Advanced donor age does not increase risk of hepatocellular carcinoma recurrence after liver transplantation: a retrospective two-centre analysis using competing risk analysis.

The impact of donor age on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation is still debated. Between 2002 and 2014, all patients transplanted for HCC in 2 European liver transplantation tertiary centres were retrospectively reviewed. Risk factors for HCC recurrence were assessed using competing risk analysis, and the impact of donor age < or ≥65 years and < or ≥80 years was specifically evaluated after propensity score matching. 728 patients transplanted with a median follow-up of 86 months were analysed. The 1-, 3- and 5-year recurrence rates were 4.9%, 10.7% and 13.9%, respectively. In multivariable analysis, recipient age (sHR: 0.96 [0.93; 0.98], P < 0.01), number of lesions (sHR: 1.05 [1.04; 1.06], P < 0.001), maximum size of the lesions (sHR: 1.37 [1.27; 1.48], P < 0.01), presence of a hepatocholangiocarcinoma (sHR: 6.47 [2.91; 14.38], P < 0.01) and microvascular invasion (sHR: 3.48 [2.42; 5.02], P < 0.01) were significantly associated with HCC recurrence. After propensity score matching, neither donor age ≥65 (P = 0.29) nor donor age ≥80 (P = 0.84) years increased the risk of HCC recurrence. In conclusion, donor age was not found to be a risk factor for HCC recurrence. Patients listed for HCC can receive a graft from an elderly donor without compromising the outcome.

Development and Validation of a Comprehensive Model to Estimate Early Allograft Failure Among Patients Requiring Early Liver 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.

Machine Perfusions in Liver Transplantation: The Evidence-Based Position Paper of the Italian Society of Organ and Tissue Transplantation.

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 Role of Salvage Transplantation in Patients Initially Treated With Open Versus Minimally Invasive Liver Surgery: An Intention-to-Treat Analysis.

Despite gaining wide consensus in the management of hepatocellular carcinoma (HCC), minimally invasive liver surgery (MILS) has been poorly investigated for its role in the setting of salvage liver transplantation (SLT). A multicenter retrospective analysis was carried out in 6 Italian centers on 211 patients with HCC who were initially resected with open (n = 167) versus MILS (n = 44) and eventually wait-listed for SLT. The secondary endpoint was identification of risk factors for posttransplant death and tumor recurrence. The enrolled patients included 211 HCC patients resected with open surgery (n = 167) versus MILS (n = 44) and wait-listed for SLT between January 2007 and December 2017. We analyzed the intention-to-treat survival of these patients. MILS was the most important protective factor for the composite risk of delisting, posttransplant patient death, and HCC recurrence (OR, 0.26; 95% confidence interval [CI], 0.11-0.63; P = 0.003). MILS was also the only independent protective factor for the risk of post-SLT patient death (OR, 0.29; 95% CI, 0.09-0.93; P = 0.04). After propensity score matching, MILS was the only independent protective factor against the risk of delisting, posttransplant death, and HCC recurrence (OR, 0.22; 95% CI, 0.07-0.75; P = 0.02). On the basis of the current analysis, MILS seems protective over open surgery for the risk of delisting, posttransplant patient death, and tumor recurrence. Larger prospective studies balancing liver function and tumor stage are strongly favored to better clarify the beneficial effect of MILS for HCC patients eventually referred to SLT.

Sustained virological response with 16-week glecaprevir/pibrentasvir after failure to sofosbuvir/velpatasvir in post-transplant severe HCV recurrence in HIV.

Direct-acting antivirals (DAAs) demonstrated high efficacy and safety even in the post-liver transplant (LT) setting and in HIV-infected patients, but data are very limited in the early post-LT period with the most recently available DAA. Two HIV/HCV-coinfected LT recipients (both grafts from HIV/HCV-negative donors) experienced early HCV recurrence with severe hepatitis and were treated with sofosbuvir/velpatasvir for 12 weeks. Unfortunately, both patients failed: one (genotype 4d) showed virological breakthrough at week 3 with resistance-associated substitutions (RASs) for both NS5A and NS5B, while the other (genotype 1a) experienced virological relapse without RAS. Both progressed to fibrosing cholestatic hepatitis and were successfully retreated with glecaprevir/pibrentasvir for 16 weeks achieving sustained virological response. The higher prevalence of RAS in experienced genotype 4 patients and the long time to viral suppression observed in subjects with fibrosing cholestatic hepatitis should be taken into account, considering longer treatment duration to increase the chances of achieving sustained virological response.

The current role of laparoscopic resection for HCC: a systematic review of past ten years.

The use of laparoscopic liver resection (LLR) has progressively spread in the last 10 years. Several studies have shown the superiority of LLR to open liver resection (OLR) in term of perioperative outcomes. With this review, we aim to systematically assess short-term and long-term major outcomes in patients who underwent LLR for hepatocellular carcinoma (HCC) in order to illustrate the advantages of minimally invasive liver surgery. Through an advanced PubMed research, we selected all retrospective, prospective, and comparative clinical trials reporting short-term and long-term outcomes of any series of patients with diagnosis of HCC who underwent laparoscopic or robotic resection. Reviews, meta-analyses, or case reports were excluded. None of the patients included in this review has received a previous locoregional treatment for the same tumor nor has undergone a laparoscopic-assisted procedure. We considered morbidity and mortality for evaluation of major short-term outcomes, and overall survival (OS) and disease-free survival (DFS) for evaluation of long-term outcomes. A total of 1,501 patients from 17 retrospective studies were included, 15 studies compare LLR with OLR. Propensity-score matching (PSM) analysis was used in 11 studies (975 patients). The majority of the studies included patients with good liver function and a single HCC. Cirrhosis at pathology ranged from 33% to 100%. Overall mortality and morbidity ranges were 0-2.4% and 4.9-44% respectively, with most of the complications being Clavien-Dindo grade I or II (range: 3.9-23.3% vs. 0-9.52% for Clavien I-II and ≥ III respectively). The median blood loss ranged from 150 to 389 mL; the range of the median duration of surgery was 134-343 minutes. The maximum rate of conversion was 18.2%. The median duration of hospitalization ranged from 4 to 13 days. The ranges of overall survival rates at 1-, 3- and 5-year were 72.8-100%, 60.7-93.5% and 38-89.7% respectively. The ranges of disease free survival rates at 1-, 3- and 5-year were 45.5-91.5%, 20-72.2% and 19-67.8% respectively. The benefits of LLR in term of complication rate, blood loss, and duration of hospital stay make this procedure an advantageous alternative to OLR, especially for cirrhotic patients in whom the use of LLR reduces the risk of post-hepatectomy liver failure. The limits of LLR can be overcome by robotic surgery, which could therefore be preferred. Further benefits of minimally invasive surgery derive from its ability to reduce the formation of adhesions in view of a salvage liver transplant. In conclusion, the results of this review seem to confirm the safety and feasibility of LLR for HCC as well as its superiority to OLR according to perioperative outcomes.

Liver Grafts From Donors After Circulatory Death on Regional Perfusion With Extended Warm Ischemia Compared With Donors After Brain Death.

Donation after circulatory death (DCD) in Italy constitutes a relatively unique population because of the requirement of a no-touch period of 20 minutes. The first aim of this study was to compare liver transplantations from donors who were maintained on normothermic regional perfusion after circulatory death and suffered extended warm ischemia (DCD group, n = 20) with those from donors who were maintained on extracorporeal membrane oxygenation (ECMO) and succumbed to brain death (ECMO group, n = 17) and those from standard donors after brain death (donation after brain death [DBD] group, n = 52). Second, we conducted an explorative analysis on the DCD group to identify relationships between the donor characteristics and the transplant outcomes. The 1-year patient survival for the DCD group (95%) was not significantly different from that of the ECMO group (87%; P = 0.47) or the DBD group (94%; P = 0.94). Graft survival was slightly inferior in the DCD group (85%) because of a high rate of primary nonfunction (10%) and retransplantation (15%) but was not significantly different from the ECMO group (87%; P = 0.76) or the DBD group (91%; P = 0.20). Although ischemic cholangiopathy was more frequent in the DCD group (10%), this issue did not adversely impact graft survival because none of the recipients underwent retransplantation due to biliary complications. Moreover, the DCD recipients were more likely to develop posttransplant renal dysfunction with the need for renal replacement therapy. Further analysis of the DCD group showed that warm ischemia >125 minutes and an Ishak fibrosis score of 1 at liver biopsy negatively impacted serum creatinine and alanine transaminase levels in the first posttransplant week, respectively. In conclusion, our findings encourage the use of liver grafts from DCD donors maintained by regional perfusion after proper selection.

Evolution of pancreatectomy with en bloc venous resection for pancreatic cancer in Italy. Retrospective cohort study on 425 cases in 10 pancreatic referral units.

INTRODUCTION: The aim of this study is to analyze the evolution of pancreatectomy with venous resection in 10 referral Italian centers in the last 25 years. METHODS: A multicenter database of 425 patients submitted to pancreatectomy with venous resection between 1991 and 2015 was retrospectively analyzed. Patients were classified in 5 periods: 1 (1991-1995); 2 (1996-2000); 3 (2001-2005); 4 (2006-2010); 5 (2011-2015). Indications and outcomes were compared according to the period of surgery. RESULTS: Nineteen patients were operated in period 1, 28 in period 2, 91 in period 3, 140 in period 4, and 147 in period 5. Use of neoadjuvant therapy increased from 0% in period 1 and 2-12.1% in period 5. Postoperative complications ranged from 46.3% to 67.8%, and mortality from 5.3% to 9.2%. Median survival progressively increased, from 6 months in period 1-16 months in period 2, 24 months in period 3 and 4 and 35 months in period 5 (p = 0.004). Period, venous and nodal invasion were significant prognostic factors for survival. CONCLUSION: Management and outcomes of pancreatectomy with venous resection have evolved in the last 25 years in Italy. Improvement in patients' multidisciplinary management has lead to significant improvement of median survival.

Split liver technique with middle hepatic vein reconstruction on livers from transplant hepatectomies: a useful tool for surgical improvement.

Livers removed during transplant hepatectomies could represent a useful anatomic ex vivo resource for surgical training, since they are intact and not altered by post-mortem changes yet. The aim of this study is to investigate the effectiveness of such kind of surgical training applied on some hepatic surgery techniques. In the present paper, we focused on split liver operation and middle hepatic vein (MHV) bipartition/reconstruction, since these procedures have a quite long learning curve. Seven native livers were submitted to split liver procedure by a senior resident assisted by a fully trained hepatic surgeon. Pre-splitting ultrasound mapping was compared to pre-operative CT scan. The whole graft was divided into two hemi-livers and the MHV into two hemi-confluents and reconstructed by venous or arterial patches obtained by deceased donor iliac homograft. Water tightness of the anastomosis was confirmed by hydro-pneumatic test and bench portal perfusion. Reduction in operating time was considered an indirect indicator of surgical skill improvement. In all cases, the US confirmed the anatomical distribution of MHV tributaries observed by pre-transplant CT scan. The "ex situ" splitting procedures and MHV bipartition and reconstruction were performed in all native livers in the usual time required for liver transplantation bench surgery (range 50-75 min). Liver grafts removed during hepatectomy could represent a useful resource of intact organs to perform surgical training and boost surgical confidence. In our initial experience, the study of venous drainage of the MHV and application of liver splitting technique and MHV reconstruction resulted technically feasible.

Prognostic role of nodal ratio, LODDS, pN in patients with pancreatic cancer with venous involvement.

BACKGROUND: The UICC/AJCC TNM staging system classifies lymph nodes as N0 and N1 in pancreatic cancer. Aim of the study is to determine whether the number of examine nodes, the nodal ratio (NR) and the logarithm odds of positive lymph nodes (LODDS) may better stratify the prognosis of patients undergoing pancreatectomy combined with venous resection for pancreatic cancer with venous involvement. METHODS: A multicenter database of 303 patients undergoing pancreatectomy in 9 Italian referral centers was analyzed. The prognostic impact of number of retrieved and examined nodes, NR, LODDS was analyzed and compared with ROC curves analysis, Pearson test, univariate and multivariate analysis. RESULTS: The number of metastatic nodes, pN, the NR and LODDS was significantly correlated with survival at multivariate analyses. The corresponding AUC for the number of metastatic nodes, pN, the NR and LODDS were 0.66, 0.69, 0.63 and 0.65, respectively. The Pearson test showed a significant correlation between the number of retrieved lymph nodes and number of metastatic nodes, pN and the NR. LODDS had the lower coefficient correlation. Concerning N1 patients, the NR, the LODDS and the number of metastatic nodes were able to significantly further stratify survival (p = 0.040; p = 0.046; p = 0.038, respectively). CONCLUSIONS: The number of examined lymph nodes, the NR and LODDS are useful for further prognostic stratification of N1 patients in the setting of pancreatectomy combined with PV/SMV resection. No superiority of one over the others methods was detected.

Liver transplantation in the treatment of severe iatrogenic liver injuries.

The place of liver transplantation in the treatment of severe iatrogenic liver injuries has not yet been widely discussed in the literature. Bile duct injuries during cholecystectomy represent the leading cause of liver transplantation in this setting, while other indications after abdominal surgery are less common. Urgent liver transplantation for the treatment of severe iatrogenic liver injury may-represent a surgical challenge requiring technically difficult and time consuming procedures. A debate is ongoing on the need for centralization of complex surgery in tertiary referral centers. The early referral of patients with severe iatrogenic liver injuries to a tertiary center with experienced hepato-pancreato-biliary and transplant surgery has emerged as the best treatment of care. Despite widespread interest in the use of liver transplantation as a treatment option for severe iatrogenic injuries, reported experiences indicate few liver transplants are performed. This review analyzes the literature on liver transplantation after hepatic injury and discusses our own experience along with surgical advances and future prospects in this uncommon transplant setting.

Consequences of Increases in Antibiotic Resistance Pattern on Outcome of Pancreatic Resection for Cancer.

BACKGROUND: The role of drug-resistance infections on surgical outcomes is controversial. The aim of the study was to determine whether increase antibiotic resistance was an independent risk factor for development of major non-infectious postoperative complications. METHODS: This work included a multicenter cohort study of patients who underwent pancreatic resections for cancer over a 3-year interval. The primary outcome was major non-infectious complication rate developing after the occurrence of multi-drug sensitive (MDS) infection, multi-drug-resistant infection (MDR), and extensive drug-resistant (XDR) infection. Multivariate logistic regression models were used to adjust for patient and operative effects. RESULTS: Eligible patients (517) were selected for the analysis. One hundred and thirteen (21.8%) patients had major non-infectious complications with a rate of 12.9% in the no infection group, 29.3% in the MSD, 41.5% in the MDR, and 58.8% in the XDR (p < 0.001). The median time of infection occurrence was postoperative days 4 (2-7 IQR) and 7 (3-12 IQR) non-infectious complications. At multivariate analysis, the risk of having major non-infectious complications was 2.67 (95% CI 1.24-5.77, P = 0.012) for MDR, 5.04 (95% CI 2.35-10.80, P < 0.001) for MDR, and 9.64 (95% CI 2.71-34.28, P < 0.001) for XDR. CONCLUSION: Antimicrobial resistance is significantly associated with the risk of major non-infectious morbidity.

The European Policy for Liver Allocation in Patients Affected by Hepatocellular Carcinoma.

The main goal of allocation system is to guarantee an equal access to the limited resource of liver grafts for every class of patients on the waiting list, balancing between the ethical principles of equity, utility, benefit, need, and fairness. The aim of this review was to analyze liver allocation policies among these organizations, focusing on HCC. The European area considered for this analysis included 6 macro-areas or countries, which are congregated from the same policy of liver sharing and allocation. By this definition, the 6 areas identified are: Centro Nazionale Trapianti (CNT) in Italy; Eurotransplant (Germany, the Netherlands, Belgium, Luxembourg, Austria, Hungary, Slovenia, and Croatia); Organizacion Nacional de Transplantes (ONT) in Spain; Etablissement francais des Greffes (EfG) in France; NHS Blood Transplant (NHSBT) in the United Kingdom and Ireland; Scandiatransplant (Sweden, Norway, Finland, Denmark, and Iceland); Romanian National Policy. Each identified area, as network for organ sharing in Europe, adopts a basic allocation system that consider a policy center oriented or patient oriented. Priorization of patients affected by HCC in the waiting list for deceased donors liver transplant worldwide is dominated by 2 main principles: urgency and utility. The main message of this review is the absence of a common organs allocation policy over the Eurpean countries. Despite that, long-term survival of the community of patients listed for transplant due to HCC results, however, highly acceptable in Europe and comparable to the long-term survial reported in the UNOS register.