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Biliary tract complications (BTCs) still burden liver transplantation (LT). The wide reporting variability highlights the absence of systematic screening. From 2000 to 2009, simultaneous liver biopsy and direct biliary visualization were prospectively performed in 242 recipients at 3 and 6 months (n = 212, 87.6%) or earlier when indicated (n = 30, 12.4%). Median follow-up was 148 (107-182) months. Seven patients (2.9%) experienced postprocedural morbidity. BTCs were initially diagnosed in 76 (31.4%) patients; 32 (42.1%) had neither clinical nor biological abnormalities. Acute cellular rejection (ACR) was present in 27 (11.2%) patients and in 6 (22.2%) BTC patients. Nine (3.7%) patients with normal initial cholangiography developed BTCs after 60 (30-135) months post-LT. BTCs directly lead to 7 (2.9%) re-transplantations and 14 (5.8%) deaths resulting in 18 (7.4%) allograft losses. Bile duct proliferation at 12-month biopsy proved an independent risk factor for graft loss (P = 0.005). Systematic biliary tract and allograft evaluation allows the incidence and extent of biliary lesions to be documented more precisely and to avoid erroneous treatment of ACR. The combination 'abnormal biliary tract-canalicular proliferation' is an indicator of worse graft outcome. BTCs are responsible for important delayed allograft and patient losses. These results underline the importance of life-long follow-up and appropriate timing for re-transplantation., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

The best minimally invasive procedure for living-donor kidney retrieval remains debated. Our objective was to assess trans-peritoneal (TP) and retro-peritoneal (RP) hand-assisted laparoscopic donor nephrectomy (HALDN). In this single-center retrospective study, we analyzed results from 317 living-donor renal transplants (RT) performed between 2008 and 2016. Donor and recipient outcomes were compared between TP-HALDN (n = 235) and RP-HALDN (n = 82). Conversion to open nephrectomy (0.4% vs 0%; P = 1.000), intra-operative complications (1.7% vs 1.2%; P = 1.000), and 1-year overall post-operative complications (11.9% vs 17.1%; P = .258) rates were similar in TP-HALDN and RP-HALDN. Overall surgical site infections were higher in RP-HALDN (6.1% vs 1.7%; P = .053), whereas incisional hernias were only recorded following TP-HALDN (3.4% vs 0%; P = .118). The duration of the procedure was 11-minute shorter for TP-HALDN than RP-HALDN (P < .001) but extraction time was equivalent (2, IQR 1.5-2.5 minutes; P = 1.000). RT following TP-HALDN and RP-HALDN showed comparable one-year death-censored allograft survival (97% vs 98.8%; P = .685), primary non-function (0.4% vs 0%; P = .290), delayed graft function (1.3% vs 4.9%; P = .077), and urological complications (2.6% vs 4.9%; P = .290) rates. In our series, donor and recipient outcomes were not substantially affected by the approach used for donor nephrectomy. TP-HALDN and RP-HALDN were both safe and effective., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In the field of transplantation, expression of HLA-G, a nonclassical HLA molecule with immunosuppressive functions and limited gene polymorphism, is considered beneficial for graft acceptance; various studies have aimed to demonstrate this role in transplantation. Recently, in other clinical conditions, it has been observed that insulin resistance was associated with HLA-G14bpins/del polymorphism, the most studied regulatory polymorphism of this molecule. In the present study, plasma levels of the soluble form of HLA-G (sHLA-G) were analyzed in kidney transplant recipients (n = 103) with different HLA-G14bpins/del genotypes. In a group of 26 recipients, sHLA-G was detected before and after transplantation (1 year) to evaluate early variations. In 77 recipients, sHLA-G was detected after transplantation (3-24 years) and correlated with occurrence of long-term post-transplant morbidity (diabetes mellitus, hyperlipidemia, hypertension, obesity, etc.)., Methods: Levels of sHLA-G were measured in plasma with an enzyme-linked immunosorbent assay; HLA-G14bpins/del and HLA-G+3142C>G genotypes were assessed using direct polymerase chain reaction., Results: Plasma levels of sHLA-G significantly decreased during the first year after transplantation (P = .019); no significant correlations were found with genotypes or early post-transplant events. Lower levels of sHLA-G were found in recipients with post-transplant diabetes mellitus or obesity carrying the HLA-G14bpins/ins (P = .006 and P = .003, respectively) or HLA-G+3142G/G genotypes., Conclusions: A complex modulation of HLA-G, which includes both immunologic and metabolic effects, could affect the risk for long-term post-transplant morbidity in kidney transplant recipients. Associations of HLA-G, diabetes, and obesity deserve to be investigated by deeply exploring HLA-G regulatory variants., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Recent studies indicate that a group of patients with cirrhosis receiving a liver transplantation for hepatocellular cancer (HCC) beyond the Milan Criteria (MC) can achieve a similar outcome compared to patients within these criteria. This study aims to investigate the value of the Asan critera (AC), up-to-7 criteria (UT7), French alpha-foetoprotein (AFP) model and Metroticket 2.0 (MT2.0) model compared to the MC., Methods: 526 patients transplanted for non-metastatic HCC were analyzed. Patient groups within and beyond MC and extended criteria were determined according to radiological assessment and AFP value at listing., Results: Overall survival (OS) and recurrence (RR) rates were similar between patients within MC and all extended criteria. Five-year OS within MC was 71.3% compared to 70.9% for AC, 71.4% for UT7, 69.7% for AFP-model and 71.0% for MT2.0 criteria. Five-year RR within MC was 12.3% compared to 13.5% for AC, 13.0% for UT7, 14.3% for AFP-model and 13.2% for MT2.0 criteria. Patients beyond MC but within the extended criteria had tendency towards higher recurrence., Conclusions: All validated extended criteria (AC, UT7, AFP-model and MT2.0) could be proposed as alternatives to the MC with similar outcome. Prospective data are awaited to assess recurrence beyond MC., Competing Interests: Declaration of competing interest No conflict of interest reported in relation to the presented work., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Human leukocyte antigen (HLA)-G is a non-classical HLA molecule with immunomodulant and immunosuppressive functions, involved in transplantation tolerance. HLA-G14bp ins/del polymorphism in exon 8 has been associated with allograft rejection and kidney transplant outcome, with controversial results. We investigated associations of HLA-G14bp ins/del polymorphism on onset of some of the main post-transplant risk factors, like excess body weight, lipid abnormalities, increased fasting plasma glucose. Polymorphisms of cytokines with both immunosuppressive and metabolic effects were also assessed for comparisons and associated analysis., Methods: The present study involved kidney transplant recipients (n = 173) in which body mass index, cholesterol, triglycerides, fasting plasma glucose were registered in the first years after transplantation and analyzed in association with genotypes. Presence of hypertension and smoking habits, demographic, transplant-related and therapeutic data of patients were also recorded. Polymerase chain reaction, sequence-specific primer amplification and Taqman allelic discrimination techniques were used for genotyping of HLA-G14bp ins/del, interleukin (IL)-10(-1082G > A,-819 T > C,-592A > C), transforming growth factor-β(+ 869 T > C,+915C > G), IL-6(-174G > C), tumor necrosis factor-α(-308G > A) and IL-18(-137G > C,-607C > A). Effects of genotypes on clinical markers at each time point (pre-transplant and 1 to 5 years after transplant) were analyzed using a repeated-measures general linear model analysis; adjustment for potential confounders was performed., Results: Results showed that HLA-G14bp ins/ins was significantly associated with obesity, in particular after transplantation (3 years, p = 0.002, OR = 4.48, 95% CI:1.76-11.41). Post-transplant body mass index was significantly increased in HLA-G14bp ins/ins carriers (3 and 4 years, p = 0.033 and p = 0.044); effects of HLA-G14bp genotypes on post-transplant BMI were confirmed by using repeated-measures analysis and after controlling for confounding variables. Cytokine genotypes did not associate with the examined factors., Conclusions: The study of transplanted patients allowed to evidence a potential relationship between post-transplant weight gain and HLA-G14bp ins/del polymorphism, previously involved in rejection for its immunosuppressive/tolerogenic activity. This novel association could widen the knowledge of the role and functions of HLA-G molecules in diseases and transplantation.

A bstract : Since the introduction of Milan Criteria, all scoring models describing the prognosis of hepatocellular cancer (HCC) after liver transplantation (LT) have been exclusively based on characteristics available at surgery, therefore neglecting the intention-to-treat principles. This study aimed at developing an intention-to-treat model through a competing-risk analysis. Using data available at first referral, an upper limit of tumor burden for downstaging was identified beyond which successful LT becomes an unrealistic goal. Twelve centers in Europe, United States, and Asia (Brussels, Sapienza Rome, Padua, Columbia University New York, Innsbruck, Medanta-The Medicity Dehli, Hong Kong, Kyoto, Kaohsiung Taiwan, Mainz, Fukuoka, Shulan Hospital Hangzhou) created a Derivation (n = 2318) and a Validation Set (n = 773) of HCC patients listed for LT between January2000-March 2017. In the Derivation Set, the competing-risk analysis identified two independent covariables predicting post-transplant HCC-related death: combined HCC number and diameter (SHR = 1.15; p < 0.001) and alpha-fetoprotein (AFP) (SHR = 1.80; p < 0.001). WE-DS Model showed good diagnostic performances at internal and external validation. The identified upper limit of tumor burden for downstaging was AFP ≤ 20 ng/mL and up-to-twelve as sum of HCC number and diameter; AFP = 21-200 and up-to-ten; AFP = 201-500 and up-to-seven; AFP = 501-1000 and up-to-five. The WE-DS Model proposed here, based on morphologic and biologic data obtained at first referral in a large international cohort of HCC patients listed for LT, allowed identifying an upper limit of tumor burden for downstaging beyond which successful LT, following downstaging, results in a futile transplantation., Competing Interests: The authors declare no conflict of interest.

Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out [25.2%]) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre-LT levels of alpha-fetoprotein, Model for End-Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest-risk patients (HALTHCC 0-5) had lower rates of VI and PDC than the highest-risk patients (HALTHCC > 35) (VI, 7.7%[ 1.2-14.2] vs. 70.6% [48.3-92.9] and PDC:4.6% [0.1%-9.8%] vs. 47.1% [22.6-71.5]; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C-index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C-index = 0.71) and OS (C-index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre-LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted., (© 2019 by the American Association for the Study of Liver Diseases.)

The possible existence of yet undiscovered human tumorigenic viruses is still under scrutiny. The development of large-scale sequencing technologies, coupled with bioinformatics techniques for the characterization of metagenomic sequences, have provided an invaluable tool for the detection of unknown, infectious, tumorigenic agents, as demonstrated by several recent studies. However, discoveries of novel viruses possibly associated with tumorigenesis are scarce at best. Here, we apply a rigorous bioinformatics workflow to investigate in depth tumor metagenomes from a small but carefully selected cohort of immunosuppressed patients. While a variegated bacterial microbiome was associated with each tumor, no evidence of the presence of putative oncoviruses was found. These results are consistent with the major findings of several recent papers and suggest that new human tumorigenic viruses are not common even in immunosuppressed populations.

Background: During the last decades, several risk factors for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) have been investigated. However, the impact of two important drivers of oncogenesis, namely the immunosuppression and the treatment of acute cellular rejection (ACR) have been marginally addressed. This study aimed at investigating the impact of ACR treatment on the incidence of tumor recurrence in a large European HCC-LT population., Methods: Seven hundred and eighty-one adult patients transplanted between February 1, 1985 and June 30, 2016 were retrospectively analyzed. After propensity score match, 116 patients treated for ACR using steroid boluses were compared with 115 patients who did not present any ACR or a histologic but clinical irrelevant ACR., Results: Steroid boluses treated patients had a 18-fold higher overall incidence of HCC recurrence than those non-treated patients (16.4% vs. 0.9%; P<0.0001). At multivariate Cox regression analysis, steroid boluses used to treat ACR were an independent risk factor for HCC recurrence (HR=14.2; 95% CI: 1.8-110.4; P = 0.010)., Conclusions: The decision to treat ACR as well as to reinforce immunosuppression load should be cautiously taken in view of the presented results. Prospective studies are needed to further elucidate the clinical impact of immunosuppression on HCC recurrence after transplantation., (Copyright © 2019 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: During the last decades, deceased-donor liver transplantation (DDLT) has gained a place in the therapeutic algorithm of well-selected patients harbouring non-resectable secondary liver tumors. Living-donor LT (LDLT) might represent a valuable means to further expand this indication for LT., Methods: Between 1985 and 2016, twenty-two adults were transplanted because of neuroendocrine (n = 18, 82%) and colorectal metastases (n = 4, 18%); 50% received DDLT and 50% LDLT. In LDLT, 4 (36%) right and 7 (64%) left grafts were used; the median graft-to-recipient-weight ratios (GRWR) were 1.03% (IQR 0.86%-1.30%) and 0.59% (IQR 0.51%-0.91%), respectively. Median post-LT follow-up was 64 months (IQR 17-107) in the DDLT group and 40 months (IQR 35-116) in the LDLT group. DDLT and LDLT recipients were compared in terms of overall survival, graft survival, postoperative complications and recurrence., Results: The 1- and 5-year actuarial patient survivals were 82% and 55% after DDLT, 100% and 100% after LDLT, respectively (P < 0.01). One- and 5-year actuarial graft survivals were 73% and 36% after DDLT, 91% and 91% after LDLT (P < 0.01). The outcomes of right or left LDLT were comparable. Donor hepatectomy proved safe, and one donor experienced a Clavien IIIb complication. Bilirubin peak was significantly lower after left hepatectomy compared with that after right hepatectomy [1.3 (IQR 1.2-2.2) vs. 3.3 (IQR 2.3-5.2) mg/dL; P = 0.02]., Conclusions: The more recent LDLT series compared favorably to our DDLT series in the treatment of secondary liver malignancies. The absence of portal hypertension and the use of smaller left grafts make recipient and donor surgeries safe. The safety of the procedures and lack of interference with the scarce allograft pool are expected to lead to a more frequent use of LDLT in the field of transplant oncology., (Copyright © 2019 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

The gastrointestinal stromal tumor (GIST) is a digestive neoplasm of mesenchymal lineage. The treatment strategy for receptor tyrosine kinase-mutated GISTs is well defined. Wild-type GISTs (WT-GISTs) respond unsatisfactorily to specific kinase inhibitors. Moreover, evidence shows that repeat surgery has limited benefit. We report the case of a young female patient who was diagnosed with liver metastatic WT-GIST, after initial radical resection and adjuvant therapy with molecular targeted drugs. Due to the disease progression, a two-stage surgery was performed, with the removal of extrahepatic lesions followed by a total hepatectomy. The patient is disease-free after 4 years from liver transplantation (LT), performed under everolimus-based immunosuppression. The treatment of WT-GISTs remains a significant challenge due to the frequent resistance to tyrosine kinase inhibitors (TKIs). Liver transplantation might represent an effective treatment option for such disease., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria (MC), the benefit of locoregional therapies (LRTs) in the context of liver transplantation (LT) is still debated. Initial biases in the selection between treated and untreated patients have yielded conflicting reported results. The study aimed to identify, using a competing risk analysis, risk factors for HCC-dependent LT failure, defined as pretransplant tumor-related delisting or posttransplant recurrence. The study was registered at www.clinicaltrials.gov (identification number NCT03723304). In order to offset the initial limitations of the investigated population, an inverse probability of treatment weighting (IPTW) analysis was used: 1083 MC-in patients (no LRT = 182; LRT = 901) were balanced using 8 variables: age, sex, Model for End-Stage Liver Disease (MELD) value, hepatitis C virus status, hepatitis B virus status, largest lesion diameter, number of nodules, and alpha-fetoprotein (AFP). All the covariates were available at the first referral. After the IPTW, a pseudo-population of 2019 patients listed for LT was analyzed, comparing 2 homogeneous groups of untreated (n = 1077) and LRT-treated (n = 942) patients. Tumor progression after LRT was the most important independent risk factor for HCC-dependent failure (subhazard ratio [SHR], 5.62; P < 0.001). Other independent risk factors were major tumor diameter, AFP, MELD, patient age, male sex, and period of wait-list registration. One single LRT was protective compared with no treatment (SHR, 0.51; P < 0.001). The positive effect was still observed when 2-3 treatments were performed (SHR, 0.66; P = 0.02), but it was lost in the case of ≥4 LRTs (SHR, 0.80; P = 0.27). In conclusion, for MC-in patients, up to 3 LRTs are beneficial for success in intention-to-treat LT patients, with a 49% to 34% reduction in failure risk compared with untreated patients. This benefit is lost if more LRTs are required. A poor response to LRT is associated with a higher risk for HCC-dependent transplant failure., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Introduction: : To date, there are no studies investigating whether laparoscopic cholecystectomy (LC) is technically more complex in patients waiting for kidney transplant. The aim of this study is to create a user-friendly score to identify high-risk cases for complex LC integrating end-stage renal disease (ESRD)., Materials and Methods: We retrospectively analysed 321 patients undergoing LC during the period 2014-2016. Two groups were compared: ESRD group (n = 25) versus control group (n = 296). Concerning statistical analysis, continuous variables were compared using Kruskal-Wallis' test, dummy variables with Chi-square test or Fisher's exact test when appropriate. A multivariable logistic regression analysis was performed to identify risk factors for complex LC. A backward conditional method was used to design the final model., Results: : Seventy out of 321 (21.8%) cases were considered as complex, with a higher prevalence in the ESRD group (32.0 vs. 20.9%; P = 0.2). Using a multivariable logistic regression analysis, we formulated a score based on the independent risk factors for complex LC: 4×(previous cholecystitis) +5 × (previous ESRD) +1 × (age per decade) +2 × (previous open abdominal surgery). High-risk cases (score ≥ 10) were more commonly reported in the ESRD group (72.0 vs. 24.7%; P < 0.0001)., Conclusion: : Although several scores investigating the risk for complex LC have been proposed, none of them has focused on ESRD. This is the first series demonstrating that ESRD is an independent risk factor for technical complexity in LC. We developed a score to offer surgeons an extra tool for pre-operative evaluation of patients requiring LC., Competing Interests: None

Background: Liver transplantation is the treatment for end-stage liver diseases and well-selected malignancies. The allograft shortage may be alleviated with living donation. The initial UCLouvain experience of adult living-donor liver transplantation (LDLT) is presented., Methods: A retrospective analysis of 64 adult-to-adult LDLTs performed at our institution between 1998 and 2016 was conducted. The median age of 29 (45.3%) females and 35 (54.7%) males was 50.2 years (interquartile range, IQR 32.9-57.5). Twenty-two (34.4%) recipients had no portal hypertension. Three (4.7%) patients had a benign and 33 (51.6%) a malignant tumor [19 (29.7%) hepatocellular cancer, 11 (17.2%) secondary cancer and one (1.6%) each hemangioendothelioma, hepatoblastoma and embryonal liver sarcoma]. Median donor and recipient follow-ups were 93 months (IQR 41-159) and 39 months (22-91), respectively., Results: Right and left hemi-livers were implanted in 39 (60.9%) and 25 (39.1%) cases, respectively. Median weights of right- and left-liver were 810 g (IQR 730-940) and 454 g (IQR 394-534), respectively. Graft-to-recipient weight ratios (GRWRs) were 1.17% (right, IQR 0.98%-1.4%) and 0.77% (left, 0.59%-0.95%). One- and five-year patient survivals were 85% and 71% (right) vs. 84% and 58% (left), respectively. One- and five-year graft survivals were 74% and 61% (right) vs. 76% and 53% (left), respectively. The patient and graft survival of right and left grafts and of very small (<0.6%), small (0.6%-0.79%) and large (≥0.8%) GRWR were similar. Survival of very small grafts was 86% and 86% at 3- and 12-month. No donor died while five (7.8%) developed a Clavien-Dindo complication IIIa, IIIb or IV. Recipient morbidity consisted mainly of biliary and vascular complications; three (4.7%) recipients developed a small-for-size syndrome according to the Kyushu criteria., Conclusions: Adult-to-adult LDLT is a demanding procedure that widens therapeutic possibilities of many hepatobiliary diseases. The donor procedure can be done safely with low morbidity. The recipient operation carries a major morbidity indicating an important learning curve. Shifting the risk from the donor to the recipient, by moving from the larger right-liver to the smaller left-liver grafts, should be further explored as this policy makes donor hepatectomy safer and may stimulate the development of transplant oncology., (Copyright © 2019 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of the study is to evaluate whether intra-operative induction with anti-lymphocytic serum (ALS) is superior to no induction in adult liver transplantation (LT)., Background: The efficacy of ALS induction remains inconclusive in LT, because of poorly designed trials., Methods: A randomized controlled trial was conducted, including 206 adults (>15 years) and comparing tacrolimus monotherapy (TAC, n = 109) and tacrolimus plus a single, intraoperative, high-dose (9 mg/kg), rabbit anti-T-lymphocyte globulins (ATLG; n = 97). All patients had similar follow-up, including Banff-scored biopsies. Rejection was considered clinically relevant and treated if pathologic and biochemical changes were concordant. The primary endpoint was immunosuppression minimization to monotherapy; secondary endpoints were biopsy-proven rejection, clinical rejection, patient (PS) and graft (GS) survival., Results: At 1 year, 79/81 (96.3%) ATLG and 101/102 (99.0%) TAC patients were steroid-free (P = 0.585); 28 (34.6%) ATLG, and 31 (30.4%) TAC patients were on double-drug immunosuppression (P = 0.633). One-year PS and GS of ATLG and TAC patients were 84% and 92% (P = 0.260) and 76% and 90% (P = 0.054).Despite significantly a fewer day-7 moderate-to-severe acute cellular rejections (ACR) in ATLG group (10.0% vs 24.0% in TAC group, P = 0.019), cumulative proportion of patients experiencing steroid-sensitive (11.3% ATLG vs 14.7% TAC, P = 0.539), steroid-resistant (2.1% ATLG vs 3.7% TAC, P = 0.686) and chronic rejection (1.0% ATLG vs 0.9% TAC, P = 1.000) were similar. ATLG administration brought about greater hemodynamic instability and blood products use (P = 0.001)., Conclusions: At 1 year from LT, ATLG induction did not significantly affect immunosuppressive load, treated rejection, patient, and graft survival. The observed adverse events justify a modification of dosing and timing of ATLG infusion. Long-term results are required to judge the ATLG possible benefits on immunosuppressive load and tolerance induction.

Background: Standard-criteria donation after circulatory death (DCD) kidney transplants (KTx) have higher primary nonfunction, delayed graft function (DGF), and rejection rates than age-matched donation after brain death (DBD) but similar graft survival. Data on expanded-criteria DCD are conflicting and many centers remain concerned regarding their use., Methods: In this single-center observational study with 5-year follow-up, we analyzed data from 112 primary DCD Maastricht category-III single KTx receiving similar organ preservation and maintenance immunosuppression. Patients were sorted as young DCD (donor <60 years, 72 recipients) or old DCD (donor ≥60 years, 40 recipients). Old DCD outcomes were compared with young DCD and to a DBD control group (old DBD, donor ≥60 years, 40 recipients)., Results: After 5 years, old DCD showed lower patient survival (66% vs 85%; P = 0.014), death-censored graft survival (63% vs 83%; P = 0.001), and Modification of Diet in Renal Disease estimated glomerular filtration rate (34, 27.0-42.0 mL/min per 1.73 m 2 vs 45.0, 33.0-58.0 mL/min per 1.73 m 2 ; P = 0.021) than young DCD with higher DGF (70% vs 47.2%; P = 0.029) and graft thrombosis (12.5% vs 1.4%; P = 0.021). Comparison between old DCD and old DBD showed similar 5-year patient survival (66% vs 67%; P = 0.394) and death-censored graft survival (63% vs 69%; P = 0.518) but higher DGF (70% vs 37.5%; P = 0.007) and lower estimated glomerular filtration rate (34, 27.0-42.0 mL/min per 1.73 m 2 vs 41, 40.0-42.0 mL/min per 1.73 m 2 ; P = 0.029). Multivariate Cox regression analysis showed that donor 60 years or older (hazard ratio, 3.135; 95% confidence interval, 1.716-5.729; P < 0.001) and induction with anti-IL2-receptor-α monoclonal antibody (hazard ratio, 0.503; 95% confidence interval, 0.269-0.940, P = 0.031 in favor of induction with rabbit antithymocyte globulin) are independent predictors of transplant loss., Conclusions: Overall, single KTx from DCD Maastricht category-III donors 60 years or older have inferior outcomes than KTx from donors younger than 60 years. Comparison with age-matched DBD showed similar patient and graft survivals. However, the discrepancy in graft function between DCD and DBD deserves further investigation., Competing Interests: The authors declare no funding or conflicts of interest.

Vascular tumours of the liver represent an underrated chapter of medical and surgical hepatology. These tumours cover a wide spectrum ranging from the frequent and most benign hepatic haemangioma (HH), via the rare and intermediately aggressive hepatic epithelioid haemangioendothelioma (HEHE) to the rare and most malignant hepatic haemangiosarcoma (HHS). In contrast to the treatment algorithms for hepatocellular and cholangiocellular cancer, the diagnostic and therapeutic approaches to HEHE and HHS are not well developed. The related uncertainty is explained by their rare occurrence and their protean clinical, morphological (imaging) and histopathological presentation and behaviour. This article gives an update about these particular tumours based on the analysis of the recent literature and of the studies on vascular tumours published by the European Liver Intestine Transplantation Association (ELITA)-European Liver Transplant Registry (ELTR). It focuses also on the place of liver transplantation (LT) in the respective therapeutic algorithms. The differential diagnosis between these vascular and other tumour types may be very difficult. Correct diagnosis is of utmost importance and is based on a high index of clinical suspicion and on the integration of clinical, radiological, histological [including immunohistochemistry (IHC) and molecular biology findings]. Surgery, be it partial or total hepatectomy (LT), should be proposed whenever possible, because it is the therapeutic mainstay. In HEHE, LT provides excellent results, with long-term disease-free survivals (DFS) reaching 75%. Good results can be obtained even in case of (frequent) extrahepatic spread. Based on the extensive ELITA-ELTR study a HEHE-LT prognostic score has been proposed in order to estimate the risk of recurrence after LT. In contrast, results of surgery and LT are extremely poor for HHS, for the almost invariably rapid recurrence (within 6 months) and related death within 2 years. LT remains a contraindication for HHS. Due to the still important recurrence rate after surgical resection (25% in HEHE and almost 100% in HHS), there is an urgent need to develop pharmacological treatments targeting angiogenic and non-VEGF angiogenic pathways. To date, some prospective pilot studies and case reports have shown some short-term stabilisation of the disease in small groups of patients. In order to make progress, combination of surgery, anti-angiogenic and immunotherapy seems worthwhile. To complete the panel of vascular liver tumours, infantile haemangioendothelioma, haemangiopericytoma, nodular regenerative hyperplasia (NRH) and hepatic small vessel neoplasms (HSVN) are also discussed., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Lifelong immunosuppression (IS) after liver transplantation is associated with severe adverse effects and increased recipients' morbidity and mortality. Clinical operational tolerance has been reported in up to 40% in very well-selected recipients. Longterm survival and cost savings within the Italian national health system in operational tolerant recipients is reported. Seventy-five liver recipients were enrolled for IS withdrawal at our institution during the period from April 1998 to December 2015. The study population comprised 32 (42.7%) tolerant patients; 41 (54.7%) nontolerant patients needing uptake of IS after clinical or biopsy-proven rejection; and 2 (2.7%) immediate nontolerant patients who developed early rejection after the first drug reduction. The primary endpoint of the study was to assess the longterm patients and graft outcome; the secondary endpoint was the assessment of cost savings in the context of IS withdrawal. The follow-up was 95.0 months (interquartile range, 22.5-108.5 months). IS withdrawal did not result in patient nor graft loss and resulted in a major cost savings reaching about €630,000. In conclusion, longterm IS withdrawal represents a remarkable cost savings in the health care of liver recipients without exposing them to graft loss., (© 2018 by the American Association for the Study of Liver Diseases.)

The role of pathological findings after locoregional treatments as predictors of hepatocellular cancer recurrence after liver transplantation has been poorly addressed. The aim of the study was to identify the role of remnant vital tissue (RVT) of the target lesion in predicting hepatocellular cancer recurrence. Two hundred and seventy-six patients firstly undergoing locoregional treatment and then transplanted between January 2010 and December 2015 in four European Transplant Centres (i.e. Rome Tor Vergata, Birmingham, Brussels and Ancona) were enrolled in the study to investigate the role of pathological response at upfront locoregional treatment. At multivariable Cox regression analysis, RVT ≥2 cm was a strong independent risk factor for post-LT recurrence (HR = 5.6; P < 0.0001). Five-year disease-free survival rates were 60.8%, 80.9% and 95.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. When only Milan Criteria-IN patients were analysed, similar results were reported, with 5-year disease-free survival rates of 58.1%, 79.0% and 94.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. RVT is an important determinant of tumour recurrence after liver transplantation performed for hepatocellular cancer. Its discriminative power looks to be evident also in a Milan-IN setting, suggesting to more liberally use locoregional treatments also in these patients., (© 2018 Steunstichting ESOT.)

: This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 "low risk" cases, and may serve as reference to assess outcome of single or any groups of patients., Objective: To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups., Background: Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative., Methods: Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score ≤20 points, a balance of risk score ≤9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff., Results: Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were ≤4 days for ICU stay, ≤18 days for hospital stay, ≤59% for patients with severe complications (≥ Grade III) and ≤42.1 for 1-year CCI. Comparisons with the next higher risk group (model for end stage liver disease 21-30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values., Conclusions: Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.

Background and Objectives: Renal transplant recipients (RTRs) have a 2- to 7-fold risk of developing a neoplasm compared to general population. Bladder urothelial neoplasms in this cohort has an incidence of 0.4-2%. Many reports describe a more aggressive behavior. The objective of this study is to describe oncologic characteristics of bladder urothelial neoplasms in RTRs and to evaluate its recurrence, progression, and survival rates., Methods: A retrospective multicentered study was performed evaluating all de novo bladder urothelial neoplasms cases in RTRs from 1988 to 2014. Descriptive statistical analysis and evaluation of recurrence, progression, and survival rates were performed., Results: A total of 28 de novo bladder transitional cell carcinomas (TCCs) were identified (incidence rate 0.64%). Cancer-specific survival rates were 100, 75, and 70% after 1, 5, and 10 years, respectively. Age at diagnosis superior to 60 years was found to be a statistically significant variable for recurrence risk. Progression rate was 14%. Presence of CIS was significantly associated with progression. All cancer-specific deaths were in the high-risk group and all were progressions from non-muscle invasive to muscle invasive bladder cancer., Conclusions: Bladder urothelial neoplasms following renal transplant is associated with a trend toward worst prognosis. Early aggressive treatments, such as early radical cystectomy, might be advisable to reduce cancer-specific deaths., (© 2018 S. Karger AG, Basel.)

The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing to discriminate between "high-" and "low-benefit" patients. To do so, the concept of intention-to-treat (ITT) survival benefit of LT has been created. Data of 2,103 adult HCC patients consecutively enlisted during the period 1987-2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non-LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (Model for End-Stage Liver Disease, alpha-fetoprotein, Milan-Criteria status, and radiological response) displayed a high effect in terms of delta benefit. According to these risk factors, four benefit groups were identified. Patients with three to four factors ("no-benefit group"; n = 405 of 2,103; 19.2%) had no benefit of LT compared to alternative treatments. Conversely, patients without any risk factor ("large-benefit group"; n = 108; 5.1%) yielded the highest benefit from LT reaching 60 months., Conclusion: The ITT transplant survival benefit presented here allows physicians to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equitable method of organ allocation. Patients without benefit should be de-listed, whereas patients with large benefit ratio should be prioritized for LT. (Hepatology 2017;66:1910-1919)., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: The use of des-gamma-carboxy prothrombin (DCP) as a predictor of the risk of recurrence of hepatocellular cancer (HCC) after liver transplant (LT) has recently gained interest, especially in view of the recent extension of the eligibility criteria of these patients for LT. The aim of the present study is to look into this important matter based on a systematic review and meta-analysis., Methods: A systematic literature review about the role of DCP in the specific setting of LT for HCC has been conducted., Results: Three selected studies, which showed a high rate of homogeneity (I2 = 0.0%), confirmed that the tumor marker DCP is a useful predictive factor, indicating a 5-fold increased risk for HCC recurrence after LT (p<0.001)., Conclusions: The meta-analysis enabled us to underline the importance of DCP in the refinement of the eligibility criteria of HCC patients for LT. This information, based on Japanese studies performed in the setting of living-donor LT only, needs further validation in the Western world both in the setting of post-mortem and living-donor LT.

Liver transplantation (LT) has originally been designed to treat hepatobiliary malignancies. The initial results of LT for hepatocellular cancer (HCC) were, however, dismal this mainly due to the poor patient selection procedure. Better surgical and perioperative care and, especially, the refinement of selection criteria led to a major improvement of results, making HCC nowadays (again!) one of the leading indications for LT. This evolution is clearly shown by the innumerable reports aiming to further extend inclusion criteria for LT in HCC patients. Nonetheless, the vast majority of papers only deals with morphologic (tumour diameter and number) and (only recently) biologic (tumour markers and response to locoregional treatment) parameters to do so. Curiously enough, the role of both the immune competent state of the recipient as well as the impact of both immunosuppression (IS) type and load has been very poorly addressed in this context, even if it has been shown for a long time, based on both basic and clinical research, that they all play a key role in the outcome of any oncologic treatment and in the development of de novo as well as recurrent tumours. This chapter aims to give, after a short introductive note about the currently used inclusion criteria of HCC patients for LT and about the role of IS in carcinogenesis, a comprehensive overview of the actual literature related to the impact of different immunosuppressive drugs and schemes on outcome of LT in HCC recipients. Unfortunately, up to now solid conclusions cannot be drawn due to the lack of high-level evidence studies caused by the heterogeneity of the studied patient cohorts and the lack of prospectively designed and randomized studies. Based on long-term personal experience with immunosuppressive handling in LT some proposals for further clinical research and practice are put forward. The strategy of curtailing and minimising IS should be explored in the growing field of transplant oncology taking thereby into account the immunological privilege of the liver allograft. These strategies will become more and more compelling when further extending the indications in which adjuvant chemotherapy will probably become an inherent part of the therapeutic scheme of HCC liver recipients., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The role of alpha-fetoprotein (AFP) in the specific setting of the diagnosis and prognosis of patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still controversial. Recently, a marked interest for this marker has been reported, mainly related to its ability to predict the outcome of HCC patients after LT. The growing number of papers in PubMed indicates that AFP has begun a "second life" in the particular context of LT. Looking at the most recent International Guidelines on HCC, it looks obvious that time is ripe to reevaluate the value of AFP in relation to its prognostic ability to identify HCC patients at high-risk for drop-out before and recurrence after LT. Many discrepancies exist worldwide regarding the use of biomarkers in HCC. In contrast to the Western world, AFP is widely used in Asian countries, the reason why being unclear. Indeed, in the (merely Western-dominated) HCC treatment algorithms, the role of AFP as a prognostic tumor marker is still considered to be "under investigation". One should however realize that the underestimation of the value of AFP in the LT context will hamper further refinements of both the liver allograft allocation process and the selection of the best candidates for this procedure. Moreover, AFP has an important role to play in the monitoring of bridging and/or downstaging procedures bringing eventually the patient to transplantation. So, time has come to reconsider the role and value of AFP (dynamics) in the field of transplant oncology., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Impaired would healing is a known adverse effect of chronic immunosuppression. Solid-organ transplant recipients undergoing major abdominal surgery have an increased risk of wound-related complications compared with the general population. In this subset of patients, surgical site infections and wound dehiscence must be aggressively treated to avoid sepsis, graft loss, and death. Recently, topical application of platelet-rich plasma has been proposed as an alternative therapeutic option to enhance wound healing in difficult cases. Unfortunately, randomized controlled trials evaluating the efficacy of platelet-rich plasma compared with standard or advanced wound management are lacking, and the literature mostly refers to anecdotal reports in patients with no evidence of wound infection. This report documents a kidney transplant recipient who experienced spontaneous bladder rupture because of gangrenous cystitis. After an exploratory laparotomy and bladder repair, the patient developed a deep surgical site infection by multidrug resistant Acinetobacter baumannii and extensive wound dehiscence. Advanced wound management and vacuum-assisted closure therapy were ineffective. Topical homologous platelet-rich gel was used resulting in significant wound healing, without infections or immunologic complications.

Objective: A novel and easy prognostic score based on the combination of pre-operatively available variables in patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) has been developed from a long waiting time (WT) training set and then validated in a short-WT set., Summary of Background Data: The role of radiological response to loco-regional therapies, alpha-fetoprotein modification, inflammatory markers, and length of WT has been recently shown to be important selection criteria for the risk of intention-to-treat (ITT)-death and recurrence., Methods: The training set consisted of 179 HCC patients listed for LT during the period January 2000 to December 2012 from the UCL Brussels Transplant Centre; the validation set consisted of 110 patients listed during the period January 2005 to December 2014 from the Ancona Liver Centre., Results: The proposed Time-Radiological-response-Alpha-fetoprotein-INflammation (TRAIN) score was the best predictor of microvascular invasion. A TRAIN score ≥1.0 excellently stratified both the investigated populations in terms of ITT and recurrence survivals. When compared with Milan criteria, the proposed score allowed obtaining an increase of potentially transplantable patients (+8.9% in training set and 24.6% in validation set) without additive recurrence risks., Conclusions: The proposed TRAIN score is an easy selection tool based on variables available before LT. This score enables the selection process to be refined in the 2 different scenarios of long and short WT. In case of longer WT, the score is better at predicting risk of death during the WT; in case of short WT, the score is better at identifying risk of post-LT recurrence.

Background: For more than forty years, graftectomy has been the standard treatment of spontaneous renal transplant rupture. However, recent evidences suggest that graft salvage strategies can be safely pursued, even in difficult cases., Case Presentation: We report on a thirty-nine-year-old woman who received a deceased donor kidney transplant and experienced spontaneous allograft rupture due to acute rejection. The rupture was further complicated by urinary leakage. The kidney and the ureter were successfully repaired. Eight years after transplantation, graft function is still excellent., Conclusion: Due to the lack of transplantable organs and the long time usually spent on the waiting list, graftectomy should be only considered in case of refractory haemodynamic instability or compromised graft viability.

Coupled plasma filtration adsorption (CPFA) is an extracorporeal treatment based on plasma filtration associated with an adsorbent cartridge and hemofiltration. CPFA is able to remove inflammatory mediators and it has been used to treat severe sepsis, septic shock and multiple organ dysfunction syndrome. Limited experience exists on the use of CPFA after solid organ transplantation. We report our experience with CPFA in 2 kidney transplant recipients with post-nephrolithotomy septic shock and severe unexplained rhabdomyolysis. In both the cases, excellent results were observed. In selected cases, CPFA can be safely and effectively used in patients with a solid organ transplant. However, additional studies are needed in this particular setting, to further investigate the potential role of CPFA for the treatment of other conditions associated with excessive inflammation, such as in rheumatologic disorders and delayed graft function., (© 2015 The Author(s) Published by S. Karger AG, Basel.)

Context: Obesity is characterized by decreased insulin-stimulated glucose uptake in muscle and shift from glucose to lipid oxidation, the so-called metabolic inflexibility. Biliopancreatic diversion (BPD), a mainly malabsorptive bariatric operation, determines a prompt improvement of insulin resistance, but the mechanisms are still unclear., Objective: We aimed to estimate the response of glucose transporter 4 (GLUT4) and hexokinase-II (HKII) gene expression to hyperinsulinemia before and after surgical treatment with a BPD or dietary-induced weight loss. The association with 24-hour energy expenditure and its different components-diet-induced thermogenesis (DIT), resting energy expenditure, physical activity (PA) of daily living, and physical exercise-was also determined. DESIGN, SETTING, AND MAIN OUTCOME MEASURES: Case-control study: 20 subjects, BPD vs diet-induced weight loss. Four subjects withdrew in the surgical arm and 1 subject withdrew in the dietary arm. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp. Energy expenditure was assessed by indirect calorimetry over 24 hours. Muscle biopsies were obtained during the clamp to measure gene expression: GLUT4 and HKII., Results: Insulin sensitivity increased significantly (P < .01) only after BPD (0.101 ± 0.012 to 0.204 ± 0.033 μmol/kg/min/pM). Enhanced GLUT4 and HKII mRNA levels were observed after surgery (P < .0001 and P = .021, respectively), whereas they were not affected by diet-induced weight loss. Carbohydrate oxidation (P = .0027), DIT (P = .033), PA (P = .036), and energy expenditure during the exercise (P = .017) increased only in the BPD group., Conclusions: BPD improved impaired glucose metabolism and insulin resistance through increased glucose uptake, glycogen synthesis, and glucose oxidation. Furthermore, the concomitant increase in DIT, PA, and exercise in BPD patients may partly explain their ability to sustained long-term weight loss and may contribute to the improved insulin sensitivity.

Background: The effectiveness of restrictive procedures has been inferior to that of malabsorbitive ones. Recent variants of restrictive procedures, i.e., gastric banding and sleeve gastrectomy, confirm the strive for more efficacious solutions with less complications. We investigated the balance between effectiveness and complications for a new restrictive procedure, a Transoral Endoscopic Vertical Gastroplasty (TOGa®), Methods: Seventy-nine morbidly obese patients were submitted to one out of three surgical procedures: TOGa® (29 patients), laparoscopic gastric bypass (LRYGBP; 20 patients), and biliopancreatic diversion (BPD; 30 patients). Mean BMI were 41.7 (35.4-46.6), 44.8 (36.4-54), and 47.5 (41-60.3), respectively. All the patients reached a 2-year follow-up., Results: In TOGa® group BMI, respectively at 12 and 24 months, was 34.5 and 35.5, with 44 and 48.3% of patients with BMI lower than 35. In LRYGBP group, BMI was 30.7 and 29.2 kg/m(2), with 80 and 85% of patients with BMI < 35. In BPD group, BMI was 30 and 29.6 kg/m(2), with 100 and 93.3% of patients with BMI < 35. In TOGa® group, 59% of patients with an initial BMI < 45 reached a BMI < 35, in comparison to 48% recorded in the whole group and to 14.3% in patients with initial BMI ≥ 45., Conclusions: In selected patients, TOGa®, was associated with good results after two years in terms of weight loss, even in comparison with LRYGBP and BPD. Minimal trauma, absence of complications, and short hospital stay justify this procedure for patients with low BMI.