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Introduction: Short Bowel Syndrome (SBS) is a rare gastrointestinal disorder associated with Intestinal Failure (SBS-IF) that leads to morbidity, mortality, and a burden on healthcare costs. Intestine Transplantation (IT) is a treatment option for patients with SBS-IF as it replaces the missing or diseased intestine and offers the potential for return to normal activities and intestinal function. This study aims to describe the clinical course and demographical and clinical characteristics of subjects with SBS-IF who underwent IT in Brazil., Methods: This retrospective observational study included all SBS-IF patients who underwent IT in two reference centers in Brazil from April 2011 to December 2021., Results: A total of 7 young male participants were included in the study. The most frequent underlying condition was surgical complications, followed by intestinal volvulus and incisional hernia. The most frequent indication for IT was a hepatic disease associated with total Parenteral Nutrition (PN). The main type of IT performed was intestine only. The median time from underlying condition to IT was 67.3 (16.5‒88.5) months. The mean (SD) number of yearly hospitalizations per patient was 0.5 (0.3). The most common reason for hospitalization was PN-related complications. Sixty exams were performed in-hospital and 53 in the outpatient setting., Conclusion: The findings of this study may be helpful to understand better the journey of patients with SBS-IF to IT in Brazil, providing real-world evidence to develop health policy guidelines and improve the quality of life of these patients., Competing Interests: Declaration of competing interest The authors declare the following conflicts of interest: YLB; MHMR; LH; RAAP: ADWL: APCSB; IC; GGR; FM; and LACA: Has acted as speaker in Takeda Distribuidora Ltda in medical-scope events. CYS and BF are employees of Takeda Distribuidora Ltda, Brazil., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Background and Aim: While it is currently assumed that liver assessment is only possible during normothermic machine perfusion (NMP), there is uncertainty regarding a reliable and quick prediction of graft injury during ex situ hypothermic oxygenated perfusion (HOPE). We therefore intended to test, in an international liver transplant cohort, recently described mitochondrial injury biomarkers measured during HOPE before liver transplantation., Study Design: Perfusate samples of human livers from 10 centers in 7 countries with HOPE-experience were analyzed for released mitochondrial compounds, i.e. flavin mononucleotide (FMN), NADH, purine derivates and inflammatory markers. Perfusate FMN was correlated with graft loss due to primary non-function or symptomatic non-anastomotic biliary strictures (NAS), and kidney failure, as well as liver injury after transplantation. Livers deemed unsuitable for transplantation served as negative control., Results: We collected 473 perfusate samples of human DCD (n=315) and DBD livers (n=158). Fluorometric assessment of FMN in perfusate was validated by mass spectrometry (R=0.7011,p<0.0001). Graft loss due to primary non-function or cholangiopathy was predicted by perfusate FMN values (c-statistic mass spectrometry 0.8418 (95%CI 0.7466-0.9370,p<0.0001), c-statistic fluorometry 0.7733 (95%CI 0.7006-0.8461,p<0.0001). Perfusate FMN values were also significantly correlated with symptomatic NAS and kidney failure, and superior in prediction of graft loss when compared to conventional scores derived from donor and recipient parameters, such as the donor risk index and the balance of risk score. Mitochondrial FMN values in liver tissues of non-utilized livers were low, and inversely correlated to high perfusate FMN values and purine metabolite release., Conclusions: This first international study validates the predictive value of the mitochondrial co-factor FMN, released from complex I during HOPE, and may therefore contribute to a better risk stratification of injured livers before implantation., Impact and Implications: Analysis of 473 perfusates, collected from 10 international centers during hypothermic oxygenated perfusion (HOPE), revealed that mitochondria derived flavin mononucleotide (FMN) values in perfusate is predictive for graft loss, cholangiopathy, and kidney failure after liver transplantation. This result is of high clinical relevance, as recognition of graft quality is urgently needed to improve the safe utilization of marginal livers. Ex-situ machine perfusion approaches, such as HOPE, are therefore likely to increase the number of useable liver grafts., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Acute-on-chronic liver failure (ACLF) is a leading cause of death in cirrhotic patients. This study aims to describe the outcomes of in-patients with ACLF at a liver transplantation (LT) center in Brazil., Methods: Retrospective study analyzing patient data from 2017 to 2022. Re-transplant cases and patients without previous chronic liver disease were excluded. The ACLF diagnosis was based on the European Association for the Study of the Liver-Chronic Liver Failure criteria and assessments repeated on days 3 and 7 after the initial diagnosis., Results: Among 381 patients, 10.49% (n = 40) were diagnosed with ACLF. Bacterial infection was the most common precipitating factor (45%). Kidney failure occurred in 65% of the cases. The 28-day mortality rate was 35% and varied according to ACLF severity at diagnosis, from single organ failure (ACLF-1) at 22% to three organ failures (ACLF-3) at 60%. Eighteen patients (45%) were transplanted with a 100% 28-day survival rate. For ACLF-3 cases at diagnosis (n = 15), the 28-day and 1-year survival rates with a transplant (n = 4) were 100% and 80%, respectively, and without transplant (n = 11), 10 and 0%, respectively., Conclusions: ACLF was associated with high mortality rates. LT was an effective therapeutic option, particularly for ACLF-3 cases.

Dynamic organ preservation is a relatively old technique which has regained significant interest in the last decade. Machine perfusion (MP) techniques are applied in various fields of solid organ transplantation today. The first clinical series of ex situ MP in liver transplantation was presented in 2010. Since then, the number of research and clinical applications has substantially increased. Despite the notable beneficial effect on organ quality and recipient outcome, MP is still not routinely used in liver transplantation. Based on the enormous need to better preserve organs and the subsequent demand to continuously innovate and develop perfusion equipment further, this technology is also beneficial to test and deliver future therapeutic strategies to livers before implantation. This article summarizes the various challenges observed during the current shift from static to dynamic liver preservation in the clinical setting. The different organ perfusion strategies are discussed first, together with ongoing clinical trials and future study design. The current status of research and the impact of costs and regulations is highlighted next. Factors contributing to costs and other required resources for a worldwide successful implementation and reimbursement are presented third. The impact of research on cost-utility and effectivity to guide the tailored decision-making regarding the optimal perfusion strategy is discussed next. Finally, this article provides potential solutions to the challenging field of innovation in healthcare considering the various social and economic factors and the role of clinical, regulatory, and financial stakeholders worldwide., Competing Interests: J.V.G. consults for and received grants from Organ Recovery Systems (Itasca, IL) and consults for GATT Technologies. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The 2023 Joint Annual Congress of the International Liver Transplantation Society, European Liver and Intestine Transplant Association, and Liver Intensive Care Group of Europe were held in Rotterdam, the Netherlands, from May 3 to 6, 2023. This year, all speakers were invited to attend the Congress in person for the first time since the COVID-19 pandemic. The congress was attended by 1159 registered delegates from 54 countries representing 5 continents, with the 10 countries comprising the bulk of the delegates. Of the 647 abstracts initially submitted, 542 were eventually presented at the meeting, coming from 38 countries (mainly North America, Europe, and Asia) and 85% of them (462 abstracts) came from only 10 countries. Fifty-three (9.8%) abstracts, originated from 17 countries, were submitted under the Basic/Translational Scientific Research category, a similar percentage as in 2022. Abstracts presented at the meeting were classified as (1) ischemia and reperfusion injury, (2) machine perfusion, (3) bioengineering and liver regeneration, (4) transplant oncology, (5) novel biomarkers in liver transplantation, (6) liver immunology (rejection and tolerance), and (7) artificial intelligence and machine learning. Finally, we evaluated the number of abstracts commented in the Basic and Translational Research Committee-International Liver Transplantation Society annual reports over the past 5 y that resulted in publications in peer-reviewed journals to measure their scientific impact in the field of liver transplantation., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Machine perfusion of solid human organs is an old technique, and the basic principles were presented as early as 1855 by Claude Barnard. More than 50 years ago, the first perfusion system was used in clinical kidney transplantation. Despite the well-known benefits of dynamic organ preservation and significant medical and technical development in the last decades, perfusion devices are still not in routine use. This article describes the various challenges to implement this technology in practice, critically analyzing the role of all involved stakeholders, including clinicians, hospitals, regulatory, and industry, on the background of regional differences worldwide. The clinical need for this technology is discussed first, followed by the current status of research and the impact of costs and regulations. Considering the need for strong collaborations between clinical users, regulatory bodies, and industry, integrated road maps and pathways required to achieve a wider implementation are presented. The role of research development, clear regulatory pathways, and the need for more flexible reimbursement schemes is discussed together with potential solutions to address the most relevant hurdles. This article paints an overall picture of the current liver perfusion landscape and highlights the role of clinical, regulatory, and financial stakeholders worldwide., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Normothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH >7.65 and bicarbonate levels >25 mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608)., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Although hypothermic oxygenated perfusion (HOPE) improves posttransplant outcomes, setting up machine perfusion programs may be subjected to specific obstacles under different conditions. This study aims to describe the establishment of HOPE in a real-life setting in Brazil., Methods: Extended criteria donors in donation after brain death organs preserved by HOPE were accepted for higher-risk candidates needing expedited transplantation, perceived as those who would benefit most from the technique because of its limited availability. Extended criteria donors was defined by the Eurotransplant criteria. High-risk transplant candidates were characterized by suboptimal surgical conditions related to the recipient or the procedure., Results: Six HOPE-preserved grafts were transplanted from February 2022 to August 2022. The mean donor risk index was 1.7 (SD 0.5). One organ was severely steatotic, and 3 had an anticipated cold ischemia time above 12 h. Recipients' mean model for end-stage liver disease was 28.67 (SD 6.79), with 1 case of retransplant, 1 of refractory ascites, and 1 of acute-on-chronic liver failure. The mean cold ischemia time was 5 h 42 min (SD 82 min), HOPE 6 h 3 min (SD 150 min), and total preservation time 11 h 46 min (SD 184 min). No case had early allograft dysfunction. The mean length of hospital stay was 10 d with 100% graft and patient survival and no ischemic cholangiopathies at a median follow-up of 15 mo (min 12, max 18). Costs and country-specific legal regulations for device utilization were the major hurdles to implementing the program., Conclusion: We presented a pathway to introduce and rationalize the use of HOPE in a scenario of challenging donor-recipient matching with good results. These findings may aid in implementing machine perfusion programs, especially in settings with limited resources or complex transplant logistics., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: The existing literature suggests that exercise for cirrhotic patients is safe and favours significant improvement to their physical capacity. However, exercise training for this population and how to deliver activities, especially in severe stages of the disease and while waiting for a liver transplant (LT), remain undefined., Aim: To review the existing exercise prescriptions for cirrhotic patients on the waiting list for LT, their results for frailty evolution and their effect on clinical outcomes., Methods: A systematic review was performed following the Preferred Reporting Review and Meta-Analysis guidelines and searching the PubMed, MEDLINE, and Scopus databases. The keyword "liver transplant" was used in combination with the free terms "frailty" and "exercise" for the literature review. Clinical studies that evaluated the effect of a regular training program, independent of supervision or the duration or intensity of physical exercise, in cirrhotic patients on the waiting list for LT were reviewed. The data on safe physical activity prescriptions following Frequency, Intensity, Time, and Type recommendations were extracted and summarised., Results: Nine articles met the inclusion criteria for this review. Various instruments for frailty assessment were used, frequently in combination. Five studies prescribed physical activity for patients, one in-person and four to be performed remotely and unsupervised. The remaining four studies only used a self-report instrument to assess the level of physical activity. None reported adverse events related to exercise training. The exercise frequency mainly varied from daily to a minimum of twice per week. The intensity depended on frailty and included increasing levels of activity. The type of exercise was predominantly a combination of aerobic and resistance training. The duration of exercise varied from 4 to 12 wk. Three articles evaluated the effect of the exercise program on clinical outcomes, reporting a reduction in 90-d readmission rates post-transplant and improved frailty scores, as well as improved survival of cirrhotic patients waiting for LT., Conclusion: Routine frailty assessment is essential for this population. Although more robust evidence is required, the prescription of exercise is safe and can improve patients' functional capacity, improving pre- and post-LT outcomes., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Organ perfusion technology is increasingly used in many countries, with a focus, however, on the Western world. This study investigates the current international trends and obstacles to the broader routine implementation of dynamic perfusion concepts in liver transplantation., Methods: A web-based anonymous survey was launched in 2021. Experts of all involved specializations from 70 centers in 34 countries were contacted, based on the published literature and experience in the field of abdominal organ perfusion., Results: Overall, 143 participants from 23 countries completed the survey. Most respondents were male (67.8%) and transplant surgeons (64.3%) working at university hospitals (67.9%). The majority had experience with organ perfusion (82%), applying mainly hypothermic machine perfusion (HMP; 38%) and other concepts. While most (94.4%) expect a higher utilization of marginal organs with machine perfusion, the majority considers HMP the best technique to reduce liver discard-rates. While most respondents (90%) believed machine perfusion should be fully commissioned, the lack of funding (34%) and knowledge (16%) as well as limited staff (19%) were the three main obstacles to a routine clinical implementation., Conclusion: Although dynamic preservation concepts are increasingly used in clinical practice, significant challenges remain. Specific financial pathways, uniform regulations, and tight collaborations among involved experts are needed to achieve wider global clinical use.

Competing Interests: The authors declare no funding or conflicts of interest.

Background: Despite its association with higher postoperative morbidity and mortality, the use of extended criteria donor (ECD) livers for transplantation has increased globally due to the high demand for the procedure., Aim: To investigate the prevalence of ECD in donation after brain death (DBD) and its impact on organ acceptance for transplantation., Methods: Retrospective analysis of DBD organ offers for liver transplantation between 2017 and 2020 in a high-volume transplant centre. The incidence of the Eurotransplant risk factors to define an ECD (ET-ECD) among DBD donors and the likelihood of organ acceptance over the years were analysed. The relationship between organ refusal for transplantation, the occurrence, and the number of ET-ECD was assessed by simple and multiple logistic regression adjustment., Results: A total of 1619 organ donors were evaluated. Of these, 78.31% ( n = 1268) had at least one ET-ECD criterion. There was an increase in the acceptance of ECD DBD organs for transplantation (1 criterion: from 23.40% to 31.60%; 2 criteria: from 13.10% to 27.70%; 3 criteria: From 6.30% to 13.60%). For each addition of one ET-ECD variable, the estimated chance of organ refusal was 64.4% higher (OR 1.644, 95%CI 1.469-1.839, P < 0.001). Except for the donor serum sodium > 165 mmol/L ( P = 0.310), all ET-ECD criteria increased the estimated chance of organ refusal for transplantation., Conclusion: A high prevalence of ECD DBD was observed. Despite the increase in their utilisation, the presence and the number of extended donor criteria were associated with an increased likelihood of their refusal for transplantation., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The American Transplant Congress 2022, which took place between June 4th and June 8th of 2022, was a hybrid meeting with in-person attendance in Boston-MA and a real-time virtual experience via an online platform. First, we identified abstracts discussing machine perfusion preservation for all organs, a hot topic and approach that may develop into the new gold standard of organ preservation in the near future. A total of 39 abstracts on organ machine preservation were presented at the meeting. Next, we selected abstracts which focus on advances including new approaches to organ preservation, promising biomarkers, ex-situ treatment including cellular therapies, and novel research areas. Here, we summarized the latest developments on machine perfusion preservation in both experimental and clinical studies., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in patients with chronic liver disease and is characterized by acute decompensation, organ failure and high short-term mortality. Partially due to the lack of universal diagnostic criteria, the actual ACLF prevalence remains unclear; nevertheless, it is expected to be a highly prevalent condition worldwide. Earlier transplantation is an effective protective measure for selected ACLF patients. Besides liver trans-plantation, diagnosing and treating precipitant events and providing supportive treatment for organ failures are currently the cornerstone of ACLF therapy. Although new clinical specific therapies have been researched, more studies are necessary to assess safety and efficacy. Therefore, future ACLF management strategies must consider measures to improve access to liver transplantation because the time window for this life-saving therapy is frequently narrow. Thus, an urgent and global discussion about allocation and prioritization for transplantation in critically ill ACLF patients is needed because there is evidence suggesting that the current model may not portray their waitlist mortality. In addition, while donor organ quality is meant to be a prognostic factor in the ACLF setting, recent evidence suggests that machine perfusion of the liver may be a safe tool to improve the donor organ pool and expedite liver transplantation in this scenario., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Normothermic machine perfusion (NMP) allows objective assessment of donor liver transplantability. Several viability evaluation protocols have been established, consisting of parameters such as perfusate lactate clearance, pH, transaminase levels, and the production and composition of bile. The aims of this study were to assess 3 such protocols, namely, those introduced by the teams from Birmingham (BP), Cambridge (CP), and Groningen (GP), using a cohort of high-risk marginal livers that had initially been deemed unsuitable for transplantation and to introduce the concept of the viability assessment sensitivity and specificity. To demonstrate and quantify the diagnostic accuracy of these protocols, we used a composite outcome of organ use and 24-month graft survival as a surrogate endpoint. The effects of assessment modifications, including the removal of the most stringent components of the protocols, were also assessed. Of the 31 organs, 22 were transplanted after a period of NMP, of which 18 achieved the outcome of 24-month graft survival. The BP yielded 94% sensitivity and 50% specificity when predicting this outcome. The GP and CP both seemed overly conservative, with 1 and 0 organs, respectively, meeting these protocols. Modification of the GP and CP to exclude their most stringent components increased this to 11 and 8 organs, respectively, and resulted in moderate sensitivity (56% and 44%) but high specificity (92% and 100%, respectively) with respect to the composite outcome. This study shows that the normothermic assessment protocols can be useful in identifying potentially viable organs but that the balance of risk of underuse and overuse varies by protocol., (© 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion., Methods: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival., Results: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001)., Conclusion: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Several clinical studies have demonstrated the safety, feasibility, and efficacy of machine perfusion in liver transplantation, although its economic outcomes are still underexplored. This review aimed to examine the costs related to machine perfusion and its associated outcomes., Methods: Expert opinion of several groups representing different machine perfusion modalities. Critical analysis of the published literature reporting the economic outcomes of the most used techniques of machine perfusion in liver transplantation (normothermic and hypothermic ex situ machine perfusion and in situ normothermic regional perfusion)., Results: Machine perfusion costs include disposable components of the perfusion device, perfusate components, personnel and facility fees, and depreciation of the perfusion device or device lease fee. The limited current literature suggests that although this upfront cost varies between perfusion modalities, its use is highly likely to be cost-effective. Optimization of the donor liver utilization rate, local conditions of transplant programs (long waiting list times and higher MELD scores), a decreased rate of complications, changes in logistics, and length of hospital stay are potential cost savings points that must highlight the expected benefits of this intervention. An additional unaccounted factor is that machine perfusion optimizing donor organ utilization allows patients to be transplanted earlier, avoiding clinical deterioration while on the waiting list and the costs associated with hospital admissions and other required procedures., Conclusion: So far, the clinical benefits have guided machine perfusion implementation in liver transplantation. Albeit there is data suggesting the economic benefit of the technique, further investigation of its costs to healthcare systems and society and associated outcomes is needed., (© 2021 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Objective: To understand the professionals´ perception of the use of deceased donor liver for transplantation, the reasons to decline them, and propose strategies to increase their use safely., Methods: This is a cross-sectional, descriptive qualitative-quantitative study. Professionals working with liver transplantation answered a self-administered, structured, and electronic questionnaire comprising 17 questions distributed into four sessions (demographic factors, perception of use of organs, reasons for disposal, and measures to favor their usage)., Results: A total of 42 professionals participated in the study. The rate of use of organs was considered low by 71.43% (n=30) of respondents or very low by 19.05% (n=8). Everyone agreed that it was possible to increase it. Thirty-one (73.81%) participants believed the expansion of the population of extended criteria donors affected this index negatively. Donor-related conditions were the most frequent category of reasons for refusing a liver for transplantation, being the findings during organ retrieval the most frequent reason in clinical practice. Enhanced training of intensive care teams in the treatment of donors was the primary measure selected to favor the use of the organs, followed by investment in new technologies to optimize its preservation/evaluate its function before transplantation., Conclusion: Implementation of strategies to increase the rate of acceptance of livers is expected. Improvements in donor intensive care and implementation of new preservation technologies should favor the use of the organs.

The realm of extended criteria liver transplantation created the 'adjacent possible' for dynamic organ preservation. Machine perfusion of the liver greatly expanded donor organ preservation possibilities, reaching before unattainable goals, including the mitigation of ischemia-reperfusion injury, viability assessment, and organ reconditioning prior to transplantation. However, current scientific evidence lacks uniformity between studies, perfusion protocols, and acceptance criteria. Construction of collaborative research networks for sharing knowledge should, therefore, enable the development of high-level evidence and guidelines for machine perfusion utilization, including donor acceptance criteria. Finally, this approach shall guarantee conditions for further progress to occur., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

This review aims to summarize the current evidence on the treatment of viral hepatitis, focusing on its clinical management. Also, future treatment options and areas of potential research interest are detailed. PubMed and Scopus databases were searched for primary studies published within the last ten years. Keywords included hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus, hepatitis D virus (HDV), hepatitis E virus, and treatment. Outcomes reported in the studies were summarized, tabulated, and synthesized. Significant advances in viral hepatitis treatment were accomplished, such as the advent of curative therapies for hepatitis C and the development and improvement of hepatitis A, hepatitis B, and hepatitis E vaccination. Drugs that cure hepatitis B, going beyond viral suppression, are so far unavailable; however, targeted antiviral drugs against HBV (immunomodulatory therapies and gene silencing technologies) are promising approaches to eradicating the virus. Ultimately, high vaccination coverage and large-scale test-and-treat programmes with high screening rates may eliminate viral hepatitis and mitigate their burden on health systems. The development of curative hepatitis C treatment renewed the enthusiasm for curing hepatitis B, albeit further investigation is required. Novel therapeutic options targeting HDV life cycle are currently under clinical investigation., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background & Aims: Early allograft dysfunction (EAD) following liver transplantation (LT) negatively impacts graft and patient outcomes. Previously we reported that the liver graft assessment following transplantation (L-GrAFT 7 ) risk score was superior to binary EAD or the model for early allograft function (MEAF) score for estimating 3-month graft failure-free survival in a single-center derivation cohort. Herein, we sought to externally validate L-GrAFT 7 , and compare its prognostic performance to EAD and MEAF., Methods: Accuracies of L-GrAFT 7 , EAD, and MEAF were compared in a 3-center US validation cohort (n = 3,201), and a Consortium for Organ Preservation in Europe (COPE) normothermic machine perfusion (NMP) trial cohort (n = 222); characteristics were compared to assess generalizability., Results: Compared to the derivation cohort, patients in the validation and NMP trial cohort had lower recipient median MELD scores; were less likely to require pretransplant hospitalization, renal replacement therapy or mechanical ventilation; and had superior 1-year overall (90% and 95% vs. 84%) and graft failure-free (88% and 93% vs. 81%) survival, with a lower incidence of 3-month graft failure (7.4% and 4.0% vs. 11.1%; p <0.001 for all comparisons). Despite significant differences in cohort characteristics, L-GrAFT 7 maintained an excellent validation AUROC of 0.78, significantly superior to binary EAD (AUROC 0.68, p = 0.001) and MEAF scores (AUROC 0.72, p <0.001). In post hoc analysis of the COPE NMP trial, the highest tertile of L-GrAFT 7 was significantly associated with time to liver allograft (hazard ratio [HR] 2.17, p = 0.016), Clavien ≥IIIB (HR 2.60, p = 0.034) and ≥IVa (HR 4.99, p = 0.011) complications; post-LT length of hospitalization (p = 0.002); and renal replacement therapy (odds ratio 3.62, p = 0.016)., Conclusions: We have validated the L-GrAFT 7 risk score as a generalizable, highly accurate, individualized risk assessment of 3-month liver allograft failure that is superior to existing scores. L-GrAFT 7 may standardize grading of early hepatic allograft function and serve as a clinical endpoint in translational studies (www.lgraft.com)., Lay Summary: Early allograft dysfunction negatively affects outcomes following liver transplantation. In independent multicenter US and European cohorts totaling 3,423 patients undergoing liver transplantation, the liver graft assessment following transplantation (L-GrAFT) risk score is validated as a superior measure of early allograft function that accurately discriminates 3-month graft failure-free survival and post-liver transplantation complications., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Brazil, like most countries in the world, experiences the expansion of extended criteria donors, mainly due to the aging of the population and the obesity epidemic. Concerns regarding the quality of these organs along with the vast territorial areas of the country compromise the utilization rate of livers from donors and aggravate the discrepancy between the number of liver transplants performed and the needed. Ex situ liver machine perfusion offers superior preservation for livers from extended criteria donors, limiting cold ischaemia time and offering the possibility of evaluation of their function before transplantation as well as the reconditioning of marginal organs. Objections such as the financial cost, difficulty in transporting the device between hospitals, and demand of trained professionals in the handling of the device must be pondered with the possibility of increasing the number of transplants and the utilisation rate of donor organs. The optimal use of this resource, through the careful selection of donors and the appropriate technical and scientific knowledge, can ensure an effective and successful implementation of this technology.

Tubulovillous adenomas of the duodenal ampulla are rare neoplasms. The present report describes a case with radiological-endoscopic and pathological correlation in which the patient underwent duodenal pancreatectomy with good postoperative progression. With advanced imaging methods, especially magnetic resonance and endoscopic ultrasound, locoregional aspects and extraluminal, lymphovascular, and metastatic invasion have been increasingly discussed as contributors to therapeutic decision making. This progression improves lesion staging and is especially useful in selecting eligible candidates for endoscopic treatment.

Background: Pre-clinical research with multi-potent adult progenitor cells (MAPC® cells, Multistem, Athersys Inc., Cleveland, Ohio) suggests their potential as an anti-inflammatory and immunomodulatory therapy in organ transplantation. Normothermic machine perfusion of the liver (NMP-L) has been proposed as a way of introducing therapeutic agents into the donor organ. Delivery of cellular therapy to human donor livers using this technique has not yet been described in the literature. The primary objectives of this study were to develop a technique for delivering cellular therapy to human donor livers using NMP-L and demonstrate engraftment. Methods: Six discarded human livers were perfused for 6 h at 37°C using the Liver Assist (Organ Assist, Groningen). 50 × 106 CMPTX-labeled MAPC cells were infused directly into the right lobe via the hepatic artery (HA, n = 3) or portal vein (PV, n = 3) over 20 min at different time points during the perfusion. Perfusion parameters were recorded and central and peripheral biopsies were taken at multiple time-points from both lobes and subjected to standard histological stains and confocal microscopy. Perfusate was analyzed using a 35-plex multiplex assay and proteomic analysis. Results: There was no detrimental effect on perfusion flow parameters on infusion of MAPC cells by either route. Three out of six livers met established criteria for organ viability. Confocal microscopy demonstrated engraftment of MAPC cells across vascular endothelium when perfused via the artery. 35-plex multiplex analysis of perfusate yielded 13 positive targets, 9 of which appeared to be related to the infusion of MAPC cells (including Interleukin's 1b, 4, 5, 6, 8, 10, MCP-1, GM-CSF, SDF-1a). Proteomic analysis revealed 295 unique proteins in the perfusate from time-points following the infusion of cellular therapy, many of which have strong links to MAPC cells and mesenchymal stem cells in the literature. Functional enrichment analysis demonstrated their immunomodulatory potential. Conclusion: We have demonstrated that cells can be delivered directly to the target organ, prior to host immune cell population exposure and without compromising the perfusion. Transendothelial migration occurs following arterial infusion. MAPC cells appear to secrete a host of soluble factors that would have anti-inflammatory and immunomodulatory benefits in a human model of liver transplantation., (Copyright © 2020 Laing, Stubblefield, Wallace, Roobrouck, Bhogal, Schlegel, Boteon, Reynolds, Ting, Mirza, Newsome, Mergental and Afford.)

There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirty-one livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring re-transplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia.

Introduction: The combination of hypothermic and normothermic machine perfusion (HMP+NMP) of the liver provides individual benefits of both techniques, improving the rescue of marginal organs. The aim of this study was to investigate the effect on the bioenergetic status and the oxidative-mediated tissue injury of an uninterrupted combined protocol of HMP+NMP using a single haemoglobin-based oxygen carrier (HBOC)-based perfusate., Methods: Ten discarded human donor livers had either 2 hours of dual hypothermic oxygenated perfusion (D-HOPE) with sequential controlled rewarming (COR) and then NMP using the HBOC-based perfusate uninterruptedly (cold-to-warm group); or 2 hours of hypothermic oxygenated perfusion (HOPE) with an oxygen carrier-free perfusate, followed by perfusate exchange and then NMP with an HBOC-based perfusate. Markers of liver function, tissue adenosine triphosphate (ATP) levels and tissue injury were systematically assessed., Results: The hypothermic phase downregulated mitochondrial respiration and increased ATP levels in both groups. The cold-to-warm group presented higher arterial vascular resistance during rewarming/NMP (p = 0.03) with a trend of lower arterial flow (p = 0.09). At the end of NMP tissue expression of markers of reactive oxygen species production, oxidative injury and inflammation were comparable between the groups., Conclusion: The uninterrupted combined protocol of HMP+NMP using an HBOC-based perfusate-cold-to-warm MP-mitigated the oxidative-mediated tissue injury and enhanced hepatic energy stores, similarly to an interrupted combined protocol; however, it simplified the logistics of this combination and may favour its clinical applicability., Competing Interests: The machine perfusion research was funded by the Queen Elizabeth Hospital Birmingham Charity’s Liver Foundation UK. YLB is funded by the NIHR Wellcome Trust. Hemopure® was provided free of charge by Hemoglobin Oxygen Therapeutics LLC. The company has not had any role in the study design, data collection, analysis, interpretation or manuscript preparation. The authors are employees of the University Hospital Birmingham or the University of Birmingham and none of them received any payment or have any conflict of interest related to this manuscript. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Background: Acute-on-chronic liver failure (ACLF) is an entity comprising an acute deterioration of liver function in cirrhotic patients, associated with organ failure(s) and high short-term mortality. We aimed to identify predictive factors for short-term mortality in patients admitted with ACLF that may benefit most from liver transplantation., Methods: Retrospective analysis of patients admitted in ACLF to a tertiary intensive care unit between 2013 and 2017 was performed. The EASL-CLIF acute-on-chronic liver failure in cirrhosis (CANONIC) criteria were used to define ACLF grade. Multivariable analysis using 28-day mortality as an end-point was performed, including severity-of-disease scores and clinical parameters., Results: Seventy-seven patients were admitted in ACLF over the study period. The commonest aetiology of liver disease was alcohol related 52/77(68%) and the commonest precipitant of ACLF was variceal haemorrhage 38/77(49%). Overall 28-day mortality was 42/77(55%) [ACLF-(grade)1:3/42(7%); ACLF-2:10/42(24%); and, ACLF-3:29/42(69%);p = 0.002]. On multivariable analysis MELD ≥ 26 [odds ratio(OR) = 11.559; 95% confidence interval(CI):2.820-47.382;p = 0.001], ACLF-3 (OR = 3.287; 95%CI:1.047-10.325;p = 0.042) at admission and requirement for renal replacement therapy (OR = 5.348; 95%CI:1.385-20.645;p = 0.015) were independently associated with 28-day mortality., Conclusion: Patients admitted with ACLF to intensive care have a high mortality rate. Defined early thresholds at admission can identify patients at the highest risk that may benefit most from liver transplantation., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Strategies to increase the use of steatotic donor livers are required to tackle the mortality on the transplant waiting list. We aimed to test the efficacy of pharmacological enhancement of the lipid metabolism of human livers during ex situ normothermic machine perfusion to promote defatting and improve the functional recovery of the organs. Because of steatosis, 10 livers were discarded and were allocated either to a defatting group that had the perfusate supplemented with a combination of drugs to enhance lipid metabolism or to a control group that received perfusion fluid with vehicle only. Steatosis was assessed using tissue homogenate and histological analyses. Markers for lipid oxidation and solubilization, oxidative injury, inflammation, and biliary function were evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and in-gel protein detection. Treatment reduced tissue triglycerides by 38% and macrovesicular steatosis by 40% over 6 hours. This effect was driven by increased solubility of the triglycerides (P = 0.04), and mitochondrial oxidation as assessed by increased ketogenesis (P = 0.008) and adenosine triphosphate synthesis (P = 0.01) were associated with increased levels of the enzymes acyl-coenzyme A oxidase 1, carnitine palmitoyltransferase 1A, and acetyl-coenzyme A synthetase. Concomitantly, defatted livers exhibited enhanced metabolic functional parameters such as urea production (P = 0.03), lower vascular resistance, lower release of alanine aminotransferase (P = 0.049), and higher bile production (P = 0.008) with a higher bile pH (P = 0.03). The treatment down-regulated the expression of markers for oxidative injury as well as activation of immune cells (CD14; CD11b) and reduced the release of inflammatory cytokines in the perfusate (tumor necrosis factor α; interleukin 1β). In conclusion, pharmacological enhancement of intracellular lipid metabolism during normothermic machine perfusion decreased the lipid content of human livers within 6 hours. It also improved the intracellular metabolic support to the organs, leading to successful functional recovery and decreased expression of markers of reperfusion injury., (Copyright © 2019 The Authors. Liver Transplantation published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Parameters of retrieval surgery are meticulously documented in the United Kingdom, where up to 40% of livers are donation after circulatory death (DCD) donations. This retrospective analysis focuses on outcomes after transplantation of DCD livers, retrieved by different UK centers between 2011 and 2016. Donor and recipient risk factors and the donor retrieval technique were assessed. A total of 236 DCD livers from 9 retrieval centers with a median UK DCD risk score of 5 (low risk) to 7 points (high risk) were compared. The majority used University of Wisconsin solution for aortic flush with a median hepatectomy time of 27-44 minutes. The overall liver injury rate appeared relatively high (27.1%) with an observed tendency toward more retrieval injuries from centers performing a quicker hepatectomy. Among all included risk factors, the UK DCD risk score remained the best predictor for overall graft loss in the multivariate analysis (P < 0.001). In high-risk and futile donor-recipient combinations, the occurrence of liver retrieval injuries had negative impact on graft survival (P = 0.023). Expectedly, more ischemic cholangiopathies (P = 0.003) were found in livers transplanted with a higher cumulative donor-recipient risk. Although more biliary complications with subsequent graft loss were found in high-risk donor-recipient combinations, the impact of the standardized national retrieval practice on outcomes after DCD liver transplantation was minimal., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Longstanding research describes the mechanisms whereby the restoration of blood flow and reoxygenation (reperfusion) aggravates the ischaemic injury caused by a period of anoxia to a donor liver. This phenomenon, called ischaemia-reperfusion injury (IRI), leads to parenchymal cell death, microcirculatory failure, and inflammatory immune response. Clinically, IRI is the main factor responsible for the occurrence of posttransplant graft dysfunction and ischaemic-type biliary lesions. While extended criteria donor livers are more vulnerable to IRI, their utilisation is required to address the shortfall in donor organs. Thus, the mitigation of IRI should drive the setting of a new benchmark for marginal organ preservation. Herein, strategies incorporating different modalities of machine perfusion of the liver to alleviate IRI are discussed in conjunction with advantages and disadvantages of individual protocols. Techniques leading to reperfusion of the liver during machine perfusion ( in situ normothermic regional perfusion and ex situ normothermic machine perfusion) may mitigate IRI by shortening the ischaemic period of the organs. This benefit potentially escalates from the minimum level, obtained following just partial alleviation of the ischaemic period, to the maximum level, which can be potentially achieved with ischaemia-free organ transplantation. Techniques that do not lead to reperfusion of the liver during machine perfusion (hypothermic, subnormothermic, and controlled-oxygenated rewarming) optimise mitochondrial oxidative function and replenish cellular energy stores, thereby lowering reactive oxygen species production as well as the activation of downstream inflammatory pathways during reperfusion. Further mechanistic insights into IRI may guide the development of donor-specific protocols of machine perfusion on the basis of the limitations of individual categories of extended criteria donor organs., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose.

Background: Unplanned hospital readmission after pancreaticoduodenectomy (PD) is usually due to surgical complications and has significant clinical and economic impact. This study developed a risk score to predict 30-day readmission after PD., Methods: Patients undergoing PD between 2009 and 2016 were reviewed from a prospective database. Predictors of readmission were identified using a multivariable logistic regression model, from which a points-based risk scoring system was derived., Results: 81 of 518 patients (15.6%) were readmitted within 30 days. History of cardiac disease ([odds ratio] OR = 2.12; 95% CI: 1.12-4.56), CRP>140 mg/L on post-operative day 3 (OR = 2.34; 95% CI: 1.37-4.35) and comprehensive complication index >14 (OR = 1.74; 95% CI: 1.03-2.85) were independent predictors of readmission. The regression coefficients were used to generate a risk score with excellent calibration (p = 0.917) and good discrimination (c-index = 0.65; 95% CI: 0.58-0.71; p < 0.001). Patients were categorised as low, moderate and high risk, with readmission rates of 6.4%, 13.4% and 23.0% respectively (p < 0.001)., Conclusion: The risk score identifies patients at high risk of readmission after pancreaticoduodenectomy. Such patients may benefit from pre-discharge imaging and/or enhanced follow-up, which may potentially reduce the impact of readmissions., (Copyright © 2018. Published by Elsevier Ltd.)

Hypothermic oxygenated perfusion (HOPE) and normothermic perfusion are seen as distinct techniques of ex situ machine perfusion of the liver. We aimed to demonstrate the feasibility of combining both techniques and whether it would improve functional parameters of donor livers into transplant standards. Ten discarded human donor livers had either 6 hours of normothermic perfusion (n = 5) or 2 hours of HOPE followed by 4 hours of normothermic perfusion (n = 5). Liver function was assessed according to our viability criteria; markers of tissue injury and hepatic metabolic activity were compared between groups. Donor characteristics were comparable. During the hypothermic perfusion phase, livers down-regulated mitochondrial respiration (oxygen uptake, P = 0.04; partial pressure of carbon dioxide perfusate, P = 0.04) and increased adenosine triphosphate levels 1.8-fold. Following normothermic perfusion, those organs achieved lower tissue expression of markers of oxidative injury (4-hydroxynonenal, P = 0.008; CD14 expression, P = 0.008) and inflammation (CD11b, P = 0.02; vascular cell adhesion molecule 1, P = 0.05) compared with livers that had normothermic perfusion alone. All livers in the combined group achieved viability criteria, whereas 40% (2/5) in the normothermic group failed (P = 0.22). In conclusion, this study suggests that a combined protocol of hypothermic oxygenated and normothermic perfusions might attenuate oxidative stress, tissue inflammation, and improve metabolic recovery of the highest-risk donor livers compared with normothermic perfusion alone., (Copyright © 2018 The Authors. Liver Transplantation published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Aim: To review the clinical impact of machine perfusion (MP) of the liver on biliary complications post-transplantation, particularly ischaemic-type biliary lesions (ITBL)., Methods: This systematic review was performed in accordance with the Preferred Reporting Systematic Reviews and Meta-Analysis (PRISMA) protocol. The following databases were searched: PubMed, MEDLINE and Scopus. The keyword "liver transplantation" was used in combination with the free term "machine perfusion". Clinical studies reporting results of transplantation of donor human livers following ex situ or in situ MP were analysed. Details relating to donor characteristics, recipients, technique of MP performed and post-operative biliary complications (ITBL, bile leak and anastomotic strictures) were critically analysed., Results: Fifteen articles were considered to fit the criteria for this review. Ex situ normothermic MP was used in 6 studies, ex situ hypothermic MP in 5 studies and the other 4 studies investigated in situ normothermic regional perfusion (NRP) and controlled oxygenated rewarming. MP techniques which have per se the potential to alleviate ischaemia-reperfusion injury: Such as hypothermic MP and NRP, have also reported lower rates of ITBL. Other biliary complications, such as biliary leak and anastomotic biliary strictures, are reported with similar incidences with all MP techniques. There is currently less clinical evidence available to support normothermic MP as a mitigator of biliary complications following liver transplantation. On the other hand, restoration of organ to full metabolism during normothermic MP allows assessment of hepatobiliary function before transplantation, although universally accepted criteria have yet to be validated., Conclusion: MP of the liver has the potential to have a positive impact on post-transplant biliary complications, specifically ITBL, and expand extended criteria donor livers utilisation., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose.

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) and liver transplantation (LT). Our study focused on changing trends of liver related HCC etiologies during the last years in Latin America., Methods: From a cohort of 2761 consecutive adult LT patients between 2005 and 2012 in 17 different centers, 435 with HCC were included. Different periods including years 2005-2006, 2007-2008, 2009-2010 and 2011-2012 were considered. Etiology of liver disease was confirmed in the explant., Results: Participating LT centers per country included 2 from Brazil (n=191), 5 transplant programs from Argentina (n=98), 2 from Colombia (n=65), 4 from Chile (n=49), 2 from Mexico (n=12), and 1 from Peru (n=11) and Uruguay (n=9). Chronic hepatitis C infection was the leading cause of HCC in the overall cohort (37%), followed by HBV (25%) and alcoholic liver disease (17%). NAFLD and cryptogenic cirrhosis accounted for 6% and 7%, respectively. While HCV decreased from 48% in 2005-06 to 26% in 2011-12, NAFLD increased from 1.8% to 12.8% during the same period, accounting for the third cause of HCC. This represented a 6-fold increase in NAFLD-HCC, whereas HCV had a 2-fold decrease. Patients with NAFLD were older, had lower pre-LT serum AFP values and similar 5-year survival and recurrence rates than non-NAFLD., Conclusion: There might be a global changing figure regarding etiologies of HCC in Latin America. This epidemiological change on the incidence of HCC in the world, although it has been reported, should still be confirmed in prospective studies., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Long-standing research has shown that increased lipid content in donor livers is associated with inferior graft outcomes posttransplant. The global epidemic that is obesity has increased the prevalence of steatosis in organ donors, to the extent that it has become one of the main reasons for declining livers for transplantation. Consequently, it is one of the major culprits behind the discrepancy between the number of donor livers offered for transplantation and those that go on to be transplanted. Steatotic livers are characterized by poor microcirculation, depleted energy stores because of an impaired capacity for mitochondrial recovery, and a propensity for an exaggerated inflammatory response following reperfusion injury culminating in poorer graft function postoperatively. Ex situ machine perfusion, currently a novel method in graft preservation, is showing great promise in providing a tool for the recovery and reconditioning of marginal livers. Hence, reconditioning these steatotic livers using machine perfusion has the potential to increase the number of liver transplants performed. In this review, we consider the problematic issues associated with fatty livers in the realm of transplantation and discuss pharmacological and nonpharmacological options that are being developed to enhance recovery of these organs using machine perfusion and defatting strategies., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Increased use of high-risk allografts is critical to meet the demand for liver transplantation. We aimed to identify criteria predicting viability of organs, currently declined for clinical transplantation, using functional assessment during normothermic machine perfusion (NMP). Twelve discarded human livers were subjected to NMP following static cold storage. Livers were perfused with a packed red cell-based fluid at 37°C for 6 hours. Multilevel statistical models for repeated measures were employed to investigate the trend of perfusate blood gas profiles and vascular flow characteristics over time and the effect of lactate-clearing (LC) and non-lactate-clearing (non-LC) ability of the livers. The relationship of lactate clearance capability with bile production and histological and molecular findings were also examined. After 2 hours of perfusion, median lactate concentrations were 3.0 and 14.6 mmol/L in the LC and non-LC groups, respectively. LC livers produced more bile and maintained a stable perfusate pH and vascular flow >150 and 500 mL/minute through the hepatic artery and portal vein, respectively. Histology revealed discrepancies between subjectively discarded livers compared with objective findings. There were minimal morphological changes in the LC group, whereas non-LC livers often showed hepatocellular injury and reduced glycogen deposition. Adenosine triphosphate levels in the LC group increased compared with the non-LC livers. We propose composite viability criteria consisting of lactate clearance, pH maintenance, bile production, vascular flow patterns, and liver macroscopic appearance. These have been tested successfully in clinical transplantation. In conclusion, NMP allows an objective assessment of liver function that may reduce the risk and permit use of currently unused high-risk livers., (© 2018 by the American Association for the Study of Liver Diseases.)

Introduction: Pharmacological defatting of rat hepatocytes and hepatoma cell lines suggests that the same method could be used to ameliorate macrovesicular steatosis in moderate to severely fatty livers. However there is no data assessing the effects of those drugs on primary human liver cells. We aimed to determine the effectiveness of a pharmacological cocktail in reducing the in vitro lipid content of primary human hepatocytes (PHH). In addition we sought to determine the cytotoxicity of the cocktail towards non-parenchymal liver cells., Methods: Steatosis was induced in PHH by supplementation with a combination of saturated and unsaturated free fatty acids. This was followed by addition of a defatting drug cocktail for up to 48 hours. The same experimental method was used with human intra-hepatic endothelial cells (HIEC) and human cholangiocytes. MTT assay was used to assess cell viability, triglyceride quantification and oil red O staining were used to determine intracellular lipids content whilst ketone bodies were measured in the supernatants following experimentation., Results: Incubation of fat loaded PHH with the drugs over 48 hours reduced the intracellular lipid area by 54%, from 12.85% to 5.99% (p = 0.002) (percentage of total oil red O area), and intracellular triglyceride by 35%, from 28.24 to 18.30 nmol/million of cells (p<0.001). Total supernatant ketone bodies increased 1.4-fold over 48 hours in the defatted PHH compared with vehicle controls (p = 0.002). Moreover incubation with the drugs for 48 hours increased the viability of PHH by 11%, cholangiocytes by 25% whilst having no cytotoxic effects on HIEC., Conclusion: These data demonstrate that pharmacological intervention can significantly decrease intracellular lipid content of PHH, increase fatty acids β-oxidation whilst being non-toxic to PHH, HIEC or cholangiocytes., Competing Interests: The authors have declared that no competing interests exist.

Background: Loco-regional complications of transarterial chemoembolization (TACE) may adversely affect technical aspects of the liver transplantation (LT). This study reviewed the impact of those complications on postoperative outcomes encompassing implications on graft selection., Methods: A retrospective, propensity score matching (1:1) analysis accounting for donor and recipient confounders was performed on a dataset of patients undergoing LT for hepatocellular carcinoma. Outcomes of patients who had TACE (TACE-group) were compared with those who did not (NoTACE-group)., Results: A total of 57 matched pairs were analyzed. TACE achieved effective tumor control (Pre-TACE vs Post-TACE; Median: 44 mm [interquartile range: 43-50] vs 17 mm [0-36]; P = .002) on imaging follow-up. TACE group had, at the hepatectomy, higher incidence of ischemia-related complications (adhesions of the necrotic tumor, cholecystitis, and/or bile duct necrosis) (40.4% vs 10.5%; P = .001). Overall major post-LT complications rate (Dindo-Clavien ≥3) were similar (P = .134). Those in the TACE group with donors after circulatory death (DCD) had 4.6% 90-day mortality and 54.3% major complication rate compared to 6.9% and 77.3% (P = .380 and P = .112, respectively)., Conclusion: TACE was an effective bridging procedure that may complicate LT inducing ischemic-related complications; nevertheless, it has not shown repercussions on mortality or morbidity after the procedure, even using donors after circulatory death., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Heterogeneous data has been reported regarding liver transplantation (LT) for hepatocellular carcinoma (HCC) in Latin America. We aimed to describe treatment during waiting list, survival and recurrence of HCC after LT in a multicenter study from Latin America., Material and Methods: Patients with HCC diagnosed prior to transplant (cHCC) and incidentally found in the explanted liver (iHCC) were included. Imaging-explanted features were compared in cHCC (non-discordant if pre and post-LT were within Milan, discordant if pre-LT was within and post-LT exceeding Milan)., Results: Overall, 435 patients with cHCC and 92 with iHCC were included. At listing, 81% and 91% of cHCC patients were within Milan and San Francisco criteria (UCSF), respectively. Five-year survival and recurrence rates for cHCC within Milan, exceeding Milan/within UCSF and beyond UCSF were 71% and 16%; 66% and 26%; 46% and 55%, respectively. Locoregional treatment prior to LT was performed in 39% of cHCC within Milan, in 53% beyond Milan/within UCSF and in 83% exceeding UCSF (p &lt; 0.0001). This treatment difference was not observed according to AFP values (≤100, 44%; 101-1,000, 39%, and &gt; 1,000 ng/mL 64%; p = 0.12). Discordant imaging-explanted data was observed in 29% of cHCC, showing lower survival HR 2.02 (CI 1.29; 3.15) and higher recurrence rates HR 2.34 when compared to AFP &lt;100 ng/mL. Serum AFP &gt; 1,000 ng/mL at listing was independently associated with a higher 5-year recurrence rate and a HR of 3.24 when compared to AFP &lt;100 ng/mL., Conclusion: Although overall results are comparable to other regions worldwide, pre-LT treatment not only considering imaging data but also AFP values should be contemplated during the next years.

Purpose of the Review: Machine perfusion (MP) is a novel technology recently introduced in liver transplantation, redefining the current practice of organ preservation and pushing the limits of high-risk liver utilisation. This review highlights the key benefits of machine perfusion over conventional static cold storage (SCS), demonstrated in human liver research and clinical transplants., Recent Findings: The first clinical trials have demonstrated both safety and feasibility of MP. The most recent transplant series and result from a randomised trial suggest the technology is superior to SCS. The key benefits include extended period of organ preservation, decreased incidence of early allograft dysfunction and reduction of biliary complications. Normothermic liver perfusion allows viability testing to guide transplantability of the highest-risk organs. This technology also provides opportunities for therapeutic interventions to improve liver function and quality in organs that are currently declined for clinical use., Summary: Machine perfusion is likely to transform the liver preservation pathway and to improve utilisation of high-risk grafts., Competing Interests: Compliance with Ethical StandardsThe authors declare that they have no conflict of interest.This article does not contain any studies with human or animal subjects performed by any of the authors.

Ischaemia-reperfusion injury (IRI) is the leading cause of injury seen in the liver following transplantation. IRI also causes injury following liver surgery and haemodynamic shock. The first cells within the liver to be injured by IRI are the liver sinusoidal endothelial cells (LSEC). Recent evidence suggests that LSEC co-ordinate and regulates the livers response to a variety of injuries. It is becoming increasingly apparent that the cyto-protective cellular process of autophagy is a key regulator of IRI. In particular LSEC autophagy may be an essential gatekeeper to the development of IRI. The recent availability of liver perfusion devices has allowed for the therapeutic targeting of autophagy to reduce IRI. In particular normothermic machine liver perfusion (NMP-L) allow the delivery of pharmacological agents to donor livers whilst maintaining physiological temperature and hepatic flow rates. In this review we summarise the current understanding of endothelial autophagy and how this may be manipulated during NMP-L to reduce liver IRI., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.

Introduction: The use of marginal or extended criteria donor livers is increasing. These organs carry a greater risk of initial dysfunction and early failure, as well as inferior long-term outcomes. As such, many are rejected due to a perceived risk of use and use varies widely between centres. Ex situ normothermic machine perfusion of the liver (NMP-L) may enable the safe transplantation of organs that meet defined objective criteria denoting their high-risk status and are currently being declined for use by all the UK transplant centres., Methods and Analysis: Viability testing and transplantation of marginal livers is an open-label, non-randomised, prospective, single-arm trial designed to determine whether currently unused donor livers can be salvaged and safely transplanted with equivalent outcomes in terms of patient survival. The procured rejected livers must meet predefined criteria that objectively denote their marginal condition. The liver is subjected to NMP-L following a period of static cold storage. Organs metabolising lactate to ≤2.5 mmol/L within 4 hours of the perfusion commencing in combination with two or more of the following parameters-bile production, metabolism of glucose, a hepatic arterial flow rate ≥150 mL/min and a portal venous flow rate ≥500 mL/min, a pH ≥7.30 and/or maintain a homogeneous perfusion-will be considered viable and transplanted into a suitable consented recipient. The coprimary outcome measures are the success rate of NMP-L to produce a transplantable organ and 90-day patient post-transplant survival., Ethics and Dissemination: The protocol was approved by the National Research Ethics Service (London-Dulwich Research Ethics Committee, 16/LO/1056), the Medicines and Healthcare Products Regulatory Agency and is endorsed by the National Health Service Blood and Transplant Research, Innovation and Novel Technologies Advisory Group. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications., Trial Registration Number: NCT02740608; Pre-results., Competing Interests: Competing interests: RWL and YB receive salary as Wellcome Trust research fellows., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Liver transplantation is the criterion standard treatment for hepatocellular carcinoma, but tumor recurrence remains a problem leading to a worse prognosis. We aimed to evaluate factors associated with recurrence of hepatocellular carcinoma and survival after this procedure., Methods: We retrospectively reviewed data from 101 patients submitted to liver transplantation because of hepatocellular carcinoma from January 2005 to January 2012 at our single center. Univariate and multivariate analyses were performed to identify preoperative factors and histologic findings associated with lower survival rates and recurrence. The significance level was 5%., Results: There was recurrence in 10 cases (9.9%), with an average time of 25.28 ± 26.92 months. Microvascular invasion (P = .005; hazard ratio [HR], 4.94; 95% confidence interval [CI], 1.42-17.12) was an independent factor for recurrence. Microvascular invasion (P = .035; HR, 1.87; 95% CI, 1.04-3.25) and tumors outside the criteria of the University of San Francisco (P = .046; HR, 1.81; 95% CI, 1.01-3.25) were independent factors for the risk of death. Poorly differentiated tumors had a higher level of alphafetoprotein (P = .03), and values <100 ng/mL were associated with well differentiated tumors., Conclusions: Microvascular invasion was associated with recurrence and lower survival. Tumors outside the criteria of the University of California, San Francisco had lower survival. Alpha-fetoprotein levels >100 ng/mL were associated with poorly differentiated tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Cytomegalovirus (CMV) is a common opportunistic pathogen in patients with HIV. It is also a major cause of gastrointestinal ulcers in patients with acquired immunodeficiency syndrome (AIDS). CMV pseudotumor in the stomach is a rare cause of digestive tract obstruction., Case Report: In this study we report a male patient infected with HIV in 2002. In 2014 he evolved C3 stage AIDS with pre-pyloric gastric ulcer which provoked deformity and pseudotumoral aspect of the gastric outlet. Endoscopic biopsy confirmed CMV infection. He underwent Roux-en-Y gastroenteroanastomosis with good recovery., Conclusions: CMV infection should be considered as an agent in gastric lesions in HIV-infected patients. Roux-en-Y gastroenteroanastomosis is a surgical option for this group of patients, allowing improvements in quality of life and decreasing risks of perioperative complications.