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BACKGROUND Malignant and benign neuroendocrine tumors (NET) share many histopathological features. Liver transplantation (LT) is one of the liver-directed therapies for neuroendocrine liver metastases (NELM). The aim of this study was to determine the outcomes of patients undergoing LT for NELM. MATERIAL AND METHODS This was a retrospective study that included 19 patients who underwent LT for unresectable NELM between December 1989 and December 2022 in the Department of General, Transplant, and Liver Surgery of the Medical University of Warsaw. Kaplan-Meier estimator and Cox proportional hazards regression were used for statistical analyses. RESULTS The primary tumor was located most frequently in the pancreas. The median follow-up was 72.5 months. The overall survival (OS) was 94.7%, 88.0%, 88.0%, 70.4%, and 49.3% after 1, 3, 5, 10, and 15 years, respectively. Accordingly, the recurrence-free survival (RFS) rates were 93.8%, 72.9%, 64.8%, 27.8%, and 27.8% after 1, 3, 5, 10, and 15 years, respectively. Ki-67 index ≥5% was found as a risk factor for both worse OS (hazard ratio (HR) 7.13, 95% confidence intervals (95% CI) 1.32-38.63, P=0.023) and RFS (HR 13.68, 95% CI 1.54-121.52, P=0.019). Recipient age ≥55 years was a risk factor for worse RFS (P=0.046, HR 5.47, 95% CI 1.03-29.08). Multivariable analysis revealed Ki-67 ≥5% as the sole independent factor for worse OS (HR 13.78, 95% CI 1.48-128.56, P=0.021). CONCLUSIONS Patients with unresectable NELM achieve great OS and satisfying RFS after LT. The risk factors associated with worse outcomes are attributed to primary tumor aggressiveness.

Background & Aims: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical approaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT., Methods: An international, observational web registry was launched in 2020. Cases of complex PVT undergoing first LT performed with RPA, LGA, PCA, or CPA were recorded and updated through 12/2021., Results: A total of 140 cases were available for analysis: 74 RPA, 18 LGA, 20 PCA, and 28 CPA. Transplants were primarily performed with whole livers (98%) in recipients with median (IQR) age 58 (49-63) years, model for end-stage liver disease score 17 (14-24), and cold ischemia 431 (360-505) minutes. Post-operatively, 49% of recipients developed acute kidney injury, 16% diuretic-responsive ascites, 9% refractory ascites (29% with CPA, p <0.001), and 10% variceal hemorrhage (25% with CPA, p = 0.002). After a median follow-up of 22 (4-67) months, patient and graft 1-/3-/5-year survival rates were 71/67/61% and 69/63/57%, respectively. On multivariate Cox proportional hazards analysis, the only factor significantly and independently associated with all-cause graft loss was non-physiological portal vein reconstruction in which all graft portal inflow arose from recipient systemic circulation (hazard ratio 6.639, 95% CI 2.159-20.422, p = 0.001)., Conclusions: Alternative forms of portal vein anastomosis achieving physiological portal inflow (i.e., at least some recipient splanchnic blood flow reaching transplant graft) offer acceptable post-transplant results in LT candidates with complex PVT. On the contrary, non-physiological portal vein anastomoses fail to resolve portal hypertension and should not be performed., Impact and Implications: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation. Results of this international, multicenter analysis may be used to guide clinical decisions in transplant candidates with complex PVT. Extra-anatomical portal vein anastomoses that allow for at least some recipient splanchnic blood flow to the transplant allograft offer acceptable results. On the other hand, anastomoses that deliver only systemic blood flow to the allograft fail to resolve portal hypertension and should not be performed., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Despite inconsistent evidence, international guidelines underline the importance of perioperative hyperoxygenation in prevention of postoperative infections. Further, data on safety and efficacy of this method in liver transplant setting are lacking. The aim was to evaluate efficacy and safety of postoperative hyperoxygenation in prophylaxis of infections after liver transplantation., Methods: In this randomized controlled trial, patients undergoing liver transplantation were randomly assigned to either 28% or 80% fraction of inspired oxygen (FiO 2 ) for 6 postoperative hours. Infections occurring during 30-day post-transplant period were the primary outcome measure. Secondary outcome measures included 90-day mortality, 90-day severe morbidity, 30-day pulmonary complications, durations of hospital and intensive care unit stay, and 5-day postoperative bilirubin concentration, alanine and aspartate transaminase activity, and international normalized ratio (INR) (clinicatrials.gov NCT02857855)., Results: A total of 193 patients were included and randomized to 28% (n = 99) and 80% (n = 94) FiO 2 . With similar patient, operative, and donor characteristics in both groups, infections occurred in 34.0% (32/94) of patients assigned to 80% FiO 2 as compared to 23.2% (23/99) of patients assigned to 28% FiO 2 (p = 0.112). Patients randomized to 80% FiO 2 more frequently developed severe complications (p = 0.035), stayed longer in the intensive care unit (p = 0.033), and had higher bilirubin concentration over first 5 post-transplant days (p = 0.043). No significant differences were found regarding mortality, duration of hospital stay, pulmonary complications, and 5-day aspartate and alanine transaminase activity and INR., Conclusions: Postoperative hyperoxygenation should not be used for prophylaxis of infections after liver transplantation due to the lack of efficacy., Trial Registration: ClinicalTrials.gov NCT02857855. Registered 7 July 2016., (© 2023. The Author(s).)

Objective: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons., Background: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC., Methods: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers., Results: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001)., Conclusion: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To define benchmark cutoffs for redo liver transplantation (redo-LT)., Background: In the era of organ shortage, redo-LT is frequently discussed in terms of expected poor outcome and wasteful resources. However, there is a lack of benchmark data to reliably evaluate outcomes after redo-LT., Methods: We collected data on redo-LT between January 2010 and December 2018 from 22 high-volume transplant centers. Benchmark cases were defined as recipients with model of end stage liver disease (MELD) score ≤25, absence of portal vein thrombosis, no mechanical ventilation at the time of surgery, receiving a graft from a donor after brain death. Also, high-urgent priority and early redo-LT including those for primary nonfunction (PNF) or hepatic artery thrombosis were excluded. Benchmark cutoffs were derived from the 75th percentile of the medians of all benchmark centers., Results: Of 1110 redo-LT, 373 (34%) cases qualified as benchmark cases. Among these cases, the rate of postoperative complications until discharge was 76%, and increased up to 87% at 1-year, respectively. One-year overall survival rate was excellent with 90%. Benchmark cutoffs included Comprehensive Complication Index CCI ® at 1-year of ≤72, and in-hospital and 1-year mortality rates of ≤13% and ≤15%, respectively. In contrast, patients who received a redo-LT for PNF showed worse outcomes with some values dramatically outside the redo-LT benchmarks., Conclusion: This study shows that redo-LT achieves good outcome when looking at benchmark scenarios. However, this figure changes in high-risk redo-LT, as for example in PNF. This analysis objectifies for the first-time results and efforts for redo-LT and can serve as a basis for discussion about the use of scarce resources., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Over the last few years, transplant centers have started to use various intraoperative renal replacement therapy (ioRRT) modalities during liver transplantation (LT) in patients with pre-existing renal impairment. Here, we present a study on the safety and clinical outcomes of intraoperative hemodialysis (ioHD) performed using a mobile dialysis system during LT., Patients and Methods: We retrospectively analyzed 102 adult patients undergoing LT with ioHD; pre-existing renal failure and/or intraoperative metabolic derangement were ioHD treatment indications., Results: Our study cohort consisted of three groups: LT with preoperative serum creatinine (sCr) ​< ​2 ​mg/dL (Group 1:n ​= ​22), LT with preoperative sCr ≥2 ​mg/dL (Group 2:n ​= ​73), and simultaneous liver-kidney transplantation (Group 3:n ​= ​7). Among the procedures, 30% were re-transplantations. The mean calculated Model for End-stage Liver Disease score in Group 2 was 39.2, and 67% of patients were hospitalized in the intensive care unit. Patients in Group 1 were less acutely ill but developed severe intraoperative derangements and, therefore, underwent urgent ioHD intraoperatively. However, it was delayed when compared to Group 2. All groups achieved post-reperfusion potassium levels <4 ​mmol/L and a decrease in central venous pressure. No serious procedural complications occurred. Post-reperfusion syndrome occurred in 12.7% of patients. Elevated mortality was likely due to the high illness severity in the cohort., Conclusions: Performing ioHD with a mobile dialysis system during LT was safe and effective, while being easier to perform than continuous techniques. Its effect on intra- and postoperative outcomes should be addressed in a study with a control group., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2022. Published by Elsevier B.V.)

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I 2 index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival., (© 2022 American Association for the Study of Liver Diseases.)

Background: The futility of liver transplantation in elderly recipients remains under debate in the HCV eradication era., Methods: The aim was to assess the effect of older age on outcome after liver transplantation. We used the ELTR to study the relationship between recipient age and post-transplant outcome. Young and elderly recipients were compared using a PSM method., Results: A total of 10,172 cases were analysed. Recipient age >65 years was identified as an independent risk factor associated with reduced patient survival (HR:1.42 95%CI:1.23-1.65,p < 0.001). After PSM, 2124 patients were matched, and the same association was found between elderly recipients and patient survival and graft survival (p < 0.001). As hepatocellular carcinoma and alcoholic cirrhosis were independent prognostic factors for patient and graft survival a propensity score-matching was performed for each. Patient and graft survival were significantly worse (p < 0.05) in the alcoholic cirrhosis elderly group. However, patient and graft survival in the hepatocellular carcinoma cohort were similar (p > 0.05) between groups., Conclusion: Liver transplantation is an acceptable and safe curative option for elderly transplant candidates, with worse long-term outcomes compare to young candidates. The underlying liver disease for liver transplantation has a significant impact on the selection of elderly patients., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. All rights reserved.)

Background: Cold ischemia time (CIT) is one of the most significant variables affecting graft survival after liver transplantation. The aim of this study was to identify other predictors of worse graft survival depending on the duration of cold ischemia., Methods: This retrospective cohort study included data of liver transplant recipients and donors in the period from 2014 to 2019. A total of 724 patients were analyzed after excluding retransplatations and urgent operations. Using receiver operating characteristic analysis, we identified CIT value which divides into 2 clinically different subgroups with respect to 5-year graft loss. Within those 2 subgroups, we performed Cox proportional hazard analysis with time to graft loss as endpoint., Results: The optimal cut-off point for CIT was identified as 496 minutes. Model of end-stage liver disease score, recipient body mass index, and donor sodium concentration showed no significant effect on time to graft loss in either subgroup. For 3 factors we observed a significant effect on time to graft loss in subgroup CIT ≥496 min: transfused red cell concentrate units (hazard ratio [HR] 1.05; 95% confidence interval [CI] 1.00-1.09; P = .02), transfused fresh frozen plasma units (HR 1.04; 95% CI 1.00-1.08; P = .08), and a recipient age of >60 years (HR 1.81; 95% CI 1.10-2.98; P = .02)., Conclusions: Predictive ability of well-known risk factors for worse outcomes after liver transplantation depend on the length of cold ischemia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: This study aimed to examine the effect of transaminases' activities in the first posttransplant day on early (90-day) and late (5-year) graft survival., Methods: This retrospective cohort study included 612 patients after liver transplantation (LT) in the period between 2015 and 2019. Patients with acute liver failure and with vascular complications after LT were excluded. The natural logarithms of alanine transaminase (ALT) and aspartate transaminase (AST) were used for analyses using the logistic regression and Cox proportional hazards regression models. The optimal cut-off point for transaminases was determined using receiver operating characteristic curves. The 5-year graft survival was calculated after previously excluding the patients with 90-day graft loss., Results: The ALT and AST were risk factors for 90-day graft loss (odds ratio 2.16; 95% CI 1.45-3.23; P < .001 and 2.23; 95% CI 1.55-3.19; P < .001, respectively). The optimal cut-off for ALT and AST in prediction of 90-day graft loss was ≥1030 and ≥3899 U/L; area under the curve 0.694 (95% CI 0.602-0.786; P < .001), with 11.3% and 97.1% positive predictive value (PPV) and negative predictive (NPV) value, and 0.673 (95% CI 0.575-0.772; P < .001), with 18.4% PPV and 95.6% NPV, respectively. The activities of AST and ALT on first posttransplant day were not identified as risk factors for late graft loss (P = .924 and P = .629, respectively)., Conclusions: Early post-transplant transaminase activities can be used to determine early liver graft loss; however, their utility is lost for assessing the late graft survival., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Early liver retransplantation after liver transplantation (LT) is the ultimate salvage procedure for irreversible graft failure. The aim of this study was to assess the impact of early retransplantation on 90-day and 5-year patient survival., Methods: This retrospective cohort study included 2185 patients after LT in the period between 1997 and 2019. First, the patients undergoing first retransplantation within 6 months after initial LT were compared with naïve LT patients for early mortality (within 90 days). Second, to assess late survival, the patients who had retransplantation and survived at least 90 days post LT were compared with naïve LT patients for 5-year overall survival. The patients undergoing late retransplantation (>6 months) were excluded from analyses. Fisher's exact test was used to compare groups for early survival and log-rank test for late survival., Results: The cumulative 1-, 3-, and 5-year overall survival was 87.0%, 79.9%, 75.0%, respectively, and did not differ significantly between the groups. The patients undergoing early retransplantation had lower 90-day survival rate of 89.2% as compared to 95.7% for naïve LT patients (P < .001)., Conclusions: The early liver retransplantation has profound impact on post-LT 90-day survival; however, patients who survive that period can achieve long overall survival comparable with naïve LT patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Simultaneous liver and kidney transplants (SLKT) represent 1.1% of all liver transplants in Poland. Patients undergoing SLKT experience a longer operation time and concurrent kidney dysfunction may aggravate metabolic derangement associated with the procedure. The benefits of intraoperative dialysis (ioHD) in these patients have not been determined., Methods: A retrospective observational study of all adult patients undergoing SLKT in our center from January 2009 till December 2016., Results: Study group consisted of 10 patients with End-Stage Kidney Disease (0.9% of all liver transplants): 6 patients treated with ioHD during SLKT (group 1) and 4 patients managed conservatively (group 2). All recipients were on chronic dialysis. The mean calculated Model for End-Stage Liver Disease score was 21 ± 0.9 in group 1 and 30 ± 9.5 in group 2 (P = .009). The mean preoperative serum potassium was 4.7 ± 0,6 mmol/L in group 1 and 3.97 ± 1,02 in group 2. Intraoperative serum potassium levels were comparable between the groups, but the maximum lactate and minimum bicarbonate levels were significantly worse in group 2. Postreperfusion syndrome occurred in no patient. Dialysis circuit clotting occurred in 50% of ioHD. Six patients (2 in group 1) required renal replacement therapy after SLKT; no patient was on dialysis on discharge. Three patients died within 1 year after surgery (2 in group 2)., Conclusions: No patient developed intraoperative hyperkalemia or postreperfusion syndrome. We observed a high frequency of circuit system clotting during ioHD. Clinical benefits of intraoperative hemodialysis during SLKT need to be determined in a larger study., (Copyright © 2022. Published by Elsevier Inc.)

To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Knowledge of living donor liver transplantation (LDLT) for autoimmune liver diseases (AILDs) is scarce. This study analyzed survival in LDLT recipients registered in the European Liver Transplant Registry with autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis (PSC) and the non-autoimmune disorder alcohol-related cirrhosis. In total, 29 902 individuals enrolled between 1998 and 2017 were analyzed, including 1003 with LDLT. Survival from >90 days after LDLT for AILDs in adults was 85.5%, 74.2%, and 58.0% after 5, 10, and 15 years. Adjusted for recipient age, sex, and liver transplantation era, adult PSC patients receiving LDLT showed increased mortality compared to donation after brain death (DBD) (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.36-2.80, p < .001). Pediatric PSC patients showed also increased mortality >90 days after LDLT compared to DBD (HR = 3.00, 95% CI 1.04-8.70, p = .043). Multivariate analysis identified several risk factors for death in adult PSC patients receiving LDLT including a male donor (HR = 2.49, p = .025). Adult PSC patients with LDLT versus DBD conferred increased mortality from disease recurrence (subdistribution hazard ratio [subHR] = 5.36, p = .001) and biliary complications (subHR = 4.40, p = .006) in multivariate analysis. While long-term outcome following LDLT for AILD is generally favorable, PSC patients with LDLT compared to DBD might be at increased risk of death., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The influence of sex on primary sclerosing cholangitis (PSC), pre- and postliver transplantation (LT) is unclear. Aims are to assess whether there have been changes in incidence, profile, and outcome in LT-PSC patients in Europe with specific emphasis on sex., Methods: Analysis of the European Liver Transplant Registry database (PSC patients registered before 2018), including baseline demographics, donor, biochemical, and clinical data at LT, immunosuppression, and outcome., Results: European Liver Transplant Registry analysis (n = 6463, 32% female individuals) demonstrated an increasing number by cohort (1980-1989, n = 159; 1990-1999, n = 1282; 2000-2009, n = 2316; 2010-2017, n = 2549) representing on average 4% of all transplant indications. This increase was more pronounced in women (from 1.8% in the first cohort to 4.3% in the last cohort). Graft survival rate at 1, 5, 10, 15, 20, and 30 y was 83.6%, 70.8%, 57.7%, 44.9%, 30.8%, and 11.6%, respectively. Variables independently associated with worse survival were male sex, donor and recipient age, cholangiocarcinoma at LT, nondonation after brain death donor, and reduced size of the graft. These findings were confirmed using a more recent LT population closer to the current standard of care (LT after the y 2000)., Conclusions: An increasing number of PSC patients, particularly women, are being transplanted in European countries with better graft outcomes in female recipients. Other variables impacting outcome include donor and recipient age, cholangiocarcinoma, nondonation after brain death donor, and reduced graft size., Competing Interests: M.A.H. is a consultant to Roche and Novartis. M.B. has received grant funding via her institution from Gilead, is a consultant to Intercept, and has received honoraria for lectures sponsored by Abbvie, Astellas, Novartis, and Intercept. The other authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course., Design: Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed., Results: From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10-30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15-19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44-102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31-170)., Conclusions: Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Liver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe., Methods: This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019., Results: A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p <0.0001). The 1-year probability of survival after LT for patients with ACLF was 81% (95% CI 74-87). Pre-LT arterial lactate levels >4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or -2 and 50% for ACLF-3., Conclusion: The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more precise prognostic assessment of patients with ACLF., Lay Summary: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonised to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified to help select patients with favourable outcomes., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

BACKGROUND Renal dysfunction in the peri-transplant period appears to complicate both short- and long-term outcome of liver transplantation (LT). The aim of this study was to analyze the impact of selected clinical features in the peri-liver transplant period, as well calcineurin inhibitor, particularly tacrolimus given after LT, on kidney function in a single liver transplant center's experience. MATERIAL AND METHODS A total 125 consecutive liver-grafted individuals (82 M, 43 F), mean age 50±13 y (with alcohol-related liver disease in 48 (38%) patients) were included into the study. Their clinical data were collected in the database until 46 months of follow-up, and the Python packages Pandas (version 0.22.0) and scikit-learn (version 0.21.3) were used for data analysis. RESULTS More advanced liver disease as judged by Child-Pugh class and MELD score differed significantly patients with preserved (serum creatinine SCr <1.5 mg/dL) and impaired (SCr ≥1.5 mg/dL) kidney function before LT. Older age and higher SCr pre-LT were associated with higher levels of SCr after LT in 2 time-points. SCr before LT was correlated with delta SCr for the highest and last recorded value (P<0.0001). Higher amounts of transfused colloids during surgery were associated with increased delta SCr for the highest value (P=0.019) after grafting in logistic regression analysis. There were no associations between SCr after LT and duration of anhepatic phase, urine output ≤100 mL/h, or post-reperfusion syndrome during transplantation (all P>0.05). There were no associations between SCr after LT and tacrolimus trough levels in analyses of correlations and linear regression analyses (all P>0.05). CONCLUSIONS We found that pretransplant serum creatinine was the only factor affecting kidney function after LT in our liver transplant center. The restricted fluid policy was safe and effective in terms of long-term renal function. The role of kidney-saving immunosuppressive protocols in preserving renal function long-term after LT was also confirmed.

Perioperative use of probiotics serves as efficient prophylaxis against postoperative infections after liver transplantation, yet data on long-term effects of pre-transplant probiotic intake is lacking. The aim of this study was to assess the effects of pre-transplant probiotic administration on long-term results of liver transplantation. This was secondary analysis of a randomized trial. Patients were randomized to receive either 4-strain probiotic or placebo before liver transplantation. Five year graft survival was set as the primary end-point. Secondary end-points comprised serum bilirubin and C-reactive protein (CRP) concentration, international normalized ratio (INR), serum transaminases and gamma-glutamyl transferase (GGT) activity. Study group comprised 44 patients, of whom 21 received probiotics and 23 received placebo with 5-year graft survival of 81.0% and 87.0%, respectively (p = 0.591). Patients in the probiotic arm exhibited lower INR (p = 0.001) and CRP (p = 0.030) over the first 6 post-transplant months. In the absence of hepatitis B or C virus infection, pre-transplant administration of probiotics also reduced aspartate transaminase activity (p = 0.032). In the intervention arm, patients receiving probiotics for under and over 30 days had 5-year graft survival rates of 100% and 66.7%, respectively (p = 0.061). Duration of probiotic intake > 30 days was additionally associated with increased INR (p = 0.031), GGT (p = 0.032) and a tendency towards increased bilirubin (p = 0.074) over first 6 post-transplant months. Pre-transplant administration of probiotics has mild positive influence on 6-month allograft function, yet should not exceed 30 days due to potential negative effects on long-term outcomes. (ClinicalTrials.gov Identifier: NCT01735591).

BACKGROUND The impact of packed red blood cells (PRBCs) and fresh frozen plasma (FFP) transfusions in patients with hepatocellular cancer (HCC) undergoing liver transplantation has rarely been evaluated. The aim of the current study was to assess the impact of intraoperative transfusions on posttransplant outcomes. MATERIAL AND METHODS This retrospective cohort study was based on 229 HCC transplant recipients. The primary outcome measure was 5-year recurrence-free survival. Secondary outcome measures comprised overall and long-term survival at 5 years and 90-day mortality. Cox proportional hazard models and logistic regression were used to assess risk factors. RESULTS After adjustment for potential confounders, no association was found with respect to tumor recurrence for PRBCs (P=0.368) or FFP (P=0.081) transfusions. Similarly, PRBC transfusion (P=0.623) and FFP transfusion (P=0.460) had no impact on survival between 90 days and 5 years. PRBC transfusion increased the risk of 90-day mortality (P=0.005), while FFP transfusion was associated with a lower risk (P=0.036). CONCLUSIONS Intraoperative transfusions of blood products does not impair recurrence-free and long-term survival of patients with HCC undergoing liver transplantation. Intraoperative PRBC transfusion increases the risk of early mortality, whereas adequate supplementation of FFP plays a protective role.

Background: Selected patients with unresectable perihilar cholangiocarcinoma (p-CCA) are now considered as candidates for liver transplant, provided they fulfill a strict perioperative treatment and staging protocol. The aim of this study was to examine the outcomes of patients after liver transplant with incidental p-CCA found in the liver explants., Methods: A cohort of 10 patients with incidental p-CCA after liver transplant in the period between 1994 and 2019 was included in this retrospective analysis. All patients with this diagnosis were scheduled for transplant because of primary sclerosing cholangitis. The primary and secondary endpoints comprised patient's death and tumor recurrence, respectively, assessed over a 5-year postoperative period., Results: Patient median age was 35 years (range, 32-42 years). Median size of the tumor was 3.0 cm (range, 2.5-4.0 cm). Five patients (50%) had metastases to local lymph nodes. Overall survival was 100%, 37.5%, and 18.8% after the first, third, and fifth postoperative year, respectively, with median survival of 21 months. Patient age (P = .827), R1 resection status (P = .144), tumor diameter (P = .432), and presence of lymph node metastases (P = .663) were not significantly associated with overall survival. Recurrence-free survival was 60.0% after the first postoperative year and 22.5% after the third and fifth postoperative years, with median recurrence-free survival of 13.6 months. No significant predictors of tumor recurrence were found., Conclusions: Incidental p-CCA in patients with primary sclerosing cholangitis undergoing liver transplant is associated with universally very high risk of postoperative tumor recurrence and short expected survival., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cholangiocarcinoma is the primary liver tumor forming from the biliary epithelium. Two major subtypes of this disease are distinguished because of the initial location: the extra- and intrahepatic form. The latter disease is currently a controversial indication for liver transplant (LT). The aim of this study was to evaluate the outcomes of LT of patients with intrahepatic cholangiocarcinoma., Methods: Based on postoperative histopathologic examination of the explanted liver, 8 patients with intrahepatic cholangiocarcinoma were identified from all LT recipients in the period between 1994 and 2019 and included in this retrospective cohort study. Four of the patients received transplants with a preoperative diagnosis of hepatocellular carcinoma; the remaining tumors were incidental findings. Patient survival was the primary outcome measure., Results: Six recipients had solitary lesion with a maximum tumor diameter of 6 cm. The median carbohydrate antigen 19-9 concentration prior to LT was 52.3 U/mL. The overall survival was 75.0%, 37.5%, and 25% after the first, third, and fifth year, respectively, with a median survival of 18 months. Age (P = .758), carbohydrate antigen 19-9 (P = .282), largest tumor size (P = .862), and the sum of the number of lesions and diameter of the largest tumor (P = .530) were not significantly associated with overall survival. Recurrence-free survival was 71.4% after 1 year and 28.6% after 3 and 5 years. Correspondingly, no significant predictors of worse recurrence-free survival were found., Conclusions: Intrahepatic cholangiocarcinoma remains associated with a very high risk of recurrence and dismal survival after LT irrespective of macroscopic disease burden., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular tumor with indolent behavior in terms of malignancy. The treatment of choice is either resection in the case of resectable lesions or liver transplantation (LT) for the disseminated intrahepatic form. The aim of this study was to investigate the outcomes of patients with HEHE treated by LT., Material and Methods: There were 18 patients with HEHE who underwent LT between 2002 and 2018 included in this retrospective study. The study group was comprised of young recipients (median age of 39 years) and mainly women (15 of 18; 83.3%). Two recipients had concomitant tumors of epithelioid hemangioendothelioma in the liver and lungs prior to LT. The survival probability was calculated using the Kaplan-Meier estimator., Results: According to histopathological data, none of the patients had a macrovascular invasion. In 4 patients (22.2%), the disease had spread to the hilar lymph nodes. The maximum diameter of the tumor in the studied group was 18 cm. The survival probability after 1, 5, and 15 years was 94.0%, 82.6%, and 41.3%, respectively. No disease recurrence was observed during a median follow-up of 65.9 months., Conclusion: Liver transplantation provides favorable outcomes for selected patients with a hepatic form of epithelioid hemangioendothelioma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There are scarce data on the impact of COVID-19 pandemic on liver transplantation (LT) in Europe. The aim of this study was to obtain a preliminary data on incidence, management, and outcome of COVID-19 in liver transplant recipients and candidates in Europe. An Internet-based survey was sent to the centers affiliated with European Liver Transplant Registry (ELTR). One hundred nine out of 149 (73%) of ELTR centers located in 28 European countries (93%) responded. Ninety-four (86%) of the centers tested all donors, and 75 (69%) centers tested all LT recipients for SARS-CoV-2. Seventy-three (67%) centers selected recipients for LT in the COVID-19 pandemic, whereas 33% did not. Eighty-eight centers reported COVID-19 infection in 57 LT candidates and in 272 LT recipients. Overall crude incidence of COVID-19 among LT candidates and recipients was estimated 1.05% (range 0.5-20%) and 0.34% (range 0.1-4.8%), respectively, and it was significantly higher among candidates (P < 0.001). Crude rate of death was 18% (10/57) among candidates and 15% (36/244) among recipients. This first large-scale European snapshot study clearly shows that both LT candidates and recipients are at a high risk for COVID-19. These results plead for an early and pro-active screening of COVID-19 symptoms in these populations., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Orthotopic liver transplantation (LT) is a technically complex surgical procedure associated with a major risk of hemodynamic instability and metabolic derangement, especially in patients with coexisting renal dysfunction. Some centers have applied intraoperative renal replacement therapy (ioRRT) to support patients with preoperative renal failure and prevent critical complications. Although there is a strong theoretical rationale for this treatment, there remains a paucity of definite data demonstrating its benefits., Methods: This was a retrospective observational study of all adult patients undergoing intraoperative dialysis in our center from January 2010 till December 2016., Results: The study group consisted of 88 patients with a mean MELD score of 31.4. Six patients underwent simultaneous liver and kidney transplantation. Forty-four (50%) recipients were admitted to the intensive care unit before transplantation, and 19 (21.6%) needed mechanical ventilation. Twenty-eight (31.8%) of the procedures were retransplantations, and 40 (45.4%) patients had been undergoing renal replacement therapy before LT. The mean preoperative serum creatinine was 2.82 ± 1.13 mg/dL. The majority of patients (54.5%) was operated on using the veno-venous bypass technique. The mean arterial blood pH and potassium levels after reperfusion were 7.2 ± 0.12 and 4.04 ± 0.95 mmol/L, respectively. Postreperfusion syndrome (PRS) occurred in 11 (13.9%) patients in whom dialysis started at least 15 minutes before reperfusion. Dialysis circuit clotting occurred in 9.1% of cases. There were no other adverse events of ioRRT., Conclusion: Our data suggests that intraoperative dialysis in severely ill patients with a high MELD score is safe and effective. Lower than expected PRS occurrence needs to be confirmed in a study with a control group., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BACKGROUND Gestational weight gain (GWG) is an important index influencing perinatal outcomes. Inappropriate weight gain during pregnancy is strongly associated with multiple pregnancy complications. In pregnant liver transplant recipients whose risk of adverse pregnancy outcomes is already high, this aspect may be even more significant. The present study analyzed the gestational weight gain in female liver transplant recipients and its effect on neonatal complications. MATERIAL AND METHODS A cohort study of retrospective data was performed in the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw. There were 23 patients who fulfilled all inclusion criteria. The gestational weight gain was analyzed in the context of pre-pregnancy BMI, immunosuppression, and perinatal outcomes. RESULTS The preterm delivery rate was 39.13% and GWG increased according to the duration of pregnancy. The model adjusted to week of delivery revealed no association between weight gain and the length of pregnancy (p=0.82). GWG in liver transplant recipients did not affect hypotrophy incidence, adverse perinatal outcomes, or caesarian delivery rate. A positive correlation between GWG and neonatal birth weight was observed (p=0.06). One patient, with coexisting PIH, had a stillbirth at 23 weeks. In all other cases, the 5-min Apgar score was 10 points. CONCLUSIONS Current obstetrical recommendations do not consider patients with chronic diseases undergoing immunosuppressive treatment. Proper counselling and preparing liver transplant recipients for pregnancy, especially optimizing maternal pre-pregnancy BMI, may be an important element in improving perinatal outcomes by lowering the risk of maternal complications. GWG itself is not relevant as a predictor of term gestation, but it might be important in achieving eutrophic fetus growth.

Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1 normal " (N = 129), T cell-mediated rejection (TCMR) "R2 TCMR " (N = 37), early injury "R3 injury " (N = 61), and fibrosis "R4 late " (N = 8). Groups differed in median time posttransplant, for example, R3 injury 99 days vs R4 late 3117 days. R2 TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3 injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4 late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2 TCMR correlated with histologic rejection although with many discrepancies, and R4 late with fibrosis. R2 TCMR , R3 injury , and R4 late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2 TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The aim of this study was to analyze longterm patient and graft survival after liver transplantation for autoimmune hepatitis (AIH-LT) from the prospective multicenter European Liver Transplant Registry. Patient and liver graft survival between 1998 and 2017 were analyzed. Patients after AIH-LT (n = 2515) were compared with patients receiving LT for primary biliary cholangitis (PBC-LT; n = 3733), primary sclerosing cholangitis (PSC-LT; n = 5155), and alcohol-related cirrhosis (AC-LT; n = 19,567). After AIH-LT, patient survival was 79.4%, 70.8%, and 60.3% and graft survival was 73.2%, 63.4%, and 50.9% after 5, 10, and 15 years of follow-up. Overall patient survival was similar to patients after AC-LT (P = 0.44), but worse than after PBC-LT (hazard ratio [HR], 1.48; P < 0.001) and PSC-LT (HR, 1.19; P = 0.002). AIH-LT patients were at increased risk for death (HR, 1.37-1.84; P < 0.001) and graft loss (HR, 1.35-1.80; P < 0.001) from infections compared with all other groups and had a particularly increased risk for lethal fungal infections (HR, 3.38-4.20; P ≤ 0.004). Excluding patients who died within 90 days after LT, risk of death after AIH-LT was superior compared with AC-LT (HR, 0.84; P = 0.004), worse compared with PBC-LT (HR, 1.38; P < 0.001) and similar compared with PSC-LT (P = 0.93). Autoimmune hepatitis (AIH) patients with living donor liver transplantation (LDLT) showed reduced survival compared with patients receiving donation after brain death (HR, 1.96; P < 0.001). In AIH-LT patients, overall survival is inferior to PBC-LT and PSC-LT. The high risk of death after AIH-LT is caused mainly by early fatal infections, including fungal infections. Patients with LDLT for AIH show reduced survival., (Copyright © 2020 The Authors. Liver Transplantation published by Wiley Periodicals Inc., on behalf of American Association for the Study of Liver Diseases.)

Objective: To assess the potential influence of replacing Milan criteria with simple risk scores on outcomes of hepatocellular carcinoma (HCC) patients undergoing liver transplantation., Summary Background Data: Several risk scores combining morphological and biological features were recently proposed for precise selection of HCC patients for transplantation., Methods: This retrospective study included 282 HCC liver transplant recipients. Recurrence-free survival (RFS), the primary outcome measure, was evaluated according to Metroticket 2.0 model and French AFP model with Milan criteria serving as benchmark., Results: Patients were well stratified with respect to RFS by Milan criteria, Metroticket 2.0 criteria, and AFP model cut-off ≤2 points (all P < 0.001) with c-statistics of 0.680, 0.695, and 0.681, respectively. Neither Metroticket 2.0 criteria (0.014, Z = 0.023; P = 0.509) nor AFP model (-0.014, Z = -0.021; P = 0.492) provided significant net reclassification improvement. Both patients within the Metroticket 2.0 criteria and AFP model ≤2 points exhibited heterogeneous recurrence risk, dependent upon alpha-fetoprotein (P = 0.026) and tumor number (P = 0.024), respectively. RFS of patients beyond Milan but within Metroticket 2.0 criteria (75.3%) or with AFP model ≤2 points (74.1%) was inferior to that observed for patients within Milan criteria (87.1%; P = 0.067 and P = 0.045, respectively). Corresponding microvascular invasion rates were 37.2% and 50.0%, compared with 13.6% in patients within Milan criteria (both P < 0.001). Moreover, Milan-out status was associated with significantly higher recurrence risk in subgroups within Metroticket 2.0 criteria (P = 0.021) or AFP model ≤2 points (P = 0.014)., Conclusion: Utilization of simple risk scores for liver transplant eligibility assessment leads to selection of patients at higher risk of posttransplant HCC recurrence.

Macrovascular invasion is considered a contraindication to liver transplantation for hepatocellular carcinoma (HCC) due to a high risk of recurrence. The aim of the present multicenter study was to explore the outcome of HCC patients transplanted after a complete radiological regression of the vascular invasion by locoregional therapies and define sub-groups with better outcomes. Medical records of 45 patients were retrospectively reviewed, and imaging was centrally assessed by an expert liver radiologist. In the 30 patients with validated diagnosis of macrovascular invasion, overall survival was 60% at 5 years. Pretransplant alpha-fetoprotein (AFP) value was significantly different between patients with and without recurrence (P = 0.019), and the optimal AFP cutoff was 10ng/ml (area under curve = 0.78). Recurrence rate was 11% in patients with pretransplant AFP < 10ng/ml. The number of viable nodules (P = 0.008), the presence of residual HCC (P = 0.036), and satellite nodules (P = 0.001) on the explant were also significantly different between patients with and without recurrence. Selected HCC patients with radiological signs of vascular invasion could be considered for transplantation, provided that they previously underwent successful treatment of the macrovascular invasion resulting in a pretransplant AFP < 10 ng/ml. Their expected risk of post-transplant HCC recurrence is 11%, and further prospective validation is needed., (© 2020 Steunstichting ESOT.)

Infections remain an important cause of morbidity and mortality early after liver transplantation. The aim of this prospective longitudinal study was to evaluate clinical utility of c-reactive protein (CRP), procalcitonin, and neutrophil-to-lymphocyte ratio (NLR) in surveillance of infections early after liver transplantation in intensive care setting. A total of 60 liver transplant recipients were included. CRP, procalcitonin, and NLR assessed at 12-hour intervals were primary variables of interest. Infections and severe complications during postoperative intensive care unit stay were the primary and secondary end-points, respectively. Infections and severe complications were diagnosed in 9 and 17 patients, respectively. Only peak CRP beyond first 48 hours was associated with infections (p = 0.038) with AUC, positive and negative predictive value of 0.728, 42.9% and 92.2%, respectively (cut-off: 142.7 mg/L). Peak procalcitonin over first 60 hours was the earliest predictor (p = 0.050) of severe complications with AUC, positive and negative predictive value of 0.640, 53.3% and 80.0%, respectively (cut-off: 42.8 ng/mL). In conclusion, while CRP, procalcitonin, and NLR cannot be used for accurate diagnosis of infections immediately after liver transplantation, peak CRP beyond 48 hours and peak procalcitonin over first 60 hours may be used for initial exclusion of infections and prediction of severe complications, respectively.

Background: A complete pathologic response (CPR) after neoadjuvant treatment is reported to be associated with an exceptionally low risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic role of CPR in liver transplantation for HCC., Methods: This retrospective cohort study was based on 222 HCC transplant recipients. Incidence of recurrence and survival at 5 years were the primary and secondary outcome measures, respectively. Competing risk analyses were applied to evaluate recurrence incidence and its predictors. Propensity score matching was performed to compare the outcomes for patients after neoadjuvant treatment with and without CPR., Results: Neoadjuvant treatment was performed for 127 patients, 32 of whom achieved CPR (25.2%). Comparison of baseline characteristics showed that the patients with CPR were at lowest baseline recurrence risk, followed by treatment-naïve patients and patients without CPR. Adjusted for potential confounders, CPR did not have any significant effects on tumor recurrence. No significant net reclassification improvement was noted after addition of CPR to existing criteria. Neoadjuvant treatment without CPR was associated with increased risk of recurrence in subgroups within the Milan criteria (p = 0.016), with alpha-fetoprotein concentration (AFP) model not exceeding 2 points (p = 0.021) and within the Warsaw criteria (p = 0.007) compared with treatment-naïve patients who were at risk similar to those with CPR. The 5-year incidences of recurrence in propensity score-matched patients with and without CPR were respectively 14.0% and 15.9% (p = 0.661), with corresponding survival rates of 73.2% and 67.4%, respectively (p = 0.329)., Conclusions: The findings showed that CPR is not independently associated with long-term outcomes after liver transplantation for HCC.

Introduction: Everolimus after liver transplant (LT) has been used to minimize the use of calcineurin inhibitors (CNIs), optimize renal function, and prevent recurre nce of hepatocellular carcinoma (HCC)., Objectives: We aimed to analyze a single‑center experience with switching from CNIs to everolimus in immunossupressive treatment of LT recipients., Patients and Methods: A total of 108 LT recipients (men, 65.7%; mean [SD] age, 53.2 [11.1] years) were prospectively enrolled into the study. In all patients, everolimus and CNIs were introduced (target trough levels of 3 to 6 ng/ml and 3 to 5 ng/ml, respectively). After 3 months, CNIs were discontinued in patients who tolerated everolimus well, while everolimus dosage was increased (blood trough levels, 6-12 ng/ml)., Results: Everolimus monotherapy was introduced in 32 patients (29.6%), while a combination therapy with everolimus and CNIs was continued in 76 patients (70.4%). However, during a mean follow‑up of 27 months (range, 4-50 months), everolimus was withdrawn in 25 patients (33%) due to side effects. In the everolimus‑monotherapy group, all patients continued the therapy (P <0.005), but dyslipidemia was more frequent than in patients receiving everolimus and CNIs (40.6% vs 14.5%; P <0.03). Creatinine levels improved significantly in both groups: combination therapy, from 1.58 mg/dl to 1.24 mg/dl after 3 months, and everolimus monotherapy, from 1.19 mg/dl to more than 1 mg/dl. Renal function in the everolimus group was better than in the combination-therapy group (P <0.04). Recurrence of HCC was observed in both groups: combination therapy (9/46 [19.6%]) and everolimus monotherapy (1/17 [5.9%]; P <0.01)., Conclusions: This study showed that switching from CNIs to everolimus after LT allowed a safe weaning of CNIs and an improvement in creatinine levels. In patients on everolimus monotherapy, we observed dyslipidemia as a dose‑dependent side effect of the drug as well as a lower risk of HCC recurrence.

Background: We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study., Methods: Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score-matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004)., Results: In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T., Conclusions: PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.

BACKGROUND Orthotopic liver transplantation (OLT) is the standard of care for end-stage liver disease. The Charlson Comorbidity Index (CCI) was originally created to assess the survival rate of patients with chronic diseases, although it was modified and adopted in OLT recipients as CCI-OLT. MATERIAL AND METHODS In total of 248 consecutive liver transplant recipients with viral cirrhosis in 98 (39.5%) patients were included. CCI-OLT was calculated assigning a weight of 3 to chronic obstructive pulmonary disease; weight of 2 to coronary artery disease, connective tissue disease, and renal insufficiency; and a weight of 1 to diabetes mellitus. RESULTS CCI-OLT was significantly correlated with recipient age (p<0.001; R=0.333) and was a significant risk factor for early post-transplant mortality (p=0.004). The presence of diabetes mellitus significantly increased the odds of early mortality (p=0.010). The optimal cut-off for CCI-OLT in prediction of mortality during the first 90 days after transplantation was ≥1, with an AUROC of 0.780 (95% CI: 0.670-0.891; p<0.001). Increasing CCI-OLT was a significant risk factor for worse 5-year post-transplant survival (p=0.001), along with coronary artery disease (p=0.008) and diabetes mellitus (p=0.021). The optimal cut-off for prediction of 5-year mortality for CCI-OLT was ≥1, with the AUROC of 0.638 (95% CI: 0.544-0.733; p=0.004). CONCLUSIONS CCI-OLT is a useful tool for measuring the effect of pretransplant comorbidities and to stratify the effect of risk on both short- and long-term outcomes after OLT. Recipient age and diabetes strongly affected short-term survival after OLT, and metabolic and vascular complications were the leading causes of death at 5 years after OLT.

Surgical resection is the only potentially curative treatment for patients with cholangiocarcinoma. For both perihilar cholangiocarcinoma (pCCA) and intrahepatic cholangiocarcinoma (iCCA), 5-year overall survival of about 30% has been reported in large series. This review addresses several challenges in surgical management of cholangiocarcinoma. The first challenge is diagnosis: a biopsy is typically avoided because of the risk of seeding metastases and the low yield of a brush of the bile duct. However, about 15% of patients with suspected pCCA are found to have a benign diagnosis after resection. The second challenge is staging; even with the best preoperative imaging, a substantial percentage of patients has occult metastatic disease detected at staging laparoscopy or early recurrence after resection. The third challenge is an adequate volume and function of the future liver remnant, which may require preoperative biliary drainage and portal vein embolization. The fourth challenge is a complete resection: a positive bile duct margin is not uncommon because the microscopic biliary extent of disease may be more extensive than perceived on imaging. The fifth challenge is the high post-operative mortality that has decreased in very high volume Asian centres, but remains about 10% in many Western referral centres. The sixth challenge is that even after a complete resection most patients develop recurrent disease. Recent randomized controlled trials found conflicting results regarding the benefit of adjuvant chemotherapy. The final challenge is to determine which patients with cholangiocarcinoma should undergo liver transplantation rather than resection., (© 2019 The Authors. Liver International published by John Wiley & Sons Ltd.)

BACKGROUND The classical cardiovascular risk factors and changes in the circulatory system secondary to end-stage liver disease (ESLD) are associated with an increased risk of cardiac abnormalities (CAs) in patients waiting for liver transplantation (LTx). The aim of this study was to assess the relationship between the etiology of liver disease and the presence of CAs in patients qualified for LTx. MATERIAL AND METHODS The study enrolled patients qualified to LTx due to ESLD at the Clinical Hospital of the Medical University of Warsaw between 2013 and 2016. Out of 396 patients: 65, 157, 117, and 57 had ESLD due to the alcoholic liver disease (ALD), viral infections (VIR), autoimmune disorders (AUTO), and different etiologies (OTHER), respectively. RESULTS An increased frequency of hypertension and diabetes mellitus were observed in ALD and VIR groups, while for hyperlipidemia, the highest rates were observed in ALD and AUTO groups. Significant differences in CAs rates were observed for resting tachycardia, prolonged QT interval, bradycardia, and left ventricular diastolic dysfunction. After adjustment for age, MELD, and Child-Pugh scores, hyperlipidemia (26% vs. 7-15%, p<0.048) was most frequently observed in the AUTO group, while poor aerobic capacity (49% vs. 21-34%, p<0.009) dominated in the OTHER group. CONCLUSIONS The frequency of hyperlipidemia, and poor aerobic capacity were directly related to the etiology of liver disease, while the remaining associations resulted from effects of age, MELD, and Child-Pugh score.

Background: The importance of primary biliary cholangitis as an indication for liver transplantation has probably been influenced by the introduction of therapies, and changes in selection criteria and disease epidemiology., Aims: To assess the time trends in liver transplantation for primary biliary cholangitis and to evaluate the characteristics of the patient population during the past three decades., Methods: Patients undergoing liver transplantation from 1986 to 2015 in centres reporting to the European Liver Transplantation Registry were included. We excluded combined organ transplantations and patients <18 years. Trends were assessed using linear regression models., Results: We included 112 874 patients, of whom 6029 (5.3%) had primary biliary cholangitis. After an initial increase in the first decade, the annual number of liver transplantation for primary biliary cholangitis remained stable at around 200. The proportion of liver transplantations for primary biliary cholangitis decreased from 20% in 1986 to 4% in 2015 (P < 0.001). Primary biliary cholangitis was the only indication showing a consistent proportional decrease throughout all decades. From the first to the third decade, the age at liver transplantation increased from 54 (IQR 47-59) to 56 years (IQR 48-62) and the proportion of males increased from 11% to 15% (both P < 0.001)., Conclusions: We have found a proportional decrease in primary biliary cholangitis as indication for liver transplantation. However, despite treatment with ursodeoxycholic acid and improved disease awareness, the absolute annual number of liver transplantations has stabilised., (© 2018 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.)

BACKGROUND In living donor liver transplantation (LDLT), 2 patients undergo surgery, and the advantages and disadvantages for both patients should be considered. This study evaluated the long-term quality of life in living liver donors, and its impact on their activities of daily living focusing on mood and mental health. MATERIAL AND METHODS In total, 101 living liver donors (69 female and 32 male patients, median age of 36.8 years) were surveyed at a median time of 61.8 months after liver donation (range 7-169 months). The generic Short Form Health Survey (SF-36), the Patient Health Questionnaire 9 (PHQ-9), and the Questionnaire of Physical Activity (IPAQ) were used. The results of SF-36 were compared to a matched control group (n=72) using the Wilcoxon test; the SF-36, the PHQ-9, and the IPAQ scores were analyzed using Spearman's rank correlation. Linear regression model was used to check for dependencies between variables of interest. The IPAQ results were compared between the study group and the general Polish population. RESULTS There were no significant differences in the SF-36 domains between the study group and control group except body pain, which was higher in the living liver donor group (P<0.05). In 30.6% of patients, the PHQ-9 survey revealed mood disturbances. The PHQ-9 scores were higher in female-donors (P<0.05). Both summary scores of the SF-36 correlated to the PHQ-9 (P<0.001). In 89.1% of patients, physical activity was below the population norm and was lower in female donors than in male donors (P<0.01). CONCLUSIONS LDLT had no impact on donors' physical and mental health. Physical activity of living liver donors was lower than that of the general population. The SF-36 and the IPAQ measures seem to be reliable in the care of living liver donors. The PHQ-9 survey results and the inclination to depression of female living liver donors requires further study.

Background: Transjugular intrahepatic portosystemic shunt system (TIPS) is a well-recognized method of treatment of symptomatic portal hypertension in patients awaiting liver transplantation. The effectiveness of TIPS treatment in patients after liver transplantation is still not fully established. Indications for both groups of patients, with and without liver graft, are similar and include bleeding from gastrointestinal varices, ascites, pleural effusion, and Budd-Chiari syndrome. Feasibility of TIPS in emergency treatment in patients after OLTx due to life-threatening hemorrhage is not well described., Materials and Methods: Patients, after OLTx performed using classical, non-piggyback technique had severe hemorrhages from gastrointestinal varices due to lost graft function. Patients were in an unstable condition, required blood transfusions on admittance and monitoring in Intensive Care Unit. TIPS were implanted urgently, after unsuccessful endoscopic treatment, as a life-saving procedure., Results: In all cases, the procedure was successfully completed. The bleeding did not reoccur during the postoperative course., Conclusion: TIPS procedure appears to be justified as a bridge to a planned retransplantation, or as a treatment of choice in patients disqualified from retransplantation. Emergency performance of the TIPS procedure as a treatment for acute variceal bleeding should still be considered individually for each patient and only as a procedure leading to further treatment.

The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience., (© 2018 Steunstichting ESOT.)

Background & Aims: Direct-acting antivirals (DAAs) have dramatically improved the outcome of patients with hepatitis C virus (HCV) infection including those with decompensated cirrhosis (DC). We analyzed the evolution of indications and results of liver transplantation (LT) in the past 10 years in Europe, focusing on the changes induced by the advent of DAAs., Methods: This is a cohort study based on data from the European Liver Transplant Registry (ELTR). Data of adult LTs performed between January 2007 to June 2017 for HCV, hepatitis B virus (HBV), alcohol (EtOH) and non-alcoholic steatohepatitis (NASH) were analyzed. The period was divided into different eras: interferon (IFN/RBV; 2007-2010), protease inhibitor (PI; 2011-2013) and second generation DAA (DAA; 2014-June 2017)., Results: Out of a total number of 60,527 LTs, 36,382 were performed in patients with HCV, HBV, EtOH and NASH. The percentage of LTs due to HCV-related liver disease varied significantly over time (p <0.0001), decreasing from 22.8% in the IFN/RBV era to 17.4% in the DAA era, while those performed for NASH increased significantly (p <0.0001). In the DAA era, the percentage of LTs for HCV decreased significantly (p <0.0001) from 21.1% (first semester 2014) to 10.6% (first semester 2017). This decline was more evident in patients with DC (HCV-DC, -58.0%) than in those with hepatocellular carcinoma (HCC) associated with HCV (HCV-HCC, -41.2%). Conversely, three-year survival of LT recipients with HCV-related liver disease improved from 65.1% in the IFN/RBV era to 76.9% in the DAA era, and is now comparable to the survival of recipients with HBV infection (p = 0.3807)., Conclusions: In Europe, the number of LTs due to HCV infection is rapidly declining for both HCV-DC and HCV-HCC indications and post-LT survival has dramatically improved over the last three years. This is the first comprehensive study of the overall impact of DAA treatment for HCV on liver transplantation in Europe., Lay Summary: After the advent of direct-acting antivirals in 2014, a dramatic decline was observed in the number of liver transplants performed both in patients with decompensated cirrhosis due to hepatitis C virus (HCV), minus 60%, and in those with hepatocellular carcinoma associated with HCV, minus 41%. Furthermore, this is the first large-scale study demonstrating that the survival of liver transplant recipients with HCV-related liver disease has dramatically improved over the last three years and is now comparable to the survival of recipients with hepatitis B virus infection. The reduction in HCV-related indications for LT means that there is a greater availability of livers, at least 600 every year, which can be allocated to patients with indications other than HCV., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Background: Cardiovascular events (CVE) contribute to serious complications and death after liver transplantation (LT). Troponin I (TnI) level >0.07 mg/L and prior cardiac disease are known to be the independent predictors for posttransplant CVE. We evaluated single-center cardiac workup to predict early cardiovascular morbidity and mortality after LT., Patients and Methods: We recruited 105 consecutive liver transplant recipients (male/female, 59/46; mean age, 51.66 ± 11.67 years). The cardiological assessment at evaluation for LT included medical history, electrocardiogram, echocardiography, Holter monitoring, and exercise test. We collected data regarding CVE including hypotonia with catecholamine usage, arrhythmia, sudden cardiac death, pulmonary edema, and myocardial infarction within 7 days after LT., Results: CVE during LT occurred in 42 recipients (40%) and after LT in 9 patients (8.57%). Proposed cutoff level of TnI >0.07 mg/L did not correlate with CVE during operation (P = .73) or after LT (P = .47). CVE during LT was associated with arterial hypertension in medical history (P <.001), right ventricular systolic pressure (P< .05), and clinical scores: Child-Pugh (P = .04), Model for End-Stage Liver Disease (MELD) (P = .04), MELD incorporating serum sodium (P<.03), and integrated MELD score (P = .01). CVE after LT correlated only with arrhythmia (P<.001) and catecholamine usage (P < .05) perioperatively. Of interest, catecholamine usage during LT was associated with prolonged stay at the intensive care unit (P < .05)., Conclusion: The single-center algorithm with noninvasive cardiac procedures without TnI assessment is optimal in evaluation before LT; however, medical history and severity of the liver disease are crucial for short-term cardiovascular morbidity after LT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Despite worldwide debate on optimal selection of patients with hepatocellular carcinoma (HCC) for liver transplantation, the Milan criteria remain the benchmark for comparisons. Moreover, morphologic tumor features are universally considered important in pretransplant patient evaluation. The aim of this study was to establish the diagnostic accuracy of multiphasic computed tomography (CT) in assessing HCC burden before liver transplantation with special reference to Milan criteria fulfillment., Methods: This retrospective study was based on a data from 27 HCC patients after liver transplantation with available CT performed within 30 days pretransplant. CT results were compared with explant pathology with respect to Milan criteria fulfillment, tumor number, and diameter of the largest tumor., Results: Out of 19 patients within the Milan criteria on CT, 3 fell beyond the criteria on explant pathology with a gross underestimation rate of 15.8%. Out of 8 patients beyond the Milan criteria on CT, 3 were within the criteria on explant pathology with a gross overestimation rate of 37.5%. Regarding tumor number, CT was accurate only in 14 patients (51.9%), while overestimation and underestimation occurred in 5 (18.5%) and 8 (29.6%) patients, respectively. Overestimation and underestimation of largest tumor size by at least 1 cm occurred in 4 (14.8%) and 7 (25.9%) patients, respectively., Discussion: Multiphasic CT is associated with a remarkable risk of both under- and overestimation of HCC burden before transplantation. Transplant eligibility should not be solely based on CT results., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Hepatic artery thrombosis (HAT) is one of the most severe complications after liver transplantation (LT). HAT can lead to early graft loss and retransplantation or death of the recipient., Methods: This retrospective cohort study was conducted using data from patients treated between January 2008 and December 2013 in the Department of General, Transplant and Liver Surgery at the Medical University of Warsaw. A total of 750 patients underwent LT over this period., Results: HAT occurred in 27 patients (2.1%). The median DRI was 1.414 (IQR 1.103-1.578) points and median donor age was 47 (IQR 33-56) years. The optimal cut-off value of DRI in predicting HAT was ≥1.328 points. The cutoff point was characterized by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 88.0%, 41.3%, 5.5% and 98.9%, respectively (AUC = 0.605, 95% CI 0.477-0.733). A DRI ≥1.328 was a significant risk factor for HAT (OR = 5.16, 95% confidence interval [CI] 1.529-17.48, P = .008). The optimal cutoff point for donor age was 50 years and was characterized by sensitivity, specificity, PPV, and NPV of 66.7%, 55.8%, 5.3%, and 97.8%, respectively. Donor age ≥50 years (OR = 2.53, 95% CI 1.123-5.714, P = .025) was a significant risk factor for HAT., Conclusion: DRI is a clinically relevant factor that allows estimating the risk of HAT after liver transplantation from a deceased donor. To reduce the incidence of this complication, the allocation of organs taken from donors at DRI exceeding 1.328 for recipients without other HAT risk factors should be considered., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cardiovascular events (CVE) might occur in 20% to 70% of liver transplant recipients, and major CVE are associated with poor long-term survival. Overall, the ability to identify patients at the highest risk of death after liver transplantation (LT) has been improved. Abnormal pretransplant troponin I (TnI) level is regarded as one of predictors of postoperative CVE. We evaluated the number of early CVE after LT and the impact of pretransplant TnI on cardiovascular morbidity., Patients and Methods: We prospectively enrolled 110 consecutive liver transplant recipients (M/F 67/43, age 53.3 ± 10.4 years, 32.7% with hepatitis C virus). Seven of them (6.4%) were on urgent protocol and 3 patients (2.7%) had re-LT. TnI level was measured at listing for LT and directly after LT; clinical outcomes were observed within the first 7 days after LT., Results: CVE during LT occurred in 51 recipients (46.4%). CVE after LT at the intensive care unit were noticed in 13 patients (11.8%). One patient (0.9%) died in the first 7 days after LT. The level of TnI >0.07 did not correlate with CVE during operation and 7 days after LT (P > .05), but the subgroup with TnI >0.07 before LT had a trend with higher TnI after LT (P = .065). Recipients with hepatitis C virus had a trend for higher TnI after LT (P = .061). CVE directly after LT correlated significantly with Child-Pugh (P = .01), Model for End-Stage Liver Disease (MELD), MELD incorporating serum sodium, and integrated MELD scales (P < .001)., Conclusion: In our single-center algorithm, TnI with canonical cutoff value of 0.07 was not an effective predictor for cardiac outcomes shortly after LT in our population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Prolonged initial intensive care unit (ICU) stay after liver transplantation (LT) is associated with prolonged total hospitalization, increased hospital mortality, and impaired patient and graft survival. Recent data suggested that model for end-stage liver disease (MELD) score at the time of LT and the length of surgery were the two independent risk factors for an ICU stay longer than 3 days after LT. We further identified factors influencing prolonged ICU stay in single-center liver graft recipients., Patients and Methods: One hundred fifty consecutive LT recipients (M/F 94/56, median age 55 (range, 39-60), 36% with viral hepatitis, were prospectively enrolled into the study. Associations between clinical factors and prolonged ICU stay were evaluated using logistic regression models. Receiver operating characteristic curves were analyzed to determine the appropriate cutoffs for continuous variables. Threshold for significance was P ≤ .05., Results: Highly prolonged (≥8 days) and moderately prolonged (≥6 days) postoperative ICU stay was noted in 19 (12.7%) and 59 (39.3%) patients, respectively. Serum bilirubin (P = .001) and creatinine concentrations (P = .011), international normalized ratio (P = .004), and sodium-MELD (P < .001) were all significantly associated with postoperative intensive care unit stay over or equal to 75th percentile (6 days). Sodium-MELD was significantly associated with postoperative care unit stay greater or equal to the 90th percentile (8 days; P = .018)., Conclusions: Sodium-MELD might be a novel risk factor of prolonged ICU stay in this single-center experience., (Copyright © 2018 Elsevier Inc. All rights reserved.)