Rescue Liver Transplantation for Posthepatectomy Liver Failure: A Systematic Review and Survey of an International Experience.

BACKGROUND: Rescue liver transplantation (LT) is the only life-saving option for posthepatectomy liver failure (PHLF) whenever it is deemed as irreversible and likely to be fatal. The goals were to perform a qualitative systematic review of rescue LT for PHLF and a survey among various international LT experts. METHODS: A literature search was performed from 2000 to 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Population, Intervention, Comparison, Outcome framework, and to this, the authors' experience was added. The international online open survey included 6 cases of PHLF extracted from the literature and submitted to 976 LT experts. The primary outcome was whether experts would consider rescue LT for each case. Interrater agreement among experts was calculated using the free-marginal multirater kappa methodology. RESULTS: The review included 40 patients. Post-LT mortality occurred in 8 (20%) cases (7/28 with proven cancer and 1/12 with benign disease). In the long term, 6 of 21 (28.6%) survivors with cancer died of recurrence (median = 38 mo) and 15 (71.4%) were alive with no recurrence (median = 111 mo). All 11 survivors with benign disease were alive and well (median = 39 mo). In the international survey among experts in LT, the percentage agreement to consider rescue LT was 28%-98%, higher for benign than for malignant disease ( P = 0.011). Interrater agreement for the primary endpoint was low, expected 5-y survival >50% being the strongest independent predictor to consider LT. CONCLUSIONS: Rescue LT for PHLF may achieve good results in selected patients. Considerable inconsistencies of decision-making exist among LT experts when considering LT for PHLF.

Liver transplant selection criteria and outcomes in critically ill patients with ACLF.

Background & Aims: Retrospective studies have reported good results with liver transplantation (LTx) for acute-on-chronic liver failure (ACLF) in selected patients. The aim of this study was to evaluate the selection process for LTx in patients with ACLF admitted to the intensive care unit (ICU) and to assess outcomes. Methods: This prospective, non-interventional, single high-volume center study collected data on patients with ACLF admitted to the ICU between 2017-2020. Results: Among 200 patients (mean age: 55.0 ± 11.2 years and 74% male), 96 patients (48%) were considered potential candidates for LTx. Unfavourable addictology criteria (n = 76) was the main reason for LTx ineligibility. Overall, 69 patients were listed for LTx (34.5%) and 50 were transplanted (25% of the whole population). The 1-year survival in the LTx group was significantly higher than in the non-transplanted group (94% vs. 15%, p <0.0001). Among patients eligible for LTx, mechanical ventilation during the first 7 days of ICU stay and an increase in the number of organ failures at day 3 were associated with the absence of LTx or death (odds ratio 9.58; 95% CI 3.29-27.89; p <0.0001 for mechanical ventilation and odds ratio 1.87; 95% CI 1.08-3.24; p <0.027 for increasing organ failures). The probability of not being transplanted in patients with ACLF under mechanical ventilation is >85.4% in those experiencing an increase of 2 organ failures since admission or >91% if experiencing an increase >2 organ failures, at which point futility could be considered. Conclusion: This prospective analysis of outcomes of patients with ACLF admitted to the ICU highlights the drastic nature of selection in this setting. Unfavourable addictology criteria, mechanical ventilation and increasing number of organ failures since admission were predictive of absence of LTx, futility and death. Impact and implications: Liver transplantation (LT) is the best therapeutic option in selected cirrhotic patients admitted to the ICU with acute on chronic liver failure. However, the selection criteria are poorly described and based on retrospective studies. This is the first prospective study that aimed to describe the selection process for LT in a transplant center. Patients with ACLF should be admitted to the ICU and evaluated within a short period of time for LT. In the context of organ shortage, eligibility for LT and either absence of LT, futility of care or death are better clarified in our study. These are mainly determined by prolonged respiratory failure and worsening of organ failures since ICU admission. Considering worldwide variations in the etiology and definition of ACLF, transplant availability and a narrow therapeutic window for transplant further prospective studies are awaited.

Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival.

The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

Evidence for Alloimmune Sinusoidal Injury in De Novo Nodular Regenerative Hyperplasia After Liver Transplantation.

Posttransplant nodular regenerative hyperplasia (NRH) mostly remains unexplained. Microvascular injury due to antibody-mediated rejection (AMR) is suspected, but lack of donor specific antibody (DSA) testing makes it difficult to prove. Centered around a 1-year period of routine DSA testing, concomitant protocol, and indicated posttransplant liver biopsies (LB), recipients with NRH (n = 18) were compared with a matched control group (n = 36). All index, previous, and subsequent LB were reviewed. Both groups were similar in terms of demographics, timing of index LB, and DSA. In the index LB, the NRH group had higher sinusoidal C4d positivity (p = 0.029) and perisinusoidal fibrosis (p = 0.034), both independently associated with NRH (p = 0.038 and 0.050, respectively). Features of "possible" chronic AMR were detected in 28.5% of the NRH group without a known cause and 0% of the control group (p = 0.009). The NRH group had more preceding indicated LB with increased incidence of rejection and biliary obstruction pattern. In the follow-up histology, overall, sinusoidal and portal C4d positivity, sinusoidal microvasculitis, and perisinusoidal fibrosis were also higher (all p < 0.050). In conclusion, we provide evidence towards the hypothesis that some cases of posttransplant NRH are related to preceding active and persistent AMR. Large multicenter studies with protocol DSA testing are required to confirm.

HLA-DP diversity is associated with improved response to SARS-Cov-2 vaccine in hematopoietic stem cell transplant recipients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients show lower humoral vaccine responsiveness than immunocompetent individuals. HLA diversity, measured by the HLA evolutionary divergence (HED) metrics, reflects the diversity of the antigenic repertoire presented to T cells, and has been shown to predict response to cancer immunotherapy. We retrospectively investigated the association of HED with humoral response to SARS-CoV-2 vaccine in allo-HSCT recipients. HED was calculated as pairwise genetic distance between alleles at HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 loci in recipients and their donors. Low anti-spike IgG levels (<30 BAU/mL) were associated with short time from allo-SCT and low donor DPB1-HED, mostly related to donor DPB1 homozygosity. The diversity of donor HLA-DP molecules, assessed by heterozygosity or sequence divergence, may thus impact the efficacy of donor-derived CD4 T cells to sustain vaccine-mediated antibody response in allo-HSCT recipients.

TACE and conformal radiotherapy vs. TACE alone for hepatocellular carcinoma: A randomised controlled trial.

Background & Aims: Transcatheter arterial chemoembolisation (TACE) is recommended for patients with hepatocellular carcinoma devoid of macrovascular invasion or extrahepatic spread but not eligible for curative therapies. We compared the efficacy and safety of the combination of a single TACE and external conformal radiotherapy (CRT) vs. classical TACE. Methods: TACERTE was an open-labelled, randomised controlled trial with a 1:1 allocation rate to two or three TACE (arm A) or one TACE + CRT (arm B). Participants had a mean age of 70 years, and 86% were male. The aetiology was alcohol in 85%. The primary endpoint was liver progression-free survival (PFS) in the intention-to-treat population. The typical CRT schedule was 54 Gy in 18 sessions of 3 Gy. Results: Of the 120 participants randomised, 64 were in arm A and 56 in arm B; 100 participants underwent the planned schedule and defined the 'per-protocol' group. In intention-to-treat participants, the liver PFS at 12 and 18 months were 59% and 19% in arm A and 61% and 36% in arm B (hazard ratio [HR] 0.69; 95% CI 0.40-1.18; p = 0.17), respectively. In the per-protocol population, treated liver PFS tended to be better in arm B (HR 0.61; 95% CI 0.34-1.06; p = 0.081) than in arm A. Liver-related grade III-IV adverse events were more frequent in arm B than in arm A. Median overall survival reached 30 months (95% CI 23-35) in arm A and 22 months (95% CI 15.7-26.2) in arm B. Conclusions: Although TACE + CRT tended to improve local control, this first Western randomised controlled trial showed that the combined strategy failed to increase PFS or overall survival and led more frequently to liver-related adverse effects. Impact and implications: Hepatocellular carcinoma is frequently treated by arterial embolisation of the tumour and more recently by external radiotherapy. We tried to determine whether combination of the two treatments (irradiation after embolisation) might produce interesting results. Our results in this prospective randomised study were not able to demonstrate a beneficial effect of combining embolisation and irradiation in these patients. On the contrary, we observed more adverse effects with the combined treatment. Clinical Trials Registration: NCT01300143.

Indocyanine green fluorescence patterns of hepatocellular carcinoma correlate with pathological and molecular features.

BACKGROUND: Intraoperative Indocyanine Green Dye (ICG) routinely used in hepatobiliary surgery identifies different fluorescent patterns of hepatocellular carcinoma (HCC), a highly heterogeneous cancer. We aimed to correlate these patterns with gene mutations and extensive pathological features beyond the well-known tumor differentiation. METHODS: Between February 2017 and December 2019, 21 HCC in 16 consecutive patients who underwent intraoperative ICG fluorescence imaging were included. Pathological review was performed by one pathologist blinded to fluorescence features. Random forest machine learning algorithm correlated pathological features of the tumor, peritumoral and non-tumoral liver, and gene mutations from a 28 gene-panel with rim and intra-lesion fluorescence. RESULTS: Three HCC had negative intra-lesion and rim-like emission, 7 HCC had homogeneous pattern and 11 heterogeneous patterns in whom 3 with rim-like emission. Rim emission was associated with peritumoral vascular changes, lower differentiation and lower serum AFP level. Homogeneous intra-lesion fluorescence was associated with lower necrosis rate, thinner capsule, absence of peritumoral liver changes, and higher serum AFP level. Heterogeneous HCC without rim harbored lesser TP53 and ARID1A mutations. CONCLUSION: Tumoral and peri-tumoral fluorescence classification of HCC yielded a possible intraoperative pathological and molecular characterization. These preliminary observations could lead to intraoperative refinement in surgical strategy.

Nodular Regenerative Hyperplasia Is Not a Rare Condition After Liver Transplantation: Incidence, Predictive Factors, and Impact on Survival.

BACKGROUND: The objectives of this study were to evaluate incidence and to identify the risk factors of occurrence and the predictive factors of symptomatic forms of nodular regenerative hyperplasia (NRH) after liver transplantation (LT). METHODS: To identify risk factors of NRH following LT, we included 1648 patients transplanted from 2004 to 2018 and compared the patients developing NRH after LT to those who did not. To identify predictive factors of symptomatic NRH, we selected 115 biopsies displaying NRH and compared symptomatic to asymptomatic forms. Symptomatic NRH was defined as the presence of ascites, esophageal varices, hepatic encephalopathy, portal thrombosis, retransplantation, or death related to NRH. RESULTS: The incidence of NRH following LT was 5.1%. In multivariate analysis, the independent factor of developing NRH after LT was the donor's age (odds ratio [OR] = 1.02; confidence interval, 1.01-1.03; P = 0.02). Symptomatic forms occurred in 29 (25.2%) patients: 19 (16.5%) patients presented with ascites, 13 (11.3%) with esophageal varices, 4 (3.5%) with hepatic encephalopathy, and 8 (7%) with portal thrombosis. The median period before the onset of symptoms was 8.4 (1.5-11.3) y after LT. The spleen size at diagnosis/before LT ratio (OR = 12.5; 114.17-1.37; P = 0.0252) and thrombectomy during transplantation (OR = 11.17; 1.48-84.11; P = 0.0192) were associated with symptomatic NRH in multivariate analysis. CONCLUSIONS: NRH following LT is frequent (5.1%) and leads to symptomatic portal hypertension in 25.2% of patients. Using older grafts increases the risk of developing NRH after LT. Clinicians should screen for signs of portal hypertension, particularly in measuring spleen size.

Defining Surgical Difficulty of Liver Transplantation.

OBJECTIVE: To define technically Diff-LT. SUMMARY OF BACKGROUND DATA: Currently, there is no acknowledged definition of Diff-LT. METHODS: This retrospective study included all first consecutive liver-only transplantations performed in 2 centers from 2011 to 2015. Diff-LT was defined as the combination of the number of blood units transfused, cold ischemia time, and duration of operation, all at or above the median value of the entire population. The correlation of Diff-LT with short- (including the comprehensive complication index) and long-term outcomes was assessed. Outcomes were also compared to the 90-day benchmark cutoffs of LT. Predictors of Diff-LT were identified by multivariable analysis, first using only recipient data and then using all recipient, donor, graft, and surgical data. RESULTS: The study population included 467 patients. The incidence of Diff- LT was 18.8%. Diff-LT was associated with short-term outcomes, including the comprehensive complication index and mortality, but not with patient or graft long-term survival. Previous abdominal surgery, intensive care unitbound at the time of LT, split graft use, nonstandard arterial reconstruction, and porto-systemic shunt ligation were independent predictors of Diff-LT. The proportion of variables below the corresponding LT 90-day benchmark cutoffs was 8/13 (61.5%) for non-Diff-LT, and 4/13 (30.8%) for Diff-LT. CONCLUSIONS: Diff-LT, as defined, occurred frequently. Adjusting modifiable variables might decrease the risk of Diff-LT and improve the postoperative course. This definition of Diff-LT might be useful for patient information, comparison between centers and surgeons, and as a metric in future trials.

Tumors located in the central column of the liver are associated with increased surgical difficulty and postoperative complications following open liver resection for colorectal metastases.

BACKGROUND: To assess the impact of difficult location (based on preoperative computed tomography) of liver metastases from colorectal cancer (LMCRC) on surgical difficulty, and occurrence of severe postoperative complications (POCs). METHODS: A retrospective single-centre study of 911 consecutive patients with LMCRC who underwent hepatectomy by the open approach between 1998 and 2011, before implementation of laparoscopic surgery to obviate approach selection bias. LMCRC with at least one of the following four features on preoperative imaging: tumor invading the hepatocaval confluence or retro-hepatic inferior vena cava, centrally located (Segments 4,5,8) and >10 cm in diameter, abutting the supra-hilar area, or involving the paracaval portion or caudate process of Segment 1; were considered as topographically difficult (top-diff). Independent predictors of surgical difficulty assessed by number of blood units transfused, duration of ischemia, and number of sessions of pedicle clamping during surgery and of severe POCs were identified by multivariate analysis before, and after propensity score matching. RESULTS: Top-diff tumor location independently predicted surgical difficulty. Severe POCs were associated with the tumor location [top-diff vs. topographically non difficult (non top-diff)], preoperative portal vein embolization, and variables related to surgical difficulty. CONCLUSION: LMCRC in difficult location independently predicts surgical difficulty and severe POCs.

A systematic review of auxiliary liver transplantation of small-for-size grafts in patients with chronic liver disease.

Background & Aims: The shortage of liver grafts continues to worsen. Because the expanded use of small-for-size grafts (SFSGs) would substantially alleviate this shortage, we aimed to analyse the available knowledge on auxiliary liver transplantation (ALT) with SFSGs in patients with chronic liver disease (CLD) to identify opportunities to develop ALT with SFSGs in patients with CLD. Methods: This is a systematic review on ALT using SFSGs in patients with CLD. The review was completed by updates obtained from the authors of the retained reports. Results: Heterotopic ALT was performed in 26 cases between 1980 and 2017, none for SFGS stricto sensu, and auxiliary partial orthotopic liver transplantation (APOLT) in 27 cases (from 1999 to 2021), all for SFSG. In APOLT cases, partial native liver resection was performed in most of cases, whereas the second-stage remnant native liver hepatectomy was performed in 9 cases only. The median graft-to-body weight ratio was 0.55, requiring perioperative or intraoperative portal modulation in 16 cases. At least 1 complication occurred in 24 patients following the transplant procedure (morbidity rate, 89%). Four patients (4/27, 15%) died after the APOLT procedure. At the long term, 19 (70%) patients were alive and well at 13 months to 24 years (median, 4.5 years) including 18 with the APOLT graft in place and 1 following retransplantation. Conclusions: Despite high postoperative morbidity, and highly reported technical variability, the APOLT technique is a promising technique to use SFSGs in patients with CLD, achieving satisfactory long-term results. The results need to be confirmed on a larger scale, and a standardised technique could lead to even better results. Lay summary: At the cost of a high postoperative morbidity, the long-term results of APOLT for small-for-size grafts are good. Standardisation of the procedure and of portal modulation remain needed.

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.

BACKGROUND: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. METHODS: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. FINDINGS: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI -∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8-27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI -0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17-0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33-2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16-0·47] and 0·21 [0·13-0·32]). INTERPRETATION: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. FUNDING: The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

BACKGROUND: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-ß-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING: Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

The impact of advanced patient age in liver transplantation: a European Liver Transplant Registry propensity-score matching study.

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

Donor HLA Class 1 Evolutionary Divergence Is a Major Predictor of Liver Allograft Rejection : A Retrospective Cohort Study.

BACKGROUND: The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. OBJECTIVE: To assess the potential effect of donor or recipient HED on liver transplant rejection. DESIGN: Retrospective cohort study. SETTING: Liver transplant units. PATIENTS: 1154 adults and 113 children who had a liver transplant between 2004 and 2018. MEASUREMENTS: Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. RESULTS: In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. LIMITATION: The DSAs were measured only in children. CONCLUSION: Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. PRIMARY FUNDING SOURCE: Institut National de la Santé et de la Recherche Médicale.

2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation.

BACKGROUND: Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA). AIM: This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence. METHODS: Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations. RESULTS: Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4 weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1 year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen. CONCLUSIONS: These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.

Should we use liver grafts repeatedly refused by other transplant teams?

BACKGROUND & AIMS: In France, liver grafts that have been refused at least 5 times can be "rescued" and allocated to a centre which chooses a recipient from its own waiting list, outside the patient-based allocation framework. We explored whether these "rescued" grafts were associated with worse graft/patient survival, as well as assessing their effect on survival benefit. METHODS: Among 7,895 candidates, 5,218 were transplanted between 2009 and 2014 (336 centre-allocated). We compared recipient/graft survival between patient allocation and centre allocation, considering a selection bias and the distribution of centre-allocation recipients among the transplant teams. We used a propensity score approach and a weighted Cox model using the inverse probability of treatment weighting method. We also explored the survival benefit associated with centre-allocation grafts. RESULTS: There was a significantly higher risk of graft loss/death in the centre allocation group compared to the patient allocation group (hazard ratio 1.13; 95% CI 1.05-1.22). However, this difference was no longer significant for teams that performed more than 7% of the centre-allocation transplantations. Moreover, receiving a centre-allocation graft, compared to remaining on the waiting list and possibly later receiving a patient-allocation graft, did not convey a poorer survival benefit (hazard ratio 0.80; 95% CI 0.60-1.08). CONCLUSIONS: In centres which transplanted most of the centre-allocation grafts, using grafts repeatedly refused for top-listed candidates was not detrimental. Given the organ shortage, our findings should encourage policy makers to restrict centre-allocation grafts to targeted centres. LAY SUMMARY: "Centre allocation" (CA) made it possible to save 6 out of 100 available liver grafts that had been refused at least 5 times for use in the top-listed candidates on the national waiting list. In this series, the largest on this topic, we showed that, in centres which transplanted most of the CA grafts, using grafts repeatedly refused for top-listed candidates did not appear to be detrimental. In the context of organ shortage, our results, which could be of interest for any country using this CA strategy, should encourage policy makers to reassess some aspects of graft allocation by restricting CA grafts to targeted centres, fostering the "best" matching between grafts and candidates on the waiting list.