Discarded livers tested by normothermic machine perfusion in the VITTAL trial: Secondary end points and 5-year outcomes.

Normothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH >7.65 and bicarbonate levels >25 mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608).

Where Are We Now with Liver Transplantation in Neuroendocrine Neoplasms? The Place of Liver Transplantation for Grades 1 and 2 Well-Differentiated Unresectable Liver Metastatic Neuroendocrine Tumours.

PURPOSE OF REVIEW: This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. RECENT FINDINGS: In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.

Liver transplantation for isolated unresectable colorectal liver metastases - Protocol for a service evaluation in the United Kingdom - UKCoMET study.

BACKGROUND: Liver transplantation (LT) for unresectable colorectal liver metastases (CRCLM) demonstrates good overall survival for selected patients in contemporary studies, with 5-year survival of 80%. A Fixed Term Working Group (FTWG), set up by NHS Blood and Transplant (NHSBT) Liver Advisory Group (LAG), advised whether CRCLM should be considered for LT in United Kingdom. Their recommendation was that LT may be undertaken for isolated and unresectable CRCLM using strict selection criteria as a national clinical service evaluation. METHODS: Opinions were sought from colorectal cancer/LT patient representatives, experts in colorectal cancer surgery/oncology, LT surgery, hepatology, hepatobiliary radiology, pathology, and nuclear medicine, and appropriate patient selection criteria, referral and transplant listing pathways were identified. RESULTS: This paper summarises selection criteria for LT in United Kingdom for isolated and unresectable CRCLM patients, and highlights referral framework and pre-transplant assessment criteria. Finally, oncology-specific outcome measures to be utilised for assessing applicability of LT are described. CONCLUSION: This service evaluation represents a significant development for colorectal cancer patients in United Kingdom and a meaningful step forward in the field of transplant oncology. This paper details the protocol for the pilot study, scheduled to begin in the fourth quarter of 2022 in United Kingdom.

Safety of Intraoperative Blood Salvage During Liver Transplantation in Patients With Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

OBJECTIVE: The effects of intraoperative blood salvage (IBS) on time to tumor recurrence, disease-free survival and overall survival in hepatocellular carcinoma (HCC) patients undergoing liver transplantation were assessed to evaluate the safety of IBS. BACKGROUND: IBS is highly effective to reduce the use of allogeneic blood transfusion. However, the safety of IBS during liver transplantation for patients with HCC is questioned due to fear of disseminating malignant cells. METHODS: Comprehensive searches through June 2021 were performed in 8 databases. The methodological quality of included studies was assessed using the Robins-I tool. Meta-analysis with the generic inverse variance method was performed to calculate pooled hazard ratios (HRs) for disease-free survival, HCC recurrence and overall survival. RESULTS: Nine studies were included (n=1997, IBS n=1200, no-IBS n=797). Use of IBS during liver transplantation was not associated with impaired disease-free survival [HR=0.90, 95% confidence interval (CI)=0.66-1.24, P=0.53, IBS n=394, no-IBS n=329], not associated with increased HCC recurrence (HR=0.83, 95% CI=0.57-1.23, P=0.36, IBS n=537, no-IBS n=382) and not associated with impaired overall survival (HR=1.04, 95% CI=0.79-1.37, P=0.76, IBS n=495, no-IBS n=356). CONCLUSIONS: Based on available observational data, use of IBS during liver transplantation in patients with HCC does not result in impaired disease-free survival, increased HCC recurrence or impaired overall survival. Therefore, use of IBS during liver transplantation for HCC patients is a safe procedure.

Introduction of the Concept of Diagnostic Sensitivity and Specificity of Normothermic Perfusion Protocols to Assess High-Risk Donor Livers.

Normothermic machine perfusion (NMP) allows objective assessment of donor liver transplantability. Several viability evaluation protocols have been established, consisting of parameters such as perfusate lactate clearance, pH, transaminase levels, and the production and composition of bile. The aims of this study were to assess 3 such protocols, namely, those introduced by the teams from Birmingham (BP), Cambridge (CP), and Groningen (GP), using a cohort of high-risk marginal livers that had initially been deemed unsuitable for transplantation and to introduce the concept of the viability assessment sensitivity and specificity. To demonstrate and quantify the diagnostic accuracy of these protocols, we used a composite outcome of organ use and 24-month graft survival as a surrogate endpoint. The effects of assessment modifications, including the removal of the most stringent components of the protocols, were also assessed. Of the 31 organs, 22 were transplanted after a period of NMP, of which 18 achieved the outcome of 24-month graft survival. The BP yielded 94% sensitivity and 50% specificity when predicting this outcome. The GP and CP both seemed overly conservative, with 1 and 0 organs, respectively, meeting these protocols. Modification of the GP and CP to exclude their most stringent components increased this to 11 and 8 organs, respectively, and resulted in moderate sensitivity (56% and 44%) but high specificity (92% and 100%, respectively) with respect to the composite outcome. This study shows that the normothermic assessment protocols can be useful in identifying potentially viable organs but that the balance of risk of underuse and overuse varies by protocol.

A coordinated national UK liver transplant program response, prioritizing waitlist recipients with the highest need, provided excellent outcomes during the first wave of the COVID-19 pandemic.

INTRODUCTION: Healthcare provision has been severely affected by COVID-19, with specific challenges in organ transplantation. Here, we describe the coordinated response to, and outcomes during the first wave, across all UK liver transplant (LT) centers. METHODS: Several policy changes affecting the liver transplant processes were agreed upon. These included donor age restrictions and changes to offering. A "high-urgency" (HU) category was established, prioritizing only those with UKELD > 60, HCC reaching transplant criteria, and others likely to die within 90 days. Outcomes were compared with the same period in 2018 and 2019. RESULTS: The retrieval rate for deceased donor livers (71% vs. 54%; P < .0001) and conversion from offer to completed transplant (63% vs. 48%; P < .0001) was significantly higher. Pediatric LT activity was maintained; there was a significant reduction in adult (42%) and total (36%) LT. Almost all adult LT were super-urgent (n = 15) or HU (n = 133). We successfully prioritized those with highest illness severity with no reduction in 90-day patient (P = .89) or graft survival (P = .98). There was a small (5% compared with 3%; P = .0015) increase in deaths or removals from the waitlist, mainly amongst HU cohort. CONCLUSIONS: We successfully prioritized LT recipients in highest need, maintaining excellent outcomes, and waitlist mortality was only marginally increased.

Incidence of Gastrointestinal Bleeding After Transesophageal Echocardiography Use in Orthotopic Liver Transplantation.

The risk of upper gastrointestinal bleeding (UGIB) after transesophageal echocardiography (TEE) in patients with high grade esophageal varices (EV) that are undergoing Orthotopic Liver transplantation (OLT) is poorly understood. This was a retrospective single-centre cohort study in all patients that underwent OLT at Queen Elizabeth Hospital Birmingham between September 2016 and September 2018. The primary outcome was to determine the incidence of UGIB in patients that have undergone OLT with EV that received TEE. 401 patients were included in the study, of which 320 (80%) received TEE. The incidence of post-operative UGIB in patients that received TEE was 1.6% (5/320) in the entire cohort: 2.7% (4/149) in patients with no evidence of EV and 0.6% (1/171) in patients with EV. UGIB occurred in 1 patient with grade 2 EV and did not occur in patients with grade 1 or 3 EV. The incidence of UGIB in patients that received TEE was not statistically different to patients that did not: 1.6% (5/320) vs. 3.7% (3/81) p = 0.218. In conclusion, in patients that underwent OLT, intra-operative TEE use was associated with low rates of UGIB, even in cohorts with high grade EV. This suggests that TEE is a relatively safe method of haemodynamic monitoring in patients undergoing OLT.

Meta-analysis of interrupted versus continuous suturing for Roux-en-Y hepaticojejunostomy and duct-to-duct choledochocholedochostomy.

AIMS: To compare outcomes of interrupted (IS) and continuous (CS) suturing techniques for Roux-en-Y hepaticojejunostomy and duct-to-duct choledochocholedochostomy. METHODS: The study protocol was prospectively registered in PROSPERO (registration number: CRD42021286294). A systematic search of MEDLINE, CENTRAL, and Web of Science and bibliographic reference lists were conducted (last search: 14th March 2022). All comparative studies reporting outcomes of IS and CS in hepaticojejunostomy and choledochocholedochostomy were included and their risk of bias was assessed using ROBINS-I tool. Overall biliary complications, bile leak, biliary stricture, cholangitis, liver abscess, and anastomosis time were the evaluated outcome parameters. RESULTS: Ten comparative studies (2 prospective and 8 retrospective) were included which reported 1617 patients of whom 1186 patients underwent Roux-en-Y hepaticojejunostomy (IS: 789, CS: 397) and the remaining 431 patients underwent duct-to-duct choledochocholedochostomy (IS: 168, CS: 263). Although use of IS for hepaticojejunostomy was associated with significantly longer anastomosis time (MD: 14.15 min, p=0.0002) compared to CS, there was no significant difference in overall biliary complications (OR: 1.34, p=0.11), bile leak (OR: 1.64, p=0.14), biliary stricture (OR: 0.84, p=0.65), cholangitis (OR: 1.54, p=0.35), or liver abscess (OR: 0.58, p=0.40) between two groups. Similarly, use of IS for choledochocholedochostomy was associated with no significant difference in risk of overall biliary complications (OR: 0.92, p=0.90), bile leak (OR: 1.70, p=0.28), or biliary stricture (OR: 1.07, p=0.92) compared to CS. CONCLUSIONS: Interrupted and continuous suturing techniques for Roux-en-Y hepaticojejunostomy or duct-to-duct choledochocholedochostomy seem to have comparable clinical outcomes. The available evidence may be subject to confounding by indication with respect to diameter of bile duct. Future high-quality research is encouraged to report the outcomes with respect to duct diameter and suture material.

Interhemispheric plasticity is mediated by maximal potentiation of callosal inputs.

Central or peripheral injury causes reorganization of the brain's connections and functions. A striking change observed after unilateral stroke or amputation is a recruitment of bilateral cortical responses to sensation or movement of the unaffected peripheral area. The mechanisms underlying this phenomenon are described in a mouse model of unilateral whisker deprivation. Stimulation of intact whiskers yields a bilateral blood-oxygen-level-dependent fMRI response in somatosensory barrel cortex. Whole-cell electrophysiology demonstrated that the intact barrel cortex selectively strengthens callosal synapses to layer 5 neurons in the deprived cortex. These synapses have larger AMPA receptor- and NMDA receptor-mediated events. These factors contribute to a maximally potentiated callosal synapse. This potentiation occludes long-term potentiation, which could be rescued, to some extent, with prior long-term depression induction. Excitability and excitation/inhibition balance were altered in a manner consistent with cell-specific callosal changes and support a shift in the overall state of the cortex. This is a demonstration of a cell-specific, synaptic mechanism underlying interhemispheric cortical reorganization.

Impact of an enhanced recovery after surgery protocol on short-term outcomes in elderly patients undergoing pancreaticoduodenectomy.

BACKGROUND: To determine whether the short-term benefits associated with an enhanced recovery after surgery programme (ERAS) following pancreaticoduodenectomy (PD) vary with age. METHODS: 830 consecutive patients who underwent PD between January 2009 and March 2019 were divided according to age: elderly (≥75 years) vs. non-elderly patients (<75 years). Within each age group, cohort characteristics and outcomes were compared between patients treated pre- and post-ERAS (ERAS was systematically introduced in December 2012). Univariable and multivariable analysis were then performed, to assess whether ERAS was independently associated with length of hospital stay (LOS). RESULTS: Of the entire cohort, 577 of 830 patients (69.5%) were managed according to an ERAS protocol, and 170 patients (20.5%) were aged ≥75 years old. Patients treated post-ERAS were significantly more comorbid than those pre-ERAS, with a mean Charlson Comorbidity Index of 4.6 vs. 4.1 (p < 0.001) and 6.0 vs. 5.7 (p = 0.039) for the non-elderly and elderly subgroups, respectively. There were significantly fewer medical complications in non-elderly patients treated post-ERAS compared to pre-ERAS (12.4% vs. 22.4%; p = 0.002), but not in elderly patients (23.6% vs. 14.0%; p = 0.203). On multivariable analysis, ERAS was independently associated with reduced LOS in both elderly (14.8% reduction, 95% CI: 0.7-27.0%, p = 0.041) and non-elderly patients (15.6% reduction, 95% CI: 9.2-21.6%, p < 0.001), with the effect size being similar in each group. CONCLUSION: ERAS protocols can be safely applied to patients undergoing pancreaticoduodenectomy irrespective of age. Implementation of an ERAS protocol was associated with a significant reduction in postoperative LOS in both elderly and non-elderly patients, despite higher comorbidity in the post-ERAS period.

Circuit-Specific Plasticity of Callosal Inputs Underlies Cortical Takeover.

Injury induces synaptic, circuit, and systems reorganization. After unilateral amputation or stroke, this functional loss disrupts the interhemispheric interaction between intact and deprived somatomotor cortices to recruit deprived cortex in response to intact limb stimulation. This recruitment has been implicated in enhanced intact sensory function. In other patients, maladaptive consequences such as phantom limb pain can occur. We used unilateral whisker denervation in male and female mice to detect circuitry alterations underlying interhemispheric cortical reorganization. Enhanced synaptic strength from the intact cortex via the corpus callosum (CC) onto deep neurons in deprived primary somatosensory barrel cortex (S1BC) has previously been detected. It was hypothesized that specificity in this plasticity may depend on to which area these neurons projected. Increased connectivity to somatomotor areas such as contralateral S1BC, primary motor cortex (M1) and secondary somatosensory cortex (S2) may underlie beneficial adaptations, while increased connectivity to pain areas like anterior cingulate cortex (ACC) might underlie maladaptive pain phenotypes. Neurons from the deprived S1BC that project to intact S1BC were hyperexcitable, had stronger responses and reduced inhibitory input to CC stimulation. M1-projecting neurons also showed increases in excitability and CC input strength that was offset with enhanced inhibition. S2 and ACC-projecting neurons showed no changes in excitability or CC input. These results demonstrate that subgroups of output neurons undergo dramatic and specific plasticity after peripheral injury. The changes in S1BC-projecting neurons likely underlie enhanced reciprocal connectivity of S1BC after unilateral deprivation consistent with the model that interhemispheric takeover supports intact whisker processing.SIGNIFICANCE STATEMENT Amputation, peripheral injury, and stroke patients experience widespread alterations in neural activity after sensory loss. A hallmark of this reorganization is the recruitment of deprived cortical space which likely aids processing and thus enhances performance on intact sensory systems. Conversely, this recruitment of deprived cortical space has been hypothesized to underlie phenotypes like phantom limb pain and hinder recovery. A mouse model of unilateral denervation detected remarkable specificity in alterations in the somatomotor circuit. These changes underlie increased reciprocal connectivity between intact and deprived cortical hemispheres. This increased connectivity may help explain the enhanced intact sensory processing detected in humans.

Safety of intra-operative blood salvage during liver transplantation in patients with hepatocellular carcinoma, a propensity score-matched survival analysis.

Intra-operative blood salvage (IBS) reduces the use of allogeneic blood transfusion. However, safety of IBS during liver transplantation (LT) for hepatocellular carcinoma (HCC) is questioned due to fear for dissemination of circulating malignant cells. This study aims to assess safety of IBS. HCC patients who underwent LT from January 2006 through December 2019 were included. Patients in whom IBS was used were propensity score matched (1:1) to control patients. Disease-free survival and time to HCC recurrence were assessed with Cox regression models and competing risk models. IBS was used in 192/378 HCC LT recipients, and 127 patients were propensity score matched. Cumulative disease-free survival at 12 and 60 months was 85% and 63% for the IBS group versus 90% and 68% for the no-IBS group. Use of IBS was not associated with impaired disease-free survival (HR 1.07, 95%CI: 0.65-1.76, P = 0.800) nor with increased HCC recurrence (Cause-specific cox model: HR 0.79, 95%CI: 0.36-1.73, P = 0.549, Fine and Gray model: HR: 0.79, 95%CI 0.40-1.57, P = 0.50). In conclusion, IBS during LT did not increase the risk for HCC recurrence. IBS is a safe procedure in HCC LT recipients to reduce the need for allogenic blood transfusion.

Health-related quality of life, uncertainty and coping strategies in solid organ transplant recipients during shielding for the COVID-19 pandemic.

Strict isolation of vulnerable individuals has been a strategy implemented by authorities to protect people from COVID-19. Our objective was to investigate health-related quality of life (HRQoL), uncertainty and coping behaviours in solid organ transplant (SOT) recipients during the COVID-19 pandemic. A cross-sectional survey of adult SOT recipients undergoing follow-up at our institution was performed. Perceived health status, uncertainty and coping strategies were assessed using the EQ-5D-5L, Short-form Mishel Uncertainty in Illness Scale (SF-MUIS) and Brief Cope, respectively. Interactions with COVID-19 risk perception, access to health care, demographic and clinical variables were assessed. The survey was completed by 826 of 3839 (21.5%) invited participants. Overall, low levels of uncertainty in illness were reported, and acceptance was the major coping strategy (92%). Coping by acceptance, feeling protected, self-perceived susceptibility to COVID-19 were associated with lower levels of uncertainty. Health status index scores were significantly lower for those with mental health illness, compromised access to health care, a perceived high risk of severe COVID-19 infection and higher levels of uncertainty. A history of mental health illness, risk perceptions, restricted healthcare access, uncertainty and coping strategies was associated with poorer HRQoL in SOT recipients during strict isolation. These findings may allow identification of strategies to improve HRQoL in SOT recipients during the pandemic.

The effects of resection margin and KRAS status on outcomes after resection of colorectal liver metastases.

BACKGROUND: The aim of this study was to investigate the influence of resection margin status in patients with KRAS mutations (mt-KRAS) when compared to those with wild-type KRAS (wt-KRAS) on long-term outcomes in patients with resected CRLM. METHODS: All patients who underwent resection of CRLM with curative intent between January 2011 and December 2016 and had a KRAS type recorded were included in the study. Overall survival (OS), as well as death-censored overall (RFS) and liver-specific (LS-RFS) recurrence-free survival between KRAS types and the margin status within KRAS subgroups were compared using Cox regression models. RESULTS: Data were available for N = 500 patients (30.4% mt-KRAS). mt-KRAS status was independently associated with significantly shorter OS. Within the wt-KRAS subgroup, smaller margins were found to be associated with significantly shorter death-censored LS-RFS (p < 0.001), with HRs of 1.93 (p = 0.005) for 1-4 mm margins and 2.83 (p < 0.001) for <1 mm margins, relative to those with clear margins. No such association was observed in the mt-KRAS subgroup (p = 0.721). CONCLUSION: The resection margin status is of greater importance in patients with wt-KRAS. Such information could be useful in the operative planning, especially for those with multiple metastatic deposits, and also in the post-operative counselling and surveillance based on the margin and KRAS status.

Liver Resection and role of Extended Histology (LiREcH study) in patients with multifocal colorectal cancer liver metastases.

BACKGROUND: The aim of this study is to assess the correlation between the margin status on the specimen side (Rs) and that from the patient side (base of resection) (Rp) and the influence of positive margins (R1s and R1p) on cancer related outcomes in patients with colorectal liver metastases (CRLM). METHODS: In this prospective study, patients undergoing non-anatomical resection (NAR) of multifocal CRLM, with suspected close resection margins were included. The primary outcome evaluated was the correlation of Rs and Rp. RESULTS: Twenty-three patients had 89 NARs, and CUSA samples from the base of 36 specimens were analysed. Among 36 specimens where extended histology (EH) was performed, margin status on the specimen side (Rs) was positive in 69.4% (25/36), whereas on the patient side, the margin (Rp) was positive in only 8.3% (3/36) of specimens. On univariate analysis, there was no significant difference in the site-specific recurrence at previous resection with regards to Rs positivity (P = 0.56) and Rp positivity (P = 0.48). CONCLUSION: There is a poor correlation between Rs and Rp and the local recurrence rates in the liver. These results might further support that tumour biology is more relevant than the margin status in patients with multifocal CRLM.

Variations between the anatomical and functional distribution, based on 99m technetium -mebrofinate SPECT-CT scan, in patients at risk of post hepatectomy liver failure.

BACKGROUND: The aim of the current study is to investigate the variations of anatomical (LVRem%) and functional remnant volumes (fLVRem%) and the dynamic uptake of Technetium-Mebrofinate (FRLF) measured from 99m Technetium-Mebrofinate SPECT-CT scan (TMSCT) in patients at high risk of post-hepatectomy liver failure (PHLF). METHODS: Variations in the measures of LVRem% and fLVRem% were assessed. The predictive accuracies of LVRem%, fLVRem% and FRLF with respect to PHLF were reported. RESULTS: From the N = 92 scans performed, LVRem% and fLVRem% returned identical results in 15% of cases, and ±10 percentage points in 79% of cases. Some patients had larger discrepancies, with difference of >10 percentage points in 21% of cases. The difference was significant in those with primary liver cancers (-4.4 ± 9.2, p = 0.002). For the N = 29 patients that underwent surgery as planned on TMSCT, FRLF was a strong predictor of PHLF, with an AUROC of 0.83 (p = 0.005). CONCLUSION: TMSCT is emerging as a useful modality in pre-operative assessment of patients undergoing major liver resection. For those with primary liver cancer, there is a significant variation in the anatomical and functional distributions that needs considered in surgical planning. Reduced FRLF, measured as the dynamic uptake in the future liver remnant, is a strong predictor of PHLF.

An international multicenter study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise.

BACKGROUND & AIMS: The outbreak of COVID-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources. METHODS: We performed an international multicenter study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the quadripartite equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources. RESULTS: Seventeen large- and medium-sized liver transplant centers from 12 countries across 4 continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - recipient outcome, donor/graft safety, waiting list mortality and healthcare resources - for 7 countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic. CONCLUSIONS: This four-dimensional model of quadripartite equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems. LAY SUMMARY: There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources during the COVID-19 pandemic. We describe a four-dimensional model of quadripartite equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems.

Hypothermic Oxygenated Liver Perfusion (HOPE) Prevents Tumor Recurrence in Liver Transplantation From Donation After Circulatory Death.

OBJECTIVE: The aim of this study was to investigate tumor recurrence after liver transplantation for hepatocellular carcinoma (HCC), with and without hypothermic oxygenated liver perfusion (HOPE) before transplantation. PATIENTS AND METHODS: We analyzed all liver recipients with HCC, transplanted between January 2012 and September 2019 with donation after circulatory death (DCD) livers after previous end-ischemic HOPE-treatment (n = 70, Center A). Tumor parameters and key confounders were compared to consecutive recipients with HCC, transplanted during the same observation period with an unperfused DBD liver (n = 70). In a next step, we analyzed unperfused DCD (n = 70) and DBD liver recipients (n = 70), transplanted for HCC at an external center (Center B). RESULTS: Tumor parameters were not significantly different between HOPE-treated DCD and unperfused DBD liver recipients at Center A. One-third of patients were outside established tumor thresholds, for example, Milan criteria, in both groups. Despite no difference in tumor load, we found a 4-fold higher tumor recurrence rate in unperfused DBD livers (25.7%, 18/70), compared to only 5.7% (n = 4/70) recipients with tumor recurrence in the HOPE-treated DCD cohort (P = 0.002) in Center A. The tumor recurrence rate was also twice higher in unperfused DCD and DBD recipients at the external Center B, despite significant less cases outside Milan. HOPE-treatment of DCD livers resulted therefore in a 5-year tumor-free survival of 92% in HCC recipients, compared to 73%, 82.7%, and 81.2% in patients receiving unperfused DBD or DCD livers, from both centers. CONCLUSION: We suggest that a simple machine liver perfusion approach appears advantageous to protect from HCC recurrence after liver transplantation, despite extended tumor criteria.

Outcome after ex situ or ante situm liver resection with hypothermic perfusion and auto-transplantation: A single-centre experience in adult and paediatric patients.

BACKGROUND: Evolving surgical technology and medical treatment have led to an expansion of indications to enable resection of large hepatic tumours with involvement of other abdominal structures. METHODS: Twelve extended liver and abdominal resections, either ex situ with auto-transplantation of the liver remnant or ante situm with veno-venous bypass (VVBP) were performed between 2016 and 2018. We describe our preoperative assessment, compare surgical strategies and assess outcomes. RESULTS: The median age of the 10 adult patients was 50.5 years with a majority suffering from sarcoma-like tumours. The two paediatric patients were 3 and 8 years of age, both with hepatoblastoma. Two patients underwent ex situ resections with auto-transplantation of the liver remnant, and nine patients had ante situm tumour removal with the use of VVBP in four. All patients achieved a good immediate liver function. Local infection and acute kidney injury were found in two patients. One patient underwent biliary reconstruction for bile leak. Tumour recurrence was seen in seven patients (58.3%), with four lung metastases. Five patients died from tumour recurrence (41.7%) during the follow-up. CONCLUSION: Extreme liver resections should be performed in experienced centres, where surgical subspecialties are available with access to cardiovascular support. Additionally, experience in split and living-donor liver transplantation is beneficial.

Recurrence patterns of pancreatic cancer after pancreatoduodenectomy: systematic review and a single-centre retrospective study.

BACKGROUND: Positive margins in pancreatoduodenectomy (PD) for pancreatic cancer, specifically the superior mesenteric artery (SMA) margin, are associated with worse outcomes. Local therapies targeting these margins could impact on recurrence. This study analysed recurrence-patterns to identify whether strategies to control local disease could have a meaningful impact. METHODS: (I) Systematic review to define recurrence patterns and resection margin status. (II) Additional retrospective study of PD performed at our centre. RESULTS: In the systematic review, 23/617 evaluated studies were included (n = 3815). Local recurrence was observed in 7-69%. SMA margin (6 studies) was positive in 15-35%. In the retrospective study (n = 204), local recurrence was more frequently observed with a positive SMA margin (66 vs.45%; p = 0.005). Furthermore, in a multivariate cox-proportional hazard model, only a positive SMA margin was associated with disease recurrence (HR 1.615; 95%CI 1.127-2.315; p = 0.009). Interestingly, median overall survival was 20 months and similar for patients who developed local only, metastases only or simultaneous recurrence (p = 0.124). CONCLUSION: Local recurrence of pancreatic cancer is common and associated with similar mortality rates as those who present with simultaneous or metastatic recurrence. Involvement of the SMA margin is an independent predictor for disease progression and should be the target of future adjuvant local therapies.