Multidrug-resistant bacterial infections after liver transplantation: Prevalence, impact, and risk factors.

BACKGROUND & AIMS: Infections by multidrug-resistant bacteria (MDRB) are an increasing healthcare problem worldwide. This study analyzes the incidence, burden, and risk factors associated with MDRB infections after liver transplant(ation) (LT). METHODS: This retrospective, multicenter cohort study included adult patients who underwent LT between January 2017 and January 2020. Risk factors related to pre-LT disease, surgical procedure, and postoperative stay were analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of MDRB infections within the first 90 days after LT. RESULTS: We included 1,045 LT procedures (960 patients) performed at nine centers across Spain. The mean age of our cohort was 56.8 ± 9.3 years; 75.4% (n = 782) were male. Alcohol-related liver disease was the most prevalent underlying etiology (43.2.%, n = 451). Bacterial infections occurred in 432 patients (41.3%) who presented with a total of 679 episodes of infection (respiratory infections, 19.3%; urinary tract infections, 18.5%; bacteremia, 13.2% and cholangitis 11%, among others). MDRB were isolated in 227 LT cases (21.7%) (348 episodes). Enterococcus faecium (22.1%), Escherichia coli (18.4%), and Pseudomonas aeruginosa (15.2%) were the most frequently isolated microorganisms. In multivariate analysis, previous intensive care unit admission (0-3 months before LT), previous MDRB infections (0-3 months before LT), and an increasing number of packed red blood cell units transfused during surgery were identified as independent predictors of MDRB infections. Mortality at 30, 90, 180, and 365 days was significantly higher in patients with MDRB isolates. CONCLUSION: MDRB infections are highly prevalent after LT and have a significant impact on prognosis. Enterococcus faecium is the most frequently isolated multi-resistant microorganism. New pharmacological and surveillance strategies aimed at preventing MDRB infections after LT should be considered for patients with risk factors. IMPACT AND IMPLICATIONS: Multidrug-resistant bacterial infections have a deep impact on morbidity and mortality after liver transplantation. Strategies aimed at improving prophylaxis, early identification, and empirical treatment are paramount. Our study unveiled the prevalence and main risk factors associated with these infections, and demonstrated that gram-positive bacteria, particularly Enterococcus faecium, are frequent in this clinical scenario. These findings provide valuable insights for the development of prophylactic and empirical antibiotic treatment protocols after liver transplantation.

The role of HBIG in real life for patients undergoing liver transplantation due to HDV-related cirrhosis.

Recommended post-liver transplant (LT) prophylaxis in patients with hepatitis delta includes a nucleos(t)ide analogue (NA) and anti-hepatitis B immunoglobulin (HBIG) indefinitely. We analysed the use of HBIG in real-life clinical practice and its impact on HBV/HDV recurrence in 174 HDV-related LT patients from 10 Spanish liver transplant centres (1988-2018). Median post-LT follow-up was 7.8 (2.3-15.1) years and patient survival at 5 years was 90%. Most patients (97%) received HBIG in the immediate post-LT, but only 42% were on HBIG at the last control. Among those discontinuing HBIG, the median time on treatment was 18 (7-52) months. Post-LT HBsAg+ was detected in 16 (9%) patients and HBV-DNA in 12 (7%). Despite HBsAg positivity, HDV recurrence was reported only in three patients (1.7%), all of whom were not receiving NA and had discontinued HBIG. Our data suggest that a finite HBIG prophylaxis in HDV-LT is feasible, especially if high-barrier NAs are used.

Donor Atheromatous Disease is a Risk Factor for Hepatic Artery Thrombosis After Liver Transplantation.

The increasing age of liver donors and transplant candidates, together with the growing prevalence of metabolic comorbidities, could impact the risk of vascular complications after liver transplantation. We enrolled a consecutive cohort of adult patients undergoing liver transplantation from 2012 to 2021 who had a blinded pathological assessment of atherosclerosis in the donor and recipient hepatic arteries (HA). Patients receiving partial or reduced grafts, retransplantation, or combined organ transplantation were excluded. The relationship between HA atherosclerosis and HA thrombosis after liver transplantation was evaluated using logistic regression in the whole study cohort and in a propensity score-matched subpopulation. Among 443 eligible patients, 272 had a full pathological evaluation of the donor and recipient HA and were included in the study. HA atheroma was present in 51.5% of donors and in 11.4% of recipients. HA thrombosis occurred in 16 patients (5.9%), being more likely in patients who received a donor with HA atherosclerosis than in those without (10.7% vs. 0.8%; p < 0.001). Donor HA atherosclerosis was an independent risk factor of HA thrombosis (OR = 17.79; p = 0.008), and this finding was consistent in the propensity score-matched analysis according to age, sex, complex arterial anastomosis, and alcoholic liver disease (OR = 19.29; p = 0.007). Atheromatous disease in the recipient had no influence on the risk of HA thrombosis (OR = 1.70; p = 0.55). In conclusion, patients receiving donors with HA atherosclerosis are at increased risk for HA thrombosis after liver transplantation. The evaluation of the donor graft vasculature could guide antiplatelet therapy in the postoperative period.

Diagnosis and management of Abernethy syndrome.

Abernethy syndrome (AS or extrahepatic portosystemic shunt) is an uncommon congenital malformation consisting of agenesis or hypoplasia of the portal vein (PV) in such a way that splanchnic venous blood drains directly into the systemic circulation through aberrant communications, resulting in a portosystemic shunt that bypasses the liver AS is an underdiagnosed condition with unknown incidence and complication rate given that symptoms are usually absent. AS identification is increasingly common because of improved imaging techniques, hence prognostic implications and clinical management need be understood. This editorial reviews the natural history of AS and its diagnostic-therapeutic implications, illustrating the process with a series of cases from our institution.

Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation.

Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.

Enumeration and Characterization of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Circulating tumor cells (CTCs), and particularly circulating cancer stem cells (cCSC), are prognostic biomarkers for different malignancies and may be detected using liquid biopsies. The ex vivo culture of cCSCs would provide valuable information regarding biological aggressiveness and would allow monitoring the adaptive changes acquired by the tumor in real time. In this prospective pilot study, we analyzed the presence of EpCAM+ CTCs using the IsoFlux system in the peripheral blood of 37 patients with hepatocellular carcinoma undergoing transarterial chemoembolization (TACE). The average patient age was 63.5 ± 7.9 years and 91.9% of the patients were men. All patients had detectable CTCs at baseline and 20 patients (54.1%) showed CTC aggregates or clusters in their peripheral blood. The increased total tumor diameter (OR: 2.5 (95% CI: 1.3-4.8), p = 0.006) and the absence of clusters of CTCs at baseline (OR: 0.2 (95% CI: 0.0-1.0), p = 0.049) were independent predictors of a diminished response to TACE. Culture of cCSC was successful in five out of thirty-three patients, mostly using negative enrichment of CD45- cells, ultra-low adherence, high glucose, and a short period of hypoxia followed by normoxia. In conclusion, the identification of clusters of CTCs before TACE and the implementation of standardized approaches for cCSC culture could aid to predict outcomes and to define the optimal adjuvant therapeutic strategy for a true personalized medicine in hepatocellular carcinoma.

Development of a Prediction Model for Short-Term Remission of Patients with Crohn's Disease Treated with Anti-TNF Drugs.

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn's disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.

Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.

Decreased Long-Term Severe Acute Respiratory Syndrome Coronavirus 2-Specific Humoral Immunity in Liver Transplantation Recipients 12 Months After Coronavirus Disease 2019.

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 < 0.001). Vaccinated LT recipients showed higher antibody levels compared with unvaccinated patients (P < 0.001); antibody levels reached after vaccination were comparable to those observed in nontransplanted individuals (P = 0.70). In LT patients, a longer interval since transplantation (odds ratio, 1.10; 95% confidence interval, 1.01-1.20) was independently associated with persistence of anti-nucleocapsid IgG antibodies 1 year after infection. In conclusion, compared with nontransplanted patients, LT recipients show a lower long-term persistence of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, SARS-CoV-2 vaccination after COVID-19 in LT patients achieves a significant increase in antibody levels, comparable to that of nontransplanted patients.

Malignancy of intraductal papillary neoplasm of the bile duct.

Intraductal papillary neoplasm of the bile duct (IPNB) is an uncommon disease which was first included in the World Health Organization classification of neoplasms in 2010. A 64-year-old female was admitted to the hospital because of a hepatic lesion incidentally diagnosed during acute cholangitis. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) showed a well delimited 70 mm mass, with a predominant cystic component and hyperenhancement of papillary internal branching, consistent with a hydatid cyst. However, malignancy could not be excluded. The patient rapidly developed an acute abdomen syndrome, thus precluding a liver biopsy. A new urgent CT was performed to rule out a complication of the cystic lesion. A left hepatectomy was performed and the anatomopathological study confirmed the diagnosis of IPNB with a focus of cholangiocarcinoma therein. During follow up, the patient developed peritoneal carcinomatosis, received palliative chemotherapy and finally died.

Endoscopic findings unrelated to portal hypertension in patients with liver cirrhosis undergoing a varicose vein screening programme. / Hallazgos endoscópicos no relacionados con hipertensión portal en pacientes con cirrosis hepática sometidos a un programa de cribado de varices.

AIM: To determine the prevalence of endoscopic lesions unrelated with portal hypertension in patients with cirrhosis. PATIENTS AND METHODS: Cross-sectional study including a consecutive cohort of patients with liver cirrhosis enrolled in a screening program of oesophageal varices who underwent an upper gastrointestinal endoscopy from November, 2013, to November, 2018. Clinical predictors of endoscopic lesions unrelated to portal hypertension were analyzed by univariate and multivariate logistic regression. RESULTS: A total of 379 patients were included. The most frequent aetiology of liver disease was alcohol consumption (60.4%). The prevalence of endoscopic lesions unrelated with portal hypertension was 39.6% (n=150). Among 96 patients with peptic lesions, urease was obtained in 56.2% of patients (positive in 44.4% of them). The prevalence of endoscopic lesions unrelated to portal hypertension was not associated with age, gender, liver function or ultrasound findings of portal hypertension. The prevalence of endoscopic lesions unrelated to portal hypertension was not associated with age, gender, liver function or ultrasound findings of portal hypertension. Smokers had a trend to increased prevalence of endoscopic lesions unrelated to portal hypertension (43.2% vs. 34.6%; p=0.09), particularly peptic ulcer (6.4% vs. 0.6%; p=0.05) and peptic duodenitis (17.3% vs. 6.3%; p=0.002). Active smoking was the only independent predictor of peptic ulcer or duodenitis (OR=2.56; p=0.017). CONCLUSION: Active smoking is a risk factor for endoscopic lesions unrelated to portal hypertension. This finding should be further investigated to reassess endoscopic screening programs in cirrhotic smokers.

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.

Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.

BACKGROUND & AIMS: The incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate. METHODS: We performed a prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 recruited during the Spanish outbreak from 28 February to 7 April, 2020. The primary outcome was severe COVID-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardised 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 hospitalised patients were analysed 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 the 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. A total of 12 patients were admitted to the ICU (10.8%). The mortality rate was 18%, which was lower than in the matched general population (SMR = 95.5 [95% CI 94.2-96.8]). Overall, 35 patients (31.5%) met criteria of severe COVID-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (relative risk = 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 the 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. LAY SUMMARY: 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 hospitalised patients.

Histological sub-classification of cirrhosis using collagen proportionate area in patients with chronic hepatitis C.

Collagen proportionate area (CPA, %) is used to quantify liver fibrosis. Here, we assessed CPA performance to sub-classify cirrhosis. CPA was measured in explanted livers from consecutively transplanted patients for hepatitis C virus-related cirrhosis. Model for end-stage liver disease (MELD), Child-Pugh score and decompensating events (ascites, variceal bleeding, non-obstructive jaundice and encephalopathy) were recorded at the time of liver transplant. Of the 154 patients, 24%, 12%, 35%, 24% and 5% had zero, one, two, three and four previous decompensating events. Patients with decompensation had significantly higher CPA than those without (25.1 ± 8.4 vs 15.8 ± 5.5, P < .001). Decompensation was independently associated with CPA, bilirubin and albumin or with CPA and MELD score. CPA did not differ between patients with one, two, three or four decompensating events (22.2 ± 6.3 vs 26.6 ± 8.9 vs 24.5 ± 7.7 vs 24.4 ± 10.9, P = .242). Overall, CPA correlates with the clinical severity of cirrhosis until the advent of decompensation but not with subsequent decompensating events.

Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity. AIMS: To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients. METHODS: Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG. RESULTS: A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496). CONCLUSION: Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.

Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and a major cause of cancer-related death worldwide. There is no ideal biomarker allowing early diagnosis of HCC and tumor surveillance in patients receiving therapy. Liquid biopsy, and particularly circulating tumor cells (CTCs), have emerged as a useful tool for diagnosis and monitoring therapeutic responses in different tumors. In the present manuscript, we evaluate the current evidence supporting the quantitative and qualitative assessment of CTCs as potential biomarkers of HCC, as well as technical aspects related to isolation, identification, and classification of CTCs. Although the dynamic assessment of CTCs in patients with HCC may aid the decision-making process, there are still many uncertainties and technical caveats to be solved before this methodology has a true impact on clinical practice guidelines. More studies are needed to identify the optimal combination of surface markers, to increase the efficiency of ex-vivo expansion of CTCs, or even to target CTCs as a potential therapeutic strategy to prevent HCC recurrence after surgery or to hamper tumor progression and extrahepatic spreading.

Interaction between tacrolimus, MELD score and acute kidney injury after liver transplantation. Analysis on a large contemporary bicenter meld-era series.

BACKGROUND: Acute kidney injury (AKI) after liver transplantation (LT) is a common problem with complex management. The aims were to analyze the profile of AKI-RIFLE categories in the post-transplant setting of a wide multicentre cohort of patients in the MELD era and to specifically determine the effect of tacrolimus-based (TACRO) immunosuppressive regimes on the development of AKI. METHODS: A retrospective analysis of 550 (2007-2012) consecutive patients transplanted at Reina Sofia, Cordoba, and King's College Hospital, London, was performed. Inclusion criterion was to have CNI as part of initial immunosuppression immediately after LT. RESULTS: After exclusion criteria, a total of 477 patients were analyzed. Incidence of AKI within the first 2 weeks after LT was 65.8% (AKI-Risk), 41.3% (AKI-Injury), and 12.3% (AKI-Failure). The development of any type of AKI had no impact on short- and/or long-term survival up to 3 years after the transplant. Moreover, AKI was almost universal in the early post-transplant period and TACRO trough concentrations during the first 2 weeks after the transplant were not predictors of AKI in none of its categories in the multivariate analyses. CONCLUSIONS: Low-TACRO-based regimes were not as useful as expected in the prevention of AKI when analyzed in the context of a large contemporary LT series.

Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.

Cardiovascular morbidity and mortality is increased post-liver transplantation even in recipients with no pre-existing risk factors.

BACKGROUND/AIMS: Post-liver transplant (LT) metabolic syndrome (PTMS) and cardiovascular (CVS) mortality are becoming increasingly prevalent following sustained improvements in post-LT survival. We investigated the prevalence and predictors of PTMS and CVS complications in a cohort of consecutive LT recipients. METHODS: We reviewed prospectively collected data of patients (n = 928) who underwent LT (1995-2013) and survived at least 1-year post-LT or died before that due to a major CVS complication. RESULTS: Median follow-up was 85 months (IQR = 106). The prevalence of PTMS was 22.4% and it developed de novo in 183 recipients (19.7%). A total of 187 (20.2%) patients developed at least one CVS event post-LT within a median of 49 months (IQR = 85). Overall mortality rate was 22.6% (n = 210). Causes of death were CVS events (n = 45, 21.4%), malignancies (21%), liver-related deaths (20%) and infections (6.7%). Independent predictors of major CVS events were: documented CVS disease pre-LT (Hazard Ratio (HR) = 3.330; 95% CI = 1.620-6.840), DM (HR = 1.120; 95% CI 1.030-1.220), hypertension (HR = 1.140; 95% CI 1.030-1.270), dyslipidaemia (HR = 1.140; 95% CI 1.050-1.240) and creatinine levels at 1 year (HR = 1.010; 95% CI = 1.005-1.013). Among LT recipients without pre-LT CVS disease or MS components (n = 432), 85 recipients developed ≥1 CVS events (19.7%) with independent predictors being DM (HR = 1.150; 95% CI = 1.010-1.320), creatinine levels at 1 year (HR = 1.020; 95% CI = 1.010-1.030) and hypertension (HR = 1.190; 95% CI = 1.040-1.360). CONCLUSIONS: Post-LT patients are at increased risk of CVS morbidity even in the absence of pre-existing metabolic risk factors. Renal sparing immunosuppressive protocols might reduce CVS events post-LT.

mTOR Expression in Liver Transplant Candidates with Hepatocellular Carcinoma: Impact on Histological Features and Tumour Recurrence.

(1) Background: The mammalian target of rapamycin (mTOR) pathway activation is critical for hepatocellular carcinoma (HCC) progression. We aimed to evaluate the mTOR tissue expression in liver transplant (LT) patients and to analyse its influence on post-LT outcomes. (2) Methods: Prospective study including a cohort of HCC patients who underwent LT (2012⁻2015). MTOR pathway expression was evaluated in the explanted liver by using the "PathScan Intracellular Signalling Array Kit" (Cell Signalling). Kaplan-Meier and Cox regression analyses were performed to evaluate post-LT HCC recurrence. (3) Results: Forty-nine patients were included (average age 56.4 ± 6, 14.3% females). Phospho-mTOR (Ser2448) was over-expressed in peritumoral tissue as compared with tumoral tissue (ΔSignal 22.2%; p < 0.001). The mTOR activators were also increased in peritumoral tissue (phospho-Akt (Thr308) ΔSignal 18.2%, p = 0.004; phospho-AMPKa (Thr172) ΔSignal 56.3%, p < 0.001), as they were the downstream effectors responsible for cell growth/survival (phospho-p70S6K (Thr389) ΔSignal 33.3%, p < 0.001 and phospho-S6RP (Ser235/236) ΔSignal 54.6%, p < 0.001). MTOR expression was increased in patients with multinodular HCC (tumoral p = 0.01; peritumoral p = 0.001). Increased phospho-mTOR in tumoral tissue was associated with higher HCC recurrence rates after LT (23.8% vs. 5.9% at 24 months, p = 0.04). (4) Conclusion: mTOR pathway is over-expressed in patients with multinodular HCC and is it associated with increased post-LT tumour recurrence rates.