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Simple Summary This review proposes a comprehensive overview of the main prognostic systems for HCC classified as prognostic scores, staging systems, or combined systems. Prognostic systems for HCC are usually compared in terms of homogeneity, monotonicity of gradients, and discrimination ability. However, despite the great number of published studies comparing HCC prognostic systems, it is rather difficult to identify a system that could be universally accepted as the best prognostic scheme for all HCC patients encountered in clinical practice. In order to give a contribute in this topic, we conducted a study aimed at externally validate the MESH score and the CNLC classification using the ITA.LI.CA database. Abstract Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described.

Background Although isolated caudate lobe (CL) liver resection is not a contraindication for minimally invasive liver surgery (MILS), feasibility and safety of the procedure are still poorly investigated. To address this gap, we evaluate data on the Italian prospective maintained database on laparoscopic liver surgery (IgoMILS) and compare outcomes between MILS and open group. Methods Perioperative data of patients with malignancies, as colorectal liver metastases (CRLM), hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), non-colorectal liver metastases (NCRLM) and benign liver disease, were retrospectively analyzed. A propensity score matching (PSM) analysis was performed to balance the potential selection bias for MILS and open group. Results A total of 224 patients were included in the study, 47 and 177 patients underwent MILS and open isolated CL resection, respectively. The overall complication rate was comparable between the two groups; however, severe complication rate (Dindo–Clavien grade ≥ 3) was lower in the MILS group (0% versus 6.8%, P = ns). In-hospital mortality was 0% in both groups and mean hospital stay was significantly shorter in the MILS group (P = 0.01). After selection of 42 MILS and 43 open CL resections by PSM analysis, intraoperative and postoperative outcomes remained similar except for the hospital stay which was not significantly shorter in MILS group. Conclusions This multi-institutional cohort study shows that MILS CL resection is feasible and safe. The surgical procedure can be technically demanding compared to open resection, whereas good perioperative outcomes can be achieved in highly selected patients.

Laparoscopic liver resection (LLR) for Hepatocellular carcinoma (HCC) is a safe procedure. Repeat surgery is more often required, and the role of minimally invasive liver surgery (MILS) is not yet clearly defined. The present study analyzes data compiled by the Italian Group of Minimally Invasive Liver Surgery (IGoMILS) on LLR. To compare repeated LLR with the first LLR for HCC is the primary endpoint. The secondary endpoint was to evaluate the outcome of repeat LLR in the case of primary open versus primary MILS surgery. The data cohort is divided into two groups. Group 1: first liver resection and Group 2: Repeat LLR. To compare the two groups a 3:1 Propensity Score Matching is performed to analyze open versus MILS primary resection. Fifty-two centers were involved in the present study, and 1054 patients were enrolled. 80 patients underwent to a repeat LLR. The type of resection was different, with more major resections in the group 1 before matching the two groups. After propensity score matching 3:1, each group consisted of 222 and 74 patients. No difference between the two groups was observed. In the subgroup analysis, in 44 patients the first resection was performed by an open approach. The other 36 patients were resected with a MILS approach. We found no difference between these two subgroups of patients. The present study in repeat MILS for HCC using the IGoMILS Registry has observed the feasibility and safety of the MILS procedure.

BackgroundPatients colonized with carbapenem-resistant Enterobacteriaceae (CRE) are at higher risk of developing CRE infection after liver transplantation (LT), with associated high morbidity and mortality. Prediction model for CRE infection after LT among carriers could be useful to target preventive strategies.MethodsMultinational multicenter cohort study of consecutive adult patients underwent LT and colonized with CRE before or after LT, from January 2010 to December 2017. Risk factors for CRE infection were analyzed by univariate analysis and by Fine-Gray subdistribution hazard model, with death as competing event. A nomogram to predict 30- and 60-day CRE infection risk was created.ResultsA total of 840 LT recipients found to be colonized with CRE before (n = 203) or after (n = 637) LT were enrolled. CRE infection was diagnosed in 250 (29.7%) patients within 19 (interquartile range [IQR], 9–42) days after LT. Pre- and post-LT colonization, multisite post-LT colonization, prolonged mechanical ventilation, acute renal injury, and surgical reintervention were retained in the prediction model. Median 30- and 60-day predicted risk was 15% (IQR, 11–24) and 21% (IQR, 15–33), respectively. Discrimination and prediction accuracy for CRE infection was acceptable on derivation (area under the curve [AUC], 74.6; Brier index, 16.3) and bootstrapped validation dataset (AUC, 73.9; Brier index, 16.6). Decision-curve analysis suggested net benefit of model-directed intervention over default strategies (treat all, treat none) when CRE infection probability exceeded 10%. The risk prediction model is freely available as mobile application at https://idbologna.shinyapps.io/CREPostOLTPredictionModel/.ConclusionsOur clinical prediction tool could enable better targeting interventions for CRE infection after transplant.

Background: Increased expertise with minimally invasive liver surgery (MILS) could cause an unjustified extension of indications to resect liver benign disease (BD). The aim of this study was to evaluate the operative risk of MILS for BD and if implementation and diffusion of MILS have widened indications for BD resection. Methods: A prospective study including centers with > 6 MILS for BD, enrolled in the I Go MILS registry from January 2015 to October 2016. Cysts fenestrations were excluded. Results: Eight hundred eighteen MILS were performed in 15 centers. One hundred seventy-three of these (21.1%) were for BD: conversion rate was 6.9%, postoperative mortality and morbidity rates were 0 and 13.9%. During the same period, 3713 liver resections (open + MILS) were performed and 407 (11.0%) were for BD. A time-trend analysis showed that the total number of MILS and the number of MILS for malignant disease significantly increased, but this increasing trend was not documented for the number of MILS for BD, which remained stable during the study period of time. This trend was confirmed for the overall rate of resected BD (open + MILS) that remained stable. Discussion: BD represents a valid indication for MILS. For BD, 21.1% of MILS was performed, rate significantly lower than that previously reported in Italy. Although an evident growth of the use of MILS was observed during the time period analysis in Italy, this trend did not correspond to an increased number of MILS for BD, and the overall rate of resected BD was comparable to that reported in previous large open series.

Background Female sex has been reported as an independent predictor of severe post-liver transplantation (LT) chronic kidney disease. We performed a by sex post-hoc analysis of the SURF study, that investigated the prevalence of renal impairment following LT, aimed at exploring possible differences between sexes in the prevalence and course of post-LT renal damage. Methods All patients enrolled in the SURF study were considered evaluable for this sex-based analysis, whose primary objective was to evaluate by sex the proportion of patients with estimated Glomerular Filtration Rate (eGFR) 2 at inclusion and follow-up visit. Results Seven hundred thirty-eight patients were included in our analysis, 76% males. The proportion of patients with eGFR 2 was significantly higher in females at initial study visit (33.3 vs 22.8%; p = 0.005), but also before, at time of transplantation (22.9 vs 14.7%; p = 0.0159), as analyzed retrospectively. At follow-up, such proportion increased more in males than in females (33.9 vs 26.0%, p = 0.04). Mean eGFR values decreased over the study in both sexes, with no significant differences. Statistically significant M/F differences in patient distribution by O’Riordan eGFR levels were observed at time of transplant and study initial visit (p = 0.0005 and 0.0299 respectively), but not at follow-up. Conclusions Though the limitation of being performed post-hoc, this analysis suggests potential sex differences in the prevalence of renal impairment before and after LT, encouraging further clinical research to explore such differences more in depth.

Immunosuppression after liver transplantation (LT) is presently based on use of calcineurin inhibitors (CNI), although they are associated with an increased incidence of renal dysfunction, cardiovascular complications, and de novo and recurrent malignancies. Over the past decade, mammalian target of rapamycin inhibitors have received considerable attention as immunosuppressants because they are associated with a more favorable renal profile versus CNI, as well as antiproliferative activity in clinical studies. Comprehensive guidelines on use of everolimus (EVR) in LT are still lacking. In Italy, a project, named Everolimus: the road to long-term functioning, was initiated to collect the experience on EVR after LT with the aim of providing guidance for transplant clinicians. Herein, recommendations by this national consensus group, based on Delphi methodology, are presented. Consensus was reached on 20 of the 23 statements proposed, and their level of evidence, grade of recommendation, and percent of agreement are reported. Statements are grouped into 4 areas: (A) renal function; (B) time of EVR introduction, CNI reduction and elimination, and risk for graft rejection; (C) antiproliferative effects of EVR; and (D) management of EVR-related adverse events. The high level of consensus shows that there is good agreement on the routine use of EVR in predefined clinical scenarios, especially in light of posttransplant nephrotoxicity and other adverse events associated with long-term administration of CNIs.

Infections are a major complication of solid organ transplants (SOTs). This study aimed to describe recipients’ characteristics, and the frequency and etiology of infections and transplant outcome in liver and lung SOTs, and to investigate exposures associated to infection and death in liver transplant recipients. The study population included recipients of SOTs performed in Italy during a 1-year period in ten Italian lung transplant units and eight liver transplant units. Data on comorbidities, infections, retransplantation, and death were prospectively collected using a web-based system, with a 6-month follow-up. The cumulative incidence of infection was 31.7% and 47.8% in liver and lung transplants, respectively, with most infections occurring within the first month after transplantation. Gram-negatives, which were primarily multidrug-resistant, were the most frequent cause of infection. Death rates were 0.42 per 1000 recipient-days in liver transplants and 1.41 per 1000 recipient-days in lung transplants. Infection after SOT in adult liver recipients is associated to an increased risk of death (OR = 13.25; p-value < 0.001). Given the frequency of infection caused by multidrug-resistant microorganisms in SOT recipients in Italy and the heavy impact of infections on the transplant outcome, the reinforcement of surveillance and control activities to prevent the transmission of multidrug-resistant microorganisms in SOT recipients represents a priority. The implementation of the study protocol in liver and lung transplant units and the sharing of results have increased the awareness about the threat due to antimicrobial resistance in the country.

Since Italian liver allocation policy was last revised (in 2012), relevant critical issues and conceptual advances have emerged, calling for significant improvements. We report the results of a national consensus conference process, promoted by the Italian College of Liver Transplant Surgeons (for the Italian Society for Organ Transplantation) and the Italian Association for the Study of the Liver, to review the best indicators for orienting organ allocation policies based on principles of urgency, utility, and transplant benefit in the light of current scientific evidence. MELD exceptions and hepatocellular carcinoma were analyzed to construct a transplantation priority algorithm, given the inequity of a purely MELD-based system for governing organ allocation. Working groups of transplant surgeons and hepatologists prepared a list of statements for each topic, scoring their quality of evidence and strength of recommendation using the Centers for Disease Control grading system. A jury of Italian transplant surgeons, hepatologists, intensivists, infectious disease specialists, epidemiologists, representatives of patients' associations and organ-sharing organizations, transplant coordinators, and ethicists voted on and validated the proposed statements. After carefully reviewing the statements, a critical proposal for revising Italy's current liver allocation policy was prepared jointly by transplant surgeons and hepatologists.

Prognostic assessment of patients with hepatocellular carcinoma (HCC) at the time of diagnosis remains controversial and becomes even more complex at the time of restaging when new variables need to be considered. The aim of the current study was to evaluate the prognostic utility of restaging patients before proceeding with additional therapies for HCC. Two independent Italian prospective databases were used to identify 1,196 (training cohort) and 648 (validation cohort) consecutive patients with HCC treated over the same study period (2008-2015) who had complete restaging before decisions about additional therapies. The performance of the Italian Liver Cancer (ITA.LI.CA) prognostic score at restaging was compared with that of the Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer, and Cancer of the Liver Italian Program systems. A multivariable Cox survival analysis was performed to identify baseline, restaging, or dynamic variables that were able to improve the predictive performance of the prognostic systems. At restaging, 35.3% of patients maintained stable disease; most patients were either down-staged by treatment (27.2%) or had disease progression (37.5%). The ITA.LI.CA scoring system at restaging demonstrated the best prognostic performance in both the training and validation cohorts (c-index 0.707 and 0.722, respectively) among all systems examined. On multivariable analysis, several variables improved the prognostic ability of the ITA.LI.CA score at restaging, including progressive disease after the first treatment, Model for End-Stage Liver Disease at restaging, and choice of nonsurgical treatment as additional therapy. A new ITA.LI.CA restaging model was created that demonstrated high discriminative power in both the training and validation cohorts (c-index 0.753 and 0.745, respectively). Conclusion: Although the ITA.LI.CA score demonstrated the best prognostic performance at restaging, other variables should be considered to improve the prognostic assessment of patients at the time of deciding additional therapies for HCC.

Background & Aims The role of hepatic resection for hepatocellular carcinoma (HCC) in different Barcelona Clinic Liver Cancer (BCLC) stages is controversial. We aimed at measuring the survival benefit of resection vs. non-surgical-therapies in each BCLC stage. Methods Using the ITA.LI.CA database, we identified 2090 BCLC A, B, and C HCC patients observed between 2000 and 2012: 550 underwent resection, 1046 loco-regional therapy (LRT), and 494 best supportive care (BSC). A multivariate log-logistic model was chosen to predict median survival (MS) after resection vs. MS after LRT or BSC. The results were expressed as net survival benefit of resection: (MS resection - MS LRT)/MS BSC. Results After stratifying for BCLC stage, the median net survival benefit of resection over LRT was: BCLC 0 = 62% (40%, 82%), A = 45% (13%, 65%), B = 46% (9%, 76%), C = -16% (-55%, 33%). Model for end-stage liver disease (MELD) score >9, Child B class, and performance status (PST) = 2 were the main risk factors for liver resection. 1181 Child A patients (57%) with MELD ≤9 and PST 9 or PST = 2 or Child B class), resection did not prove any survival benefit over LRT. Conclusions Resection could result in survival benefit over LRT for HCC patients regardless of their BCLC stage, provided that liver dysfunction (Child B or MELD >9) and PST >1 are absent.

Background & Aims Significant proportion of Hepatocellular Carcinoma (HCC) cases are diagnosed in stage B of Barcelona Clinic Liver Cancer (BCLC) algorithm, in which the standard of care is Transcatheter Arterial ChemoEmbolization (TACE). We aimed to ascertain adherence to current guidelines, survival and prognostic factors in BCLC stage B patients. Methods From 3027 HCC cases recruited from 1986 to 2008 by the Italian Liver Cancer group (2430 with data allowing a correct allocation in the BCLC system), a retrospective analysis was conducted on those diagnosed in BCLC stage B (405 patients, 17%). Statistics were performed with Kaplan–Meier (log rank) method and Cox multivariate analysis. Results Median overall survival in BCLC stage B patients was 25 months (Confidence Interval - C.I. - 22–28 months) with a 5-year survival of 18%. Child–Pugh class, oesophageal varices and Alpha-foetoprotein (AFP) were the independent predictors of survival. TACE was applied in 40% of cases and did not offer the longest survival in comparison with surgical or percutaneous treatments (median 27 months vs. 37 and 36 months, respectively) (P

Donor-recipient match is a matter of debate in liver transplantation. D-MELD (donor age × recipient biochemical model for end-stage liver disease [MELD]) and other factors were analyzed on a national Italian database recording 5946 liver transplants. Primary endpoint was to determine factors predictive of 3-year patient survival. D-MELD cutoff predictive of 5-year patient survival 1628). At 3 years, the odds ratio (OR) for death was 2.03 (95% confidence interval [CI], 1.44-2.85) in D-MELD class C versus B. The OR was 0.40 (95% CI, 0.24-0.66) in class A versus class B. Other predictors were hepatitis C virus (HCV; OR = 1.42; 95% CI, 1.11-1.81), hepatitis B virus (HBV; OR = 0.69; 95% CI, 0.51-0.93), retransplant (OR = 1.82; 95% CI, 1.16-2.87) and low-volume center (OR = 1.48; 95% CI, 1.11-1.99). Cox regressions up to 90 months confirmed results. The hazard ratio was 1.97 (95% CI, 1.59-2.43) for D-MELD class C versus class B and 0.42 (95% CI, 0.29-0.60) for D-MELD class A versus class B. Recipient age, HCV, HBV and retransplant were also significant. The 5yrsPS

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

Background & Aims:The current organ allocation system for liver transplantation (LT) creates an imbalance between patients with and without hepatocellular carcinoma (HCC). We describe a model designed to re-establish allocation equity among patient groups using transplant benefit as the common endpoint. Methods:We enrolled consecutive adult patients entering the waiting list (WL group, n = 2697) and undergoing LT (LT group, n = 1702) during the period 2004‐2009 in the North Italy Transplant program area. Independent multivariable regressions (WL and LT models) were created for patients without HCC and for those with stage T2 HCC. Monte Carlo simulation was used to create distributions of transplant benefit, and covariates such as Model for End-stage Liver Disease (MELD) and alpha-fetoprotein (AFP) were combined in regression equations. These equations were then calibrated to create an ‘‘MELD equivalent’’ which matches HCC patients to non-HCC patients having the same numerical MELD score. Results:Median 5 year transplant benefit was 15.12 months (8.75‐25.35) for the non-HCC patients, and 28.18 months (15.11‐36.38) for the T2-HCC patients (p

Background: Patients undergoing liver transplantation for hepatocellular carcinoma within the Milan criteria (single tumour ≤5 cm in size or ≤3 tumours each ≤3 cm in size, and no macrovascular invasion) have an excellent outcome. However, survival for patients with cancers that exceed these criteria remains unpredictable and access to transplantation is a balance of maximising patients' chances of cure and organ availability. The aim of this study was to explore the survival of patients with tumours that exceed the Milan criteria, to assess whether the criteria could be less restrictive, enabling more patients to qualify as transplant candidates, and to derive a prognostic model based on objective tumour characteristics, to see whether the Milan criteria could be expanded. Methods: Data on patients who underwent transplantation for hepatocellular carcinoma despite exceeding Milan criteria at different centres were recorded via a web-based survey completed by specialists from each centre. The survival of these patients was correlated retrospectively with the size of the largest tumour nodule, number of nodules, and presence or absence of microvascular invasion detected at pathology. Contoured multivariable regression Cox models produced survival estimates by means of different combinations of the covariates. The primary aim of this study was to derive a prognostic model of overall survival based on tumour characteristics, according to the main parameters used in the Tumour Node Metastasis classification. The secondary aim was the identification of a subgroup of patients with hepatocellular carcinoma exceeding the Milan criteria, who achieved a 5-year overall survival of at least 70%-ie, similar to the outcome expected for patients who meet the Milan criteria. Findings: Over a 10-month period, between June 25, 2006, and April 3, 2007, data for 1556 patients who underwent transplantation for hepatocellular carcinoma were entered on the database by 36 centres. 1112 patients had hepatocellular carcinoma exceeding Milan criteria and 444 patients had hepatocellular carcinoma shown not to exceed Milan criteria at post-transplant pathology review. In the group of patients with hepatocellular carcinomas exceeding the criteria, the median size of the largest nodule was 40 mm (range 4-200) and the median number of nodules was four (1-20). 454 of 1112 patients (41%) had microvascular invasion and, for those transplanted outside the Milan criteria, 5-year overall survival was 53·6% (95% CI 50·1-57·0), compared with 73·3% (68·2-77·7) for those that met the criteria. Hazard ratios (HR) associated with increasing values of size and number were 1·34 (1·25-1·44) and 1·51 (1·21-1·88), respectively. The effect was linear for size, whereas for number of tumours, the effect tended to plateau above three tumours. The effect of tumour size and number on survival was mediated by recurrence (b=0·08, SE=0·12, p=0·476). The presence of microvascular invasion doubled HRs in all scenarios. The 283 patients without microvascular invasion, but who fell within the Up-to-seven criteria (hepatocellular carcinomas with seven as the sum of the size of the largest tumour [in cm] and the number of tumours) achieved a 5-year overall survival of 71·2% (64·3-77·0). Interpretation: More patients with hepatocellular carcinoma could be candidates for transplantation if the current dual (yes/no) approach to candidacy, based on the strict Milan criteria, were replaced with a more precise estimation of survival contouring individual tumour characteristics and use of the up-to-seven criteria. Funding: Specific funding was not used to do this study. © 2009 Elsevier Ltd. All rights reserved

Summary Background Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. Methods A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, α-fetoprotein concentrations, and treatment. Liver-transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patient's 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. Findings 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B–C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1·530 (95% CI 1·107–2·116) for BCLC A versus BCLC 0, 1·572 (1·350–1·830) for BCLC B–C versus BCLC A, and 1·470 (1·164–1·856) for BCLC D versus BCLC B–C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5-year transplant benefit of 11·19 months (IQR 10·73–11·67) for BCLC 0, 13·49 months (11·51–15·57) for BCLC A, 17·36 months (15·06–19·28) for BCLC B–C, and 28·46 months (26·38–30·34) for BCLC D. Interpretation Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B–C), regardless of the nodule number–size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. Funding None.

OBJECTIVE: To analyze in a multicenter study the potential benefit of a new prospective policy development to increase split-liver procedures for 2 adult recipients. BACKGROUND: Split-liver transplantation is an important means of overcoming organ shortages. Division of the donor liver for 1 adult and 1 pediatric recipient has reduced the mortality of children waiting for liver transplantation but the benefits or disadvantages to survival when the liver is divided for 2 adults (adult-to-adult split-liver transplant, AASLT) compared with recipients of a whole graft have not been fully investigated. METHODS: We developed a computerized algorithm in selected donors for 2 adult recipients and applied it prospectively over a 12-year period among 7 collaborative centers. Patient and graft outcomes of this cohort receiving AASLT either as full right grafts or full left grafts were analyzed and retrospectively compared with a matched cohort of adults who received a conventional whole-liver transplant (WLT). Univariate and multivariate analysis was done for selected clinical variables in the AASLT group to assess the impact on the patient outcome. RESULTS: Sixty-four patients who received the AASLT had a high postoperative complication rate (64.1% grade III and IV) and a lower 5-year survival rate than recipients of a WLT (63.3% and 83.1%) CONCLUSIONS: AASLT should be considered a surgical option for selected smaller-sized adults only in experimental clinical studies in experienced centers. Copyright © 2013 by Lippincott Williams & Wilkins.

Patients with hepatocellular carcinoma should be managed with a multidisciplinary approach framed in a network where all the diagnostic techniques and therapeutic resources are available in order to provide the optimal level of care.Given this assumption, the Coordinating Committee of the Italian Association for the Study of the Liver nominated a panel of experts to elaborate practical recommendations for the multidisciplinary management of hepatocellular carcinoma aiming to provide: (1) homogeneous and efficacious diagnostic and staging work-up, and (2) the best treatment choice tailored to patient status and tumour stage at diagnosis.The 2010 updated American Association for the Study of Liver Disease Guidelines for hepatocellular carcinoma were selected as the reference document. For each management issue, the American Association for the Study of Liver Disease recommendations were briefly summarised and discussed, according to both the scientific evidence published after their release and the clinical expertise of the Italian centres taking care of these patients. The Italian Association for the Study of the Liver expert panel recommendations are finally reported.

e15088 Background: Previously published results of the phase I/II SHELTER study demonstrated efficacy and safety of the novel pan-HDAC inhibitor resminostat in second-line treatment of HCC patients (pts) who had progressed under first-line sorafenib. As patient baseline characteristics might influence treatment outcome, an analysis of their potential influence on overall survival (OS) was performed. Methods: 45 pts with advanced-stage HCC and centrally confirmed radiologic progression under first-line sorafenib were included in a multi-center, two-arm trial. Resminostat was administered either alone or in combination with sorafenib. A Cox proportional-hazards model was used to evaluate the interaction between baseline characteristics and the effect of the two treatment groups on overall survival. Results: In the combination group, pts with Child-Pugh-A, ECOG 0 or absence of vascular invasion had a statistically significant lower risk of death compared to pts with Child-Pugh-B (HR 0.19, 95% CI 0.06-0.55), ECOG 1 (HR 0.15, 95% CI 0.05-0.44), or vascular invasion (HR 0.37, 95% CI 0.15-0.93), respectively. For pts with BCLC-B there was a strong trend, although not statistically significant, of a lower risk of death when compared to pts with BCLC-C (HR 0.43, 95% CI 0.13-1.49). Etiology, prior TACE therapy, extrahepatic spread and interval between first- and second-line treatment had no impact on overall survival in this study. Similar findings were observed in the monotherapy group. Comparing the impact of these baseline characteristics in the combination and monotherapy group, no statistically significant different influence on OS between both treatment groups was observed. Conclusions: Resminostat in combination with sorafenib provides a substantial OS benefit (median OS of 8.1 months) for advanced HCC patients who had developed progressive tumor disease under first-line sorafenib therapy. Subgroup analysis of patient baseline characteristics revealed a significant influence of Child-Pugh index, ECOG classification, and vascular invasion on overall survival, whereas e.g. the interval between first- and second-line treatment had no impact on overall survival. Clinical trial information: NCT00943449.

Objective: To evaluate improvements in operative and long-term results following surgery for hilar cholangiocarcinoma. Design: Retrospective multicenter study including 17 Italian hepatobiliary surgery units. Patients: A total of 440 patients who underwent resection for hilar cholangiocarcinoma from January 1, 1992, through December 31, 2007. Main Outcome Measures: Postoperative mortality, morbidity, overall survival, and disease-free survival. Results: Postoperative mortality and morbidity after liver resection were 10.1% and 47.6%, respectively. At multivariate logistic regression, extent of resection (rightor right extended hepatectomy) and intraoperative blood transfusion were independent predictors of postoperative mortality (P =. 03 and P =. 006, respectively); in patients with jaundice, mortality was also higher without preoperative biliary drainage than with biliary drainage (14.3% vs 10.7%). During the study period, there was an increasingly aggressive approach, with more frequent caudate lobectomies, vascular resections, and resections for advanced tumors (T stage of 3 or greater and tumors with poor differentiation). Despite the aggressive approach, the blood transfusion rate decreased from 81.0% to 53.2%, and mortality slightly decreased from 13.6% to 10.8%. Median overall survival significantly increased from 16 to 30 months (P =. 05). At multivariate analysis, R1 resection, lymph node metastases, and T stage of 3 or greater independently predicted overall and disease-free survival. Conclusions: Surgery for hilar cholangiocarcinoma has improved with decreased operative risk despite a more aggressive surgical policy. Long-term survival after liver resection has also increased, despite the inclusion of cases with more advanced hilar cholangiocarcinoma. Preoperative biliary drainage was a safe strategy before right or right extended hepatectomy in patients with jaundice. Pathologic factors independently predicted overall and disease-free survival at multivariate analysis. Arch Surg. 2012; 147(1): 26-34

Erratum to ‘‘A method for establishing allocation equity among patients with and without hepatocellular carcinoma on a common liver transplant waiting list’’ [J Hepatol 2013;60:290–297] Alessandro Vitale, Michael L. Volk, Tullia Maria De Feo, Patrizia Burra1,⇑, Anna Chiara Frigo, Rafael Ramirez Morales, Luciano De Carlis, Luca Belli, Michele Colledan, Stefano Fagiuoli, Giorgio Rossi, Enzo Andorno, Umberto Baccarani, Enrico Regalia, Marco Vivarelli, Matteo Donataccio, Umberto Cillo, on behalf of the Liver Transplantation North Italy Transplant program (NITp) working group

Background and Aims: A reduced EEG mean dominant frequency (MDF

The use of machine perfusion (MP) in liver transplantation (LT) is spreading worldwide. However, its efficacy has not been demonstrated, and its proper clinical use has far to go to be widely implemented. The Società Italiana Trapianti d’Organo (SITO) promoted the development of an evidence-based position paper. A 3-step approach has been adopted to develop this position paper. First, SITO appointed a chair and a cochair who then assembled a working group with specific experience of MP in LT. The Guideline Development Group framed the clinical questions into a patient, intervention, control, and outcome (PICO) format, extracted and analyzed the available literature, ranked the quality of the evidence, and prepared and graded the recommendations. Recommendations were then discussed by all the members of the SITO and were voted on via the Delphi method by an institutional review board. Finally, they were evaluated and scored by a panel of external reviewers. All available literature was analyzed, and its quality was ranked. A total of 18 recommendations regarding the use and the efficacy of ex situ hypothermic and normothermic machine perfusion and sequential normothermic regional perfusion and ex situ MP were prepared and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. A critical and scientific approach is required for the safe implementation of this new technology.

The safety of minimally invasive procedures during COVID pandemic remains hotly debated, especially in a country, like Italy, where minimally invasive techniques have progressively and pervasively entered clinical practice, in both the hepatobiliary and pancreatic community. A nationwide snapshot of the management of HPB minimally invasive surgery activity during COVID-19 pandemic is provided: a survey was developed and conducted within AICEP (Italian Association of HepatoBilioPancreatic Surgeons) with the final aim of conveying the experience, knowledge, and opinions into a unitary report enabling more efficient crisis management. Results from the survey (81 respondents) show that, in Italian hospitals, minimally invasive surgery maintains its role despite the COVID-19 pandemic, with the registered reduction of cases being proportional to the overall reduction of the HPB surgical activity. Respondents agree that the switch from minimally invasive to open technique can be considered as a valid option for cases with a high technical complexity. Several issues merit specific attention: screening for virus positivity should be universally performed; only expert surgical teams should operate on positive patients and specific technical measures to lower the biological risk of contamination during surgery must be followed. Future studies specifically designed to establish the true risks in minimally invasive surgery are suggested. Furthermore, a standard and univocal process of prioritization of patients from Regional Healthcare Systems is advisable. Electronic supplementary material The online version of this article (10.1007/s13304-020-00815-5) contains supplementary material, which is available to authorized users.

Introduction: The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). Methods: An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. Results: The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p < 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAP-III maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10–1.55, p < 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. Conclusion: An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction.

Background Preoperative biliary drainage may be essential to reduce the risk of postoperative liver failure after hepatectomy for perihilar cholangiocarcinoma. However, infectious complications related to preoperative biliary drainage may increase the risk of postoperative mortality. The strategy and optimal drainage method continues to be controversial. Methods This is a retrospective multicenter study including patients who underwent hepatectomy for perihilar cholangiocarcinoma between 2000 and 2016 at 14 Italian referral hepatobiliary centers. The primary end point was to evaluate independent predictors for postoperative outcome in patients undergoing liver resection for perihilar cholangiocarcinoma after preoperative biliary drainage. Results Of the 639 enrolled patients, 441 (69.0%) underwent preoperative biliary drainage. Postoperative mortality was 8.9% (12.5% after right-side hepatectomy versus 5.7% after left-side hepatectomy; P = .003). Of the patients, 40.5% underwent preoperative biliary drainage at the first admitting hospital, before evaluation at referral centers. Use of percutaneous preoperative biliary drainage was significantly more frequent at referral centers than at community hospitals where endoscopic preoperative biliary drainage was the most frequent type. The overall failure rate after preoperative biliary drainage was 43.3%, significantly higher at community hospitals than that at referral centers (52.7% v 36.9%; P = .002). Failure of the first preoperative biliary drainage was one of the strongest predictors for postoperative complications after right-side and left-side hepatectomies and for mortality after right-side hepatectomy. Type of preoperative biliary drainage (percutaneous versus endoscopic) was not associated with significantly different risk of mortality. Conclusion Failure of preoperative biliary drainage was significantly more frequent at community hospitals and it was an independent predictor for postoperative outcome. Centers’ experience in preoperative biliary drainage management is crucial to reduce the risk of failure that is closely associated with postoperative morbidity and mortality.

At the time of diagnosis synchronous colorectal cancer, liver metastases (SCRLM) account for 15–25% of patients. If primary tumour and synchronous liver metastases are resectable, good results may be achieved performing surgical treatment incorporated into the chemotherapy regimen. So far, the possibility of simultaneous minimally invasive (MI) surgery for SCRLM has not been extensively investigated. The Italian surgical community has captured the need and undertaken the effort to establish a National Consensus on this topic. Four main areas of interest have been analysed: patients’ selection, procedures, techniques, and implementations. To establish consensus, an adapted Delphi method was used through as many reiterative rounds were needed. Systematic literature reviews were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses instructions. The Consensus took place between February 2019 and July 2020. Twenty-six Italian centres participated. Eighteen clinically relevant items were identified. After a total of three Delphi rounds, 30-tree recommendations reached expert consensus establishing the herein presented guidelines. The Italian Consensus on MI surgery for SCRLM indicates possible pathways to optimise the treatment for these patients as consensus papers express a trend that is likely to become shortly a standard procedure for clinical pictures still on debate. As matter of fact, no RCT or relevant case series on simultaneous treatment of SCRLM are available in the literature to suggest guidelines. It remains to be investigated whether the MI technique for the simultaneous treatment of SCRLM maintain the already documented benefit of the two separate surgeries.

When the standard arterial reconstruction is not feasible during liver transplantation (LT), aorto-hepatic arterial reconstruction (AHAR) can be the only solution to save the graft. AHAR can be performed on the infrarenal (IR) or supraceliac (SC) tract of the aorta, but the possible effect on outcome of selecting SC versus IR reconstruction is still unclear. One hundred and twenty consecutive patients who underwent liver transplantation with AHAR in six European centres between January 2003 and December 2018 were retrospectively analysed to ascertain whether the incidence of hepatic artery thrombosis (HAT) was influenced by the type of AHAR (IR-AHAR vs. SC-AHAR). In 56/120 (46.6%) cases, an IR anastomosis was performed, always using an interposition arterial conduit. In the other 64/120 (53.4%) cases, an SC anastomosis was performed; an arterial conduit was used in 45/64 (70.3%) cases. Incidence of early (

Surgical outcomes may be associated with hospital volume and the influence of volume on minimally invasive liver surgery (MILS) is not known.Patients entered into the prospective registry of the Italian Group of MILS from 2014 to 2018 were considered. Only centres with an accrual period of at least 12 months and stable MILS activity during the enrolment period were included. Case volume was defined by the mean number of minimally invasive liver resections performed per month (MILS/month).A total of 2225 MILS operations were undertaken by 46 centres; nine centres performed more than two MILS/month (1376 patients) and 37 centres carried out two or fewer MILS/month (849 patients). The proportion of resections of anterolateral segments decreased with case volume, whereas that of major hepatectomies increased. Left lateral sectionectomies and resections of anterolateral segments had similar outcome in the two groups. Resections of posterosuperior segments and major hepatectomies had higher overall and severe morbidity rates in centres performing two or fewer MILS/month than in those undertaking a larger number (posterosuperior segments resections: overall morbidity 30·4 versus 18·7 per cent respectively, and severe morbidity 9·9 versus 4·0 per cent; left hepatectomy: 46 versus 22 per cent, and 19 versus 5 per cent; right hepatectomy: 42 versus 34 per cent, and 25 versus 15 per cent).A volume-outcome association existed for minimally invasive hepatectomy. Complex and major resections may be best managed in high-volume centres.Los resultados quirúrgicos pueden estar relacionados con el volumen de casos del hospital, pero no se conoce la influencia en la cirugía mínimamente invasiva del hígado (minimally‐invasive liver surgery, MILS). MÉTODOS: Se incluyeron los pacientes registrados en el registro prospectivo del grupo italiano de MILS desde 2014 a 2018. Solo se consideraron centros con extensión de ≥ 12 meses y actividad estable de MILS durante el periodo de reclutamiento. El volumen de casos se definió como el número de MILS efectuado por mes.Se llevaron a cabo un total de 2.225 MILS en 46 centros, 9 de ellos con 2 MILS/mes (n = 1.376 pacientes) y 37 centros con ≤ 2 MILS/mes (n = 849). La proporción de resecciones de segmentos anterolaterales disminuyó con el volumen de casos, mientras que la proporción de hepatectomías mayores aumentó. Los resultados para ambos grupos fueron similares en las seccionectomías lateral izquierda y en las resecciones del segmento anterolateral. Las resecciones del segmento posterosuperior y las hepatectomías mayores presentaron tasas más altas de morbilidad global y morbilidad grave en centros que realizaban ≤ 2 MILS/mes que en los que realizaban 2 MILS/mes (resecciones del segmento posterosuperior, morbilidad global 30,4 versus 18,7%, morbilidad grave 9,9 versus 4,0%; hepatectomía izquierda, 46,2 versus 22,0%, 19,2 versus 5,5%; hepatectomía derecha, 41,7 versus 33,8%, 25,0 versus 14.9%). CONCLUSIÓN: Se observó una asociación volumen‐resultado para la resección hepática mínimamente invasiva. Las resecciones complejas y mayores se pueden manejar mejor en centros de gran volumen.

Introduction: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been described to treat hepatocellular carcinoma (HCC) but burdened, in its pioneering phase, by high morbidity and mortality. With the advent of minimally invasive (MI) techniques in liver surgery, surgical complications, including posthepatectomy liver failure (PHLF), have been dramatically reduced. The primary endpoint of this study was to compare the short-term outcomes of MI-versus open-ALPPS for HCC, with specific focus on PHLF. Methods: Data of patients submitted to ALPPS for HCC between 2012 and 2020 were identified from the ALPPS Italian Registry. Patients receiving an MI Stage 1 (MI-ALPPS) constituted the study group, whereas the patients who received an open Stage 1 (open-ALPPS) constituted the control group. Results: Sixty-six patients were enrolled from 12 Italian centers. Stage 1 of ALPPS was performed in 14 patients using an MI approach (21.2%). MI-ALPPS patients were discharged after Stage 1 at a significantly higher rate compared with open-ALPPS (78.6% versus 9.6%, P < .001). After Stage 2, major morbidity after MI-ALPPS was 8.3% compared with 28.6% reported after open-ALPPS. Mortality was nil after MI-ALPPS. Length of hospital stay was significantly shorter in MI-ALPPS (12 days versus 22 days, P < .001). Univariate logistic regression analysis (Firth method) found that both MI-ALPPS (odds ratio [OR] = 0.05, P = .040) and partial parenchymal transection (OR = 0.04, P = .027) were protective against PHLF. Conclusion: This national multicenter study showed that a less invasive approach to ALPPS first stage was associated with a lower overall risk of PHLF.

This study aimed to assess the best achievable outcomes in laparoscopic liver resection (LLR) after risk adjustment based on surgical technical difficulty using a national registry.LLRs registered in the Italian Group of Minimally Invasive Liver Surgery registry from November 2014 to March 2018 were considered. Benchmarks were calculated according to the Achievable Benchmark of Care (ABC™). LLRs at each centre were divided into three clusters (groups I, II and III) based on the Kawaguchi classification. ABCs for overall and major morbidity were calculated in each cluster. Multivariable analysis was used to identify independent risk factors for overall and major morbidity. Significant variables were used in further risk adjustment.A total of 1752 of 2263 patients fulfilled the inclusion criteria: 1096 (62·6 per cent) in group I, 435 (24·8 per cent) in group II and 221 (12·6 per cent) in group III. The ABCs for overall morbidity (7·8, 14·2 and 26·4 per cent for grades I, II and II respectively) and major morbidity (1·4, 2·2 and 5·7 per cent) increased with the difficulty of LLR. Multivariable analysis showed an increased risk of overall morbidity associated with multiple LLRs (odds ratio (OR) 1·35), simultaneous intestinal resection (OR 3·76) and cirrhosis (OR 1·83), and an increased risk of major morbidity with intestinal resection (OR 4·61). ABCs for overall and major morbidity were 14·4 and 3·2 per cent respectively for multiple LLRs, 30 and 11·1 per cent for intestinal resection, and 14·9 and 4·8 per cent for cirrhosis.Overall morbidity benchmarks for LLR ranged from 7·8 to 26·4 per cent, and those for major morbidity from 1·4 to 5·7 per cent, depending on complexity. Benchmark values should be adjusted according to multiple LLRs or simultaneous intestinal resection and cirrhosis.Este estudio tuvo como objetivo evaluar los mejores resultados que se pueden conseguir en la resección hepática laparoscópica (laparoscopic liver resection, LLR) después del ajuste por riesgos basado en la dificultad de la técnica quirúrgica utilizando un registro nacional. MÉTODOS: Se consideraron las LLRs incluidas en el Registro del Grupo Italiano de Cirugía Hepática Mínimamente Invasiva desde 11/2014 a 03/2018. Los resultados de referencia (benchmarks) se calcularon de acuerdo con el Achievable Benchmark of Care (ABC™). Las LLRs de cada uno de los centros se dividieron en 3 grupos (Grupo I, II y III) en base a la clasificación de Kawaguchi. Se calculó el ABC de la morbilidad global y de la morbilidad mayor para cada grupo. Se realizó un análisis multivariable para identificar los factores independientes de riesgos para la morbilidad global y morbilidad mayor. Se utilizaron variables significativas para realizar ajustes de riesgo adicionales.Un total de 1.752 pacientes de los 2.263 cumplían los criterios de inclusión, de los cuales 1.096 (62,6%) se incluyeron en el Grupo I, 435 (24,8%) en el Grupo II y 221 (12,6%) en el Grupo III. El ABC de la morbilidad global (7,8%, 14,2%, 26,4%) y de la morbilidad mayor (1,4%, 2,2%, 5,7%) aumentó del Grupo I al Grupo III. El análisis multivariable mostró un incremento del riesgo para la morbilidad global asociada con múltiples LLRs (razón de oportunidades, odds ratio, OR 1,349), resección intestinal simultánea (OR 3,760) y cirrosis (OR 1,825), y para la morbilidad mayor con la resección intestinal (OR 4,606). Los ABC de la morbilidad global y morbilidad mayor fueron 14,4% y 3,2% para las LLR múltiples, 30% y 11% para la resección intestinal, y 14,9% y 4,8% para la cirrosis, respectivamente. CONCLUSIÓN: Los resultados de referencia (benchmark) para la morbilidad global y morbilidad mayor en la LLR variaron entre un 8% y un 26% y entre un 1,4% y un 5,7%, dependiendo de la complejidad. Los valores de referencia deberían ajustarse de acuerdo con la práctica de LLRs múltiples o resección intestinal simultánea y cirrosis.

Key Points Question Can the individual risk estimation for early allograft failure (EAF) be improved in view of liver retransplant? Findings In this multicenter cohort study investigating the association between donor-recipient factors and EAF, a novel Early Allograft Failure Simplified Estimation (EASE) score was developed. The score includes Model for End-stage Liver Disease score, transfused packed red blood cells, and hepatic vessel early thrombosis as well as transaminases, platelet, and bilirubin kinetics as variables on day 10 after transplant. The EASE score outperformed previous model scores, estimating EAF risk with 87% accuracy on day 90 after transplant; EASE was developed on a multicenter Italian database (1609 recipients) and validated on an external UK database (538 recipients). Meaning In this study, the EASE score rated the EAF risk (0%-100%) and identified cases at unsustainable risk to be listed for retransplant., Importance Expansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015. Objective To develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant. Design, Setting, and Participants This multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017. Main Outcomes and Measures Early allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant. Results At day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk. Conclusions and Relevance This study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers., This multicenter cohort study develops and validates a simplified comprehensive model that estimates on day 10 after liver transplant the risk of early allograft failure with 90 days among patients who undergo liver transplant.

OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862. ispartof: ANNALS OF SURGERY vol:272 issue:5 pages:855-862 ispartof: location:United States status: published

Background: Post-hepatectomy liver failure (PHLF) represents the most frequent complication after liver surgery, and the most common cause of morbidity and mortality. Aim of the study is to identify the predictors of PHLF after mini-invasive liver surgery in cirrhosis and chronic liver disease, and to develop a model for risk prediction. Methods: The present study is a multicentric prospective cohort study on 490 consecutive patients who underwent mini-invasive liver resection from the Italian Registry of Mini-invasive Liver Surgery (I go MILS). Retrospective additional biochemical and clinical data were collected. Results: On 490 patients (26.5% females), PHLF occurred in 89 patients (18.2%). The only independent predictors of PHLF were Albumin-Bilirubin (ALBI) score (OR 3.213; 95% CI 1.661–6.215; p

Background In case of bilobar colorectal liver metastases (CLM) associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been proposed. Enhanced one-stage ultrasound-guided hepatectomy (e-OSH) may represent a further solution for these patients. Aim of this study was to compare by case-match analyses the outcome of ALPPS and e-OSH. Methods Between 2012 and 2017, patients undergoing ALPPS for bilobar CLM were matched 1:2 with patients receiving e-OSH. Patients were matched according to the Fong Score (1–3/4–5), the number of CLM (3–7/≥8), the number of CLM in the left liver (1–2/≥3) and preoperative chemotherapy. All the patients in the e-OSH group had a right -sided major vascular contact. The main endpoints of the study were perioperative outcomes, overall (OS) and disease-free survival (DFS). Results Seventy-eight patients were selected (26 ALPPS and 52 e-OSH) based on matching process. The two treatments differed significantly in major morbidity (26.9% ALPPS vs 7.7% e-OSH, p = 0.017). Median OS (31.7 vs 32.6 months) and DFS (10.6 vs 7.8 months) were comparable between the two groups. Conclusions This study demonstrates that ALPPS and e-OSH for bilobar CLM achieve comparable long-term results, despite higher morbidity reported after ALPPS. These findings should drive to reposition e-OSH in managing these patients.

Objectives A prospective cohort study was conducted in Italy in order to describe the microbiologic aspects of colonization/infection by carbapenemase-producing Enterobacteriaceae (CPE) in donors and recipients of lung and liver transplants and the possible CPE transmission from donors to recipients. Methods Between 15 January 2014 and 14 January 2015, all recipients of solid organ transplants (SOT) at ten lung and eight liver transplantation centres and the corresponding donors were enrolled. Screening cultures to detect CPE were performed in donors, and screening and clinical cultures in recipients with a 28-day microbiologic follow-up after receipt of SOT. Detection of carbapenemase genes by PCR, genotyping by multilocus sequence typing, and pulsed-field gel electrophoresis and whole-genome sequencing were performed. Results Of 588 screened donors, 3.4% were colonized with CPE. Of the liver first transplant recipients (n = 521), 2.5% were colonized before receipt of SOT and 5% acquired CPE during follow-up. CPE colonization was higher in lung first transplant recipients (n = 111, 2.7% before SOT and 14.4% after SOT). CPE infections occurred in 1.9% and 5.3% of liver or lung recipients, respectively. CPE isolates were mostly Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae belonging to CG258. Three events of donor–recipient CPE transmission, confirmed by whole-genome sequencing and/or pulsed-field gel electrophoresis, occurred in lung recipients: two involving K. pneumoniae sequence type 512 and one Verona integron-encoded metallo-β-lactamase (VIM)-producing Enterobacter aerogenes. Conclusions This study showed a low risk of donor–recipient CPE transmission, indicating that donor CPE colonization does not necessarily represent a contraindication for donation unless colonization regards the organ to be transplanted. Donor and recipient screening remains essential to prevent CPE transmission and cross-infection in transplantation centres.

To implement split liver transplantation (SLT) a mandatory-split policy has been adopted in Italy since August 2015: donors aged 18-50years at standard risk are offered for SLT, resulting in a left-lateral segment (LLS) graft for children and an extended-right graft (ERG) for adults. We aim to analyze the impact of the new mandatory-split policy on liver transplantation (LT)-waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially “splittable” donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P=.009) and the pediatric LT-waiting list time dropped (229 [10-2121] vs 80 [12-2503] days [P=.045]). The pediatric (4.5% vs 2.5% [P=.398]) and adult (9.7% to 5.2% [P20kg (HR=5.113, P=.048) in LLS, and ischemic time >8hours (HR=2.475, P=.048) in ERG were identified as predictors of graft failure. A national mandatory-split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT-waiting list and priority for adult sick LT candidates.

Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells' extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet-tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC. Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells’ extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet–tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.

Objective: Laparoscopic liver resection (LLR) for Hepatocellular Carcinoma (HCC) is one of the most important indications for the minimally invasive approach. Our study aims to analyze the experience of the Italian Group of Minimally Invasive Liver Surgery with laparoscopic surgical treatment of HCC, with a focus on tumor location and how it affects morbidity and mortality. Methods: 38 centers participated in this study; 372 cases of LLR for HCC were prospectively enrolled. Patients were divided into two groups according to the HCC nodule location. Group 1 favorable location and group 2 unfavorable location. Perioperative outcomes were compared between the two groups before and after a propensity score match (PS) 1:1. Results: Before PS in group 2 surgical time was longer; conversion rate was higher; postoperative transfusion and comprehensive complication index were also higher. PS was performed with a cohort of 298 patients (from 18 centers), with 66 and 232 patients with HCC in unfavorable and favorable locations, respectively. After PS matching, 62 patients from group 1 and group 2 each were compared. Operative and postoperative course were similar in patients with HCC in favorable and unfavorable LLR locations. Surgical margins were found to be identical before and after PS. Conclusions: These results show that LLR in patients with HCC can be safely performed in all segments because of the extensive experience of all surgeons from multiple centers in performing traditional open liver surgery as well as laparoscopic surgery.

Background: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients. Patients and Methods: We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTW-adjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival. Results: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjusted multivariate survival model, treatment strategy was found to be the strongest survival predictor, irrespective of ITA.LI.CA prognostic variables and treatment period. The survival benefit of different therapies over BSC was: LT=0.19 (0.18-0.20); RES=0.40 (0.37-0.42); ABL 0.42 (0.40-0.44); IAT=0.58 (0.55-0.61); SOR=0.92 (0.87-0.97). This multivariate model was then used to predict median survival for each therapy within each ITA.LI.CA stage. Conclusion: The concept of therapeutic hierarchy was established within each ITA.LI.CA stage.

Split-liver transplantation has been proposed as an alternative to whole liver (WL) transplantation to expand the donor pool, but studies comparing adult longterm outcomes between the 2 methods are conflicting and limited. This is the first Italian multicenter study that retrospectively analyzed 119 matched-pair recipients of whole and extended right grafts (ERGs) for longterm survival outcomes. In the overall population, WL recipients showed higher patient survival at 1 (93% versus 73%), 5 (87% versus 65%), and 10 years (83% versus 60%) after transplantation compared with split-liver recipients (P < 0.001); graft survivals of WL recipients were also superior at 1 (90% versus 76%), 5 (84% versus 57%), and 10 years (81% versus 52%) posttransplant (P < 0.001). However, among the 81 matched pairs that survived the first posttransplant year, 5- and 10-year patient survivals were 90% and 81% for split recipients and 99% and 96% for whole recipients, respectively (P = 0.34). The 5- and 10-year graft survivals were also comparable: 87% and 77% for split recipients, and 86% and 82% for whole recipients (P = 0.86). Cox regression analysis identified donor age >50, donor-to-recipient weight ratio < 1, retransplantation status, and United Network for Organ Sharing I-IIA status as risk factors for partial graft use. There were no significant differences in 5-year outcomes based on center volume. In conclusion, we demonstrate that adult liver transplantation with ERGs can achieve longterm success comparable with that of whole grafts in appropriate patients but should be selectively used in patients with risk factors. Liver Transplantation 23 1384–1395 2017 AASLD.

Background: Posthepatectomy liver failure is one of the most feared complications in extended hepatic resections. In 2012, a novel two-stage liver resection was developed, able to induce rapid and extensive hypertrophy by portal vein ligation and in situ liver splitting - Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS). The technique became more widely employed but its use remained controversial due to reporting of high complication and mortality rates. Method: A national audit was performed to gather information about the safety of the procedure and to better understand the complications. The audit was offered to all high-volume hepatobiliary centers in Italy. Results: Of all Italian centers approached in January 2012, 12 centers with experience in ALPPS enrolled and participated in collection of data. Fifty patients underwent ALPPS between 2012 and 2014. In 48/50 patients completion of hepatectomy was performed successfully. Major morbidity occurred in 54% with a 20% 90-day mortality. Uni- and multivariate analysis showed that ALPPS for cholangiocarcinoma and a peak of bilirubin over 5 mg/dl between stages was associated with increase of 90 day mortality and worse survival. Discussion: It is proposed that a moratorium be introduced for classic ALPPS in cholangiocarcinoma and to abort ALPPS in patients who develop an interstage increase in bilirubin, due to the high risk of liver failure and mortality.

Background & Aims The model for end-stage liver disease (MELD) is used for organ allocation in liver transplantation (LT), but its prognostic performance is less accurate in patients with low score. We assess the outcome of patients with MELD 15.9. Conclusions In patients with low MELD (

Background: To generate a robust predictive model of Early (3 months) Graft Loss after liver transplantation, we used a Bayesian approach to combine evidence from a prospective European cohort (Liver-Match) and the United Network for Organ Sharing registry. Methods: Liver-Match included 1480 consecutive primary liver transplants performed from 2007 to 2009 and the United Network for Organ Sharing a time-matched series of 9740 transplants. There were 173 and 706 Early Graft Loss, respectively. Multivariate analysis identified as significant predictors of Early Graft Loss: donor age, donation after cardiac death, cold ischaemia time, donor body mass index and height, recipient creatinine, bilirubin, disease aetiology, prior upper abdominal surgery and portal thrombosis. Results: A Bayesian Cox model was fitted to Liver-Match data using the United Network for Organ Sharing findings as prior information, allowing to generate an Early Graft Loss-Donor Risk Index and an Early Graft Loss-Recipient Risk Index. A Donor-Recipient Allocation Model, obtained by adding Early Graft Loss-Donor Risk Index to Early Graft Loss-Recipient Risk Index, was then validated in a distinct United Network for Organ Sharing (year 2010) cohort including 2964 transplants. Donor-Recipient Allocation Model updating using the independent Turin Transplant Centre dataset, allowed to predict Early Graft Loss with good accuracy (c-statistic: 0.76). Conclusion: Donor-Recipient Allocation Model allows a reliable donor and recipient-based Early Graft Loss prediction. The Bayesian approach permits to adapt the original Donor-Recipient Allocation Model by incorporating evidence from other cohorts, resulting in significantly improved predictive capability. © 2013 Editrice Gastroenterologica Italiana S.r.l.

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

Background The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods/Design The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. Trial Register Trial registered at http://www.clinicaltrials.gov: NCT00355862 (EudraCT Number: 2005-005362-36)

It is a well-recognized fact that implementing new guidelines in clinical practice may be difficult; therefore the Italian Society for Organ and Tissue Transplantation (SITO) set out to define practical immunosuppression tools for the management of liver transplantation patients. In 2017, an Italian Working Group of liver transplant experts and hepatologists issued a set of consensus statements along with evidence-based recommendations on the use of everolimus after liver transplantation. This article presents the evidence- and consensus-based algorithms developed within the Italian Working Group, which are aimed towards guiding clinicians in the selection of immunosuppressive regimens for the management of adult liver transplant recipients in real-life practice. The liver transplant recipient population, typically managed in clinical practice, was divided into the following categories: (1) standard patients; (2) critically ill patients; (3) patients with a specific etiology; (4) patients with hepatocellular carcinoma; (5) and patients with de novo malignancies. The algorithms are divided into two parts, according to the time from transplantation (0–3 months and > 3 months) and are discussed here along with relevant supporting literature, when available. Ultimately, it is hoped that the evidence- and consensus-based algorithms developed within the Italian Working Group, and presented here, contribute to simplify, personalize, and optimize immunosuppression of liver transplantation recipients in clinical practice.

Despite the worldwide acceptance of split liver transplantation (SLT) as a strategy to expand a limited donor pool, problems still exist in its widespread application.1 The technique of “conventional” SLT divides the liver of a heart-beating donor into an extended right graft (ERG) and a left lateral segment graft (LLS), including Couinaud segments I, IV–VIII, and segments II–III, respectively.2,3 Recent single-center series of either in situ or ex situ SLT reported results comparable to whole liver transplantation (WLT).3–16 The ideal split liver donor should be between 14 and 50 years of age, with good liver function, serum sodium level

Background Women who have undergone liver transplantation (LT) enjoy better health, and possibility of childbearing. However, maternal and graft risks, optimal immunosuppression, and fetal outcome is still to clarify. Aim Aim of the study was to assess outcomes of pregnancy after LT at national level. Methods In 2019, under the auspices of the Permanent Transplant Committee of the Italian Association for the Study of the Liver, a multicenter survey including 14 Italian LT-centers was conducted aiming at evaluating the outcomes of recipients and newborns, and graft injury/function parameters during pregnancy in LT-recipients. Results Sixty-two pregnancies occurred in 60 LT-recipients between 1990 and 2018. Median age at the time of pregnancy was 31-years and median time from transplantation to conception was 8-years. During pregnancy, 4 recipients experienced maternal complications with hospital admission. Live-birth-rate was 100%. Prematurity occurred in 25/62 newborns, and 8/62 newborns had low-birth-weight. Cyclosporine was used in 16 and Tacrolimus in 37 pregnancies, with no different maternal or newborn outcomes. Low-birth-weight was correlated to high values of AST, ALT and GGT. Conclusion Pregnancy after LT has good outcome; however, maternal complications and prematurity may occur. Compliance with the immunosuppression is fundamental to ensure the stability of graft function and prevent graft-deterioration.