splanchnic mast cells increase in chronic liver and in acute-on-chronic liver diseases. We administered Ketotifen, a mast cell stabilizer, and measured the mast cells in the splanchnic organs of cholestatic rats. Material and Methods These groups were studied: sham-operated rats (S; n = 15), untreated microsurgical cholestasic rats (C; n = 20) and rats treated with Ketotifen: early (SK-e; n = 20 and CKe; n = 18), and late (SK-l; n = 15 and CK-l; n = 14). Results The cholestatic rats showed systemic and splanchnic impairments, such as ascites, portal hypertension, and biliary proliferation and fibrosis. The rats also showed a splanchnic increase of TNF-α, IL-1β and MCP-1, and a reduction of IL-4, IL-10 and antioxidants. An increase of VEGF in the ileum and mesenteric lymphatic complex was associated with a liver reduction of TGF-β1. Ketotifen reduces the degree of hepatic insufficiency and the splanchnic inflammatory mediators, as well as VEGF and TGF-ß1 levels. Ketotifen also reduces the connective tissue mast cells in the mesenteric lymphatic complex of cholestatic rats, while increases the hepatic mucosal mast cells. Conclusions In cholestatic rats, Ketotifen improves liver function and ascites, and also reduces pro-inflammatory mediators in the splanchnic area. The decrease in connective tissue mast cells in the mesenteric lymphatic complex due to the administration of Ketotifen would lead to the improvement of the inflammatory splanchnic response, and consequently the abovementioned complications

Everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study

Background and aim: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. Methods: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels <_ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. Results: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. Conclusion: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4

[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<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35 g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE‐associated discontinuation events occurred in 5.9% and 2.6%. Conclusions. In this large cohort of cirrhotic patients managed in the real‐world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.Instituto de Salud Carlos III; PI15/0015

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients

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

Safety and Efficacy of Sofosbuvir plus Simeprevir in a Spanish Cohort of 622 Cirrhotic Patients Infected with Genotypes 1 or 4

Presentation Poste

Trasplante hepatocelular: estudio de su eficacia en un modelo experimental de insuficiencia hepática aguda grave

Tesis doctoral inédita leída el 24-4-82 en la Universidad Autónoma de Madrid, Facultad de Medicin