Full-left/Full-right Liver Splitting With Middle Hepatic Vein and Caval Partition During Dual Hypothermic Oxygenated Machine Perfusion.

BACKGROUND: Split liver transplantation is a valuable means of mitigating organ scarcity but requires significant surgical and logistical effort. Ex vivo splitting is associated with prolonged cold ischemia, with potentially negative effects on organ viability. Machine perfusion can mitigate the effects of ischemia-reperfusion injury by restoring cellular energy and improving outcomes. METHODS: We describe a novel technique of full-left/full-right liver splitting, with splitting and reconstruction of the vena cava and middle hepatic vein, with dual arterial and portal hypothermic oxygenated machine perfusion. The accompanying video depicts the main surgical passages, notably the splitting of the vena cava and middle hepatic vein, the parenchymal transection, and the venous reconstruction. RESULTS: The left graft was allocated to a pediatric patient having methylmalonic aciduria, whereas the right graft was allocated to an adult patient affected by hepatocellular carcinoma and cirrhosis. CONCLUSIONS: This technique allows ex situ splitting, counterbalancing prolonged ischemia with the positive effects of hypothermic oxygenated machine perfusion on graft viability. The venous outflow is preserved, safeguarding both grafts from venous congestion; all reconstructions can be performed ex situ, minimizing warm ischemia. Moreover, there is no need for highly skilled surgeons to reach the donor hospital, thereby simplifying logistical aspects.

Liver transplantation with uncontrolled versus controlled DCD donors using normothermic regional perfusion and ex-situ machine perfusion.

In Italy, 20 minutes of continuous, flat-line electrocardiogram are required for death declaration, which significantly increases the risks of donation after circulatory death (DCD) LT. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death LT by combining normothermic regional and end-ischemic machine perfusion. However, data on uncontrolled DCD (uDCD) LT performed by this approach are lacking. This was a multicenter, retrospective study performed at 3 large-volume centers comparing clinical outcomes of uncontrolled versus controlled DCD LT. The aim of the study was to assess outcomes of sequential normothermic regional perfusion and end-ischemic machine perfusion in uncontrolled DCD liver transplantation (LT). Of 153 DCD donors evaluated during the study period, 40 uDCD and 59 donation after circulatory death grafts were transplanted (utilization rate 52% vs. 78%, p = 0.004). Recipients of uDCD grafts had higher MEAF (4.9 vs. 3.5, p < 0.001) and CCI scores at discharge (24.4 vs. 8.7, p = 0.026), longer ICU stay (5 vs. 4 d, p = 0.047), and a trend toward more severe AKI. At multivariate analysis, 90-day graft loss was associated with recipient BMI and lactate downtrend during normothermic regional perfusion. One-year graft survival was lower in uDCD (75% vs. 90%, p = 0.007) but became comparable when non-liver-related graft losses were treated as censors (77% vs. 90%, p = 0.100). The incidence of ischemic cholangiopathy was 10% in uDCD versus 3% in donation after circulatory death, p = 0.356. uDCD LT with prolonged warm ischemia is feasible by the sequential use of normothermic regional perfusion and end-ischemic machine perfusion. Proper donor and recipient selection are key to achieving good outcomes in this setting.

Dynamic surgical anatomy using 3D reconstruction technology in complex hepato-biliary surgery with vascular involvement. Results from an international multicentric survey.

INTRODUCTION: Three-dimensional liver modeling can lead to substantial changes in choosing the type and extension of liver resection. This study aimed to explore whether 3D reconstruction helps to better understand the relationship between liver tumors and neighboring vascular structures compared to standard 2D CT scan images. METHODS: Contrast-enhanced CT scan images of 11 patients suffering from primary and secondary hepatic tumors were selected. Twenty-three experienced HBP surgeons participated to the survey. A standardized questionnaire outlining 16 different vascular structures (items) having a potential relationship with the tumor was provided. Intraoperative and histopathological findings were used as the reference standard. The proper hypothesis was that 3D accuracy is greater than 2D. As a secondary endpoint, inter-raters' agreement was explored. RESULTS: The mean difference between 3D and 2D, was 2.6 points (SE: 0.40; 95 % CI: 1.7-3.5; p < 0.0001). After sensitivity analysis, the results favored 3D visualization as well (mean difference 1.7 points; SE: 0.32; 95 % CI: 1.0-2.5; p = 0.0004). The inter-raters' agreement was moderate for both methods (2D: W = 0.45; 3D: W = 0.44). CONCLUSION: 3D reconstruction may give a significant contribution to better understanding liver vascular anatomy and the precise relationship between the tumor and the neighboring structures.

Improving outcomes of in situ split liver transplantation in Italy over the last 25 years.

BACKGROUND & AIMS: Split liver transplant(ation) (SLT) is still considered a challenging procedure that is by no means widely accepted. We aimed to present data on 25-year trends in SLT in Italy, and to investigate if, and to what extent, outcomes have improved nationwide during this time. METHODS: The study included all consecutive SLTs performed from May 1993 to December 2019, divided into three consecutive periods: 1993-2005, 2006-2014, and 2015-2019, which match changes in national allocation policies. Primary outcomes were patient and graft survival, and the relative impact of each study period. RESULTS: SLT accounted for 8.9% of all liver transplants performed in Italy. A total of 1,715 in situ split liver grafts were included in the analysis: 868 left lateral segments (LLSs) and 847 extended right grafts (ERGs). A significant improvement in patient and graft survival (p <0.001) was observed with ERGs over the three periods. Predictors of graft survival were cold ischaemia time (CIT) <6 h (p = 0.009), UNOS status 2b (p <0.001), UNOS status 3 (p = 0.009), and transplant centre volumes: 25-50 cases vs. <25 cases (p = 0.003). Patient survival was significantly higher with LLS grafts in period 2 vs. period 1 (p = 0.008). No significant improvement in graft survival was seen over the three periods, where predictors of graft survival were CIT <6 h (p = 0.007), CIT <6 h vs. ≥10 h (p = 0.019), UNOS status 2b (p = 0.038), and UNOS status 3 (p = 0.009). Retransplantation was a risk factor in split liver graft recipients, with significantly worse graft and patient survival for both types of graft (p <0.001). CONCLUSIONS: Our analysis showed Italian SLT outcomes to have improved over the last 25 years. These results could help to dispel reservations regarding the use of this procedure. IMPACT AND IMPLICATIONS: Split liver transplant(ation) (SLT) is still considered a challenging procedure and is by no means widely accepted. This study included all consecutive in situ SLTs performed in Italy from May 1993 to December 2019. With more than 1,700 cases, it is one of the largest series, examining long-term national trends in in situ SLT since its introduction. The data presented indicate that the outcomes of SLT improved during this 25-year period. Improvements are probably due to better recipient selection, refinements in surgical technique, conservative graft-to-recipient matching, and the continuous, yet carefully managed, expansion of donor selection criteria under a strict mandatory split liver allocation policy. These results could help to dispel reservations regarding the use of this procedure.

Trends and Obstacles to Implement Dynamic Perfusion Concepts for Clinical Liver Transplantation: Results from a Global Web-Based Survey.

BACKGROUND: Organ perfusion technology is increasingly used in many countries, with a focus, however, on the Western world. This study investigates the current international trends and obstacles to the broader routine implementation of dynamic perfusion concepts in liver transplantation. METHODS: A web-based anonymous survey was launched in 2021. Experts of all involved specializations from 70 centers in 34 countries were contacted, based on the published literature and experience in the field of abdominal organ perfusion. RESULTS: Overall, 143 participants from 23 countries completed the survey. Most respondents were male (67.8%) and transplant surgeons (64.3%) working at university hospitals (67.9%). The majority had experience with organ perfusion (82%), applying mainly hypothermic machine perfusion (HMP; 38%) and other concepts. While most (94.4%) expect a higher utilization of marginal organs with machine perfusion, the majority considers HMP the best technique to reduce liver discard-rates. While most respondents (90%) believed machine perfusion should be fully commissioned, the lack of funding (34%) and knowledge (16%) as well as limited staff (19%) were the three main obstacles to a routine clinical implementation. CONCLUSION: Although dynamic preservation concepts are increasingly used in clinical practice, significant challenges remain. Specific financial pathways, uniform regulations, and tight collaborations among involved experts are needed to achieve wider global clinical use.

The impact of postoperative complications on oncological outcomes of liver transplantation for hepatocellular carcinoma: A competing risk analysis.

OBJECTIVE: To investigate the influence of postoperative complications on tumor-related (TRD), disease-free survival (DFS) and overall survival (OS) in patients undergoing liver transplant (LT) for hepatocellular carcinoma (HCC). METHODS: We retrospectively evaluated 425 LTs for HCC from 2010 to 2019. Postoperative complications were classified according to Comprehensive Complication Index (CCI) and the posttransplant risk of TRD assessed through Metroticket 2.0 calculator. The population was stratified into high-risk and low-risk cohorts based on the predicted TRD risk of 80%. In a second step, we re-evaluated TRD, DFS and OS of both cohorts according to a further stratification based on 47.3 points of CCI cut-off. RESULTS: In the low-risk cohort, we observed a significantly better DFS (84% vs. 46%, p<0.001), TRD (3% vs. 26%, p<0.001) and OS (89% vs. 62%, p<0.001) in the group with CCI < 47.3. In the high-risk cohort, patients with CCI < 47.3 had significantly better DFS (50% vs. 23%, p = 0.003) and OS (68% vs. 42%, p = 0.02) and a comparable TRD (22% vs. 31%, p = 0.142). CONCLUSIONS: A complicated postoperative course negatively influenced long-term survival. This poorer oncological outcome associated with in-hospital postoperative complications suggests that every effort should be made to improve the early posttransplant course in HCC patients, including a careful donor-to recipient match and use of new perfusion technologies.

Robotic Versus Laparoscopic Donor Nephrectomy: A Retrospective Bicentric Comparison of Learning Curves and Surgical Outcomes From 2 High-volume European Centers.

BACKGROUND: Although laparoscopic donor nephrectomy (LDN) represents the gold-standard technique for kidney living donation, robotic donor nephrectomy (RDN) settled as another appealing minimally invasive technique over the past decades. A comparison between LDN and RDN outcomes was performed. METHODS: RDN and LDN outcomes were compared, focusing on operative time and perioperative risk factors affecting surgery duration. Learning curves for both techniques were compared through spline regression and cumulative sum models. RESULTS: The study analyzed 512 procedures (154 RDN and 358 LDN procedures) performed between 2010 and 2021 in 2 different high-volume transplant centers. The RDN group presented a higher prevalence of arterial variations (36.2 versus 22.4%; P = 0.001) compared with the LDN cohort. No open conversions occurred; operative time (210 versus 195 min; P = 0.011) and warm ischemia time (WIT; 230 versus 180 s; P < 0.001) were longer in RDN. Postoperative complication rate was similar (8.4% versus 11.5%; P = 0.49); the RDN group showed shorter hospital stay (4 versus 5 d; P < 0.001). Spline regression models depicted a faster learning curve in the RDN group ( P = 0.0002). Accordingly, cumulative sum analysis highlighted a turning point after about 50 procedures among the RDN cohort and after about 100 procedures among the LDN group.Higher body mass index resulted as an independent risk factor for longer operative time for both techniques; multiple arteries significantly prolonged operative time in LDN, whereas RDN was longer in right kidney procurements; both procedures were equally shortened by growing surgical experience. CONCLUSIONS: RDN grants a faster learning curve and improves multiple vessel handling. Incidence of postoperative complications was low for both techniques.

Donation after circulatory death: Novel strategies to improve the liver transplant outcome.

In many countries, donation after circulatory death (DCD) liver grafts are used to overcome organ shortages; however, DCD grafts have been associated with an increased risk of complications and even graft loss after liver transplantation. The increased risk of complications is thought to correlate with prolonged functional donor warm ischaemia time. Stringent donor selection criteria and utilisation of in situ and ex situ organ perfusion technologies have led to improved outcomes. Additionally, the increased use of novel organ perfusion strategies has led to the possibility of reconditioning marginal DCD liver grafts. Moreover, these technologies enable the assessment of liver function before implantation, thus providing valuable data that can guide more precise graft-recipient selection. In this review, we first describe the different definitions of functional warm donor ischaemia time and its role as a determinant of outcomes after DCD liver transplantation, with a focus on the thresholds proposed for graft acceptance. Next, organ perfusion strategies, namely normothermic regional perfusion, hypothermic oxygenated perfusion, and normothermic machine perfusion are discussed. For each technique, clinical studies reporting on the transplant outcome are described, together with a discussion on the possible protective mechanisms involved and the functional criteria adopted for graft selection. Finally, we review multimodal preservation protocols involving a combination of more than one perfusion technique and potential future directions in the field.

Surgical Treatment of Hepatocellular Carcinoma: Multicenter Competing-risk Analysis of Tumor-related Death Following Liver Resection and Transplantation Under an Intention-to-treat Perspective.

BACKGROUND: Early-stage hepatocellular carcinoma could benefit from upfront liver resection (LR) or liver transplantation (LT), but the optimal strategy in terms of tumor-related outcomes is still debated. We compared the oncological outcomes of LR and LT for hepatocellular carcinoma, stratifying the study population into a low-, intermediate-, and high-risk class according to the risk of death at 5-y predicted by a previously developed prognostic model. The impact of tumor pathology on oncological outcomes of low- and intermediate-risk patients undergoing LR was investigated as a secondary outcome. METHODS: We performed a retrospective multicentric cohort study involving 2640 patients consecutively treated by LR or LT from 4 tertiary hepatobiliary and transplant centers between 2005 and 2015, focusing on patients amenable to both treatments upfront. Tumor-related survival and overall survival were compared under an intention-to-treat perspective. RESULTS: We identified 468 LR and 579 LT candidates: 512 LT candidates underwent LT, whereas 68 (11.7%) dropped-out for tumor progression. Ninety-nine high-risk patients were selected from each treatment cohort after propensity score matching. Three and 5-y cumulative incidence of tumor-related death were 29.7% and 39.5% versus 17.2% and 18.3% for LR and LT group ( P = 0.039), respectively. Low-risk and intermediate-risk patients treated by LR and presenting satellite nodules and microvascular invasion had a significantly higher 5-y incidence of tumor-related death (29.2% versus 12.5%; P < 0.001). CONCLUSIONS: High-risk patients showed significantly better intention-to-treat tumor-related survival after upfront LT rather than LR. Cancer-specific survival of low- and intermediate-risk LR patients was significantly impaired by unfavorable pathology, suggesting the application of ab-initio salvage LT in such scenarios.

Utilization of livers donated after circulatory death for transplantation - An international comparison.

BACKGROUND & AIMS: Liver graft utilization rates are a hot topic due to the worldwide organ shortage and the increasing number of transplant candidates on waiting lists. Liver perfusion techniques have been introduced in several countries, and may help to increase the organ supply, as they potentially enable the assessment of livers before use. METHODS: Liver offers were counted from donation after circulatory death (DCD) donors (Maastricht type III) arising during the past decade in eight countries, including Belgium, France, Italy, the Netherlands, Spain, Switzerland, the UK, and the US. Initial type-III DCD liver offers were correlated with accepted, recovered and implanted livers. RESULTS: A total number of 34,269 DCD livers were offered, resulting in 9,780 liver transplants (28.5%). The discard rates were highest in the UK and US, ranging between 70 and 80%. In contrast, much lower DCD liver discard rates, e.g. between 30-40%, were found in Belgium, France, Italy, Spain and Switzerland. In addition, we observed large differences in the use of various machine perfusion techniques, as well as in graft and donor risk factors. For example, the median donor age and functional donor warm ischemia time were highest in Italy, e.g. >40 min, followed by Switzerland, France, and the Netherlands. Importantly, such varying risk profiles of accepted DCD livers between countries did not translate into large differences in 5-year graft survival rates, which ranged between 60-82% in this analysis. CONCLUSIONS: Overall, DCD liver discard rates across the eight countries were high, although this primarily reflects the situation in the Netherlands, the UK and the US. Countries where in situ and ex situ machine perfusion strategies were used routinely had better DCD utilization rates without compromised outcomes. IMPACT AND IMPLICATIONS: A significant number of Maastricht type III DCD livers are discarded across Europe and North America today. The overall utilization rate among eight Western countries is 28.5% but varies significantly between 18.9% and 74.2%. For example, the median DCD-III liver utilization in five countries, e.g. Belgium, France, Italy, Switzerland, and Spain is 65%, in contrast to 24% in the Netherlands, UK and US. Despite this, and despite different rules and strategies for organ acceptance and preservation, 1- and 5-year graft survival rates remain fairly similar among all participating countries. A highly varying experience with modern machine perfusion technology was observed. In situ and ex situ liver perfusion concepts, and application of assessment tools for type-III DCD livers before transplantation, may be a key explanation for the observed differences in DCD-III utilization.

Clinical Impact of Spontaneous Portosystemic Shunts in Liver Transplantation: A Comprehensive Assessment Through Total Shunt Area Measurement.

BACKGROUND: The impact of spontaneous portosystemic shunts (SPSSs) on natural history of cirrhotic patients was recently evaluated through the measurement of total shunt area (TSA), a novel tool that allows a comprehensive assessment of SPSSs extension, identifying a direct correlation of higher TSA with lower patient survival. The role of SPSSs in liver transplant (LT) is still debated: we sought to investigate the clinical impact of TSA on the development of early allograft dysfunction (EAD), acute kidney injury (AKI), postoperative complications, and graft and patient survival following LT. METHODS: Preoperative imaging of 346 cirrhotic patients undergoing primary LT between 2015 and 2020 were retrospectively revised, recording the size and anatomy of each SPSS to calculate TSA. The impact of TSA and selected patient and donor characteristics on the development of EAD, AKI, and clinically relevant complications was evaluated through univariate and multivariate logistic regression, whereas their effect on graft and patient survival was investigated through Cox regression analysis. RESULTS: A TSA exceeding 78.54 mm 2 resulted as an independent risk factor for the development of EAD (odds ratio [OR]: 2.327; P = 0.003), grade 3 AKI (OR: 2.093; P = 0.041), and clinically relevant complications (OR: 1.962; P = 0.015). Moreover, higher TSA was significantly related to early graft and patient survivals, emerging as an independent risk factor for 12-mo graft loss (hazard ratio: 3.877; P = 0.007) and patient death (hazard ratio: 2.682; P = 0.018). CONCLUSIONS: Higher TSA emerged as a significant risk factor for worse postoperative outcomes following LT, supporting the need for careful hemodynamic assessment and management of patients presenting multiple/larger shunts.

Viability assessment and transplantation of fatty liver grafts using end-ischemic normothermic machine perfusion.

End-ischemic viability testing by normothermic machine perfusion (NMP) represents an effective strategy to recover liver grafts having initially been discarded for liver transplantation (LT). However, its results in the setting of significant (≥30%) macrovesicular steatosis (MaS) have not been specifically assessed. Prospectively maintained databases at two high-volume LT centers in Northern Italy were searched to identify cases of end-ischemic NMP performed to test the viability of livers with MaS ≥ 30% in the period from January 2019 to January 2022. A total of 14 cases were retrieved, representing 57.9% of NMP and 5.7% of all machine perfusion procedures. Of those patients, 10 (71%) received transplants. Two patients developed primary nonfunction (PNF) and required urgent re-LT, and both were characterized by incomplete or suboptimal lactate clearance during NMP. PNF cases were also characterized by higher perfusate transaminases, lower hepatic artery and portal vein flows at 2 h, and a lack of glucose metabolism in one case. The remaining eight patients showed good liver function (Liver Graft Assessment Following Transplantation risk score, -1.9 [risk, 13.6%]; Early Allograft Failure Simplified Estimation score, -3.7 [risk, 2.6%]) and had a favorable postoperative course. Overall, NMP allowed successful transplantation of 57% of livers with moderate-to-severe MaS. Our findings suggest that prolonged observation (≥6 h) might be required for steatotic livers and that stable lactate clearance is a fundamental prerequisite for their use.

Similar survival but higher and delayed hepatocellular carcinoma recurrence in HIV-positive compared to negative cirrhotics undergoing liver transplantation.

BACKGROUND: Liver transplantation (LT) represents the best therapeutic option for hepatocellular carcinoma (HCC) and end-stage liver disease (ESLD). Although HIV infection does not seem to lower survival rates, HCV and HCC recurrence appear more harmful. AIMS: To compare the overall survival after LT; evaluate the impact of anti-HCV direct-acting agents (DAA); assess the rate of HCC recurrence in HIV-positive and negative patients. METHODS: Subjects with HCV/HBV infection who underwent LT for HCC or ESLD from 2012 to 2019 were retrospectively evaluated. RESULTS: Study population included 299 individuals, 31 (10.4%) were HIV-positive. Overall mortality was similar (16.1% versus 19.0%, p = 0.695). HCC recurrence was observed in 6 HIV-positive (19.4%) and in 17 negative subjects (6.3%, p = 0.022). Time to relapse was 831 days in HIV-positive and 315 days in negative patients (p = 0.046). Cox model found a significant role for HIV in univariate analysis but, after adjusting for variables, extra-hepatic tumor was the only factor associated to recurrence (aHR 56.379, p < 0.001). CONCLUSIONS: Post-LT survival improved after DAA availability and HIV has no impact on mortality. A higher and delayed rate of HCC recurrence was observed in co-infected individuals: surveillance protocols should be strengthened along time in this population.

Viability Criteria during Liver Ex-Situ Normothermic and Hypothermic Perfusion.

With the increased use of extended-criteria donors, machine perfusion became a beneficial alternative to cold storage in preservation strategy for donor livers with the intent to expand donor pool. Both normothermic and hypothermic approach achieved good results in terms of mid- and long-term outcome in liver transplantation. Many markers and molecules have been proposed for the assessment of liver, but no definitive criteria for graft viability have been validated in large clinical trials and key parameters during perfusion still require optimization.In this review, we address the current literature of viability criteria during normothermic and hypothermic machine perfusion and discuss about future steps and evolution of these technologies.

A new ex-situ machine perfusion device. A preliminary evaluation using a model of donors after circulatory death pig livers.

We herein describe a new ex-situ machine perfusion device as a "technology spotlight" using a model of donors after circulatory death liver grafts procured from slaughterhouse pigs. Fourteen pig liver grafts were included. The device allowed stable perfusion in both hypothermic (n = 6) and normothermic (n = 8) conditions and no technical failure was observed. During perfusion, perfusate and bile samples were collected to assess liver metabolism and viability. An integrated adsorption device showed efficient removal of inflammatory cytokines during treatment. This preliminary experience represents the starting point for further investigations on the potential clinical benefits of cytokines and other inflammatory mediators adsorption during machine perfusion.

Donor eligibility criteria and liver graft acceptance criteria during normothermic regional perfusion: A systematic review.

Acceptance of liver grafts from donations after circulatory death (DCD) largely remains a "black box," particularly due to the unpredictability of the agonal phase. Abdominal normothermic regional perfusion (aNRP) can reverse ischemic injury early during the procurement procedure, and it simultaneously enables graft viability testing to unravel this black box. This review evaluates current protocols for liver viability assessment to decide upon acceptance or decline during aNRP. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was used, and relevant literature databases were searched. The primary outcome consisted of criteria for liver graft viability assessment. Secondary outcomes included survival, primary nonfunction (PNF), early dysfunction, and biliary complications. A total of 14 articles were included in the analysis. In all protocols, a combination of criteria was used to assess suitability of the liver for transplantation. As many as 12 studies (86%) used macroscopic assessment, 12 studies (86%) used alanine transaminase (ALT) levels in perfusate, 9 studies (64%) used microscopic assessment, and 7 studies (50%) used lactate levels as assessment criteria. The organ utilization rate (OUR) was 16% for uncontrolled donation after circulatory death (uDCD) and 64% for controlled donation after circulatory death (cDCD). The most used acceptation criterion in uDCD is ALT level (31%), while in cDCD macroscopic aspect (48%) is most used. Regarding postoperative complications, PNF occurred in 13% (6%-25%) of uDCD livers and 3% (2%-4%) of cDCD livers. In uDCD, the 1-year graft and patient survival rates were 75% (66%-82%) and 82% (75%-88%). In cDCD, the 1-year graft and patient survival rates were 91% (89%-93%) and 93% (91%-94%), respectively. In conclusion, the currently used assessment criteria consist of macroscopic aspect and transaminase levels. The acceptance criteria should be tailored according to donor type to prevent an unacceptable PNF rate in uDCD and to increase the relatively modest OUR in cDCD.