To report on a concept of liver assessment during ex situ hypothermic oxygenated perfusion (HOPE) and its significant impact on liver utilization. An analysis of prospectively collected data on donation after circulatory death (DCD) livers, treated by HOPE at our institution, during a 11-year period between January 2012 and December 2022. Four hundred and fifteen DCD Maastricht III livers were offered during the study period in Switzerland, resulting in 249 liver transplants. Of those, we performed 158 DCD III liver transplants at our institution, with 1-year patient survival and death censored graft survival (death with functioning graft) of 87 and 89%, respectively, thus comparable to benchmark graft survivals of ideal DBD and DCD liver transplants (89% and 86%). Correspondingly, graft loss for primary non-function or cholangiopathy was overall low, i.e., 7/158 (4.4%) and 11/158 (6.9%), despite more than 82% of DCD liver grafts ranked high (6-10 points) or futile risk (>10 points) according to the UK-DCD score. Consistently, death censored graft survival was not different between low-, high-risk or futile DCD III livers. The key behind these achievements was the careful development and implementation of a routine perfusate assessment of mitochondrial biomarkers for injury and function, i.e., release of flavin mononucleotide from complex I, perfusate NADH, and mitochondrial CO₂ production during HOPE, allowing a more objective interpretation of liver quality on a subcellular level, compared to donor derived data. HOPE after cold storage is a highly suitable and easy to perform perfusion approach, which allows reliable liver graft assessment, enabling surgeons to make a fact based decision on whether or not to implant the organ. HOPE-treatment should be combined with viability assessment particularly when used for high-risk organs, including DCD livers or organs with relevant steatosis. This study was supported by the Swiss National Foundation (SNF) grant 320030_189055/1 to PD.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the sixth most diagnosed malignancy worldwide. Serum alpha-fetoprotein (AFP) is the traditional, ubiquitous biomarker for HCC. However, there has been an increasing call for the use of multiple biomarkers to optimize care for these patients. AFP, AFP-L3, and prothrombin induced by vitamin K absence II (DCP) have described clinical utility for HCC, but unfortunately, they also have well established and significant limitations. Circulating tumor DNA (ctDNA), genomic glycosylation, and even totally non-invasive salivary metabolomics and/or micro-RNAS demonstrate great promise for early detection and long-term surveillance, but still require large-scale prospective validation to definitively validate their clinical validity. This review aims to provide an update on clinically available and emerging biomarkers for HCC, focusing on their respective clinical strengths and weaknesses.

Increasing donor risk, particularly in liver transplantation, where organs are often marginal, has made dynamic organ preservation techniques and viability assessment essential to safely improve organ quality and increase utilisation. However, existing viability parameters are based on routine clinical assessment in patients with acute liver failure, trauma, or liver resections. These parameters often do not correlate with clinically relevant post-transplant outcomes. This article presents a detailed protocol for the spectrophotometric quantification of Flavin mononucleotide (FMN), a marker of mitochondrial injury. FMN release from mitochondrial complex I was described many decades ago as the initial sign of ischaemia-reperfusion injury, i.e. when oxygen is reintroduced in ischaemic tissues during organ transplantation or machine perfusion. This study describes the detailed FMN quantification in donor plasma and various fluids obtained during machine perfusion, and discusses confounders, challenges, and the role of individual test components. FMN quantification was identified as an immediate organ assessment tool, demonstrating a strong correlation with graft survival and other relevant complications after human liver transplantation. The results highlight FMN quantification as a reliable and standardized method for assessing organ viability, offering significant potential for improving organ selection and better utilisation. This method could provide better a predictive value for transplant outcomes compared to existing parameters currently in use. This research received no external funding but was supported by the Catalyst grant No. CCG0280 at Cleveland Clinic Ohio, U.S. dedicated to A.S.

Liver transplantation (LT) is a key treatment for primary and secondary liver cancers, reducing tumor burden with concurrent improvement of liver function. While significant improvement in survival is noted with LT, cancer recurrence rates remain high. Mitochondrial dysfunction caused by ischemia-reperfusion injury (IRI) is known to drive tumor recurrence by creating a favorable microenvironment rich in pro-inflammatory and angiogenic factors. Therefore, strategies that decrease reperfusion injury and mitochondrial dysfunction may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes and increased use of marginal grafts. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT. The current literature was screened for the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP (“ischemia free organ transplantation”) and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Three prospective randomized controlled trials are ongoing in Europe to provide robust evidence on the impact of HOPE on cancer recurrence in LT.

Machine perfusion technologies have redefined the landscape of organ preservation by enabling not just static cold storage, but graft optimization and assessment with the opportunity for additional therapeutic interventions. Preservation solutions, traditionally developed for static cold storage, are now being adapted for use in dynamic perfusion platforms. The optimal composition for machine perfusion remains unclear as we shift to creating biologically intelligent platforms tailored to mitigate ischemia–reperfusion injury. This review presents a mechanistic framework for understanding organ preservation through the lens of shared vulnerabilities, particularly: mitochondrial dysfunction, endothelial barrier breakdown, and the activation of inflammatory cascades. We discuss the evolution of classical preservation solutions, the rationale for redox-targeted and endothelial-stabilizing additives, and the promise of modular approaches adaptable to both static cold storage and machine perfusion. By integrating recent preclinical insights, systems biology, and emerging clinical trials, we outline the path toward unified, precision-preservation strategies capable of expanding the donor pool and improving transplant outcomes.

Background.: There is currently a supply and demand mismatch in liver transplantation, with more patients needing transplants than grafts available. The use of older donors is one potential way of expanding access to viable grafts. No national study has yet reported on outcomes of liver transplants with donors ≥70 y. Methods.: The US Scientific Registry of Transplant Recipients registry was queried for deceased donor LT (1988–2021). Balance-of-risk (BAR) score was calculated for each patient. The primary outcome was graft survival. Cubic spline curves were used to evaluate the full spectrum of donor ages. Results.: A total of 148 960 livers met inclusion criteria: 5414 (3.6%) from donors ≥70 y and 4291 (2.9%) recipients ≥70 y. Within the overall cohort, graft survival decreased with increased donor and recipient age. Median graft survival within donors ≥70 y improved over time from 2.2 y (interquartile range [IQR] 0.2–9.8 y) in 1987–1999 to 9.6 y (IQR 3.2–11.6 y) in 2010–2019 (P < 0.0001). Elderly donors had equivalent outcomes to donors 70 y. In low-risk recipients, evidenced by preallocation SOFT score <5, elderly donors had comparable outcomes to young (<40 y) and middle-aged donors (40–69 y). Increasing donor age was not associated with worse graft survival in transplants performed between 2010 and 2019. Conclusions.: Donors aged ≥70 y may be more comfortably considered for deceased donor liver transplantation, especially within low-risk recipients. The BAR and SOFT scores may be a useful guide for safely expanding the use of these theoretically riskier liver grafts.