Background/Objectives: Despite the long-standing history of liver transplantation (LT) in Spain, no multicenter study has reviewed national outcomes for LT in metastatic neuroendocrine tumors (NETs). In the current era of transplant oncology, auditing these results is essential to refine patient selection and improve long-term outcomes. Methods: This retrospective observational study analyzed data from 13 centers, including 91 patients who underwent LT for NET between 1995 and 2024. Patients were stratified into two groups: Milan IN (those meeting the Milan criteria) and Milan OUT (the remainder). Results: Recurrence occurred in 57.1% of cases, and overall mortality was 51.6%. Of the 91 patients, 71 (78.0%) were Milan IN and 20 (22.0%) were Milan OUT. Five-year overall survival was 71.0% in Milan IN and 58.0% in Milan OUT, with a statistically significant difference. The 5-year disease-free survival (DFS) rate was 58.8% in Milan IN and 36.3% in Milan OUT; this difference was not statistically significant. Conclusions: In conclusion, strict adherence to Milan criteria and incorporation of modern prognostic factors are critical to optimize long-term survival in LT for NET. While the overall outcomes in this historical cohort are modest, future improvements are expected through more rigorous selection and the potential use of bridging or downstaging therapies.

CONTEXT:In liver transplantation (LT), anemia and transfusion of blood products have a negative impact on morbidity and mortality. METHODS:Multicenter, prospective observational study. The main objective was to assess whether correction of iron deficiency anemia with intravenous iron was feasible in LT candidates. Its efficacy and adverse effects were evaluated. Patients with Hb value <115g/l and ferritin values <800ng/ml were included. Based on the increase in Hb>10g/l compared to its baseline level, the analysis of 76 patients was considered. An anemia study was carried out, assigning to the study group those who met the criteria for iron deficiency anemia, which followed a protocol of administration of up to two doses of iron before LT. RESULTS:Two hundred ninety-six LT were performed during the study period, 48% of patients had an Hb value <115g/l. Forty-three patients made up the study group, in 5 patients the first dose was not administered. The second dose was administered to 55% of patients. No patient presented serious adverse effects or alterations in liver function. Hemoglobin increased compared to baseline by a median of 11.22g/l (6.47-15.97) after the first administration and 11.64g/l (6.49-16.78) after the second. CONCLUSIONS:The implementation of patient blood management in LT through the administration of intravenous iron is effective and safe. It is necessary to routinely characterize and treat the presence of iron deficiency anemia in these patients.

Contexto En el trasplante hepático (TH) la anemia y la transfusión de hemoderivados tienen un impacto negativo en la morbimortalidad. Métodos Estudio multicéntrico, prospectivo observacional. El objetivo principal fue valorar si la corrección de la anemia ferropénica con hierro intravenoso era factible en los candidatos a TH. Se evaluó su eficacia y efectos adversos. Se incluyeron los pacientes con valor de Hb<115g/l y valores de ferritina <800ng/ml. En base al incremento de la Hb>10g/l respecto a su nivel basal se consideró el análisis de 76 pacientes.Se realizó un estudio de anemia, asignando al grupo estudio los que cumplieron criterios de anemia ferropénica, que siguió un protocolo de administración de hasta 2 dosis de hierro antes del TH. Resultados Se realizaron 296 TH en el periodo del estudio, el 48% de los pacientes tenían un valor de Hb<115g/l. Cuarenta y tres pacientes conformaron el grupo estudio, en 5 pacientes no se llegó a administrar la primera dosis. La segunda dosis se administró en el 55% de los pacientes. Ningún paciente presentó efectos adversos graves ni alteración de la función hepática. La hemoglobina se incrementó respecto a la basal una mediana de 11,22g/l (6,47-15,97) tras la primera administración y de 11,64g/l (6,49-16,78) tras la segunda. Conclusiones La puesta en marcha de un programa de gestión de la sangre en el TH mediante la administración de hierro intravenoso es eficaz y segura. Es necesario caracterizar y tratar de forma rutinaria la presencia de anemia ferropénica en estos pacientes.

Introduction: The multiparametric nature of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) still leads to uncertainty with its practical management. This study aims to characterize the main posttransplant recurrence patterns of HCC and to explore the therapeutic modalities targeting recurrence. Methods: Consecutive patients who underwent LT for HCC at a single tertiary center were analyzed. The time from first recurrence to death was investigated for each site of presentation. The impact of each recurrence-targeted treatment on survival was studied. Results: Of 660 patients with HCC, any recurrence occurred in 96 (15.4%) patients with a median time to recurrence of 20.0 months (95% CI: 15.6-23.8). Patients recurred across different patters including solitary distant locations (30.8%, n = 28), liver only (24.2%, n = 22), lung (18.7%, n = 17), multi-organ disease (17.6%, n = 16), and bone (8.8%, n = 8). Multi-organ and bone recurrences had the poorest survival, while solitary distant lesions and pulmonary recurrences had the best outcomes. Each treatment modality carried a distinctive survival. Conclusions: Patients recurred across 3 patterns with different prognostic implications. The benefit of each treatment option on distinct recurrence patterns appears to be influenced by the biological behavior inherent in the recurrence pattern itself.

Sex inequities in liver transplantation (LT) have been documented in several, mostly US-based, studies. Our aim was to describe sex-related differences in access to LT in a system with short waiting times. All adult patients registered in the RETH-Spanish Liver Transplant Registry (2000–2022) for LT were included. Baseline demographics, presence of hepatocellular carcinoma, cause and severity of liver disease, time on the waiting list (WL), access to transplantation, and reasons for removal from the WL were assessed. 14,385 patients were analysed (77% men, 56.2 ± 8.7 years). Model for end-stage liver disease (MELD) score was reported for 5,475 patients (mean value: 16.6 ± 5.7). Women were less likely to receive a transplant than men (OR 0.78, 95% CI 0.63, 0.97) with a trend to a higher risk of exclusion for deterioration (HR 1.17, 95% CI 0.99, 1.38), despite similar disease severity. Women waited longer on the WL (198.6 ± 338.9 vs. 173.3 ± 285.5 days, p < 0.001). Recently, women’s risk of dropout has reduced, concomitantly with shorter WL times. Even in countries with short waiting times, women are disadvantaged in LT. Policies directed at optimizing the whole LT network should be encouraged to guarantee a fair and equal access of all patients to this life saving resource.

Background & Aims: Complex portal vein thrombosis (PVT) is a challenge in liver transplantation (LT). Extra-anatomical ap-proaches to portal revascularization, including renoportal (RPA), left gastric vein (LGA), pericholedochal vein (PCA), and cavoportal (CPA) anastomoses, have been described in case reports and series. The RP4LT Collaborative was created to record cases of alternative portal revascularization performed for complex PVT. Methods: An international, observational web registry was launched in 2020. Cases of complex PVT undergoing first LT per-formed with RPA, LGA, PCA, or CPA were recorded and updated through 12/2021.Results: A total of 140 cases were available for analysis: 74 RPA, 18 LGA, 20 PCA, and 28 CPA. Transplants were primarily performed with whole livers (98%) in recipients with median (IQR) age 58 (49-63) years, model for end-stage liver disease score 17 (14-24), and cold ischemia 431 (360-505) minutes. Post-operatively, 49% of recipients developed acute kidney injury, 16% diuretic-responsive ascites, 9% refractory ascites (29% with CPA, p <0.001), and 10% variceal hemorrhage (25% with CPA, p = 0.002). After a median follow-up of 22 (4-67) months, patient and graft 1-/3-/5-year survival rates were 71/67/61% and 69/63/57%, respectively. On multivariate Cox proportional hazards analysis, the only factor significantly and independently associated with all -cause graft loss was non-physiological portal vein reconstruction in which all graft portal inflow arose from recipient systemic circulation (hazard ratio 6.639, 95% CI 2.159-20.422, p = 0.001).Conclusions: Alternative forms of portal vein anastomosis achieving physiological portal inflow (i.e., at least some recipient splanchnic blood flow reaching transplant graft) offer acceptable post-transplant results in LT candidates with complex PVT. On the contrary, non-physiological portal vein anastomoses fail to resolve portal hypertension and should not be performed.(c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p < .001), ischemic type biliary lesions (OR 0.112, 95% CI 0.042-0.299, p < .001), graft loss (HR 0.371, 95% CI 0.267-0.516, p < .001), and patient death (HR 0.540, 95% CI 0.373-0.781, p = .001). Cold ischemia time (HR 1.004, 95% CI 1.001-1.007, p = .021) and re-transplantation indication (HR 9.552, 95% CI 3.519-25.930, p < .001) were significant independent predictors for graft loss among cDCD livers with A-NRP. While use of A-NRP helps overcome traditional limitations in cDCD liver transplantation, opportunity for improvement remains for cases with prolonged cold ischemia and/or technically complex recipients, indicating a potential role for complimentary ex situ perfusion preservation techniques.

Normothermic regional perfusion – What is the benefit?Journal of HepatologyVol. 71Issue 2PreviewWe read with great interest the recent article by Hessheimer et al. on normothermic regional perfusion (NRP) in controlled donation after circulatory death (DCD) donors in Spain.1 In this innovative national analysis, the authors compare NRP against super rapid retrieval in terms of relevant outcome parameters after liver transplantation. The results appear impressive, as they show a significant reduction of biliary complications by NRP (overall: 8 vs. 31%, ischemic cholangiopathy: 2 vs. 13%). This is also important from an economic perspective, as NRP is currently one of the cheapest machine perfusion techniques available. Full-Text PDF Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantationJournal of HepatologyVol. 70Issue 4PreviewDonation after circulatory death (DCD) donors, who are declared dead following cardiorespiratory arrest, are an increasingly common source of organs. The period of donor warm ischaemia surrounding arrest can damage the quality of organs in general and the liver in particular, because biliary cells are exquisitely susceptible to warm ischaemia.1 Thus, initial experiences with DCD liver transplantation described high rates of graft dysfunction and non-function and ischaemic type biliary lesions (ITBL). Full-Text PDF We thank Drs. Schlegel, Muiesan, and Dutkowski for their interest in our manuscript[1]Schlegel A. Muiesan P. Dutkowski P. Normothermic regional perfusion – what is the benefit?.J Hepatol. 2019; 71: 441-443Abstract Full Text Full Text PDF Scopus (1) Google Scholar and are delighted to provide clearer and updated information regarding the use of normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation. Our manuscript describes the Spanish experience with cDCD liver transplantation from national application in 2012 through 2016, comparing outcomes of transplants performed with NRP versus those performed with super rapid recovery (SRR).[2]Hessheimer A.J. Coll E. Torres F. Ruiz P. Gastaca M. Rivas J.I. et al.Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantation.J Hepatol. 2019; 70: 658-665Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Transplants were included from 20 centers, only 3 (15%) with previous experience performing uncontrolled donation after circulatory death. The results that we present can be achieved by not just perfusion and DCD “experts” but by virtually any liver transplant team. That said, the results we achieved with SRR are the same as those described by experienced centers using cDCD livers of a comparable profile,3Schlegel A. Scalera I. Perera M.T.P.R. Kalisvaart M. Mergental H. Mirza D.F. et al.Impact of donor age in donation after circulatory death liver transplantation: Is the cutoff “60” still of relevance?.Liver Transpl. 2018; 24: 352-362Crossref PubMed Scopus (65) Google Scholar, 4Croome K.P. Mathur A.K. Lee D.D. Moss A.A. Rosen C.B. Heimbach J.K. et al.Outcomes of donation after cardiac death liver grafts from donors >/= 50 years of age: a multi-center analysis.Transplantation. 2018; Google Scholar and improvements achieved with NRP are strikingly similar to those recently reported by 2 UK centers describing 43 cDCD liver transplants performed with NRP.[5]Watson C. Hunt F. Messer S. Currie I. Large S. Sutherland A. et al.In situ normothermic perfusion of livers in controlled circulatory death donation may prevent ischemic cholangiopathy and improve graft survival.Am J Transplant. 2019; Google Scholar The Letter’s authors claim the “risk” of the cDCD grafts we used was low based on a scoring system they developed.[6]Schlegel A. Kalisvaart M. Scalera I. Laing R.W. Mergental H. Mirza D.F. et al.The UK DCD risk score: a new proposal to define futility in donation-after-circulatory-death liver transplantation.J Hepatol. 2018; 68: 456-464Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The UK DCD Risk Score has not been independently validated but has found to be ineffective at predicting 1-year cDCD liver survival (its aim) in our recipients[7]Hessheimer A.J. Coll E. Ruiz P. Gastaca M. Rivas J.I. Gomez M. et al.The UK DCD risk score: still no consensus on futility in DCD liver transplantation.J Hepatol. 2019; 16Google Scholar and other British cohorts.[8]Oniscu G.C. Watson C.J.E. Wigmore S.J. Redefining futility in DCD liver transplantation in the era of novel perfusion technologies.J Hepatol. 2018; 68: 1327-1328Google Scholar The authors do correctly describe our median functional donor warm ischemia times: 12 and 15 minutes when NRP and SRR were used, respectively. Femoral cannulae were placed prior to withdrawal of ventilatory support in 87% of cases using NRP, and warm ischemia times were shorter when NRP was employed. That said, the implication that the authors consistently experience longer warm ischemia times than even those for livers recovered with SRR is surprising. Only 11 of 342 cDCD donors considered for liver donation during the study period were turned down due to prolonged warm ischemia (3%). The facts that i) indication for proceeding with cDCD in Spain is strict and predicated on likelihood of arrest within 60 minutes of withdrawal of care and ii) cDCD donors in Spain have been in intensive care 7–10 days prior to withdrawal (vs. 2–3 days in the UK)3Schlegel A. Scalera I. Perera M.T.P.R. Kalisvaart M. Mergental H. Mirza D.F. et al.Impact of donor age in donation after circulatory death liver transplantation: Is the cutoff “60” still of relevance?.Liver Transpl. 2018; 24: 352-362Crossref PubMed Scopus (65) Google Scholar, 5Watson C. Hunt F. Messer S. Currie I. Large S. Sutherland A. et al.In situ normothermic perfusion of livers in controlled circulatory death donation may prevent ischemic cholangiopathy and improve graft survival.Am J Transplant. 2019; Google Scholar may explain the consistently shorter warm ischemia times we experienced. While we did not argue in our manuscript that our discard rates are similar to those in other countries, the authors are correct in pointing this out. Between 2012 and 2016, 38% of cDCD livers recovered with SRR and 34% recovered with NRP in Spain were ultimately discarded, similar to the 33% of retrieved cDCD livers declined in 2017/2018 in the UK.[9]UK NHS Blood and Transplant. 2017/18 Organ Donation and Transplantation Activity Report. British Transplantation Society; 2018 Apr 1.Google Scholar Our figures are national averages, and individual centers have lower discard rates. Obviously, the “rate” depends on the denominator, and comparing national averages with rates described in smaller pilot studies, where pre-selection has been performed on grafts included, is misleading.[1]Schlegel A. Muiesan P. Dutkowski P. Normothermic regional perfusion – what is the benefit?.J Hepatol. 2019; 71: 441-443Abstract Full Text Full Text PDF Scopus (1) Google Scholar As in donation after brain death (DBD) liver transplantation, cDCD liver evaluation is not exact, and visual assessment by the surgical team is still the ultimate measure of viability when ex situ perfusion is not employed. The majority of cDCD livers turned down in our study were observed to be moderately-to-severely steatotic, poorly perfused, fibrotic, or cirrhotic.[2]Hessheimer A.J. Coll E. Torres F. Ruiz P. Gastaca M. Rivas J.I. et al.Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantation.J Hepatol. 2019; 70: 658-665Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar While hepatic aminotransferases in the perfusate were assessed as an indication of hepatic injury, they rose very little in most cases (only 4 livers were turned down due to rising aminotransferases), and liver viability assessment in the strictest sense was not performed. This does not mean that true viability assessment may not be performed during NRP, as bile is produced, and evaluation of bile production and biochemistry may serve as useful means to assess significant biliary injury. When NRP is employed, the cost of the cDCD process increases €2,500–5,000 with respect to standard DBD or cDCD with SRR. This cost is lower than that required to perfuse a liver ex situ, where disposable components of the machine perfusion circuit alone are at the higher end of the aforementioned range. Considering costs, one also has to keep in mind that NRP is simultaneously used to recover cDCD kidneys, pancreata, and hearts, as well, and benefits of NRP in terms of post-transplantation outcomes extend to these organs.[10]Demiselle J. Augusto J.F. Videcoq M. Legeard E. Dube L. Templier F. et al.Transplantation of kidneys from uncontrolled donation after circulatory determination of death: comparison with brain death donors with or without extended criteria and impact of normothermic regional perfusion.Transpl Int. 2016; 29: 432-442Crossref PubMed Scopus (47) Google Scholar In their final comments, the Letter’s authors call for a moratorium on widespread application of any perfusion technology in human liver transplantation pending results of randomized trials. This recommendation defies reality in countries such as Spain, France, and Italy. In Spain, the use of NRP in cDCD has risen exponentially since 2012 (Fig. 1A). In 2018, 189 cDCD livers were transplanted: 151 with NRP and 38 with SRR. NRP was applied in >200 cDCD donors at 62 hospitals, in a third of cases at non-transplant hospitals by local teams (Fig. 1B). The application of NRP is widely disseminated here and has allowed for implementation of cDCD at all levels. Given excellent post-transplant results,[2]Hessheimer A.J. Coll E. Torres F. Ruiz P. Gastaca M. Rivas J.I. et al.Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantation.J Hepatol. 2019; 70: 658-665Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar it seems improbable if not unethical that centers currently using NRP would abandon it and risk increased biliary complications and graft loss pending a level 1 clinical trial. While NRP increases upfront costs associated with cDCD transplantation compared with SRR, it may be used by both transplant and perfusion experts and less experienced professionals to treat and potentially assess the quality of multiple organs, not just the liver. At a time when healthcare systems are concerned with achieving the greatest benefit at the lowest cost, NRP appears to be the DCD perfusion strategy that best meets this need. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the Supplementary data to this article: Download .pdf (.63 MB) Help with pdf files Supplementary Data 1