A comparative study on changes in hemostasis in orthotopic and auxiliary liver transplantation in pigs

We compared blood loss and hemostasis in pigs which had undergone either orthotopic liver transplantation (OLT) (group A, n=12) or auxiliary heterotopic partial liver transplantation (APLT) (group B, n=11). Blood samples were taken at regular intervals during and after the operations. In both groups, nine animals survived longer than 24 h and data from these animals were used for analysis. Median (range) intraoperative blood loss was 825 ml (250-1500 ml) in OLT and 425 ml (300-750) in APLT (P<0.01). Routine clotting times, as the activated partial thromboplastin time, prothrombin time and thrombin time, showed no major intraoperative changes in either group. Fibrinogen levels decreased in both groups, but no significant difference was found between the two groups. The only significant difference between group A and B was a more sustained increase in fibrinolytic activity after graft recirculation in group A. Post-operatively, restoration of fibrinogen, antithrombin-III and α2-antiplasmin levels was slightly faster in group B, resulting in significantly higher levels during the first day. We conclude that, in this animal model, APLT is associated with significantly lower blood loss and less severe fibrinolytic activity, than OLT. This difference might result from the lack of an anhepatic period and the reduced surgical trauma in auxiliary heterotopic liver transplantation

Emerging pan-resistance in <i>Trichosporon </i>species:a case report

BACKGROUND: Trichosporon species are ubiquitously spread and known to be part of the normal human flora of the skin and gastrointestinal tract. Trichosporon spp. normally cause superficial infections. However, in the past decade Trichosporon spp. are emerging as opportunistic agents of invasive fungal infections, particularly in severely immunocompromised patients. Clinical isolates are usually sensitive to triazoles, but strains resistant to multiple triazoles have been reported. CASE PRESENTATION: We report a high-level pan-azole resistant Trichosporon dermatis isolate causing an invasive cholangitis in a patient after liver re-transplantation. This infection occurred despite of fluconazole and low dose amphotericin B prophylaxis, and treatment with combined liposomal amphotericin B and voriconazole failed. CONCLUSION: This case and recent reports in literature show that not only bacteria are evolving towards pan-resistance, but also pathogenic yeasts. Prudent use of antifungals is important to withstand emerging antifungal resistance

The Effects of Long-Term Graft Preservation on Intraoperative Hemostatic Changes in Liver Transplantation

We compared hemostatic changes during OLT and HLT after various periods of graft storage, to investigate whether the host liver in HLT protects the recipient from hemostatic deterioration induced by severe graft storage damage. In particular, the mechanism of fibrinolytic deterioration was investigated. The effect of prostaglandin E1 (PGE1) on these parameters was also studied

Innovation and experiential knowledge in firm exports: Applying the initial U-model

AbstractFocusing on firm export activity as an important field within international business, this study corroborates the importance of experiential knowledge as the initial Uppsala model predicts. The model builds on the belief that experiential knowledge minimizes the risk and uncertainty of export operations. Additionally, the article examines a firm's capacity to widen this knowledge through its dynamic capacities, honing in on a firm's learning function. Thus, this article analyzes the role of innovation in exporting by investigating export product innovation and export market innovation, both strategic activities that allow experiential knowledge acquisition. The article uses a firm-level official dataset from a small developing country, Chile, examining data from 2006 to 2011. The results indicate, firstly, that experiential knowledge resulting from exporting to different and geographically distant markets increases the firm's export activity. Secondly, such export market innovation takes precedence over export product innovation

Cell-free microRNAs as early predictors of graft viability during ex vivo normothermic machine perfusion of human donor livers

Background Cell-free microRNAs (miRs) have emerged as early and sensitive biomarkers for tissue injury and function. This study aimed to investigate whether the release of hepatocyte-derived microRNAs (HDmiRs) and cholangiocyte-derived miRs (CDmiRs) correlates with hepato-cholangiocellular injury and function during oxygenated, normothermic machine perfusion (NMP) of human liver grafts. Methods Donor livers (n = 12), declined for transplantation, were subjected to oxygenated NMP (6 hours) after a period of static cold storage (median 544 minutes (IQR 421-674)). Perfusate and bile samples were analyzed by qRT-PCR for HDmiR-122 and CDmiR-222. Spearman correlations were performed between miR levels and currently available indicators and classic markers. Results Both HDmiR-122 and CDmiR-222 levels in perfusate at 30 minutes of NMP strongly correlated with hepatocyte injury (peak perfusate AST) and cholangiocyte injury (peak biliary LDH). In bile, only CDmiR-222 correlated with these injury markers. For hepato-cholangiocellular function, both miRs in perfusate correlated with total bilirubin, while HDmiR-122 (in perfusate) and CDmiR-222 (in bile) correlated with bicarbonate secretion. Both the relative ratio of HDmiR-122/CDmiR-222 and AST in perfusate at 30 minutes significantly correlated with cumulative bile production, but only the relative ratio was predictive of histopathological injury after 6 hours NMP. Conclusion Early levels of HDmiR-122 and CDmiR-222, in perfusate and/or bile, are predictive of excretory functions and hepato-cholangiocellular injury after 6 hours NMP. These miRs may represent new biomarkers for graft viability and function during machine perfusion

The Influence of Hepatic Steatosis and Fibrosis on Postoperative Outcomes After Major Liver Resection of Perihilar Cholangiocarcinoma

Background: Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients. Methods: Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality. Results: Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69–2.68) or 90-day mortality (OR 1.22; 95% CI 0.62–2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41–1.41) or 90-day mortality (OR 0.60; 95% CI 0.33–1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36–4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31–4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36–4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30–3.87). Conclusion: In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA.</p

Cell-free microRNAs as early predictors of graft viability during ex vivo normothermic machine perfusion of human donor livers

Background: Cell-free microRNAs (miRs) have emerged as early and sensitive biomarkers for tissue injury and function. This study aimed to investigate whether the release of hepatocyte-derived microRNAs (HDmiRs) and cholangiocyte-derived miRs (CDmiRs) correlates with hepato-cholangiocellular injury and function during oxygenated, normothermic machine perfusion (NMP) of human liver grafts. Methods: Donor livers (n = 12), declined for transplantation, were subjected to oxygenated NMP (6 hours) after a period of static cold storage (median 544 minutes (IQR 421-674)). Perfusate and bile samples were analyzed by qRT-PCR for HDmiR-122 and CDmiR-222. Spearman correlations were performed between miR levels and currently available indicators and classic markers. Results: Both HDmiR-122 and CDmiR-222 levels in perfusate at 30 minutes of NMP strongly correlated with hepatocyte injury (peak perfusate AST) and cholangiocyte injury (peak biliary LDH). In bile, only CDmiR-222 correlated with these injury markers. For hepato-cholangiocellular function, both miRs in perfusate correlated with total bilirubin, while HDmiR-122 (in perfusate) and CDmiR-222 (in bile) correlated with bicarbonate secretion. Both the relative ratio of HDmiR-122/CDmiR-222 and AST in perfusate at 30 minutes significantly correlated with cumulative bile production, but only the relative ratio was predictive of histopathological injury after 6 hours NMP. Conclusion: Early levels of HDmiR-122 and CDmiR-222, in perfusate and/or bile, are predictive of excretory functions and hepato-cholangiocellular injury after 6 hours NMP. These miRs may represent new biomarkers for graft viability and function during machine perfusion

Evidence for a rebalanced hemostatic system in pediatric liver transplantation:A prospective cohort study

In adults with end-stage liver disease concurrent changes in pro- and antihemostatic pathways result in a rebalanced hemostasis. Children though, have a developing hemostatic system, different disease etiologies, and increased risk of thrombosis. This study aimed to assess the hemostatic state of children during and after liver transplantation. Serial blood samples were obtained from 20 children (≤16 years) undergoing primary liver transplantation (September 2017-October 2018). Routine hemostasis tests, thrombomodulin-modified thrombin generation, clot lysis times, and hemostatic proteins were measured. Reference values were established using an age-matched control group of 30 children. Thrombocytopenia was present in study patients. Von Willebrand factors were doubled and ADAMTS13 levels decreased during and after transplantation up until day 30, when platelet count had normalized. Whereas prothrombin time and activated partial thromboplastin time were prolonged during transplantation, thrombin generation was within normal ranges, except during perioperative heparin administration. Fibrinogen, factor VIII levels, and clot lysis time were elevated up until day 30. In conclusion, children with end-stage liver disease are in tight hemostatic balance. During transplantation a temporary heparin-dependent hypocoagulable state is present, which rapidly converts to a hemostatic balance with distinct hypercoagulable features that persist until at least day 30. This hypercoagulable state may contribute to the risk of posttransplant thrombosis

National consensus on a new resectability classification for perihilar cholangiocarcinoma - A modified Delphi method

Background: Currently, no practical definition of potentially resectable, borderline or unresectable perihilar cholangiocarcinoma (pCCA) is available. Aim of this study was to define criteria to categorize patients for use in a future neoadjuvant or induction therapy study. Method: Using the modified DELPHI method, hepatobiliary surgeons from all tertiary referral centers in the Netherlands were invited to participate in this study. During five online meetings, predefined factors determining resectability and additional factors regarding surgical resectability and operability were discussed. Results: The five online meetings resulted in 52 statements. After two surveys, consensus was reached in 63% of the questions. The main consensus included a definition regarding potential resectability. 1) Clearly resectable: no vascular involvement (≤90°) of the future liver remnant (FLR) and expected feasibility of radical biliary resection. 2) Clearly unresectable: non-reconstructable venous and/or arterial involvement of the FLR or no feasible radical biliary resection. 3) Borderline resectable: all patients between clearly resectable and clearly unresectable disease. Conclusion: This DELPHI study resulted in a practical and applicable resectability, or more accurate, an explorability classification, which can be used to categorize patients for use in future neoadjuvant therapy studies.</p