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BACKGROUND International travel for transplantation remains a global issue as countries continue to struggle in establishing self-sufficiency. In the United States (US), the United Network for Organ Sharing (UNOS) requires citizenship classification at time of waitlisting to remain transparent and understand to whom our organs are allocated. This study provides an assessment of patients who travel internationally for liver transplantation, and their outcomes, using the current citizenship classification employed by UNOS. METHODS Adult liver UNOS data from 2003-2019 was utilized. Patients were identified as citizens, noncitizen, nonresidents (NCNR), or noncitizen residents (NC-R) according to citizenship status. Descriptive statistics compared demographics among the waitlisted patients and demographics and donor characteristics among transplant recipients. A competing risks model was used to examine waitlist outcomes. The Kaplan-Meier method and Cox proportional hazards were used for posttransplant outcomes. RESULTS There were significant demographic differences according to citizenship group among waitlisted (n=125 652) and transplanted (n=71 536) patients. Compared with US citizens, NCNR was associated with a 9% increase in transplant (Subdistribution Hazard Ration (SHR) 1.09, 95% CI 1.00-1.18, p=0.04), and NC-R was associated with a 24% decrease transplant (SHR 0.76, 95% CI 0.72-0.79, p

BACKGROUND This study aimed to compare trends in use of drug overdose (DO) donors in adult versus pediatric liver transplants and the utilization of split liver transplantation in this donor population. METHODS The United Network for Organ Sharing database was reviewed for deceased donor liver transplants from March 2002 to December 2017. Recipients were categorized by donor mechanism of death. Donor splitting criteria was defined as age 3 times the normal limit, and body mass index ≤ 28 kg/m2. RESULTS Adult liver transplants from DO donors increased from 2% in 2002 to 15% in 2017, while pediatric liver transplants from DO donors only increased from

Despite refinements in surgical techniques for liver transplantation, liver size disparity remains one of the most common problems in patients. The general aim of this study is to estimate the size of liver volume and length of the liver in the midclavicular section and also estimate body parameters such as BMI, BSA, and BSI. The height and weight of patients going for abdominal CT were measured. The BSA, BSI and BMI were then calculated and compared to other measurements. Using MeVisLab software each patient liver volume was measured from their CT images.

Cirrhosis is characterized as the progress of regenerative nodules surrounded by fibrous bands in response to chronic hepatic injury and causes portal hypertension and end stage hepatic disease. Following liver injury, liver progenitor cells (LPCs) can be activated and differentiate into hepatocytes in order to awaken liver regeneration and reach homeostasis. Recent research has uncovered some new sources of LPCs. Here, we update the mechanisms of LPCs-mediated liver regeneration in cirrhosis by introducing the origin of LPCs and LPCs' niche with a discussion of the influence of LPC-related cells. This article analyzes the mechanism of regeneration and activation of LPCs in cirrhosis in recent years aiming to provide help for clinical application. Copyright (C) 2020, Chongqing Medical University. Production and hosting by Elsevier B.V.

Cirrhosis is characterized as the progress of regenerative nodules surrounded by fibrous bands in response to chronic hepatic injury and causes portal hypertension and end stage hepatic disease. Following liver injury, liver progenitor cells (LPCs) can be activated and differentiate into hepatocytes in order to awaken liver regeneration and reach homeostasis. Recent research has uncovered some new sources of LPCs. Here, we update the mechanisms of LPCs-mediated liver regeneration in cirrhosis by introducing the origin of LPCs and LPCs' niche with a discussion of the influence of LPC-related cells. This article analyzes the mechanism of regeneration and activation of LPCs in cirrhosis in recent years aiming to provide help for clinical application. Copyright (C) 2020, Chongqing Medical University. Production and hosting by Elsevier B.V.

Summary High‐risk combinations of recipient and graft characteristics are poorly defined for liver retransplantation (reLT) in the current era. We aimed to develop a risk model for survival after reLT using data from the European Liver Transplantation Registry, followed by internal and external validation. From 2006 to 2016, 85 067 liver transplants were recorded, including 5581 reLTs (6.6%). The final model included seven predictors of graft survival: recipient age, model for end‐stage liver disease score, indication for reLT, recipient hospitalization, time between primary liver transplantation and reLT, donor age, and cold ischemia time. By assigning points to each variable in proportion to their hazard ratio, a simplified risk score was created ranging 0–10. Low‐risk (0–3), medium‐risk (4–5), and high‐risk (6–10) groups were identified with significantly different 5‐year survival rates ranging 56.9% (95% CI 52.8–60.7%), 46.3% (95% CI 41.1–51.4%), and 32.1% (95% CI 23.5–41.0%), respectively (P, The retransplantation risk score.

There is enough clinical evidence that a T-tube use in biliary reconstruction at adult liver transplantation (LT) does not significantly modify the risk of biliary stricture/leak, and it may even sustain infective and metabolic complications. Thus, the policy on T-tube use has been globally changing, with progressive application of more restrictive selection criteria. However, there are no currently standardized indications in such change, and many LT Centers rely only on own experience and routine. A nation-wide survey was conducted among all the 20 Italian adult LT Centers to investigate the current policy on T-tube use. It was found that 20% of Centers completely discontinued the T-tube use, while 25% Centers used it routinely in all LT cases. The remaining 55% of Centers applied a selective policy, based on criteria of technical complexity of biliary reconstruction (72.7%), followed by low-quality graft (63.6%) and high-risk recipient (36.4%). A T-tube use > 50% of annual caseload was not associated with high-volume Center status (> 70 LT per year), an active pediatric or living-donor transplant program, or use of DCD grafts. Only 10/20 (50%) Centers identified T-tube as a potential risk factor for complications other than biliary stricture/leak. In these cases, the suspected pathogenic mechanism comprised bacterial colonization (70%), malabsorption (70%), interruption of the entero-hepatic bile-acid cycle (50%), biliary inflammation due to an indwelling catheter (40%) and gut microbiota changes (40%). In conclusion, the prevalence of T-tube use among the Italian LT Centers is still relatively high, compared to the European trend (33%), and the potential detrimental effect of T-tube, beyond biliary stricture/leak, seems to be somehow underestimated.

Purpose of review This article will summarize prior and recent studies comparing outcomes between living donor and deceased donor liver transplantation (LT) in adults and provide a rationale and framework for expanding living donor liver transplantation (LDLT) in Western countries to address the growing critical organ shortage. Recent findings There is a growing body of evidence demonstrating superior survival outcomes in LDLT in addition to a multitude of other advantages including shorter cold ischemia times, opportunity for pretransplant medical optimization, and expansion of transplant eligibility. Additionally, these outcomes continue to improve with center volume and experience. Summary LDLT in adults emerged in response to an effective donor organ shortage created by the critical discrepancy between donor graft supply and demand. Overcoming this organ shortage and an increasing waitlist mortality requires a liver transplant framework that fully integrates LDLT into liver disease management although continuing to fully maximize deceased donor graft utilization at experience, capable centers. Optimizing both living and deceased donor graft utilization will drastically increase patients' access to LT.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide and the search for clinically useful biomarkers is ongoing. Neighbor of Punc E11 (NOPE) is an established biomarker of murine HCC that remains undetectable in normal liver and at preneoplastic stages. OBJECTIVE: The aim of our study was to evaluate the presence of NOPE in human HCC. METHODS: Histologically confirmed HCC and corresponding non-tumor liver samples from 20 patients were analyzed for expression of NOPE using qRT-PCR and mRNA-in-situ technology in a conserved tissue context. RESULTS: In our cohort, 30% of HCC samples were expressing NOPE which proved particularly useful in non-cirrhotic HCC samples with up to 155-fold higher expression than in adult liver. Using mRNA-in-situ technology, NOPE was clearly identified within epithelial tumor cells of NOPE positive human HCCs. In our analyzed cohort, the combination of AFP with NOPE did not reach more than 40% sensitivity while GPC-3 and NOPE were complementary to each other reaching a combined sensitivity of 85.7%. CONCLUSIONS: This is the first characterization of NOPE as a potential biomarker for human HCC. Our results underline the value of NOPE as a complementing biomarker for human HCC.

Objectives Thrombocytopenia is a common problem among liver transplant recipients. However, various patterns of change in platelet counts during adult liver transplant have been reported in the literature. This study aimed to evaluate alterations in platelet count according to the surgical phase (preanhepatic, anhepatic, after reperfusion) and during the early postoperative period of liver transplant. Materials and methods Perioperative data from 100 patients undergoing deceased donor liver transplant were reviewed, including platelet count-related data. Platelet counts were measured at predefined time points throughout the procedure: immediately before induction of anesthesia, at the early neo-hepatic stage (10 min after graft reperfusion), immediately after admission to the intensive care unit posttransplant, and 6 hours posttransplant. Platelet counts were then measured daily during stay in the intensive care unit. Results Mean baseline platelet count before transplant and anesthesia was 97.92 × 109/L. A peak platelet count was seen in the early neo-hepatic stage. Platelet counts then decreased sharply in the first 6 hours after transplant. A slight decrease in platelet counts continued until the third day after the surgery; finally, on day 6 posttransplant, platelet counts increased significantly. Conclusions Our study showed a significant sudden increase in platelet counts during the early neo-hepatic phase in many liver transplant recipients. Therefore, our results suggest that it is reasonable to avoid platelet transfusion for most liver transplant recipients during transplant surgery.

Liver grafts from pediatric donors represent a small fraction of grafts transplanted into adult recipients, and their use in adults requires special consideration of donor size to prevent perioperative complications. In the past, graft weight or volume ratios have been adopted from the living donor liver transplant literature to guide clinicians; however, these metrics are not regularly available to surgeons accepting deceased donor organs. In this study, we evaluated all pediatric-to-adult liver transplants in the United Network for Organ Sharing Standard Transplant Analysis and Research database from 1987 to 2019, stratified by donor age and donor-recipient height mismatch ratio (HMR; defined as donor height/recipient height). On multivariable regression controlling for cold ischemia time, age, and transplantation era, the use of donors from ages 0 to 4 and 5 to 9 had increased risk of graft failure (hazard ratio [HR], 1.81 [P

O sistema MELD está sedimentado no Brasil. O aumento do MELD para alocação, a influência de diferentes etiologias e o desequilíbrio na lista, secundários à concessão de situções especiais têm suscitado discussões para modernização do sistema. No Brasil, cada estado é responsável pela organização da captação de órgãos, resultando dm um sistema heterogêneo. Objetivo: Análise do tempo de espera e MELD necessário para transplante, o impacto das diferentes etiologias e concessão de situações especiais no âmbito do estado do Paraná. Método: Análise de 1248 transplantes de fígado adulto entre 2010 e 2018, estratificados conforme a etiologia, MELD e tempo de espera. Resultados: Idade de 52+11,4 anos. Tempo de espera em lista de 112+197 dias. 83,78% dos casos transplantaram em período inferior a seis meses. Situações especiais foram concedidas em 8,25% (n=103) dos casos; não houve Diferença significativa no tempo de espera em lista no grupo com (110+107) e sem (112+197) situação especial. MELD do transplante (19,69+7,86), MELD corrigido (22,24+6,42). Apesar de diferente entre grupos de etiologia, o MELD não apresentou padrão de crescimento com o passar do tempo. A etiologia álcool (27,08%) e infecções virais (23,56%) foram as mais frequentes. 29,75% dos transplantes foram realizados com MELD acima de 75%; não houve modificação das etiologias mais comuns nesse subgrupo. A oferta de órgãos cresceu de 8,9 pmp (2010) para 47,7 pmp (2017). Conclusão: O impacto do progressivo aumento do MELD e tempo de espera em lista, secundários à concessão de situações especiais não são observados na lista de espera no estado do Paraná. Essa discrepância provavelmente é secundária ao contínuo crescimento, de maneira quase paralela ao número de doadores e transplantes realizados.

PURPOSE OF REVIEW This article will summarize outcomes of prior immunosuppression withdrawal trials in pediatric and adult liver transplantation and provide updates on the current status of ongoing clinical tolerance studies including evolving strategies, such as identification of reliable biomarkers or immunomodulation to achieve an earlier onset and more robust level of operational tolerance. RECENT FINDINGS Clinical tolerance studies in liver transplantation have previously been limited by inconsistent and delayed success of immunosuppressive withdrawal, lack of substantial histological analysis from liver tissue biopsy, and the inability to translate mechanistic studies to reproducible clinical outcomes. Current clinical trials are attempting to overcome these hurdles through more comprehensive and guided immunosuppression withdrawal protocols. Novel and emerging technologies are enabling investigators to identify and validate potential biomarkers of tolerance in order to predict patient subpopulations disposed towards operational tolerance. Immune cell therapy using the adoptive transfer of various cell products have been shown to be feasible and well tolerated in early phase clinical trials and ongoing. SUMMARY Tolerance studies in liver transplantation are evolving and substantial progress has been made in overcoming the challenges that have prevented the widespread implementation of immunosuppression withdrawal protocols in the clinic. Identifying more sensitive and specific predictors of immunosuppression withdrawal success and tolerance induction strategies that will allow for early tolerance will advance the field tremendously towards the goal of promoting long-term allograft survival without immunosuppression.

Survival rates for patients following liver transplantation exceed 90% at 12 months and approach 70% at 10 years. Part 1 of this guideline has dealt with all aspects of liver transplantation up to the point of placement on the waiting list. Part 2 explains the organ allocation process, organ donation and organ type and how this influences the choice of recipient. After organ allocation, the transplant surgery and the critical early post-operative period are, of necessity, confined to the liver transplant unit. However, patients will eventually return to their referring secondary care centre with a requirement for ongoing supervision. Part 2 of this guideline concerns three key areas of post liver transplantation care for the non-transplant specialist: (1) overseeing immunosuppression, including interactions and adherence; (2) the transplanted organ and how to initiate investigation of organ dysfunction; and (3) careful oversight of other organ systems, including optimising renal function, cardiovascular health and the psychosocial impact. The crucial significance of this holistic approach becomes more obvious as time passes from the transplant, when patients should expect the responsibility for managing the increasing number of non-liver consequences to lie with primary and secondary care.

Background: Tacrolimus (TAC) is widely used after liver transplantation, but the therapeutic window is narrow. Objective: The purpose was to study both donor and recipient CYP3A5*3 genotypes affecting TAC apparent clearance rate (CL/F) and investigate a TAC population pharmacokinetic (PPK) model in Chinese liver transplant recipients for potential starting-dose individualized medication. Methods: A data set of 721 TAC concentrations was obtained from 43 adult liver transplant recipients. The TAC PPK model was analyzed using nonlinear mixed-effects modeling. Potential covariates, including demographic characteristics, physiological and pathological data, concomitant medications, and CYP3A5*3 genotype, were evaluated. The final model was validated using normalized prediction distribution errors and bootstrapping. Results: A 2-compartment model with first-order absorption and elimination was used to describe TAC disposition. Population estimates of TAC, CL/F, apparent central distribution volume (V2/F), rate of absorption (Ka), and apparent peripheral distribution volume (V3/F) were 18.1 L/h (12%), 72.7 L (34%), 0.163 h−1 (17%), and 412 L (21%), respectively. The model and estimated parameters were found to be stable. Other covariates did not influence TAC CL/F. Both donor and recipient CYP3A5*1 genotypes were significantly correlated with TAC clearance, and CL/F was 1.70-fold higher in both donor and recipient CYP3A5*1 carriers than in noncarriers among Chinese liver transplant recipients. Conclusion and Relevance: A PPK model of TAC was established in Chinese adult liver transplantation recipients for starting-dose individualized medication, which can be expanded to optimize clinical efficacy and minimize toxicity with therapeutic drug monitoring.

INTRODUCTION Liver transplant anesthesiology is an evolving and expanding subspecialty, and programs have, in the past, exhibited significant variations of practice at transplant centers across the United States. In order to explore current practice patterns, the Quality & Standards Committee from the Society for the Advancement of Transplant Anesthesia (SATA) undertook a survey of liver transplant anesthesiology program directors. METHODS Program directors were invited to participate in an online questionnaire. A total of 110 program directors were identified from the 2018 Scientific Registry of Transplant Recipients (SRTR) database. Replies were received from 65 programs (response rate of 59%). RESULTS Our results indicate an increase in transplant anesthesia fellowship training and advanced training in transesophageal echocardiography (TEE). We also find that the use of intraoperative TEE and viscoelastic testing is more common. However, there has been a reduction in the use of veno-venous bypass, routine placement of pulmonary artery catheters and the intraoperative use of anti-fibrinolytics when compared to prior surveys. CONCLUSION The results show considerable heterogeneity in practice patterns across the country that continues to evolve. However, there appears to be a movement towards the adoption of specific structural and clinical practices.

BACKGROUND A paucity of evidence exists regarding risks and benefits of extracorporeal membrane oxygenation (ECMO) in adult liver transplantation. METHODS This was a systematic review conducted from January 1, 2000 to April 24, 2020 of adult liver transplant recipients (pre- or post-transplant) and donors who underwent Veno-arterial or Veno-venous ECMO cannulation. Death was the primary outcome, with graft function and complications as secondary outcomes. RESULTS Forty-one articles were identified that fit criteria. A total of 183 donors were placed on ECMO, with recipient complication profiles and mortality that mirrored rates from standard criteria donors. Sixty-one recipients were placed on ECMO intraoperatively or postoperatively. Most patients experienced at least one complication with infections as the most common cause and minimal complications specifically related to ECMO use. Multisystem organ failure (MSOF) and infections were more common among liver recipients who died compared to those who survived. Overall mortality at 90 days was 45.9%. Causes of death were most commonly MSOF and infections. CONCLUSIONS ECMO use in adult liver transplantation is a useful adjunct. Recipient morbidity and mortality from donors placed on ECMO parallel that of recipients from standard criteria donors, and morbidity and mortality of recipients placed on ECMO are similar to other ECMO populations.

The use of extracorporeal life support (ECLS) is increasingly reported in adult liver transplantation (LT). However, neither the role of ECLS in the perioperative setting for LT nor its outcomes has been well defined. We performed a retrospective chart review of all adult LT patients at our institution who received ECLS from 2004 to 2021. We also conducted a comprehensive literature search for adult LT cases that involved perioperative ECLS for respiratory or cardiac failure. Over the study period, 11 LT patients required ECLS at our institution, two for respiratory and nine for cardiac failure. Both patients with respiratory failure received ECLS as a bridge to LT and survived to discharge. Nine patients required ECLS for acute cardiac failure either intraoperatively or postoperatively, and two survived to discharge. In the literature, we identified 35 cases of respiratory failure in LT patients requiring perioperative ECLS. Applications included preoperative bridge to LT (n = 6) and postoperative rescue (n = 29), for which overall survival was 44%. We identified 31 cases of cardiac failure in LT patients requiring either ECLS or cardiopulmonary bypass for cardiac support or rescue for intraoperative or postoperative cardiac failure (n = 30). There is evidence for consideration of ECLS as a bridge to LT in patients with potentially reversible respiratory failure or as rescue therapy for respiratory failure in posttransplant patients. ECLS has a prohibitively high risk of futility in pretransplant patients with cardiac failure but may have a role in LT patients with a functioning graft and potentially reversible cardiac failure.

In the early post-transplant period, severe liver allograft compression can lead to liver necrosis, vascular complications, and even primary nonfunction (1). Although this condition is more common in pediatric recipients, it has been described in adult liver transplant (LT), especially when a large liver allograft is transplanted in a small recipient cavity and for this reason it is known as large for size syndrome (LFS)(2, 3).

Machine perfusion (MP) is an expanding area of interest in experimental and clinical liver transplantation (LT). Varied technologies and procedures have been reported, and operational standards have yet to be established. We carried out a systematic literature review on use of machine perfusion (MP) in adult liver transplantation (LT) focusing on patients’ characteristics, post-transplant complications, and outcome. The goal of this review was to analyze all clinical studies on MP. We seek to report how many clinical studies on MP existed in literature, what was the MP setting, and results. MP was investigated both as hypothermic and normothermic. Only 2 randomized controlled trials have been found. The reported studies show great heterogeneity in trial endpoints, graft viability criteria, and efficacy parameters, thus underpinning the need for introduction of more accurate taxonomy and identification of more stringent experimental and clinical objectives.

Adult hepatic progenitor cells (HPCs)/oval cells are bipotential progenitors that participate in liver repair responses upon chronic injury. Recent findings highlight HPCs plasticity and importance of the HPCs niche signals to determine their fate during the regenerative process, favoring either fibrogenesis or damage resolution. Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) are among the key signals involved in liver regeneration and as component of HPCs niche regulates HPCs biology. Here, we characterize the TGF-β-triggered epithelial–mesenchymal transition (EMT) response in oval cells, its effects on cell fate in vivo, and the regulatory effect of the HGF/c-Met signaling. Our data show that chronic treatment with TGF-β triggers a partial EMT in oval cells based on coexpression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicates that TGF-β-induced EMT is not associated with stemness but rather represents a step forward along hepatic lineage. This phenotypic transition confers advantageous traits to HPCs including survival, migratory/invasive and metabolic benefit, overall enhancing the regenerative potential of oval cells upon transplantation into a carbon tetrachloride-damaged liver. We further uncover a key contribution of the HGF/c-Met pathway to modulate the TGF-β-mediated EMT response. It allows oval cells expansion after EMT by controlling oxidative stress and apoptosis, likely via Twist regulation, and it counterbalances EMT by maintaining epithelial properties. Our work provides evidence that a coordinated and balanced action of TGF-β and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives. Stem Cells 2019;37:1108–1118

Aims Tacrolimus is a narrow therapeutic range drug that requires fine dose adjustment, for which pharmacokinetic (PK) models have been amply proposed in renal, but not in liver, transplant recipients. This study aimed to build population PK models and Bayesian estimators (BEs) in adult de novo liver transplant patients receiving either the immediate-release (Prograf, twice daily, TD) or prolonged-release (Advagraf, once daily, OD) forms to help PK-guided dose individualization. Methods In total, 160 tacrolimus concentration-time profiles (1654 samples) were collected from 80 patients, at day 7 (D7) and week 6 (W6) post-transplant. Four population PK models were developed using in-parallel parametric and nonparametric approaches for each formulation and period post-transplant. The best limited sampling strategies for estimating the area-under-the-curve (AUC) were selected by comparing predicted values to an independent dataset. Finally, the doses required to reach AUC targets were estimated using each BE and compared to the doses obtained using the trapezoidal AUC. Results Tacrolimus PK was best described using a 1-compartmental model with first-order elimination and 2 γ-distributions to describe the absorption. In the validation datasets, Bayesian AUC estimates yielded mean bias/root mean squared prediction error of −5.06%/13.43% (OD D7), 2.25%/8.51% (OD W6), −2.36%/7.27% (TD D7) and 0.87%/9.07% (TD W6) for the in-parallel parametric approach; and 8.95%/17.84% (OD D7), −0.11%/10.13% (OD W6), 3.57%/18.40% (TD D7) and 4.48%/12.59% (TD W6) for the nonparametric approach. Conclusion The BEs and limited sampling strategies proposed here are able to predict accurately and precisely tacrolimus AUC in liver patients using only 3 plasma concentrations. The dosing methods are available on our ImmunoSuppressive Bayesian dose Adjustment website (www.pharmaco.chu-limoges.fr).

Knowledge of the size of the adult liver is an essential factor in diagnosing liver disease and in the monitoring of treatment response over time. Although there are multiple methods to determine liver size using ultrasound, currently, no clinical practice guideline exists. Recently, a reference range and equation to determine liver volume using ultrasound was developed. In order to guide the development of a clinical guideline, a scoping review was conducted in order to identify the potential barriers and facilitators to the implementation of this new measurement technique in clinical practice. A total of 40 articles were included in the review. The most commonly cited barriers to guideline adherence can be divided into categories that are related to individual barriers (knowledge and attitude) and external factors (guideline and environmental). The facilitators to overcome such barriers were also identified. It was reported that implementation is most beneficial when a range of strategies that aim to address the identified barriers are used. In conclusion, this scoping review has identified barriers and facilitators to aid in the development of interventions to improve sonographers' adherence to clinical practice guidelines in the clinical environment. Refereed/Peer-reviewed

A recent study using US national registry data reported, using Cox proportional hazards (PH) models, that split-liver transplantation (SLT) has improved over time and is no more hazardous than whole-liver transplantation (WLT). However, the study methods violated the PH assumption, which is the fundamental assumption of Cox modeling. As a result, the reported hazard ratios (HRs) are biased and unreliable. This study aimed to investigate whether the risk of graft survival (GS) in SLT has really improved over time, ensuring attention to the PH assumption. This study included 80,998 adult deceased donor liver transplantation (LT) (1998-2015) from the Scientific Registry Transplant Recipient. The study period was divided into 3 time periods: era 1 (January 1998 to February 2002), era 2 (March 2002 to December 2008), and era 3 (January 2009 to December 2015). The PH assumption was tested using Schoenfeld's test, and where the HR of SLT violated the assumption, changes in risk for SLT over time from transplant were assessed. SLT was performed in 1098 (1.4%) patients, whereas WLT was used in 79,900 patients. In the Cox PH analysis, the P values of Schoenfeld's global tests were

Background Routine use of (MBR) by Roux en Y in adult Orthotopic Liver Transplantation (OLT) has not been elucidated. The usual choice of enteric drainage got expected morbidities of biliary enteric anastomosis. Patients of liver transplant clinical differences are compared. Choices, current status, efficacy, application, short and long term outcome of biliary reconstruction by (MBR) roux en Y anastomosis in adult liver transplant was compared to Conventional roux en y. Aim The primary aim of the study is to clarify the influence to the diseased liver recipient duct to the future graft biliary drainage. Methods Study of consecutive liver transplant patients was retrieved. Total Number of 1234 OLT, By the End of July 2014. Group A 16 patients of Conventional Period up to 22 March, 2006. Group B 50 patients of (MBR) up to 31 JULY 2014. Results In group A 8/16 got short and long term complication. However, in group B only 4/50 got short term problems, with no death. Conclusion In Spite of the drawback of adult OLT roux en Y hepatico-jejunal anastomosis including anatomical challenges and graft position, we developed graft survival in adults liver transplant with widened application of (MBR). There is accessible and durable intact biliary drainage choice by (MBR) hepatica enteric anastomosis for adults OLT patients that can be encouraged and advised by microscopic surgery.

The aim of this systematic review and meta-analysis was to present the outcome of deceased adult liver transplantation from octogenarian (≥80 years old) donors compared to younger grafts.A systematic search was performed on six databases to identify all available original papers that report the outcome of adult recipients who underwent liver transplantation from a deceased octogenarian donor.Overall, 39,034 liver transplantations from 12 studies were reported with 789 (2.02%) cases receiving grafts from octogenarian donors. Eight studies were included in the meta-analysis. There was no difference regarding the one, three, and five-year graft and patient survival between the recipients of livers80 years old and octogenarian grafts. There were significantly more episodes of biliary complications in the recipients of octogenarian grafts (34/459; 7.4%) in comparison to the recipients of livers80 years old (372/37074; 1.0%) (OR 0.53; 95% CI = 0.35-0.81; P 0.004; IThe short- and medium-term graft and patient survival of octogenarian liver transplantation is not inferior compared to the liver transplantation with younger grafts, however with a higher rate of biliary complications.

BACKGROUND Data regarding marijuana (MJ) use among liver transplant (LT) candidates are limited. We set out to determine the incidence and pre- and post-LT outcomes of adult LT candidates with a self-reported history of MJ use. METHODS Baseline clinical characteristics, waitlist, and post-LT outcomes of adult LT candidates from January 2010 to March 2017 were compared. RESULTS Among 2690 LT candidates, 630(23%) and 298(11%) reported a history of MJ use and use within the past 12 months, respectively. Although the proportion of MJ users increased over time(β = .76, p = .03), the proportion listed and transplanted did not change. Listing for LT increased with male (OR 1.24, 95% CI 11.01-1.52), MELD score (OR 1.08, 95% CI 1.01-1.15), HCC (OR 1.83, 95% CI 1.39-2.41) but decreased among MJ users (OR 0.67, 95% CI 0.50-0.91, p = .01). The median time to listing was longer among MJ users compared to non-users (115 vs. 87 days, p

Hepatic, pancreatic, and biliary (HPB) organoids are powerful tools for studying development, disease, and regeneration. As organoid research expands, the need for clear definitions and nomenclature describing these systems also grows. To facilitate scientific communication and consistent interpretation, we revisit the concept of an organoid and introduce an intuitive classification system and nomenclature for describing these 3D structures through the consensus of experts in the field. To promote the standardization and validation of HPB organoids, we propose guidelines for establishing, characterizing, and benchmarking future systems. Finally, we address some of the major challenges to the clinical application of organoids.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3-null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5+ liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in Dkk3-null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog-signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling., publishedVersion

The development of large spontaneous portosystemic shunts (PSS) is a common finding in liver cirrhosis. The diversion of the portal flow through PSS directly into the caval system causes progressive liver atrophy and atretic changes of the portal vein. During both living and deceased donor liver transplantation (LT), persistence of large PSS has been associated to portal flow steal phenomena causing decreased patients and graft survival. Atretic changes of the portal vein and large PSS often coexist potentially representing a technical challenge during portal vein reconstruction. We herein describe (with a didactical video) an easy augmentation patch V-venoplasty used in the presence of atretic changes of the portal vein LT.

Gene editing to correct inherited liver disorders has promise for future therapeutic intervention, but lack of effective and safe delivery of the gene-editing machinery to hepatocytes complicates its clinical application. Two studies now report efficient delivery to the liver of non-human primates, providing proof of concept for novel treatment of inherited hypercholesterolaemia.

Highlights • The global pandemic of Coronavirus Disease 2019 has drastically affected liver transplantation programs worldwide. • There was a significant decrease in the number of organ donations and liver transplantations performed in France. • The North East area which was the main Coronavirus Disease 2019 cluster area had > 25% decrease of the multiorgan procurement and liver transplantations in 2020 compared to 2019., Background The global pandemic of Coronavirus Disease 2019 (COVID-19) has potentially affected liver transplantation (LT) programs worldwide. The aim of this study was to determine whether the COVID-19 outbreak affected organ donation and LT activity in France. Methods Data on the number of brain-dead donor procurements and adult liver transplantations were compared between two periods (1st January- 31st May 2019 vs. 1st January-31st May 2020). Main findings There was a 28% decrease in the number of organ donations in 2020 (543 in 2020vs. 752 organ donations in 2019). A 22% decrease in the number of liver transplantations was also observed: 435 in 2020 vs. 556 LTs in 2019. Overall, the North East area which was the main COVID-19 cluster area, had > 25% decrease of the multiorgan procurement (-33% compared to 2019), and liver transplantation (-26% compared to 2019) activities in 2020 Conclusion This analysis confirmed that during the COVID-19 outbreak there was a significant decrease in the number of organ donations and liver transplantations performed in France.

We aimed to clarify the normal values obtained by simultaneous use of shear wave imaging and strain imaging (combinational elastography) in liver and reveal how aging influences them. In our checkup center, 257 examinees were diagnosed with normal liver based on questionnaires about liver disease and their drinking history, liver function test results, and ultrasound B-mode study findings. We estimated the values of combinational elastography and considered the correlation between the values and age. A multivariate analysis was performed concerning several features and the liver fibrosis (LF) index. We divided examinees into a younger group (

De novo HCC following transplantation in a child is a rare occurrence. Even within the adult liver transplantation population, there are a limited number of published cases. In this report, we present a case of de novo HCC found in a child, post-multivisceral transplantation. A 19-year-old boy, at the age of one, received liver and small bowel transplantation due to short gut syndrome secondary to midgut volvulus and total parenteral nutrition-associated liver disease. Eighteen years later, he was found to have a large mass involving the right hepatic dome consistent with HCC. To the best of our knowledge, this is the second reported case after gut transplantation and the third case post-liver transplantation in the pediatric population.

Objective To identify factors that accurately predict 1-year survival for liver transplant recipients with a MELD score ≥40. Background Although transplant is beneficial for patients with the highest acuity (MELD ≥40), mortality in this group is high. Predicting which patients are likely to survive for >1 year would be medically and economically helpful. Methods The Scientific Registry of Transplant Recipients database was reviewed to identify adult liver transplant recipients from 2002 through 2016 with MELD score ≥40 at transplant. The relationships between 44 recipient and donor factors and 1-year patient survival were examined using random survival forests methods. Variable importance measures were used to identify the factors with the strongest influence on survival, and partial dependence plots were used to determine the dependence of survival on the target variable while adjusting for all other variables. Results We identified 5309 liver transplants that met our criteria. The overall 1-year survival of high-acuity patients improved from 69% in 2001 to 87% in 2016. The strongest predictors of death within 1 year of transplant were patient on mechanical ventilator before transplantation, prior liver transplant, older recipient age, older donor age, donation after cardiac death, and longer cold ischemia. Conclusions Liver transplant outcomes continue to improve even for patients with high medical acuity. Applying ensemble learning methods to recipient and donor factors available before transplant can predict survival probabilities for future transplant cases. This information can be used to facilitate donor/recipient matching and to improve informed consent.

Using grafts from extended criteria donors (ECDs) and donation after circulatory death (DCD) donors is a strategy to address organ shortage in liver transplantation (LT). We studied the characteristics and outcomes of ECD and DCD grafts. We retrospectively studied consecutive adults who underwent deceased donor LT between 2006 and 2019. ECD was defined using modified Eurotransplant criteria. Our primary outcomes were graft and patient survival. A total of 798 grafts were used for LT, of which 93.1% were donation after brain death (DBD; 59.9% were also ECD) and 6.9% were DCD grafts (49.1% were also ECD). Among DBD graft recipients, donors having33% liver steatosis or 3 ECD criteria resulted in poorer graft survival. Otherwise ECD graft recipients had similar graft and patient survival compared with non-ECD graft recipients. DCD graft recipients also had similar patient survival compared with DBD recipients. However, DCD grafts from an ECD appeared to have worse outcomes. DCD graft recipients experienced higher rates of early allograft dysfunction (50.9% versus 24.7%; P 0.001) and ischemic biliopathy (16.4% versus 1.5%; P 0.001) compared with DBD graft recipients. Use of DBD grafts from ECDs did not impact outcomes unless there was significant donor steatosis or 3 Eurotransplant criteria were met. DCD graft recipients have similar patient survival compared with DBD graft recipients as long as the donor was not an ECD. We recommend that DBD donors with 3 or more ECD features or33% steatosis and DCD donors with any ECD features be used with caution in adult LT.

The survival of liver transplantation (LT) recipients has been improved remarkably in short-term. The major causes of mortality in long-term include nonimmunological causes such as cardiovascular, de novo malignancy, chronic kidney disease, and recurrence of primary disease. Rejection-related mortality is rare in the long-term after LT. We discuss nonrejection causes of long-term morbidity/mortality, risk factors, and management strategies in LT recipients. In addition, we discuss osteoporosis, contraception, and pregnancy in LT recipients.

Objective: To assess long term graft and patient survival after donor liver retransplantation in children in Australia and New Zealand during 1986–2017; to determine the factors that influence survival. Design: Retrospective cohort analysis (registry data). Setting, participants: Australia and New Zealand Liver Transplant Registry data for all liver retransplantations in children (under 18 years of age), 1986–2017, in all four paediatric and six adult liver transplantation centres in the two countries. Main outcome measures: Graft and patient survival at one, 5, 10 and 15 years. Results: 142 liver retransplantations were undertaken in children (59 during 1986–2000, 83 during 2001–2017). Kaplan–Meier survival analysis indicated that survival was significantly greater during 2001–2017 than 1986–2000 (P

AIM. Posttransplant diabetes mellitus (PTDM) is a metabolic complication that usually occurs after liver transplantation (LT) due to immunosuppression. In this study, our aim was to identify PTDM incidence after LT in our center and the potential risk factors. MATERIALS AND METHODS. In this study, 238 adult LT patients were evaluated in terms of PTDM development. RESULTS. Of 238 patients included in the study, 170 (71.4%) were male, 68 (28.6%) were female and the mean age was 43.5± 13.7 years. Of all patients, PTDM developed in 24 (10.1%). Transient-Hyperglycemia (t-HG) was detected in 31 (13%) patients. PTDM and t-HG patients had a greater body weight than non-PTDM patients (BMI kg/m(2): 27.6± 5.3, 25.8± 4.3and 23.9± 3.3, respectively p

The mammalian liver possesses a remarkable regenerative ability. Two modes of damage response have been described: (1) The “oval cell” response emanates from the biliary tree when all hepatocytes are affected by chronic liver disease. (2) A massive, proliferative response of mature hepatocytes occurs upon acute liver damage such as partial hepatectomy (PHx). While the oval cell response has been captured in vitro by growing organoids from cholangiocytes, the hepatocyte proliferative response has not been recapitulated in culture. Here, we describe the establishment of a long-term 3D organoid culture system for mouse and human primary hepatocytes. Organoids can be established from single hepatocytes and grown for multiple months, while retaining key morphological, functional and gene expression features. Transcriptional profiles of the organoids resemble those of proliferating hepatocytes after PHx. Human hepatocyte organoids proliferate extensively after engraftment into mice and thus recapitulate the proliferative damage-response of hepatocytes. Modeling the regenerative ability of the liver in response to acute damage using long-term 3D organoid cultures in mice and human cells yields proliferative hepatocytes that are able to successfully engraft in animal models.

In liver transplantation, both cold and warm ischemia times are known to impact early graft function. The extraction time is a period during the initial phase of organ cooling which occurs during deceased donor procurement. During this time, the organ is at risk of suboptimal cooling. Whether donor extraction time, the time from donor aortic cross-clamp to removal of the donor organ from the body cavity has an effect on early graft function is not known.We investigated the effect of donor extraction time on early graft function in 292 recipients of liver grafts procured locally and transplanted at our center between June 2012 and December 2016. Early graft function was assessed using the model of early allograft function score in a multivariable regression model including donor extraction time, cold ischemia time, warm ischemia time, donor risk index, and terminal donor sodium.Donor extraction time had an independent effect on early graft function measured by the model of early allograft function score (coefficient, 0.021; 95% confidence interval, 0.007-0.035; P0.01; for each minute increase of donor extraction time). Besides donor extraction time, cold ischemia time, warm ischemia time, and donor risk index had a significant effect on early graft function.We demonstrate an independent effect of donor extraction time on graft function after liver transplantation. Efforts to minimize donor extraction time could improve early graft function in liver transplantation.