Effects of Cyclodextrin Curcumin Formulation on Ischemia-Reperfusion Injury in Porcine DCD Liver Transplantation.

BACKGROUND: Curcumin is a pleiotropic antioxidant polyphenol, which has proven to be highly protective in various models of liver injury and inflammation. We hypothesized that adding a stable aqueous curcumin formulation which comprises a water-soluble cyclodextrin curcumin formulation (CDC) complex of the water-insoluble curcumin molecule (Novobion, Espoo, Finland) to preservation solution during liver procurement may reduce ischemia-reperfusion injury and improve graft function after liver transplantation using donation after circulatory death (DCD). METHODS: In a preclinical pig model of DCD-liver transplantation, livers exposed to 15' of warm ischemia were either modulated (N = 6) with a flush of preservation solution (histidine-tryptophan-ketoglutarate) containing CDC (60 µmol/L) through the vena porta and the aorta, or not (controls, N = 6) before 4 h of cold storage. Area under the curve of log serum aspartate aminotransferase, markers of graft function (lactate, glycemia, prothrombin time, and bile production), inflammation (tumor necrosis factor-alpha), and survival were monitored. RESULTS: Area under the curve of log serum aspartate aminotransferase were similar between curcumin and control groups (22.12 [20.87-24.88] versus 25.08 [22.1-26.55]; P = 0.28). No difference in the liver function markers were observed between groups except a lower serum lactate level 3-h post-reperfusion in the curcumin group (3 [1.95-6.07] versus 8.2 [4.85-13.45] mmol/L; P = 0.05). Serum tumor necrosis factor-alpha levels were similar in each group. Recipient survival rates were found similar. CONCLUSIONS: CDC added to the preservation solution in DCD liver pig model did not improve ischemia-reperfusion injury severity, liver function, or survival. Further efforts are needed to explore this strategy, particularly with dynamic preservation, which finds its way into clinical practice.

Anticoagulant Treatment of a Thrombosed Giant Portal Vein Aneurysm.

Teaching point: Anticoagulation is advised in thrombosed portal vein aneurysm (PVA) without portal hypertension.

International Hepato-Pancreato-Billiary Association (IHPBA) registry study on COVID-19 infections in HPB surgery patients.

BACKGROUND: In response to the pandemic, the International Hepato-Pancreato-Biliary Association (IHPBA) developed the IHPBA-COVID Registry to capture data on HPB surgery outcomes in COVID-positive patients prior to mass vaccination programs. The aim was to provide a tool to help members gain a better understanding of the impact of COVID-19 on patient outcomes following HPB surgery worldwide. METHODS: An online registry updated in real time was disseminated to all IHPBA, E-AHPBA, A-HPBA and A-PHPBA members to assess the effects of the pandemic on the outcomes of HPB procedures, perioperative COVID-19 management and other aspects of surgical care. RESULTS: One hundred twenty-five patients from 35 centres in 18 countries were included. Seventy-three (58%) patients were diagnosed with COVID-19 preoperatively. Operative mortality after pancreaticoduodenectomy and major hepatectomy was 28% and 15%, respectively, and 2.5% after cholecystectomy. Postoperative complication rates of pancreatic procedures, hepatic interventions and biliary interventions were respectively 80%, 50% and 37%. Respiratory complication rates were 37%, 31% and 10%, respectively. CONCLUSION: This study reveals a high risk of mortality and complication after HPB surgeries in patient infected with COVID-19. The more extensive the procedure, the higher the risk. Nonetheless, an increased risk was observed across all types of interventions, suggesting that elective HPB surgery should be avoided in COVID positive patients, delaying it at distance from the viral infection.

Effect of a Combined Drug Approach on the Severity of Ischemia-Reperfusion Injury During Liver Transplant: A Randomized Clinical Trial.

Importance: In a porcine model of liver transplant, a combined drug approach that targeted the donor graft and graft recipient reduced ischemia-reperfusion injury, a major hurdle to the success of liver transplant. Objective: To assess the effect of a clinical form of a perioperative combined drug approach delivered immediately before implantation to the procured liver and to the liver recipient on the degree of ischemia-reperfusion injury. Design, Setting, and Participants: This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020. Interventions: Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-ß, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase. Main Outcomes and Measures: The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival. Results: Of 93 randomized patients, 21 were excluded, resulting in 72 patients (36 per study arm) in the per protocol analysis (median recipient age, 60 years [IQR, 51.7-66.2 years]; 52 [72.2%] men). Peak AST serum levels were not different in the combined drug approach and control groups (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; P = .49) (to convert AST to µkat/L, multiply by 0.0167). There also were no significant differences in the secondary end points between the groups. Conclusions and Relevance: In this randomized clinical trial, the combined drug approach targeting the post-cold storage graft and the recipient did not decrease ischemic-reperfusion injury. The findings suggest that in addition to a downstream strategy that targets the preimplantation liver graft and the graft recipient, a clinically effective combined drug approach may need to include an upstream strategy that targets the donor graft during preservation. Dynamic preservation strategies may provide an appropriate delivery platform. Trial Registration: ClinicalTrials.gov Identifier: NCT02251041.

Temperature Effects on the Survival and Development of Two Pest Bark Beetles Hylurgus ligniperda F. (Coleoptera: Curculionidae) and Hylastes ater Paykull (Coleoptera: Curculionidae).

Hylurgus ligniperda (F.) and Hylastes ater (Paykull) are secondary bark beetles that have successfully spread beyond their native range, particularly into Pinus spp. plantations in the Southern Hemisphere. They feed on the phloem and cambial regions of highly stressed and recently dead Pinus spp. Here H. ligniperda and H. ater egg, larval, and pupal survival and development rates were modeled. Survival was variably influenced by temperatures depending on the life stage, but general trends were for H. ligniperda to tolerate warmer temperatures in comparison to H. ater. Nonlinear models showed 26, 29, and 34°C are the optimal temperature (maximum development rates) for the development of eggs, larvae, and pupae of H. ligniperda. In contrast, optimal temperature predictions were lower for H. ater, with estimates of 26, 22, and 23°C for the development of eggs, larvae, and pupae, respectively. H. ligniperda pre-imaginal stages were more tolerant to high temperatures, and H. ater pre-imaginal stages were more tolerant to low temperatures. Understanding the thermal requirements and limits for development for these two pests can assist in modeling emergence times, their current and potential species distribution and have potential phytosanitary applications.

A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation.

BACKGROUND & AIMS: The concept of benchmarking is established in the field of transplant surgery; however, benchmark values for donation after circulatory death (DCD) liver transplantation are not available. Thus, we aimed to identify the best possible outcomes in DCD liver transplantation and to propose outcome reference values. METHODS: Based on 2,219 controlled DCD liver transplantations, collected from 17 centres in North America and Europe, we identified 1,012 low-risk, primary, adult liver transplantations with a laboratory MELD score of ≤20 points, receiving a DCD liver with a total donor warm ischemia time of ≤30 minutes and asystolic donor warm ischemia time of ≤15 minutes. Clinically relevant outcomes were selected and complications were reported according to the Clavien-Dindo-Grading and the comprehensive complication index (CCI). Corresponding benchmark cut-offs were based on median values of each centre, where the 75th-percentile was considered. RESULTS: Benchmark cases represented between 19.7% and 75% of DCD transplantations in participating centres. The 1-year retransplant and mortality rates were 4.5% and 8.4% in the benchmark group, respectively. Within the first year of follow-up, 51.1% of recipients developed at least 1 major complication (≥Clavien-Dindo-Grade III). Benchmark cut-offs were ≤3 days and ≤16 days for ICU and hospital stay, ≤66% for severe recipient complications (≥Grade III), ≤16.8% for ischemic cholangiopathy, and ≤38.9 CCI points 1 year after transplant. Comparisons with higher risk groups showed more complications and impaired graft survival outside the benchmark cut-offs. Organ perfusion techniques reduced the complications to values below benchmark cut-offs, despite higher graft risk. CONCLUSIONS: Despite excellent 1-year survival, morbidity in benchmark cases remains high. Benchmark cut-offs targeting morbidity parameters offer a valid tool to assess the protective value of new preservation technologies in higher risk groups and to provide a valid comparator cohort for future clinical trials. LAY SUMMARY: The best possible outcomes after liver transplantation of grafts donated after circulatory death (DCD) were defined using the concept of benchmarking. These were based on 2,219 liver transplantations following controlled DCD donation in 17 centres worldwide. Donor and recipient combinations with higher risk had significantly worse outcomes. However, the use of novel organ perfusion technology helped high-risk patients achieve similar outcomes as the benchmark cohort.

Risk Analysis Frameworks Used in Biological Control and Introduction of a Novel Bayesian Network Tool.

Classical biological control, the introduction of natural enemies to new environments to control unwanted pests or weeds, is, despite numerous successful examples, associated with rising concerns about unwanted environmental impacts such as population decline of nontarget species. Recognition of these biosafety risks is globally increasing, and prerelease assessments of biological control agents (BCAs) have become more rigorous in many countries. We review the current approaches to risk assessment for BCAs as used in Australasia, Europe, and North America. Traditionally, these assessments focus on providing assurance about the specificity of a proposed BCA, generally via a list of suitable versus nonsuitable hosts determined through laboratory specificity tests (i.e., by determining the BCA's physiological host range). The outcome of interactions of proposed agents in the natural environment can differ from laboratory-based predictions. Potential nontarget host testing may be incomplete, additional ecological barriers under field conditions may limit encounters between BCA and nontargets or reduce attack levels, and BCAs could disperse to habitats beyond those used by the target species and adversely affect nontarget species. We advocate for the adoption of more comprehensive, ecologically-based, probabilistic risk assessment approaches to BCA introductions. An example is provided using a Bayesian network that can integrate information on probabilities and uncertainties of a BCA to spread and establish in new habitats, interact with nontarget species in these habitats, and eventually negatively impact the populations of these nontarget species. Our new model, Biocontrol Adverse Impact Probability Assessment, aims to be incorporated into a structured decision-making framework to support national regulatory authorities.

An Integrated Biosecurity Risk Assessment Model (IBRAM) For Evaluating the Risk of Import Pathways for the Establishment of Invasive Species.

An important aspect of analyzing the risk of unwanted organisms establishing in an area is understanding the pathways by which they arrive. Evaluating the risks of these pathways requires use of data from multiple sources, which frequently are uncertain. To address the needs of agencies responsible for biosecurity operations, we present an Integrated Biosecurity Risk Assessment Model (IBRAM) for evaluating the risk of establishment and dispersal of invasive species along trade pathways. The IBRAM framework consists of multiple linked models which describe pest entry into the country, escape along trade pathways, initial dispersal into the environment, habitat suitability, probabilities of establishment and spread, and the consequences of these invasions. Bayesian networks (BN) are used extensively to model these processes. The model includes dynamic BN components and geographic data, resulting in distributions of output parameters over spatial and temporal axes. IBRAM is supported by a web-based tool that allows users to run the model on real-world pest examples and investigate the impact of alternative risk management scenarios, to explore the effect of various interventions and resource allocations. Two case studies are provided as examples of how IBRAM may be used: Queensland fruit fly (Bactrocera tryoni) (Diptera: Tephritidae) and brown marmorated stink bug (Halyomorpha halys) (Hemiptera: Pentatomidae) are unwanted organisms with the potential to invade Aotearoa New Zealand, and IBRAM has been influential in evaluating the efficacy of pathway management to mitigate the risk of their establishment in the country.

Donor Hepatectomy and Implantation Time Are Associated With Early Complications After Liver Transplantation: A Single-center Retrospective Study.

BACKGROUND: Donor hepatectomy and liver implantation time reduce long-term graft and patient survival after liver transplantation. It is not known whether these surgical times influence early outcomes after liver transplantation. METHODS: This single-center study evaluated the effect of donor hepatectomy and implantation time on the risk of nonanastomotic biliary strictures (NAS) occurring within 1 year and of early allograft dysfunction (EAD) after deceased-donor solitary liver transplantation, adjusting for other donors, recipient, and surgical factors. RESULTS: Of 917 transplants performed between January 2000 and December 2016, 106 (11.56%) developed NAS and 247 (27%) developed EAD. Donor hepatectomy time (median 35 min, IQR: 26-46) was an independent risk factor of NAS [adjusted hazard ratio, 1.19; 95% CI, 1.04-1.35; P = 0.01]. Implantation time (median 80 min, IQR: 69-95) was independently associated with EAD [adjusted odds ratio (OR), 1.15; 95% CI,1.07-1.23; P < 0.0001). The risk of EAD was increased by anastomosis time of both portal vein (adjusted OR, 1.26; 95% CI, 1.12-14.42; P = 0.0001) and hepatic artery (adjusted OR, 1.13; 95% CI, 1.04-1.22; P = 0.005). The magnitude of these effects was similar in donation after circulatory death liver grafts. CONCLUSIONS: Donor hepatectomy and implantation time negatively affect short-term outcomes.

Evaluation of Liver Graft Donation After Euthanasia.

Importance: The option of donating organs after euthanasia is not well known. Assessment of the results of organ transplants with grafts donated after euthanasia is essential to justify the use of this type of organ donation. Objectives: To assess the outcomes of liver transplants (LTs) with grafts donated after euthanasia (donation after circulatory death type V [DCD-V]), and to compare them with the results of the more commonly performed LTs with grafts from donors with a circulatory arrest after the withdrawal of life-supporting treatment (type III [DCD-III]). Design, Setting, and Participants: This retrospective multicenter cohort study analyzed medical records and LT data for most transplant centers in the Netherlands and Belgium. All LTs with DCD-V grafts performed from the start of the donation after euthanasia program (September 2012 for the Netherlands, and January 2005 for Belgium) through July 1, 2018, were included in the analysis. A comparative cohort of patients who received DCD-III grafts was also analyzed. All patients in both cohorts were followed up for at least 1 year. Data analysis was performed from September 2019 to December 2019. Exposures: Liver transplant with either a DCD-V graft or DCD-III graft. Main Outcomes and Measures: Primary outcomes were recipient and graft survival rates at years 1, 3, and 5 after the LT. Secondary outcomes included postoperative complications (early allograft dysfunction, hepatic artery thrombosis, and nonanastomotic biliary strictures) within the first year after the LT. Results: Among the cohort of 47 LTs with DCD-V grafts, 25 organ donors (53%) were women and the median (interquartile range [IQR]) age was 51 (44-59) years. Among the cohort of 542 LTs with DCD-III grafts, 335 organ donors (62%) were men and the median (IQR) age was 49 (37-57) years. Median (IQR) follow-up was 3.8 (2.1-6.3) years. In the DCD-V cohort, 30 recipients (64%) were men, and the median (IQR) age was 56 (48-64) years. Recipient survival in the DCD-V cohort was 87% at 1 year, 73% at 3 years, and 66% at 5 years after LT. Graft survival among recipients was 74% at 1 year, 61% at 3 years, and 57% at 5 years after LT. These survival rates did not differ statistically significantly from those in the DCD-III cohort. Incidence of postoperative complications did not differ between the groups. For example, the occurrence of early allograft dysfunction after the LT was found to be 13 (31%) in the DCD-V cohort and 219 (45%) in the DCD-III cohort. The occurrence of nonanastomotic biliary strictures after the LT was found to be 7 (15%) in the DCD-V cohort and 83 (15%) in the DCD-III cohort. Conclusions and Relevance: The findings of this cohort study suggest that LTs with DCD-V grafts yield similar outcomes as LTs with DCD-III grafts; therefore, grafts donated after euthanasia may be a justifiable option for increasing the organ donor pool. However, grafts from these donations should be considered high-risk grafts that require an optimal donor selection process and logistics.

Glutaraldehyde-fixed parietal peritoneum graft conduit to replace completely the portal vein during pancreaticoduodenectomy: A case report.

INTRODUCTION: Combined total portal vein (PV) and superior mesenteric artery (SMA) resection during pancreaticoduodenectomy (PD) is a challenging task that is no longer considered as a contra-indication to achieve R0 in borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). PRESENTATION OF CASE: We report a 66-year-old female with BR-PDAC of the head of the pancreas in whom PV and SMA were replaced with a glutaraldehyde-fixed autologous peritoneo-fascial graft (APG) and a splenomesenteric arterial bypass, respectively, during the PD. DISCUSSION: When PV venorraphy or end-to-end anastomosis is not feasible, APG conduit, immediately available without extra-incision, does not need postoperative anticoagulation and is associated with a low risk of infection and thrombosis. If fixed in glutaraldehyde, handling, risk of compression when placed intra-peritoneally and long-term patency of the graft are improved. CONCLUSION: Glutaraldehyde-fixed APG is a strategy that every surgeon should bear in mind for PV replacement during PD and other HBP surgical procedures, especially if a vascular resection is unforeseen.

Image in transplantation surgery: median arcuate ligament in liver transplantation.

Low inserted median arcuate ligament (MAL) may cause extrinsic coeliac trunk compression and MAL syndrome (association of post-prandial epigastric pain, weight loss and nausea or vomiting). In liver transplantation (LT), liver graft arterial supply depends on the recipient's hepatic artery, as the gastro-duodenal artery has generally been ligated. A decreased graft arterial flow caused by coeliac trunk stenosis might induce hepatic artery thrombosis leading to graft loss. In this short report, the authors describe LT procedure during which recipient's hepatic artery pressure was dramatically decreased after ligature of the gastro-duodenal artery. Dissection and division of the MAL allowed to restore an excellent blood flow through the hepatic artery. This report reminds how important it is to be able to recognize and how to manage a stenosing MAL in LT.

Heterogeneity of Bile Duct Management in the Development of Ischemic Cholangiopathy After Liver Transplantation: Results of a European Liver and Intestine Transplant Association Survey.

BACKGROUND: Surgical factors and direct cytotoxicity of bile salts on cholangiocytes may play a role in the development of ischemic cholangiopathy (IC) after liver transplantation (LTx). There is no validated consensus on how to protect the bile ducts during procurement, static preservation, and LTx. Meanwhile, IC remains the most troublesome complication after LTx. AIM: To characterize bile duct management techniques during the LTx process among European transplant centers in cases of donation after brain death (DBD) and circulatory death (DCD). METHOD: An European Liver and Intestine Transplant Association-European Liver Transplant Registry web survey designed to conceal respondents' personal information was sent to surgeons procuring and/or transplanting livers in Europe. RESULTS: Sixty-five percent of responses came from large transplant centers (>50 procurements/y). In 8% of DBDs and 14% of DCDs the bile duct is not rinsed. In 46% of DBDs and 52% of DCDs surgeons prefer to remove the gallbladder after graft reperfusion. Protocols concerning preservation solutions (nature, pressure, volume) are extremely heterogeneous. In 54% of DBDs and 61% of DCDs an arterial back table pressure perfusion is performed. Steroids (20%-10%), heparin (72%-60%), prostacyclin (3%-7%), and fibrinolytics (4%-11%) are used as donor-protective interventions in DBD and DCD cases, respectively. In 2% of DBD and 6% of DCD cases a hepatic artery reperfusion is performed first. In 4% of DBD and 6% of DCD cases, fibrinolytics are administered through the hepatic artery during the bench and/or implantation. CONCLUSION: This European web survey shows for the first time the heterogeneity in the management of bile ducts during procurement, preservation, and transplantation in Europe. In the context of sharing more marginal liver grafts, an expert meeting must be organized to formulate guidelines to be applied to protect liver grafts against IC.

Early listeriosis after liver transplantation: Report of two cases.

Listeria monocytogenes is a rare cause of potentially lethal infection and sepsis in transplant recipients. Listeriosis is usually described after kidney or bone marrow transplant, and has been less frequently reported after liver transplantation. Here, the authors present two cases of severe Listeria infection occurring within 4 months after complicated liver transplantation in patients still recovering on the ward. The patients were successfully treated by intravenous ampicillin. These cases should remind transplant physicians that listeriosis may develop in liver transplant recipients, that food safety advice should be provided, and that intravenous ampicillin might be an effective treatment for systemic listeriosis in solid organ recipients. It is likely that trimethoprim-sulfamethoxazole prophylaxis might help prevent early listeriosis after solid organ transplantation.

Pancreas-sparing and superior mesenteric artery first approach in duodenal adenocarcinoma of the fourth portion of duodenum: A case report.

INTRODUCTION: Peroperative assessment of resectability in pancreas-sparing duodenectomy for distal duodenal (D3-D4) adenocarcinoma is challenging for surgeons. PRESENTATION OF CASE: We report a 68-year-old man with biopsy-proven adenocarcinoma of the fourth portion of duodenum which had been diagnosed with upper endoscopy and CT. A pancreas-sparing duodenectomy with loco-regional lymph node resection using the superior mesenteric artery first approach was performed. DISCUSSION: Adenocarcinoma of the fourth portion of duodenum is rare. It has non-specific symptoms. The diagnosis is difficult and is frequently delayed. Surgery is the only chance of cure. After peroperative assessment of resectability, with intraoperative ultrasound, complete exposition of the duodenum and entire dissection of the superior mesenteric artery (SMA) using the artery-first approach technique should be done to assess for tumor resectability, which should include the possibility of complete lymphadenectomy of the mesenteric root. If technically feasible, a pancreas-sparing resection should be preferred to avoid pancreatectomy-related morbi-mortality. The aim of the surgery is a R0 resection which has a 5-year survival rate between 25% and 75%. CONCLUSION: Artery-first approach of the SMA should be considered by surgeons in adenocarcinoma of the distal duodenum to identify any contra-indications to proceed further.