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Liver transplantation is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. This has necessitated the adoption of innovative technologies and strategies to protect these higher-risk grafts from the deleterious effects of traditional preservation and ischaemia reperfusion injury (IRI). The advent of normothermic machine perfusion (NMP) and rapid growth in the clinical adoption of this technology has accelerated efforts to utilise NMP as a platform for therapeutic intervention to optimise donor livers. In this review we will explore the emerging preclinical data related to ameliorating the effects of IRI, protecting the microcirculation and reducing the immunogenicity of donor organs during NMP. Exploiting the window of opportunity afforded by NMP, whereby the liver can be continuously supported and functionally assessed while therapies are directly delivered during the preservation period, has clear logistical and theoretical advantages over current preservation methods. The clinical translation of many of the therapeutic agents and strategies we will describe is becoming more feasible with widespread adaptation of NMP devices and rapid advances in molecular biology and gene therapy, which have substantially improved the performance of these agents. The delivery of novel therapeutics during NMP represents one of the new frontiers in transplantation research and offers real potential for successfully tackling fundamental challenges in transplantation such as IRI.

Background Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes. Methods In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months). Discussion This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. Trial registration ISRCTN ISRCTN14957538. Registered in October 2022.

To mitigate COVID-19-related shortage of treatment capacity, the hepatopancreatobiliary (HPB) unit of the Royal Free Hospital London (RFHL) transferred its practice to independent hospitals in Central London through the North Central London Cancer Alliance. The aim of this study was to critically assess this strategy and evaluate perioperative outcomes. Prospectively collected data were reviewed on all patients who were treated under the RFHL HPB unit in six hospitals between November 2020 and October 2021. A total of 1541 patients were included, as follows: 1246 (81%) at the RFHL, 41 (3%) at the Chase Farm Hospital, 23 (2%) at the Whittington Hospital, 207 (13%) at the Princess Grace Hospital, 12 (1%) at the Wellington Hospital and 12 (1%) at the Lister Hospital, Chelsea. Across all institutions, overall complication rate were 40%, major complication (Clavien–Dindo grade ≥ 3a) rate were 11% and mortality rates were 1.4%, respectively. In COVID-19-positive patients (n = 28), compared with negative patients, complication rate and mortality rates were increased tenfold. Outsourcing HPB patients, including their specialist care, to surrounding institutions was safe and ensured ongoing treatment with comparable outcomes among the institutions during the COVID-19 pandemic. Due to the lack of direct comparison with a non-pandemic cohort, these results can strictly only be applied within a pandemic setting.

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality. Normothermic machine perfusion of the liver improved early graft function, demonstrated by reduced peak serum aspartate transaminase levels and early allograft dysfunction rates, and improved organ utilization and preservation times, although no differences were seen in graft or patient survival.

The shortage of donor livers considered suitable for transplantation has driven the development of novel methods for organ preservation and reconditioning. Machine perfusion techniques can improve the quality of marginal livers, extend the time for which they can be preserved and enable an objective assessment of their quality and viability. These benefits can help avoid the needless wastage of organs based on hypothetical concerns regarding quality. As machine perfusion techniques are gaining traction in clinical practice, attention has now shifted to their potential applications beyond transplantation. As well as providing an update on the current status of machine perfusion in clinical practice, this Perspective discusses how this technology is being used as a tool for therapeutic interventions including defatting of steatotic livers, immunomodulation and gene therapies.Ceresa et al. discuss machine perfusion technologies for liver preservation and transplantation, including the potential of hypothermic and normothermic machine perfusion to improve preservation time and organ quality, as well as the future applications of perfusion technologies.

One of the most common cancers worldwide, primary liver cancer remains a major cause of cancer-related mortality. Hepatocellular carcinoma and cholangiocarcinoma represent the majority of primary liver cancer cases. Despite advances in the development of novel anti-cancer therapies that exploit targets within the immune system, survival rates from liver cancer remain poor. Furthermore, responses to immunotherapies, such as immune checkpoint inhibitors, have revealed limited and variable responses amongst patients with hepatocellular carcinoma, although combination immunotherapies have shown recent breakthroughs in clinical trials. This has shifted the focus towards improving our understanding of the underlying immune and molecular characteristics of liver tumours that may influence their response to immune-modulating treatments. In this review, we outline the complex interactions that occur in the tumour microenvironment of hepatocellular carcinoma and cholangiocarcinoma, respectively, from a histopathological perspective. We explore the potential role of a classification system based on immune-specific characteristics within each cancer type, the importance of understanding inter- and intra-tumoural heterogeneity and consider the future role of histopathology and novel technologies within this field.

IntroductionD-MELD score, the product of donor age and preoperative MELD score, has been introduced as a potential predictive index of survival after othrotopic liver transplant (OLT). We created D-UKELD score, the product of donor age and preoperative UKELD score, estimated its role as a predictor of graft and patient survival post OLT and compared it with D-MELD score.MethodsWe included 849 OLTs from donation after brain death (DBD) in our analysis (January 2008 – Novemeber 2019). Data were collected concerning donor and recipient characteristics, and transplant characteristics and outcomes. D-MELD and D-UKELD scores were also calculated.ResultsTime-dependent receiver operating characteristic (ROC) analysis did not provide statistically significant area under the curve (AUC) at 1, 3 or 5 years post OLT concerning graft survival for either D-MELD or D-UKELD. It also did not yield. statistically significant AUC at 3 or 5 years post OLT regarding patient survival. However, AUC was statistically significant, although mediocre, at 1 year after OLT concerning patient survival for D-MELD (AUC: 0.615, 95% CI: 0.543–0.688) and D-UKELD (AUC: 0.594, 95% CI: 0.527–0.662). The optimal cut-off points from the ROC curves at 1 year after OLT were D-MELD>1012 and D-UKELD>2640 regarding patient survival. Recipients with D-MELD>1012 had worse patient survival within the first year (p=0.00006), which remained in the multivariable analysis (HR: 1.917, 95% CI: 1.06–3.465, p=0.031). Recipients with D-UKELD>2640 had worse patient survival within the first year as well (p=0.006), but this did not remain in the multivariable analysis (HR: 1.724, 95% CI: 0.952–3.121, p=0.072).ConclusionsD-MELD and D-UKELD scores have mediocre predictive ability in regards to 1-year patient survival post DBD OLT. D-MELD>1012 is independently associated with an almost double risk of death within the first year, but D-UKLED is not independently related to worse recipient survival.

To the Editor: In the article by van Rijn et al. (April 15 issue), 1 the authors report promising results showing that hypothermic oxygenated machine perfusion of livers can ameliorate ischemic organ damage and make more organs available for transplantation. Although there are reasons for optimism, 2 critical changes to operations, regulations, and incentives will determine if such technology can increase organ supply. Similar to these results, evidence has shown that hypothermic oxygenated machine perfusion of kidneys improves short-term outcomes after transplantation. 3 Despite wider adoption, the use of this approach remains uneven in the United States. Some organ-procurement organizations use hypothermic oxygenated . . .

Introduction: By perfusing a liver with oxygenated blood, medications and nutrients at 37C, normothermic machine perfusion (NMP) may improve outcomes after liver transplantation when compared with conventional static cold storage (SCS). Herein is reported the first randomised controlled trial (RCT) comparing continuous NMP with SCS in human liver transplantation. Additional work exploring the mechanisms behind the effects of NMP is also described. Methods: This multinational RCT was initiated by the Consortium for Organ Preservation in Europe (COPE) and involved seven European transplant centres. Adult DBD and type III DCD livers were randomly assigned (1:1) to continuous NMP or SCS. The primary end point was the difference in peak-AST, requiring 220 transplants (90% power). Secondary endpoints included: organ utilisation, preservation time, early allograft dysfunction (EAD), six month graft and patient survival and ischaemic cholangiopathy on MRCP. During NMP, perfusate and bile samples were collected and subsequently analysed to provide information regarding bile salt utilisation and identify markers that may indicate organ quality. Results: 272 livers (135 SCS, 137 NMP) were enrolled, consisting of 194 DBD and 78 DCD organs. 48 livers were discarded (32 SCS [15 DBD, 17 DCD] vs 16 NMP [10 DBD, 6 DCD]; p=0.01). NMP livers experienced significantly longer preservation times than SCS (7hr 21min vs 11hr 39min; p< 0.01). Despite this, better early graft function was observed in the NMP group with regards to peak AST (974 IU/L SCS vs 485IU/L NMP; p< 0.001) and EAD (29.9% SCS vs 12.6% NMP; p=0.002) with the magnitude of these effects being greater for DCD organs (p=0.02). No measurable difference was found in radiological rates of ischaemic cholangiopathy with no demonstrable correlation between MRCP findings and clinically relevant strictures. NMP livers were found to utilise bovine bile salts effectively with bile production and several other biochemical parameters found to correlate with graft quality. Discussion: NMP livers show better early graft function than SCS in terms of peak-AST and EAD, both of which are surrogates for long-term graft outcomes. This is despite better organ utilisation and longer preservation times in the NMP group. NMP can be used to predict organ quality although it is not possible to draw conclusions about markers that may predict viability. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality. The fact that the study has definitively met its primary endpoint should now enable the exploration of the technology's wider potential.