Long-term Outcomes following Resection of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasm (A-IPMN) versus Pancreatic Ductal Adenocarcinoma (PDAC): A Propensity-score Matched Analysis.

OBJECTIVE: The aim of the present study was to compare long-term post-resection oncological outcomes between A-IPMN and PDAC. SUMMARY BACKGROUND DATA: Knowledge of long term oncological outcomes (e.g recurrence and survival data) comparing between adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) and pancreatic ductal adenocarcinoma (PDAC) is scarce. METHODS: Patients undergoing pancreatic resection (2010-2020) for A-IPMN were identified retrospectively from 18 academic pancreatic centres and compared with PDAC patients from the same time-period. Propensity-score matching (PSM) was performed and survival and recurrence were compared between A-IPMN and PDAC. RESULTS: 459 A-IPMN patients (median age,70; M:F,250:209) were compared with 476 PDAC patients (median age,69; M:F,262:214). A-IPMN patients had lower T-stage, lymphovascular invasion (51.4%vs. 75.6%), perineural invasion (55.8%vs. 71.2%), lymph node positivity (47.3vs. 72.3%) and R1 resection (38.6%vs. 56.3%) compared to PDAC(P<0.001). The median survival and time-to-recurrence for A-IPMN versus PDAC were 39.0 versus19.5months (P<0.001) and 33.1 versus 14.8months (P<0.001), respectively (median follow-up,78 vs.73 months). Ten-year overall survival for A-IPMN was 34.6%(27/78) and PDAC was 9%(6/67). A-IPMN had higher rates of peritoneal (23.0 vs. 9.1%, P<0.001) and lung recurrence (27.8% vs. 15.6%, P<0.001) but lower rates of locoregional recurrence (39.7% vs. 57.8%; P<0.001). Matched analysis demonstrated inferior overall survival (P=0.005), inferior disease-free survival (P=0.003) and higher locoregional recurrence (P<0.001) in PDAC compared to A-IPMN but no significant difference in systemic recurrence rates (P=0.695). CONCLUSIONS: PDACs have inferior survival and higher recurrence rates compared to A-IPMN in matched cohorts. Locoregional recurrence is higher in PDAC but systemic recurrence rates are comparable and constituted by their own distinctive site-specific recurrence patterns.

Precursor Epithelial Subtypes of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasms (A-IPMN): Clinicopathological Features, Recurrence and Response to Adjuvant Chemotherapy.

BACKGROUND: The clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown. METHODS: Clincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010-2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis. RESULTS: In total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31-1.01; p = 0.058]. CONCLUSIONS: Gastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype.

Adjuvant chemotherapy for adenocarcinoma arising from intraductal papillary mucinous neoplasia: multicentre ADENO-IPMN study.

BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.

A randomized trial of normothermic preservation in liver transplantation.

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.

Steatotic Donor Transplant Livers: Preservation Strategies to Mitigate against Ischaemia-Reperfusion Injury.

Liver transplantation (LT) is the only definitive treatment for end-stage liver disease, yet the UK has seen a 400% increase in liver disease-related deaths since 1970, constrained further by a critical shortage of donor organs. This shortfall has necessitated the use of extended criteria donor organs, including those with evidence of steatosis. The impact of hepatic steatosis (HS) on graft viability remains a concern, particularly for donor livers with moderate to severe steatosis which are highly sensitive to the process of ischaemia-reperfusion injury (IRI) and static cold storage (SCS) leading to poor post-transplantation outcomes. This review explores the pathophysiological predisposition of steatotic livers to IRI, the limitations of SCS, and alternative preservation strategies, including novel organ preservation solutions (OPS) and normothermic machine perfusion (NMP), to mitigate IRI and improve outcomes for steatotic donor livers. By addressing these challenges, the liver transplant community can enhance the utilisation of steatotic donor livers which is crucial in the context of the global obesity crisis and the growing need to expand the donor pool.

Invasive intraductal oncocytic papillary neoplasms (IOPN) and adenocarcimoma arising from intraductal papillary mucinous neoplasms (A-IPMN) of the pancreas: comparative analysis of clinicopathological features, patterns of recurrence and survival: a multicentre study.

BACKGROUND: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas are now considered a separate entity to intraductal papillary mucinous neoplasms (IPMN). Invasive IOPNs are extremely rare, and their recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown. METHODS: Consecutive patients undergoing pancreatic resection (2010-2020) for invasive IOPNs or adenocarcinoma arising from IPMN (A-IPMN) from 18 academic pancreatic centers worldwide were included. Outcomes of invasive IOPNs were compared with A-IPMN invasive subtypes (ductal and colloid A-IPMN). RESULTS: 415 patients were included: 20 invasive IOPN, 331 ductal A-IPMN and 64 colloid A-IPMN. After a median follow-up of 6-years, 45% and 60% of invasive IOPNs had developed recurrence and died, respectively. There was no significant difference in recurrence or overall survival between invasive IOPN and ductal A-IPMN. Overall survival of invasive IOPNs was inferior to colloid A-IPMNs (median time of survival 24.4 months vs. 86.7, months, p = 0.013), but the difference in recurrence only showed borderline significance (median time to recurrence, 22.5 months vs. 78.5 months, p = 0.132). Adjuvant chemotherapy, after accounting for high-risk features, did not reduce rates of recurrence in invasive IOPN (p = 0.443), ductal carcinoma (p = 0.192) or colloid carcinoma (p = 0.574). CONCLUSIONS: Invasive IOPNs should be considered an aggressive cancer with a recurrence rate and prognosis consistent with ductal type A-IPMN.

Risk of Recurrence after Surgical Resection for Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasia (IPMN) with Patterns of Distribution and Treatment: An International, Multicentre, Observational Study.

OBJECTIVE: This international multicentre cohort study aims to identify recurrence patterns and treatment of first and second recurrence in a large cohort of patients after pancreatic resection for adenocarcinoma arising from IPMN. SUMMARY BACKGROUND DATA: Recurrence patterns and treatment of recurrence post resection of adenocarcinoma arising from IPMN are poorly explored. METHOD: Patients undergoing pancreatic resection for adenocarcinoma from IPMN between January 2010 to December 2020 at 18 pancreatic centres were identified. Survival analysis was performed by the Kaplan-Meier log rank test and multivariable logistic regression by Cox-Proportional Hazards modelling. Endpoints were recurrence (time-to, location, and pattern of recurrence) and survival (overall survival and adjusted for treatment provided). RESULTS: Four hundred and fifty-nine patients were included (median, 70 y; IQR, 64-76; male, 54 percent) with a median follow-up of 26.3 months (IQR, 13.0-48.1 mo). Recurrence occurred in 209 patients (45.5 percent; median time to recurrence, 32.8 months, early recurrence [within 1 y], 23.2 percent). Eighty-three (18.1 percent) patients experienced a local regional recurrence and 164 (35.7 percent) patients experienced distant recurrence. Adjuvant chemotherapy was not associated with reduction in recurrence (HR 1.09;P=0.669) One hundred and twenty patients with recurrence received further treatment. The median survival with and without additional treatment was 27.0 and 14.6 months (P<0.001), with no significant difference between treatment modalities. There was no significant difference in survival between location of recurrence (P=0.401). CONCLUSION: Recurrence after pancreatic resection for adenocarcinoma arising from IPMN is frequent with a quarter of patients recurring within 12 months. Treatment of recurrence is associated with improved overall survival and should be considered.

Comparison of in-gel and in-solution proteolysis in the proteome profiling of organ perfusion solutions.

PURPOSE: The organ perfusion solution (perfusate), collected at clinically and temporally significant stages of the organ preservation and transplantation process, provides a valuable insight into the biological status of an organ over time and prior to reperfusion (transplantation) in the recipient. The objective of this study was to assess two bottom-up proteomics workflows for the extraction of tryptic peptides from the perfusate. EXPERIMENTAL DESIGN: Two different kinds of perfusate samples from kidney and liver trials were profiled using liquid chromatography-mass spectrometry (LC-MS/MS). The preparation of clean peptide mixtures for downstream analysis was performed considering different aspects of sample preparation; protein estimation, enrichment, in-gel and urea-based in-solution digestion. RESULTS: In-solution digestion of perfusate allowed identification of the highest number of peptides and proteins with greater sequence coverage and higher confidence data in kidney and liver perfusate. Key pathways identified by gene ontology analysis included complement, coagulation and antioxidant pathways, and a number of biomarkers previously linked to ischemia-reperfusion injury were also observed in perfusate. CONCLUSIONS: This study showed that in-solution digestion is a more efficient method for LC-MS/MS analysis of kidney and liver organ perfusion solutions. This method is also quicker and easier than in-gel digestion, allowing for greater sample throughput, with fewer opportunities for experimental error or peptide loss.

Preoperative planning and intraoperative real-time navigation with indocyanine green fluorescence in robotic liver surgery.

PURPOSE: We aimed at exploring indocyanine green (ICG) fluorescence wide spectrum of applications in hepatobiliary surgery as can result particularly useful in robotic liver resections (RLR) in order to overcome some technical limitations, increasing safety, and efficacy. METHODS: We describe our experience of 76 RLR performed between March 2020 and December 2022 exploring all the possible applications of pre- and intraoperative ICG administration. RESULTS: Hepatocellular carcinoma and colorectal liver metastases were the most common indications for RLR (34.2% and 26.7% of patients, respectively), and 51.3% of cases were complex resections with high IWATE difficulty scores. ICG was administered preoperatively in 61 patients (80.3%), intraoperatively in 42 patients (55.3%) and in both contexts in 25 patients (32.9%), with no observed adverse events. The most frequent ICG goal was to achieve tumor enhancement (59 patients, 77.6%), with a success rate of 94.9% and the detection of 3 additional malignant lesions. ICG facilitated evaluation of the resection margin for residual tumor and perfusion adequacy in 33.9% and 32.9% of cases, respectively, mandating a resection enlargement in 7.9% of patients. ICG fluorescence allowed the identification of the transection plane through negative staining in the 25% of cases. Vascular and biliary structures were visualized in 21.1% and 9.2% of patients, with a success rate of 81.3% and 85.7%, respectively. CONCLUSION: RLR can benefit from the routine integration of ICG fluoresce evaluation according to each individual patient and condition-specific goals and issues, allowing liver functional assessment, anatomical and vascular evaluation, tumor detection, and resection margins assessment.

Robotic central pancreatectomy: a systematic review and meta-analysis.

BACKGROUND: Central pancreatectomy is usually performed to excise lesions of the neck or proximal body of the pancreas. In the last decade, thanks to the advent of novel technologies, surgeons have started to perform this procedure robotically. This review aims to appraise the results and outcomes of robotic central pancreatectomies (RCP) through a systematic review and meta-analysis. METHODS: A systematic search of MEDLINE, Embase, and Web Of Science identified studies reporting outcomes of RCP. Pooled prevalence rates of postoperative complications and mortality were computed using random-effect modelling. RESULTS: Thirteen series involving 265 patients were included. In all cases but one, RCP was performed to excise benign or low-grade tumours. Clinically relevant post-operative pancreatic fistula (POPF) occurred in 42.3% of patients. While overall complications were reported in 57.5% of patients, only 9.4% had a Clavien-Dindo score ≥ III. Re-operation was necessary in 0.7% of the patients. New-onset diabetes occurred postoperatively in 0.3% of patients and negligible mortality and open conversion rates were observed. CONCLUSION: RCP is safe and associated with low perioperative mortality and well preserved postoperative pancreatic function, although burdened by high overall morbidity and POPF rates.

Systematic review, meta-analysis and single-centre experience of the diagnostic accuracy of intraoperative near-infrared indocyanine green-fluorescence in detecting pancreatic tumours.

BACKGROUND: During pancreatic resections assessing tumour boundaries and identifying the ideal resection margins can be challenging due to the associated pancreatic gland inflammation and texture. This is particularly true in the context of minimally invasive surgery, where there is a very limited or absent tactile feedback. Indocyanine green (ICG) fluorescence imaging can assist surgeons by simply providing valuable real-time intraoperative information at low cost with minimal side effects. This meta-analysis summarises the available evidence on the use of near-infrared fluorescence imaging with ICG for the intraoperative visualization of pancreatic tumours (PROSPERO ID: CRD42021247203). METHODS: MEDLINE, Embase, and Web Of Science electronic databases were searched to identify manuscripts where ICG was intravenously administered prior to or during pancreatic surgery and reporting the prevalence of pancreatic lesions visualised through fluorescence imaging. RESULTS: Six studies with 7 series' reporting data on 64 pancreatic lesions were included in the analysis. MINOR scores ranged from 6 to 10, with a median of 8. The most frequent indications were pancreatic adenocarcinoma and neuroendocrine tumours. In most cases (67.2%) ICG was administered during surgery. ICG fluorescence identified 48/64 lesions (75%) with 81.3% accuracy, 0.788 (95%CI 0.361-0.961) sensitivity, 1 (95%CI 0.072-1) specificity and positive predictive value of 0.982 (95%CI 0.532-1). In line with the literature, ICG fluorescence identified 5/6 (83.3%) of pancreatic lesions during robotic pancreatic resections performed at our Institution. CONCLUSION: This meta-analysis is the first summarising the results of ICG immunofluorescence in detecting pancreatic tumours during surgery, showing good accuracy. Additional research is needed to define optimal ICG administration strategies and fluorescence intensity cut-offs.

Noninvasive assessment of steatosis and viability of cold-stored human liver grafts by MRI.

PURPOSE: A shortage of suitable donor livers is driving increased use of higher risk livers for transplantation. However, current biomarkers are not sensitive and specific enough to predict posttransplant liver function. This is limiting the expansion of the donor pool. Therefore, better noninvasive tests are required to determine which livers will function following implantation and hence can be safely transplanted. This study assesses the temperature sensitivity of proton density fat fraction and relaxometry parameters and examines their potential for assessment of liver function ex vivo. METHODS: Six ex vivo human livers were scanned during static cold storage following normothermic machine perfusion. Proton density fat fraction, T1 , T2 , and T2∗ were measured repeatedly during cooling on ice. Temperature corrections were derived from these measurements for the parameters that showed significant variation with temperature. RESULTS: Strong linear temperature sensitivities were observed for proton density fat fraction (R2 = 0.61, P < .001) and T1 (R2 = 0.78, P < .001). Temperature correction according to a linear model reduced the coefficient of repeatability in these measurements by 41% and 36%, respectively. No temperature dependence was observed in T2 or T2∗ measurements. Comparing livers deemed functional and nonfunctional during normothermic machine perfusion by hemodynamic and biochemical criteria, T1 differed significantly: 516 ± 50 ms for functional versus 679 ± 60 ms for nonfunctional, P = .02. CONCLUSION: Temperature correction is essential for robust measurement of proton density fat fraction and T1 in cold-stored human livers. These parameters may provide a noninvasive measure of viability for transplantation.

Using Artificial Intelligence for Predicting Survival of Individual Grafts in Liver Transplantation: A Systematic Review.

The demand for liver transplantation far outstrips the supply of deceased donor organs, and so, listing and allocation decisions aim to maximize utility. Most existing methods for predicting transplant outcomes use basic methods, such as regression modeling, but newer artificial intelligence (AI) techniques have the potential to improve predictive accuracy. The aim was to perform a systematic review of studies predicting graft outcomes following deceased donor liver transplantation using AI techniques and to compare these findings to linear regression and standard predictive modeling: donor risk index (DRI), Model for End-Stage Liver Disease (MELD), and Survival Outcome Following Liver Transplantation (SOFT). After reviewing available article databases, a total of 52 articles were reviewed for inclusion. Of these articles, 9 met the inclusion criteria, which reported outcomes from 18,771 liver transplants. Artificial neural networks (ANNs) were the most commonly used methodology, being reported in 7 studies. Only 2 studies directly compared machine learning (ML) techniques to liver scoring modalities (i.e., DRI, SOFT, and balance of risk [BAR]). Both studies showed better prediction of individual organ survival with the optimal ANN model, reporting an area under the receiver operating characteristic curve (AUROC) 0.82 compared with BAR (0.62) and SOFT (0.57), and the other ANN model gave an AUC ROC of 0.84 compared with a DRI (0.68) and SOFT (0.64). AI techniques can provide high accuracy in predicting graft survival based on donors and recipient variables. When compared with the standard techniques, AI methods are dynamic and are able to be trained and validated within every population. However, the high accuracy of AI may come at a cost of losing explainability (to patients and clinicians) on how the technology works.

A Back-to-Base Experience of Human Normothermic Ex Situ Liver Perfusion: Does the Chill Kill?

Normothermic machine perfusion (NMP) has been shown to protect livers from injury between procurement and transplantation in a randomized controlled trial, where the machine was transported to and from the donor center. The aim of this study was to determine whether an alternative, more practical back-to-base approach after initial static cold storage would compromise beneficial outcomes. Between February 2015 and June 2018, a nonrandomized pilot study was performed at a single site. Outcomes of back-to-base livers (n = 26) were compared with those of grafts procured locally that underwent immediate NMP (n = 17). The primary outcome measure (safety) was defined as 30-day patient and graft survival. A total of 46 liver grafts were perfused with NMP, of which 3 were discarded based on poor ex situ perfusion function. The 30-day patient and graft survival in the back-to-base and local NMP groups were both 100% (primary outcome: safety). Despite significantly prolonged mean cold ischemia time (6 versus 3.2 hours; P = 0.001), the back-to-base livers demonstrated no difference in graft function, incidence of complications, or graft and patient survival. In conclusion, the back-to-base approach was safe, did not compromise the overall benefit of NMP, and offers a practical alternative to portable normothermic ex situ machine transport.

Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology.

Clinical adoption of normothermic machine perfusion (NMP) may be facilitated by simplifying logistics and reducing costs. This can be achieved by cold storage of livers for transportation to recipient centers before commencing NMP. The purpose of this study was to assess the safety and feasibility of post-static cold storage normothermic machine perfusion (pSCS-NMP) in liver transplantation. In this multicenter prospective study, 31 livers were transplanted. The primary endpoint was 30-day graft survival. Secondary endpoints included the following: peak posttransplant aspartate aminotransferase (AST), early allograft dysfunction (EAD), postreperfusion syndrome (PRS), adverse events, critical care and hospital stay, biliary complications, and 12-month graft survival. The 30-day graft survival rate was 94%. Livers were preserved for a total of 14 hours 10 minutes ± 4 hours 46 minutes, which included 6 hours 1 minute ± 1 hour 19 minutes of static cold storage before 8 hours 24 minutes ± 4 hours 4 minutes of NMP. Median peak serum AST in the first 7 days postoperatively was 457 U/L (92-8669 U/L), and 4 (13%) patients developed EAD. PRS was observed in 3 (10%) livers. The median duration of initial critical care stay was 3 days (1-20 days), and median hospital stay was 13 days (7-31 days). There were 7 (23%) patients who developed complications of grade 3b severity or above, and 2 (6%) patients developed biliary complications: 1 bile leak and 1 anastomotic stricture with no cases of ischemic cholangiopathy. The 12-month overall graft survival rate (including death with a functioning graft) was 84%. In conclusion, this study demonstrates that pSCS-NMP was feasible and safe, which may facilitate clinical adoption.

The future of organ perfusion and re-conditioning.

Organ preservation and re-conditioning using machine perfusion technologies continue to generate promising results in terms of viability assessment, organ utilization and improved initial graft function. Here, we summarize the latest findings and study the results of ex-vivo/ex-situ hypothermic (HMP) and normothermic machine perfusion (NMP) in the area of abdominal organ transplantation (kidney, liver, pancreas and intestine). We also consider the potential role of normothermic regional perfusion (NRP) to re-condition donors after circulatory death organs before retrieval. The findings from clinical studies reported to date suggest that machine perfusion will offer real benefits when compared with conventional cold preservation. Several randomized trials are expected to report their findings within the next 2 years which may shed light on the relative merits of different perfusion methods and could indicate which perfusion parameters may be most useful to predict organ quality and viability. Further work is needed to identify composite endpoints that are relevant for transplanted organs that have undergone machine preservation. Multi-centre trials to compare and analyse the combinations of NRP followed by HMP and/or NMP, either directly after organ retrieval using transportable devices or when back-to-base, are needed. The potential applications of machine preservation technology beyond the field of solid organ transplantation are also considered.

The case for normothermic machine perfusion in liver transplantation.

In recent years, there has been growing interest in normothermic machine perfusion (NMP) as a preservation method in liver transplantation. In most countries, because of a donor organ shortage, an unacceptable number of patients die while awaiting transplantation. In an attempt to increase the number of donor organs available, transplant teams are implanting a greater number of high-risk livers, including those from donation after circulatory death, older donors, and donors with steatosis. NMP maintains the liver ex vivo on a circuit by providing oxygen and nutrition at 37°C. This permits extended preservation times, the ability to perform liver viability assessment, and the potential for liver-directed therapeutic interventions during preservation. It is hoped that this technology may facilitate the enhanced preservation of marginal livers with improved posttransplant outcomes by reducing ischemia/reperfusion injury. Clinical trials have demonstrated its short-term superiority over cold storage in terms of early biochemical liver function, and it is anticipated that it may result in increased organ utilization, helping to reduce the number of wait-list deaths. However, further studies are required to demonstrate longer-term efficacy and the impact on biliary complications as well as further knowledge to exploit and maximize the potential of this exciting new technology. Liver Transplantation 24 269-275 2018 AASLD.

Cold storage or normothermic perfusion for liver transplantation: probable application and indications.

PURPOSE OF REVIEW: Preservation of the liver via normothermic machine perfusion (NMP) is rapidly becoming an area of great academic and clinical interest. This review focuses on the benefits and limitations of NMP and where the role for static cold storage may lie. RECENT FINDINGS: Clinical studies have recently been published reporting the use of NMP in liver preservation for transplantation. They have described the technology to be well tolerated and feasible with potentially improved posttransplant outcomes. NMP facilitates extended preservation times as well as the potential to increase organ utilization through viability assessment and regeneration. However, this technology is considerably more costly than cold storage and carries significant logistical challenges. Cold storage remains the gold standard preservation for standard criteria livers with good long-term patient and graft survival. SUMMARY: NMP is an exciting new technological advancement in liver preservation, which is likely to have a positive impact in liver transplantation. However, randomized controlled trials are required to justify its inclusion into standard practice and provide evidence to support its efficacy.

Defatting of donor transplant livers during normothermic perfusion-a randomised clinical trial: study protocol for the DeFat study.

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.