Hypothermic Oxygenated Perfusion Improves Extended Criteria Donor Liver Graft Function and Reduces Duration of Hospitalization Without Extra Cost: The PERPHO Study.

Few studies have evaluated the efficacy or the cost of hypothermic oxygenated perfusion (HOPE) in the conservation of extended criteria donor (ECD) grafts from donation after brain death (DBD) donors during liver transplantation (LT). We performed a prospective, monocentric study (NCT03376074) designed to evaluate the interest of HOPE for ECD-DBD grafts. For comparison, a control group was selected after propensity score matching among patients who received transplants between 2010 and 2017. Between February and November 2018, the HOPE procedure was used in 25 LTs. Immediately after LT, the median aspartate aminotransferase (AST) level was significantly lower in the HOPE group (724UI versus 1284UI; P = 0.046) as were the alanine aminotransferase (ALT; 392UI versus 720UI; P = 0.01), lactate (2.2 versus 2.7; P = 0.01) There was a significant reduction in intensive care unit stay (3 versus 5 days; P = 0.01) and hospitalization (15 versus 20 days; P = 0.01). The incidence of early allograft dysfunction (EAD; 28% versus 42%; P = 0.22) was similar . A level of AST or ALT in perfusate >800UI was found to be highly predictive of EAD occurrence (areas under the curve, 0.92 and 0.91, respectively). The 12-month graft (88% versus 89.5%; P = 1.00) and patient survival rates (91% versus 91.3%; P = 1.00) were similar. The additional cost of HOPE was estimated at € 5298 per patient. The difference between costs and revenues, from the hospital's perspective, was not different between the HOPE and control groups (respectively, € 3023 versus € 4059]; IC, -€ 5470 and € 8652). HOPE may improve ECD graft function and reduce hospitalization stay without extra cost. These results must be confirmed in a randomized trial.

Benefits of temporary portocaval shunt during orthotopic liver transplantation with vena cava preservation: A propensity score analysis.

During orthotopic liver transplantation (OLT), clamping of the portal vein induces splanchnic venous congestion and accumulation of noxious compounds. These adverse effects could increase ischemia/reperfusion injury and subsequently the risk of graft dysfunction, especially for grafts harvested from extended criteria donors (ECDs). Temporary portocaval shunt (TPCS) could prevent these complications. Between 2002 and 2013, all OLTs performed in our center were retrospectively analyzed and a propensity score matching analysis was used to compare the effect of TPCS in 686 patients (343 in each group). Patients in the TPCS group required fewer intraoperative transfusions (median number of packed red blood cells-5 versus 6; P = 0.02; median number of fresh frozen plasma-5 versus 6; P = 0.02); had improvement of postoperative biological parameters (prothrombin time, Factor V, international normalized ratio, alkaline phosphatase, and gamma-glutamyltransferase levels); and showed significant reduction of biliary complications (4.7% versus 10.2%; P = 0.006). Survival analysis revealed that TPCS improved 3-month graft survival (94.2% versus 88.6%; P = 0.01) as well as longterm survival of elderly (ie, age > 70 years) donor grafts (P = 0.02). In conclusion, the use of TPCS should be recommended especially when considering an ECD graft. Liver Transplantation 23 174-183 2017 AASLD.

Comparison of alternative arterial anastomosis site during liver transplantation when the recipient's hepatic artery is unusable.

Background: Few studies have analyzed outcomes of liver transplantation (LT) when the recipient hepatic artery (HA) was not usable. Methods: We retrospectively evaluated the outcomes of LT performed using the different alternative sites to HA. Results: Between 2002 and 2017, 1,677 LT were performed in our institution among which 141 (8.4%) with unusable recipient HA were analyzed. Four groups were defined according to the site of anastomosis: the splenic artery (SA group, n=26), coeliac trunk (CT group, n=12), aorta using or not the donor's vessel (Ao group, n=91) and aorta using a vascular prosthesis (Ao-P group, n=12) as conduit. The median number of intraoperative red blood cell transfusions was significantly increased in the Ao and Ao-P groups (5, 5, 8.5 and 16 for SA, CT, Ao and Ao-P group respectively, P=0.002), as well as fresh frozen plasma (4.5, 2.5, 10, 17 for the SA, CT, Ao and Ao-P groups respectively, P=0.001). Hospitalization duration was also significantly increased in the Ao and Ao-P groups (15, 16, 24, 26.5 days for the SA, CT, Ao and Ao-P groups respectively, P<0.001). The occurrence of early allograft dysfunction (EAD) (P=0.07) or arterial complications (P=0.26) was not statistically different. Level of factor V, INR, bilirubin and creatinine during the 7th postoperative days (POD) was significantly improved in the SA group. No difference was observed regarding graft (P=0.18) and patient (P=0.16) survival. Conclusions: In case of unusable HA, intraoperative and postoperative outcomes are improved when using the SA or CT compared to aorta.

Lateral cavo-caval shunt: an alternative veno-venous bypass in liver surgery.

When inferior vena cava (IVC) resection is mandatory during liver surgery, use of a veno-venous bypass (VVB) is usually required despite its specific related adverse events. We describe a safe and alternative technique which allows both derivation of the portal and the caval blood flow by performing a lateral cavo-caval shunt using a prosthetic graft.

High Intrapatient Variability of Tacrolimus Exposure in the Early Period After Liver Transplantation Is Associated With Poorer Outcomes.

BACKGROUND: Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT. METHODS: We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV < 40%) and high IPV (CV ≥ 40%). RESULTS: There were significantly more neurologic complications (31.2% vs 16.6%, P < 0.001), cardiovascular complications (19.7% vs 9.7%, P < 0.001), and acute renal failure requiring dialysis (8.5% vs 2.2%, P < 0.001) in the high CV group than in the low CV group. Moreover, graft survival was significantly poorer in the high CV group (hazard ratio, 1.42; 95% confidence interval, 1.04-1.95; P = 0.03). A pretransplantation elevated Model for End-Stage Liver Disease score (P < 0.001) and Child-Pugh grade (P < 0.001) were identified as risk factors for presenting a high CV. CONCLUSIONS: A high CV of TAC concentrations was found to be predictive of TAC-related toxicity and poorer survival.

Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study.

PURPOSE: Tacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TACblood), patients still present with acute cellular rejection or TAC-related toxic effects with concentrations within the therapeutic range. TAC concentration in peripheral blood mononuclear cells (TACPBMC) is considered as an efficient surrogate marker of TAC efficacy. However, it is still not applicable in daily practice. New TDM methods are therefore needed, especially during the early postoperative period. TAC is metabolized in the liver and eliminated through biliary excretion. We therefore hypothesised that TAC concentration measured in excreted bile (TACbileC) could be a relevant surrogate marker of its efficacy. METHODS: The Therapeutic Drug Monitoring of Tacrolimus Biliary Concentrations for Liver-Transplanted Patients (STABILE) study is a prospective monocentric trial. During the 7 first days after TAC therapy initiation, TACbileC was measured. The correlation between TACbileC and TACPBMC as well as between TACblood and TACPBMC was assessed. The correlations between TACbileC and liver graft function parameter or with occurrence of neurologic toxic effects were also evaluated. FINDINGS: Between May 2016 and April 2017, 41 patients were analyzed. TACbileC was significantly correlated with TACPBMC (r = 0.25, P = 0.007). However, a better correlation was found between TACPBMC and TACblood (r = 0.53, P < 0.001) and was confirmed in multivariate analysis. However, only TACbileC was significantly correlated with liver graft function, such as factor V (r = 0.40, P = 0.009) or bilirubin level (r = 0.21, P = 0.01), and significantly lower in patients presenting with neurologic toxic effects (P < 0.001). Receiver operating characteristic curve analysis found that a TACbileC level lower than 0.20 ng/mL on day 2 after TAC therapy initiation was a good predictive marker of occurrence of neurotoxic effects (AUC = 0.81). IMPLICATIONS: TACbileC is not a better surrogate maker of TAC activity than TACblood. However, TACbileC could help predict the occurrence of TAC toxic effects when a T-tube is inserted. ClinicalTrials.gov identifier: NCT02820259.

[Liver transplantation for hepatocellular carcinoma]. / Transplantation hépatique pour carcinome hépatocellulaire.

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver. It mostly develops on cirrhotic livers. Orthotopic liver transplantation is the only treatment that definitively addresses both the metachronous occurrence risk of HCC and the underlying disease. Under Milan criteria, i.e. less than 3 nodules of 3 cm max in diameter, or 1 nodule of 5 cm maximum, OLT has been shown effective and provides with survival rates almost equal to those obtained with HCC free cirrhotic patients. In Rennes, 195 patients with early HCC on cirrhotic livers have been transplanted from January 1995 to June 2005. Global and disease free 8 years patient survival rates were 73 and 70%, respectively. These results were significantly altered when the recipient was female, the cirrhosis due to C virus and the patient of B blood group. Despite these excellent results, the principal limit to the application of transplantation for HCC remains the long period of time patients have to wait for a graft. During this period of time, growth of the tumour may drop the patient out of Milan criteria and subsequently from the waiting list. The role of chemoembolisation, liver resection and thermal ablation while the patient is waiting for a graft remains debatable.

MELD-based graft allocation system fails to improve liver transplantation efficacy in a single-center intent-to-treat analysis.

BACKGROUND: Since March 2007, priority access to liver transplantation in France has been given to patients with the highest MELD scores. OBJECTIVE: To undertake an intent-to-treat comparison of center-based vs. MELD-based liver graft allocation. METHODS: Retrospective cohort analysis (patients listed 6th March 2007 to 5th March 2009; MELD period) with a matched historical cohort (patients listed 6th March 2005 to 5th March 2007; pre-MELD period) in a single high-volume center. Analysis was on an intent-to-treat basis, i.e. starting on the day of wait listing. RESULTS: Compared to pre-MELD, fewer patients with a MELD score less or equal to 14 (P=0.002), and more patients with a MELD greater or equal to 24 (P<0.05) were transplanted during the MELD period. For HCC candidates, median waiting time increased (121 vs. 54 days, P=0.01), transplantation rate halved (35% vs. 73.5%, P<0.001) and dropouts due to tumor progression increased (16% vs. 0%, P<0.001). Moreover, postoperative course did not change significantly except for infectious complications (35% vs. 24%, P=0.02); overall patient survival was 69.8 ± 3.1% vs. 76 ± 2.9% (P=0.29) and overall graft survival was 77.6 ± 3.4% vs. 82.8 ± 2.9% (P=0.29). Transplant failures were mainly due to deaths on the waiting list in the previous system, but to dropouts related to disease progression in the new system. Cirrhotic patient survival rate did not change (78.1 ± 4.4% vs. 73.5 ± 4.5%, P=0.42), while that of HCC patients decreased (65.3 ± 5.3% vs. 86.8 ± 4.4%, P=0.01). Post-transplant survival worsened significantly according to pre-transplant MELD score (P=0.009). CONCLUSION: The MELD-based graft allocation system introduced discrimination against HCC patients, whose incidence has increased dramatically, and should be reevaluated.

Risk factors for new-onset diabetes mellitus following liver transplantation and impact of hepatitis C infection : an observational multicenter study.

New-onset diabetes mellitus (NODM) remains a common complication of liver transplantation (LT). We studied incidence and risk factors in 211 French patients who had undergone a primary LT between 6 and 24 months previously. This is a cross-sectional and retrospective multicenter study. Data were collected on consecutive patients at a single routine post-LT consultation. Demographic details, immunosuppressive regimens, familial and personal histories, hepatitis status, and cardiovascular risk were analyzed to compare those who developed NODM (American Diabetes Association/World Health Organization criteria) with the others. The overall incidence of NODM was 22.7%: 24% in tacrolimus (Tac)-treated patients (n = 175; 82.9%) and 16.7% in cyclosporine-treated patients (n = 36; 17.1%). A total of 81% of the cases were diagnosed within 3 months of LT (M3). Among hepatitis C virus (HCV)-infected (HCV(+)) patients, NODM incidence was 41.7% whereas among those patients negative for this virus (HCV(-)), the incidence was only 18.9% (P = 0.008). In Tac-treated patients, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(-) patients (46.7% and 19.3%, respectively, P = 0.0014). Only 1 of 6 (16.7%) of the HCV(+) patients developed NODM on cyclosporine. Other independent pretransplantation risk factors for NODM included impaired fasting glucose (IFG) and a maximum lifetime body-mass index (BMI) over 25 kg/m2. In conclusion, emergence of NODM after LT is related to risk factors that can be detected prior to the graft, like maximum lifetime BMI, IFG, and HCV status. Tac induced a significantly higher incidence of NODM in the HCV(+) compared to the HCV(-) patients. The treatment should therefore be tailored to the patient's risk especially in case of HCV infection.

Cauda equina syndrome due to an intra-dural sacral cyst in type-1 Gaucher disease.

The authors report a rare case of type-1 Gaucher disease with neurological and haematological involvement. The first onset was epilepsy, the diagnosis of GD1 was then confirmed and the patient experienced parkinsonism. The biological analysis revealed monoclonal gammapathy and factor-II mutation. The patient's condition worsened due to cauda equina syndrome. Magnetic resonance imaging and surgery revealed an intra-thecal sacral cyst which, to our knowledge, has not been reported previously; therefore, when confronted with the fractures commonly observed in GD1, other unusual causes of spinal cord and root compression should not be overlooked.