Hypothermic machine perfusion in liver transplantation.

Dynamic preservation strategies are a promising option to improve graft quality before transplantation, and to extend preservation time for either logistic or treatment reasons. In contrast to normothermic oxygenated perfusion, which intends to mimic physiological conditions in the human body, with subsequent clinical application for up to 24 hrs, hypothermic perfusion is mainly used for a relatively short period with protection of mitochondria and subsequent reduction of oxidative injury upon implantation. The results from two randomized controlled trials, where recruitment has finished are expected this year. Both ex situ perfusion techniques are increasingly applied in clinical transplantation including recent reports on viability assessment, which could open the door for an increased liver utilization in the future.

Impact of a Patient Blood Management monitoring and feedback programme on allogeneic blood transfusions and related costs.

A Patient Blood Management programme was established at the University Hospital of Zurich, along with a monitoring and feedback programme, at the beginning of 2014 with a first analysis reported in 2015. Our study aimed to investigate the further impact of this Patient Blood Management monitoring and feedback programme on transfusion requirements and related costs. We included adult patients discharged between 2012 and 2017. A total of 213,882 patients underwent analysis: 66,659 patients in the baseline period (2012-2013); 35,309 patients in the year after the introduction of the Patient Blood Management monitoring and feedback programme (2014) and 111,914 patients in the continued sustainability period (2015-2017). The introduction of the Patient Blood Management monitoring and feedback programme reduced allogeneic blood product transfusions by 35%, from 825 units per 1000 hospital discharges in 2012 to 536 units in 2017. The most sustained effect was an approximately 40% reduction in red blood cell transfusions, from 535 per 1000 discharges to 319 units. Fewer patients were transfused in the periods after the introduction of the Patient Blood Management monitoring and feedback programme (6251 (9.4%) vs. 2932 (8.3%) vs. 8196 (7.3%); p < 0.001). Compared with 2012, the yearly OR for being exposed to any blood transfusion declined steadily after the introduction of the Patient Blood Management monitoring and feedback programme to 0.64 (95%CI 0.61-0.68; p < 0.001) in 2017. For patients requiring extracorporeal membrane oxygenation, transfusion requirements were also sustainably reduced. This reduction in allogeneic blood transfusions led to savings of 12,713,754 Swiss francs (£ 9,497,000 sterling; EUR 11,100,000; US$ 12,440,000) in blood product acquisition costs over 4 years. In-hospital mortality was not affected by the programme. The Patient Blood Management monitoring and feedback programme sustainably reduced transfusion requirements and related costs, without affecting in-hospital mortality.

Can hypothermic oxygenated perfusion (HOPE) rescue futile DCD liver grafts?

BACKGROUND: The new UK-DCD-Risk-Score has been recently developed to predict graft loss in DCD liver transplantation. Donor-recipient combinations with a cumulative risk of >10 points were classified as futile and achieved an impaired one-year graft survival of <40%. The aim of this study was to show, if hypothermic oxygenated perfusion (HOPE) can rescue such extended DCD livers and improve outcomes. METHODS: "Futile"-classified donor-recipient combinations were selected from our HOPE-treated human DCD liver cohort (01/2012-5/2017), with a minimum follow-up of one year. Main risk factors, which contribute to the classification "futile" include: elderly donors>60years, prolonged functional donor warm ischemia time (fDWIT > 30min), long cold ischemia time>6hrs, donor BMI>25 kg/m2, advanced recipient age (>60years), MELD-score>25points and retransplantation status. Endpoints included all outcome measures during and after DCD LT. RESULTS: Twenty-one donor-recipient combinations were classified futile (median UK-DCD-Risk-Score:11 points). The median donor age and fDWIT were 62 years and 36 min, respectively. After cold storage, livers underwent routine HOPE-treatment for 120 min. All grafts showed immediate function. One-year and 5-year tumor death censored graft survival was 86%. CONCLUSION: HOPE-treatment achieved excellent outcomes, despite high-risk donor and recipient combinations. Such easy, endischemic perfusion approach may open the door for an increased utilization of futile DCD livers in other countries.

Risk Assessment in High- and Low-MELD Liver Transplantation.

Allocation of liver grafts triggers emotional debates, as those patients, not receiving an organ, are prone to death. We analyzed a high-Model of End-stage Liver Disease (MELD) cohort (laboratory MELD score ≥30, n = 100, median laboratory MELD score of 35; interquartile range 31-37) of liver transplant recipients at our center during the past 10 years and compared results with a low-MELD group, matched by propensity scoring for donor age, recipient age, and cold ischemia time. End points of our study were cumulative posttransplantation morbidity, cost, and survival. Six different prediction models, including donor age x recipient MELD (D-MELD), Difference between listing MELD and MELD at transplant (Delta MELD), donor-risk index (DRI), Survival Outcomes Following Liver Transplant (SOFT), balance-of-risk (BAR), and University of California Los Angeles-Futility Risk Score (UCLA-FRS), were applied in both cohorts to identify risk for poor outcome and high cost. All score models were compared with a clinical-oriented decision, based on the combination of hemofiltration plus ventilation. Median intensive care unit and hospital stays were 8 and 26 days, respectively, after liver transplantation of high-MELD patients, with a significantly increased morbidity compared with low-MELD patients (median comprehensive complication index 56 vs. 36 points [maximum points 100] and double cost [median US$179 631 vs. US$80 229]). Five-year survival, however, was only 8% less than that of low-MELD patients (70% vs. 78%). Most prediction scores showed disappointing low positive predictive values for posttransplantation mortality, such as mortality above thresholds, despite good specificity. The clinical observation of hemofiltration plus ventilation in high-MELD patients was even superior in this respect compared with D-MELD, DRI, Delta MELD, and UCLA-FRS but inferior to SOFT and BAR models. Of all models tested, only the BAR score was linearly associated with complications. In conclusion, the BAR score was most useful for risk classification in liver transplantation, based on expected posttransplantation mortality and morbidity. Difficult decisions to accept liver grafts in high-risk recipients may thus be guided by additional BAR score calculation, to increase the safe use of scarce organs.

Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment.

UNLABELLED: The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that "very early" iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with "very early" iCCA and those with "advanced" disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the "very early" iCCA group and 33/48 (69%) the "advanced" group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the "advanced" group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. CONCLUSION: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178-1188).

Machine Perfusion of Donor Livers for Transplantation: A Proposal for Standardized Nomenclature and Reporting Guidelines.

With increasing demand for donor organs for transplantation, machine perfusion (MP) promises to be a beneficial alternative preservation method for donor livers, particularly those considered to be of suboptimal quality, also known as extended criteria donor livers. Over the last decade, numerous studies researching MP of donor livers have been published and incredible advances have been made in both experimental and clinical research in this area. With numerous research groups working on MP, various techniques are being explored, often applying different nomenclature. The objective of this review is to catalog the differences observed in the nomenclature used in the current literature to denote various MP techniques and the manner in which methodology is reported. From this analysis, we propose a standardization of nomenclature on liver MP to maximize consistency and to enable reliable comparison and meta-analyses of studies. In addition, we propose a standardized set of guidelines for reporting the methodology of future studies on liver MP that will facilitate comparison as well as clinical implementation of liver MP procedures.

Hypothermic Oxygenated Liver Perfusion: Basic Mechanisms and Clinical Application.

Dynamic preservation strategies such as hypothermic machine perfusion are increasingly discussed to improve liver graft quality before transplantation. This review summarizes current knowledge of this perfusion technique for liver preservation. We discuss optimization of perfusion conditions and current strategies to assess graft quality during cold perfusion. Next, we provide an overview of possible pathways of protection from ischemia-reperfusion injury. Finally, we report on recent clinical applications of human hypothermic machine liver perfusion.

Histopathological evidence of invasive gastric mucormycosis after transarterial chemoembolization and liver transplantation.

We describe a case of a 62-year-old diabetic woman with hepatocellular carcinoma due to chronic hepatitis B virus infection. Two weeks after orthotopic liver transplantation, endoscopy for massive upper gastrointestinal bleeding revealed a large necrotic area in the gastric fundus. The patient underwent emergency resection. Histopathologically, angioinvasive mold infection compatible with mucormycosis was diagnosed in a large area of necrosis, mimicking an atypically localized gastric ulcer. Foreign bodies originating from transarterial chemoembolization (TACE) performed 7 and 8 months earlier and 40 days before transplantation were identified in the submucosal tissue. The patient was treated with liposomal amphotericin B (LAB) for 5 weeks, followed by 7 weeks of posaconazole. Follow-up biopsies after 1 and 5 months confirmed successful treatment. Review of the radiological images of the TACE procedure showed that some of the TACE material had been diverted to the stomach via an accessory gastric branch originating from the left hepatic artery. TACE agents may be associated with chronic, refractory gastroduodenal ulcers. We hypothesize that the ischemic lesion was first colonized with presumed Mucorales mold and invasive growth was promoted by the posttransplantation immunosuppression. Careful exploration of extrahepatic collaterals during TACE may prevent this complication.

Alexis Carrel: genius, innovator and ideologist.

Alexis Carrel was a Frenchman from Lyon, who gained fame at the Rockefeller Institute in New York at the beginning of the 20th century. He was the first to demonstrate that arteriovenous anastomoses were possible. Alexis Carrel was awarded the Nobel Prize for his contributions to vascular surgery and transplantation in 1912. He was a versatile scientist, who made numerous discoveries from the design of an antiseptic solution to treat injuries during the First World War to tissue culture and engineering, and organ preservation, making him the father of solid organ transplantation. Together, with the famous aviator and engineer Charles Lindbergh, they were the first scientists capable of keeping an entire organ alive outside of the body, using a perfusion machine. Due to his many dubious ideas and his association with fascism in the 1930s and during the Second World War, many of his scientific achievements have been forgotten today and taken for granted.

Machine perfusion for 'marginal' liver grafts.

Due to the critical shortage of deceased donor grafts, clinicians are continually expanding the criteria for an acceptable liver donor to meet the waiting list demands. However, the reduced ischemic tolerance of those extended criteria grafts jeopardizes organ viability during cold storage. Machine perfusion has been developed to limit ischemic liver damage but despite its proven biochemical benefit, machine liver perfusion is not yet considered clinically due to its low practicability. In this review, we summarize our understanding of the role of machine perfusion in marginal liver preservation. The goal is to highlight advantages or disadvantages of current perfusion techniques and to explain the underlying mechanisms. We provide evidence for the need of a liver perfusion performance shortly before implantation, and point out promising designs.

Different protection mechanisms after pretreatment with glycine or alpha-lipoic acid in a rat model of warm hepatic ischemia.

BACKGROUND/AIM: Alpha-lipoic (LA) acid pretreatment has previously been described to reduce ischemia/reperfusion injury (IRI) after warm liver ischemia, whereas glycine pretreatment has been shown to be protective mostly in models of cold hepatic ischemia. The aim of this study was to determine whether glycine decreases IRI after warm hepatic ischemia. Furthermore we investigated whether doses of LA other than those used previously are also protective against IRI after warm hepatic ischemia. METHODS: Selective liver ischemia was maintained over a period of 90 min. In long-term as well as short-term experiments we studied IRI in several groups comparing animal survival as the pivotal endpoint. RESULTS: Animal survival was improved by glycine and 5,000 micromol LA, whereas all animals died within 3 days after pretreatment with 50 micromol LA. In the glycine group we observed a tendency towards decreased apoptosis-related cell death measured by the activity of caspase-3 in liver tissue and the percentage of TUNEL-positive hepatocytes in comparison to the untreated group. Serum alpha-glutathione S-transferase, lipid peroxidation, and caspase-3 activity as well as the percentage of TUNEL-positive hepatocytes and the percentage of liver necrosis were only significantly decreased by 5,000 micromol LA pretreatment. Liver tissue levels of tumor necrosis factor (TNF)alpha were reduced only in the glycine group whereas TNFalpha was increased in the untreated as well as the LA group. Levels of TNFalpha mRNA were upregulated in both the glycine- and LA-pretreated groups. CONCLUSION: Our data show that increased animal survival by glycine was accompanied by a reduced TNFalpha content in liver tissue. Protection by glycine is likely to result from a reduction in adverse TNFalpha effects. Administration of high-dose LA on the other hand led to a significant reduction in necrosis- and apoptosis-related cell death in IRI of the liver without a reduction in liver TNFalpha.

Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion.

The aim of the study was to investigate whether hypothermic oxygenated liver perfusion after cold liver preservation resuscitated metabolic parameters and whether this treatment had a benefit for liver viability upon reperfusion. We preserved rat livers either by cold storage (UW) for 10 h, or by perfusion for 3 h (oxygenated modified UW) after 10 h cold storage. We assessed viability of livers after preservation and after ischemic rewarming+normothermic reperfusion ex vivo. Ten hour cold storage reduced mitochondrial cytochrome oxidase and metabolically depleted the livers. Oxygenated perfusion after cold storage resulted in uploaded cellular energy charge and oxidized mitochondrial cytochrome oxidase. Reperfusion after 10 h cold storage increased formation of superoxid anions, release of cytosolic LDH, lipid peroxidation, caspase activities and led to disruption of sinusoidal endothelial cells. In contrast, reperfusion after 10 h cold storage+3 h hypothermic oxygenated perfusion resulted in no changes of lipid peroxidation, bile flow, energy charge, total glutathione, LDH release and of caspase activation, as compared to fresh resected livers. This study demonstrates, that a metabolically depleted liver due to cold storage can be energy recharged by short-termed cold machine perfusion. The machine perfused graft exhibited improved viability and functional integrity.

Detection of mitochondrial electron chain carrier redox status by transhepatic light intensity during rat liver reperfusion.

The aim of the study was to investigate mitochondrial electron transfer during rat liver reperfusion after cold storage and hypothermic machine perfusion. Livers from male Brown Norway rats were preserved (UW) for 10h either by cold storage (CS) or by hypothermic oxygenated perfusion extracorporal (HOPE). Transhepatic photometric analysis allowed determination of the redox status of mitochondrial cytochromes during preservation, rewarming and reperfusion. Mitochondrial electron chain carriers were inhibited at different sites with rotenone and cyanide in some experiments. reversed transcriptional polymerase chain reaction (RT-PCR) was performed after reperfusion concerning transcription of TNFalpha, caspase 9, and c-jun kinase (JNK). Increased superoxide anion formation as well as transcription of TNFalpha, caspase 9, and JNK during reperfusion after cold storage (CS) were related with completely reduced cytochromes before and during reperfusion. In contrast, hypothermic oxygenated livers (HOPE) showed oxygenated cytochromes as well as decreased superoxide anion formation and no detectable transcription of TNFalpha, caspase 9, and JNK. A similar low level of superoxide anion formation was found when electron chain transfer of cold stored livers was inhibited during reperfusion with rotenone but not with cyanide. After hypothermic oxygenation (HOPE) inhibition of mitochondrial electron chain with rotenone showed no change in formation of superoxide anion formation whereas inhibition with cyanide showed increased superoxide anion formation. Thus mitochondrial cytochrome redox status is suggested to be related: (i) with the release of reactive oxygen substances as well as (ii) with the expressions of TNFalpha, caspase 9, and JNK during reperfusion and may thus be usable as predictive marker of liver grafts.

[Adenocarcinoma of the esophagus: prognostic comparison between transthoracic esophageal resection with expanded 2-field lymph node dissection and trans-hiatal esophageal dissection with abdominal lymph node excision]. / Adenokarzinom des Oesophagus: Prognosevergleich zwischen transthorakaler Oesophagusresektion mit ereiterter 2 Feld Lymphknotendissektion und transhiataler Oesophagusdissektion mit abdomineller Lymphknotendissektion.

A retrospective analysis should compare the two operative approaches, transhiatal or transthoracic resection in patients suffering from adenocarcinoma of the esophagus. Between 1985 and 2002 123 cases were presented with adenocarcinoma of the esophagus, treated in 65% by transhiatal resection including abdominal lymph node dissection and in 35% by the transthoracic approach with standardized extended mediastinal and abdominal lymph node dissection. Hospital mortality was 14% (6/43) after transthoracic resection and 3.8% (3/80) after transhiatal resection (ns). Die number of removed and examined abdominal lymph nodes following transhiatal resection was 14.1 (mean) versus 12.3 (mean) after transthoracic resection (ns). Die number of removed and examined mediastinal lymph nodes by transhiatal resection was 6.3 (mean) versus 19.7(mean) after transthoracic resection (p < 0.001). The median survival after transthoracic approach was 19 months versus 20 months after transhiatal approach (ns). Median survival of curatively resected patients (R0) were in both operative procedures similar (21 months). A more differentiated analysis referred to the UICC stages also demonstrated no differences in the survival between transthoracic and transhiatal resection. With respect to less mortality and less morbidity after transhiatal resection and because of the not detectable prognostic advantage of the transthoracic resection we suggest the transhiatal approach as the treatment of choice in patients with adenocarcinoma of the esophagus.

Postoperative reduction of fibrinolysis as a prognostic factor of fatal outcome.

For the resection of an esophagus carcinoma a mortality rate of 2 to 30% was described. It is still unclear whether an abdominothoracic or transhiatal intervention is superior regarding the outcome. To investigate the prognostic value of fibrinolytic markers, plasmin-alpha2-antiplasmin (PAP) and D-dimer (DD) values were determined daily in the early postoperative period for 11 days. In addition, the course of PAP and DD concentrations was compared with the method of esophagectomy. Of the 28 patients enclosed in the study, 5 died between day 10 and day 34 owing to adult respiratory distress syndrome and septicemia. The PAP and DD concentrations increased in survivors after surgery until day 5 and day 7, respectively. The concentrations were twofold and 10-fold higher than the upper reference level. In contrast, four of five nonsurvivors showed an inadequate increase in PAP concentrations within the reference range, whereas the course of DD was inconspicuous. The sensitivity and specificity of PAP and DD in respect to a fatal outcome was calculated by receiver operating characteristic analysis based on all results: sensitivity 76% (PAP-cut off value 760 microg/L) and 49% (DD 6 mg/L), specificity 77% and 72%, respectively. The biochemical markers showed no significant differences between the abdominothoracic and transhiatal esophagectomy. In the abdominothoracic intervention, lower PAP and higher DD concentrations were observed. The results showed that the PAP concentrations could detect a fatal outcome within the first 5 days after surgery.

Comparison of iceball diameter and temperature distribution achieved with 3-mm accuprobe cryoprobes in porcine and human liver tissue and human colorectal liver metastases in vitro.

We aimed to assess the thermal profile and size of iceballs produced by Accuprobe cryoprobes in fresh porcine and human liver and human colorectal cancer liver metastases in vitro to allow better planning of cryosurgical treatment of liver metastases. Iceballs were produced by a 20-min single freeze cycle using 8-mm cryoprobes in pig liver in a waterbath at 37 degrees C (n = 8) and 3-mm cryoprobes in pig liver (n = 8), human liver (n = 3), and human colorectal cancer liver metastases (n = 8). The iceball diameters and the temperatures at different distances from the cryoprobe were measured. Mean iceball diameters produced by 8-mm cryoprobes in pig liver were 56.3 mm and varied from 38.7 to 39.6 mm for 3-mm cryoprobes in the different tissues used. There was no significant difference in iceball size in the different tissues. The diameter of the zone of -40 degrees C or less was approximately 44 mm using 8-mm cryoprobes in porcine liver and between 27 and 31 mm using 3-mm cryoprobes in the different tissues examined. The results may allow better preoperative planning of the cryosurgical treatment of liver metastases with Accuprobe cryoprobes.