Long-term outcome of liver transplantation for unresectable liver metastases from neuroendocrine neoplasms: a Belgian retrospective multi-centre study

peer reviewedBackground: Liver transplantation (LT) is the only curative treatment for unresectable liver metastases from neuroendocrine neoplasms (NEN-Liver-Mets). While recurrence is frequent after LT, there is limited data available in the literature on the outcome of recurrent patients. Methods: We retrospectively reviewed the medical records of all patients who underwent LT by NEN-Mets at the six LT centres in Belgium from 1986 to 2020. Patient and tumour characteristics, indication for transplantation, overall survival (OS), disease-free survival (DFS), and tumour recurrence and outcomes were analysed. Results: Forty patients underwent a LT for NEN-Liver-Mets in Belgium. Twenty-nine patients were male (74.2%) with a mean age of 41.9 and 47.1 years at the time of NEN diagnosis and LT, respectively. WHO classification was available for 32 patients and changed over time (see table below). OS post-LT at 1-, 5-, and 10-years are: 84,3%, 65,0% and 54,6% respectively, while the overall DFS are: 76.3%, 44.5% and 38.2% in the same intervals. Patients transplanted after 2010 showed better OS at 5-and 10-years (74.8% and 74.8%) when compared with patients transplanted before (60,0% and 49.5%). Twenty patients (50%) presented a NEN recurrence, of this, 14 (70%) were transplanted before 2010 and only 6 (30%) were transplanted afterwards (p=0.03). The median time for recurrence diagnosis was 12.3 months (range: 5.1 to 69.2). The most frequent recurrence treatments were surgical resection, somatostatin analogs, chemotherapy, and sunitinib therapy (8, 6, 6, and 4 patients, respectively). Survival rates were 89.5% and 56.1% at 1- and 5-years after recurrence diagnosis.Conclusions: Patients transplanted for unresectable NEN-Liver metastases had good long-term survival. Although the total recurrence rate is high, it decreased dramatically after 2010, probably due to better patient selection. Furthermore, recurrence treatment should be recommended as it may prolong patient survival

Organ reconditioning and machine perfusion in transplantation

Society’s self-sufficiency in terms of organ replacement is still far away from being achieved, given the large disparity between transplant demand and donor organ availability. In the attempt to reduce this discrepancy and expand the donor pool, the transplant community has progressively increased the utilisation of extended-criteria donors (ECD) such as older donors, donors with comorbidities and donation after circulatory death (DCD). The main challenge preventing a wider utilisation of ECD and DCD allografts is the higher susceptibility to the ischemia-reperfusion injury (IRI) (1), an unavoidable part of the transplantation process. For this reason, in the last decades, there has been an exponential development on organ reconditioning strategies, in order to enable graft resuscitation and viability assessment prior to implantation (2)

Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials.

Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation

Senolytic therapies have a place in pediatric biliary cirrhosis

Background and Aims: Premature senescence has been extensively characterized in adult chronic hepatobiliary diseases and can worsen liver function and fibrosis evolution. Since new therapeutic options are needed in pediatric biliary cirrhosis to delay liver transplantation, our aim was to investigate the presence of premature senescence in biliary atresia (BA) and to test the senolytic properties of Medicinal Signaling Cells in a preclinical model of biliary cirrhosis. Method: Senescence was investigated through senescence-associated β-galactosidase activity assay (SA-beta-gal) as well as p16 and p21 gene/protein expression in BA livers at the time of hepatoportoenterostomy (n = 5) or liver transplantation (n = 30) as compared to control livers (n = 10). Co-localized expression of senescence (gammaH2AX or p21) with CK19, HNF4alpha, alphaSMA and Ki67 was also assessed. Bile duct ligation (BDL) was performed on 2-months old rats and senescence was characterized in the model through above-mentioned techniques. Human allogeneic liver-derived progenitor cells (HALPC) were injected in BDL rats 48 hours after the surgery at high (12.5 x 106 cells/kg, n = 6) versus low dose (1.25 x 106 cells/kg, n = 6) and compared to the vehicle (n = 6). Results: Senescence was similarly increased in both BA stages as compared to control livers (SA-beta-gal: 5.9 ± 1.4 and 5.4 ± 1 vs 0.6 ± 0.1 %stained area/total, p < 0.01) and was also confirmed in BDL livers one and two weeks after the surgery (SA-beta-gal: 1.6 ± 0.6 and 6.6 ± 2.4 vs 0.2 ± 0.1 %stained area/total, p < 0.05). The pattern of senescence in BA and BDL was similar as senescence first appeared in cholangiocytes of the ductular reaction and subsequently developed in hepatocytes. HALPC transplantation at both doses decreased senescence in BDL rats (p21 gene expression: 0.4 ± 0.04 and 0.5 ± 0.1 vs 1 ± 0.2 fold change; p < 0.05). Conclusion: Premature senescence occurs in BA livers and HALPC display senolytic properties in a preclinical model of biliary cirrhosis

Senolytic therapies have a place in pediatric biliary cirrhosis

Aim of the study: Premature senescence has been extensively characterized in adult chronic hepatobiliary diseases and can worsen liver function and fibrosis evolution. Since new therapeutic options are needed in pediatric biliary cirrhosis to delay liver transplantation, our aim was to investigate the presence of premature senescence in biliary atresia (BA) and to test the senolytic properties of Medicinal Signaling Cells in a preclinical model of biliary cirrhosis. Method: Senescence was investigated through senescence-associated β-galactosidase activity assay (SA-β-gal) as well as p16 and p21 gene/protein expression in BA livers at the time of hepatoportoenterostomy (n=5) or liver transplantation (n=30) as compared to control livers (n=10). Co-localized expression of senescence (γH2AX or p21) with CK19, HNF4α, αSMA and Ki67 was also assessed. Bile duct ligation (BDL) was performed on 2-months old rats and senescence was characterized in the model through above-mentioned techniques. Human allogeneic liver-derived progenitor cells (HALPC) were injected in BDL rats 48 hours after the surgery at high (12.5 x 106 cells/kg, n=6) versus low dose (1.25 x 106 cells/kg, n=6) and compared to the vehicle (n=6). Results: Senescence was similarly increased in both BA stages as compared to control livers (SA-β-gal: 5.9±1.4 and 5.4±1 vs 0.6±0.1 %stained area/total, p<0.01) and was also confirmed in BDL livers one and two weeks after the surgery (SA-β-gal: 1.6±0.6 and 6.6±2.4 vs 0.2±0.1 %stained area/total, p<0.05). The pattern of senescence in BA and BDL was similar as senescence first appeared in cholangiocytes of the ductular reaction and subsequently developed in hepatocytes. HALPC transplantation at both doses decreased senescence in BDL rats (p21 gene expression: 0.4±0.04 fold change and 0.5±0.1 vs 1±0.2; p<0.05). Conclusion: Premature senescence occurs in BA livers and HALPC display senolytic properties in a preclinical model of biliary cirrhosi

Preservação do baço na pancreatectomia distal por trauma

OBJETIVOS: A esplenectomia simplifica a pancreatectomia distal no trauma mas tem o inconveniente de aumentar a vulnerabilidade do paciente às infecções. O objetivo é avaliar se a preservação do baço na referida cirurgia é exeqüível e segura. MÉTODOS: A preservação do baço foi feita em 52 pacientes (48%) entre 108 submetidos à pancreatectomia distal. Quarenta e cinco (86,5%) do sexo masculino e sete (13,5%) do sexo feminino. Idade variou de seis a 42 anos com média de 22,1 anos. Trauma penetrante foi a causa da lesão em 35 (67%) com 27 (77%) por arma de fogo e oito (23%) por arma branca. Contusão foi responsável pela lesão em 17 (33%). RESULTADOS: Não houve óbito. Fístula pancreática ocorreu em seis (11,5%) pacientes; coleção subfrênica em seis (11,5%); pancreatite em dois (3,8%); abcesso de parede em quatro (8%); pneumonia em quatro (8%). Quarenta pacientes tiveram lesões associadas. O ISS médio foi de 19,3. O baço apresentava lesão em 13 pacientes. Sete foram submetidos à esplenorrafia e seis à ressecção parcial. Em 51 pacientes o baço foi conservado com os vasos esplênicos. Em um caso foi feita a ligadura proximal e distal dos vasos esplênicos (técnica Warschaw). Permanência hospitalar média de 12 dias. CONCLUSÃO: A pacreatectomia distal com preservação do baço mostrou ser segura nos pacientes estáveis, mesmo na presença de lesões associadas. A ausência de óbitos e a participação de cirurgiões em fase de treinamento confirmam sua segurança

Long-term outcome of liver transplantation for neuroendocrine tumour non-resectable liver metastases: a Belgian retrospective multi-centre study

Liver transplantation (LT) is the only curative treatment for non-resectable liver metastases from neuroendocrine tumours (NET-Liver-mets). The adoption of strict indication criteria improves long-term survival. We retrospectively reviewed the medical records of all of patients who underwent LT by NET-mets at the six LT centres in Belgium from 1986 to 2020. Patient and tumour characteristics, indication for transplantation and surgical techniques, long-term survival of the patient, and tumour recurrence rate were analysed to identify prognostic factors to improve our guidelines. Forty patients underwent a LT for NET-Liver-mets in Belgium. Most patients were male (74.2%) with a mean age of 41.9 and 47.1 years at the time of NET diagnosis and liver transplantation, respectively. The location of the primary tumour was mainly the pancreas in 57.5%, followed by the small intestine in 25% of the cases, and in 84% of the patients the primary tumour was resected before LT. The post-LT overall patient survival rate at 1, 5, and 10 years are: 84,3%, 65,0% and 54,6% respectively, while the overall disease-free survival are 76,3%, 44,5% and 38.2 in the same intervals. However, the survival rate of transplant patients after 2010 at 1, 5 and 10 years is 84.2%, 74.8 and 74.8% compared to 85%, 60.0% and 49, 5% of transplanted patients before 2010. These findings suggest an improvement in the long-term survival rate for patients undergoing LT after 2010. In conclusion, our study shows that LT is a valid treatment for non-resectable liver metastasis from neuroendocrine tumours