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Chronic hepatitis B virus (HBV) infection is the major aetiology of hepatocellular carcinoma (HCC). The optimal goal of therapy, hepatitis B surface antigen (HBsAg) loss and anti‐HBs production, is achieved rarely and HBsAg‐associated HCC risk is well recognized. Here we review the role of HBsAg in HCC, the link between HBsAg and HCC recurrence post‐liver transplantation or resection, and the implications for therapy. HBV‐associated carcinogenesis is a multifactorial process. The observation that HBV‐related HCC can occur in the absence of cirrhosis is compatible with a direct oncogenic effect of the virus, which may occur via multiple mechanisms, including those mediated by both mutated and unmutated HBsAg. HCC recurrence in HBsAg‐positive patients post‐liver transplantation has been reported in 10%‐15% of patients and is likely to be because of expansion of residual HCC tumour cell populations containing integrated HBV DNA, which expand and independently replicate HBV, leading to the recurrence of both HCC and HBV. The direct role of HBsAg in HCC recurrence post‐liver resection is less clear. Cirrhosis is the most important risk factor for HCC development, and precancerous cirrhotic liver remains after resection, with the potential to undergo malignant transformation regardless of the existence of HBV‐derived oncogenic drivers. The role of HBsAg in the development of HCC and its recurrence post‐surgical intervention has multiple implications for therapy and suggests a potential role for immunotherapy in the future management of HCC, in particular post‐liver transplantation. Use of hepatitis B immunoglobulins that target HBsAg directly, alongside immune‐oncology therapies, may be relevant in this setting. [ABSTRACT FROM AUTHOR]

Background: Bile leaks after hepatic resection are serious complications associated with substantial morbidity and mortality. The aim of this prospective observational study was to determine the therapeutic success of endoscopic treatment of biliary leakage after liver resection.Patients and Methods: Grade B biliary leaks were considered for endoscopic treatment in patients after liver resection between 1/09 and 4/12. Endoscopic treatment (sphincterotomy only, plastic stent distal to leak or bridging) was defined as successful when the patient remained without symptoms after drain removal and without extravasation follow-up ERC 8 weeks later.Results: Overall rate of biliary leak was 7.4 % (61/826). 35 patients with a grade B bile leak were considered for endoscopic treatment. 22 (63 %) had bile leaks that were peripherally located, and 13 (37 %) had bile leaks at central location. In 3 patients, sphincterotomy only was performed; in 19 patients, a stent distal to the leak and in 13 patients, a bridging stent was inserted. The overall success rate was 74 % (26/35 patients). Endoscopic treatment failed in 26 % (9/35), and mortality rate was 11 % (4/35). In all patients with leaks located at the right or left hepatic duct, treatment with the bridging stent was successful.Conclusion: Endoscopic therapy for biliary leakage after liver resection is safe and effective and should be considered as a first-line therapy in patients who are suitable for an interventional, non-surgical approach. Patients with a centrally located leak who are treated with a bridging stent are more likely to benefit from endoscopic intervention. [ABSTRACT FROM AUTHOR]

Background: Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients. Methods/Design: Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7-21 days post-transplantation) to receive everolimus (trough levels 3-8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6-10 ng/mL) after entering a run-in period (3-5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis. Discussion: This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus. [ABSTRACT FROM AUTHOR]

Background: Machine perfusion (MP) in solid organ transplantation has been a topic of variable importance for decades. At the dawn of organ transplantation, MP was one of the standard techniques for preservation; today's gold standard for organ preservation for transplantation is cold storage (CS). The outcome after transplantation of solid organs has tremendously improved over the last five decades. MP has been continuously under investigation and may be an option for organ preservation in selected cases; however, there is only little evidence from clinical trials that can be used to advocate for MP as a routine organ preservation method. Methods: This article reviews the current knowledge on MP in the field of solid organ transplantation with special focus on findings from clinical trials. Conclusion: Especially in heart and lung transplantation, MP seems to be a promising tool to improve postoperative outcome, but a general evidence-based recommendation for or against an application of MP cannot be given due to the lack of the highest level of clinical evidence. Gold standards such as CS should not be left behind without good reason. Randomized clinical trials are desperately needed to further improve outcome and for better understanding of the underlying pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

It has been demonstrated that a wide variety of white blood cells and macrophages (i.e. Kupffer cells, alveolar and peritoneal macrophages and neutrophils) contain glycine-gated chloride channels. Binding of glycine on the receptor stimulates Cl influx causing membrane hyperpolarization that prevents agonist-induced influx of calcium. Since platelet-aggregation is calcium-dependent, this study was designed to test the hypothesis that glycine would inhibit platelet aggregation. Rats were fed diets rich of glycine for 5 days, while controls received isonitrogenous valine. The bleeding time and ADP- and collagen-induced platelet aggregation were measured. Dietary glycine significantly increased bleeding time about twofold compared to valine-treated controls. Furthermore, the amplitude of platelet aggregation stimulated with ADP or collagen was significantly decreased in whole blood drawn from rats fed 2.5 or 5 % dietary glycine by over 50 %. Addition of glycine in vitro (1-10 mM) also blunted rat platelet aggregation in a dose-dependent manner. Strychnine, a glycine receptor antagonist, abrogated the inhibitory effect of glycine on platelet-aggregation in vitro suggesting the glycine works via a glycine receptor. Glycine also blunted aggregation of human platelets. Further, the glycine receptor was detected in both rat and human platelets by western blotting. Based on these data, it is concluded that glycine prevents aggregation of platelets in a dose-dependent manner via mechanisms involving a glycine receptor. [ABSTRACT FROM AUTHOR]

Organ shortage has driven many transplant centers to extend their criteria for organ acceptance. Graft allocation policies have been modified accordingly. This report focuses on the impact of applying the so-called rescue allocation (RA) strategy for liver transplantation (LT) in a single center within the Eurotransplant (ET) area. Liver grafts are considered for RA when the regular organ allocation is declined by at least three centers or is averted because of donor instability/unfavorable logistical reasons, thus entering a competitive or a single-recipient rescue organ offer procedure, respectively. The accepting center has the advantage to select a recipient from its own waiting list for these RA grafts. Among 253 livers accepted at the University of Heidelberg between January 2004 and December 2006, we transplanted 85 (34%) rescue-allocated livers. The indications for LT were hepatocellular carcinoma (HCC, 43%), chronic liver disease (55%), and acute liver failure (2%). Median cold ischemia time for RA grafts was 10 h (range: 4–17). The MELD score (mean ± SD) was 13 ± 7 (range: 6–40) and was 12 ± 7 for recipients with HCC. Three (3.5%) primary non-functions (PNF) occurred after transplantation of RA livers. One-year patient and graft survival were 84% and 75%, respectively. A comparison between the recipients of RA livers and regularly allocated livers revealed no significant difference regarding initial poor function (IPF), PNF, and surgical complications. Furthermore, a median follow-up of 16 months revealed no significant difference regarding patient and graft survival between the two groups. The use of RA organs has increased the donor pool and transplantation dynamics with satisfying results. The unique possibility to match livers with recipients, which is left to the discretion of accepting center, should be judged according to the center’s experience to decrease the waiting times for a timely rescue of organs/recipients while avoiding futile transplantations. [ABSTRACT FROM AUTHOR]

The clinical experience using a novel technique of liver resection with vascular staplers for dissection of hepatic parenchyma, was documented most recently in a prospective manner. These data have clearly demonstrated for the first time that stapler hepatectomy is a safe and fast dissection technique in major liver surgery (e.g. hepatectomy) which is feasible in a routine clinical setting. [ABSTRACT FROM AUTHOR]

Stapling devices have been introduced for safety and to reduce the overall operative time in many surgical procedures. In hepatobiliary surgery, i.e. liver resection, several types of staplers are in use. While transection of hepatic vessels with vascular staplers is well established, their use in dissecting hepatic parenchyma has only been assessed recently. Its advantages were especially a low rate of biliary complications (i.e., bile fistulas, bilioma) and reduced bleeding. As expected, the operative time was decreased dramatically while both the complication rate in general and the overall costs for stapler hepatectomy were comparable with other techniques used in high-volume centers. Thus, endo-GIA vascular staplers can be safely used to dissect the hepatic parenchyma in a routine clinical setting with low incidence of surgical complications. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: In many surgical procedures, stapling devices have been introduced for safety and to reduce the overall operative time. Their use for transection of hepatic parenchyma is not well established. Thus, the feasibility of stapler hepatectomy and a risk analysis of surgical morbidity based on intraoperative data have been prospectively assessed on a routine clinical basis. Materials and Methods: From October 1, 2001, to January 31, 2005, a total of 416 patients underwent liver resection in our department. During this period endo GIA vascular staplers were used for parenchymal transection in 300 cases of primary (22%) and metastatic (57%) liver cancer, benign diseases (adenoma, focal nodular hyperplasia [FNH], cysts) (14%), gallbladder carcinoma (2%), and other tumors (5%). There were 193 (64%) major resections (i.e., removal of three segments or more) and 107 minor hepatic resections. Additional extrahepatic resections were performed in 44 (15%) patients. Results: Median values for operative time and intraoperative hemorrhage were 210 minutes and 700 ml, respectively. Further, transfusion of RBC and FFP was needed in 17% and 11% of patients, respectively. A postoperative ICU stay for >2 days was required in 18% of patients. The median postoperative hospital stay was 10 days (IQR 8–14 days). The most frequent surgical complications were bile leak (8%), wound infection (3%), and pneumothorax (2%). In 7% of cases after stapler hepatectomy a relaparotomy was necessary. Treated medical complications were pleural effusion (7%), renal insufficiency (5%), and cardiac insufficiency (3%). Risk assessment revealed that both operative time and indication for resection had significant impact on surgical morbidity. Mortality (4%) and morbidity (33%) were comparable to other high-volume centers performing conventional liver resection techniques. Conclusion: In conclusion, stapler hepatectomy can be used in a routine clinical setting with a low incidence of surgical complications. [ABSTRACT FROM AUTHOR]

Background: Chronic ethanol treatment enhances Kupffer cell sensitivity to lipopolysaccharide (LPS). In this model, CD14 in Kupffer cells was increased significantly 4 weeks after ethanol. Moreover, it was shown that prostaglandin E2 produced by activated Kupffer cells participated in the mechanism of ethanol-induced fatty liver. This study was designed to elucidate the temporal effect of chronic ethanol exposure on Kupffer cell sensitization to LPS. Methods: Rats were given ethanol every 24 hr intragastrically for up to 12 weeks, and Kupffer cells were isolated 24 hr after the final ethanol administration and cultured in RPMI 1640 with 10% fetal bovine serum. After addition of LPS to Kupffer cells, intracellular calcium ([Ca2+]i) was measured. Results: CD14 in Kupffer cells was increased approximately 2-fold, and then it decreased and returned to control levels. The LPS-induced increases in [Ca2+]i and tumor necrosis factor-α by Kupffer cells were also increased approximately 3-fold over control values, but they also returned to control levels. Triglyceride content increased with the duration of chronic ethanol treatment. At 8 weeks, prostaglandin E2 produced by Kupffer cells increased approximately 3-fold over control values and triglycerides by approximately 4-fold before gradually decreasing to basal levels. After 12 weeks of ethanol exposure, LPS-induced increases in [Ca2+]i and tumor necrosis factor-α production were only approximately 50% as high as peak levels at 4 weeks. Liver triglyceride content at 12 weeks was reduced significantly compared with values at 8 weeks. Conclusions: Kupffer cells at the early stage of chronic ethanol exposure exhibited sensitization to LPS, but this sensitivity was blunted later. This correlated with triglyceride accumulation in the liver. These data indicate that long-term alcohol exposure changes the sensitivity of rat Kupffer cells to LPS but that the magnitude of the effect is time dependent. [ABSTRACT FROM AUTHOR]

Tests the hypothesis that organ manipulation during surgery activates Kupffer cells in the rat liver. Indication that gentle manipulation during surgery activates Kupffer cells which lead to the metabolic changes dependent on prostaglandin E-2 from these cells; Benefits of modulating Kupffer cell function before organ harvest in human liver transplantation and surgery.

Deals with a study which examined the validity of the hypothesis that organ manipulation activates Kupffer cells in the liver of rats. Release of toxic mediators which impair liver function; Hypermetabolic state in liver caused by gentle in situ organ manipulation; Relationship between gentle organ manipulation and graft viability.

Determines whether intravenous glycine improves survival in rat liver transplantation. Effects of intravenous glycine on liver injury after transplantation of manipulated grafts; Prevention of gentle organ manipulation on graft viability by intravenous glycine; Minimization of harvest-related reperfusion injury with glycine infusion.

Presents information on a study which determined the intravenous infusion of glycine in rat liver transplantation. Methodology; Results and discussion.

The article describes the case of a 76-year-old male patient with intraductal papillary mucinous neoplasm (IPMN) diagnosed 3 years prior. Clinical assessment, magnetic resonance imaging (MRI) and tumor markers were performed regularly after patient's radical prostatectomy. Symptoms such as back pain, fatigue and weight loss were still been persistent. Reevaluation of the patient revealed presence of mass in the pancreas which was found to be cancerous. A total pancreatectomy was performed.

Summary: While rejection prevention with innovator tacrolimus (Tac) is one of the key factors for long‐lasting graft function, the use of generic Tac is still under debate. Thus, we performed a systematic review and meta‐analysis to provide an overview on the current body of evidence for the effect of generic Tac in adult liver (LT) and kidney transplantation (KT) with focus on both biopsy‐proven acute rejection (BPAR) and bioequivalence. A systematic literature search for trials comparing generic versus innovator Tac was conducted accordingly. Seventeen studies (5 LT, 11 KT, 1 LT/KT) including 1412 patients were identified. About 92.9% (13/14; 5/5 LT, 8/9 KT) of studies reported the same or lower BPAR with generics (pooled RR: 0.84, 95% CI: 0.65–1.09); however, de novo studies showed a significantly lower risk with generic Tac (RR: 0.75, 95% CI: 0.63–0.90), whereas conversion studies showed increased risk (RR: 1.93, 95% CI: 1.00–3.70). Bioequivalence was demonstrated primarily in studies on conversion. The current evidence is mostly based on observational data and studies showing some risk of bias. In conclusion, whereas overall there was no significant difference in terms of BPAR, there is some evidence suggesting lower BPAR risk with generic Tac for de novo use. [ABSTRACT FROM AUTHOR]

Background: Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients.Methods/design: Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7-21 days post-transplantation) to receive everolimus (trough levels 3-8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6-10 ng/mL) after entering a run-in period (3-5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis.Discussion: This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus.Trial Registration: NCT01551212 . [ABSTRACT FROM AUTHOR]

Nowadays, lab-on-chip (LOC) devices are attracting more and more attention since they show vast prospects for various biomedical applications. Usually, an LOC is a small device that serves a single laboratory function. LOCs show massive potential for organ-on-chip (OOC) device manufacturing since they could allow for research on the avoidance of various diseases or the avoidance of drug testing on animals or humans. However, this technology is still under development. The dominant technique for the fabrication of such devices is molding, which is very attractive and efficient for mass production, but has many drawbacks for prototyping. This article suggests a femtosecond laser microprocessing technique for the prototyping of an OOC-type device—a liver-on-chip. We demonstrate the production of liver-on-chip devices out of glass by using femtosecond laser-based selective laser etching (SLE) and laser welding techniques. The fabricated device was tested with HepG2(GS) liver cancer cells. During the test, HepG2(GS) cells proliferated in the chip, thus showing the potential of the suggested technique for further OOC development. [ABSTRACT FROM AUTHOR]

The authors discuss lack of guarantee for adequate liver function after liver resection and transplantation due to ischemia/reperfusion injury (IRI). They claim that IRI is unavoidable in liver transplantation (LT) and that up to 88% of patients report poor graft function after LT. The authors cite factors that contribute to IRI, which include preexisting damage and reperfusion.

Colorectal cancer (CRC) ranks third in incidence and second in mortality of all cancers worldwide. At the time of primary diagnosis, around 20% of patients already have metastatic CRC and only around 20% are candidates for radical resection. Thus, most of the patients have to undergo chemotherapy (CTx). Due to chemoresistance and side effects, novel treatment additives are crucial for controlling the disease and prolonging patient survival. The aim of this study was to evaluate probiotic supplementation and its antitumorigenic effects in an experimental CRC liver metastasis model. Six-week-old male Wistar rats received either a multispecies probiotic (1.2 × 109 CFU/daily) or placebo mixture. On day 14 of the experiment, rat CRC cells (CC531) were implanted under the liver capsule later treated by FOLFOX CTx. Change in tumor volume was measured by performing micro computed tomography (micro-CT) scanning on experimental days 28 and 34. Additionally, immunohistochemical staining with anti-MPO, anti-Ki67, and anti-CD31 were performed. Tumor apoptosis was evaluated using TUNEL staining. Micro-CT image analysis indicates that probiotic supplementation significantly inhibits tumor growth. No synergistic effects between probiotic supplementation and FOLFOX CTx was observed. Reduced tumor volume was achieved by inhibiting angiogenesis, as tumor microvascular density was significantly lower in rats receiving probiotic supplementation. This study shows that a multispecies probiotic mixture significantly reduces angiogenesis and inhibits CRC liver metastasis growth in an experimental rat model. [ABSTRACT FROM AUTHOR]

Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia–reperfusion injury (IRI). The aim of this study is to investigate the protective effect of relaxin (RLX) or/and erythropoietin (EPO) on experimental uterus IRI. Eighty rats, randomly assigned into eight groups (n = 10/group), were pretreated with either saline, 5 μg/kg human relaxin-2, 4000 IU/kg recombinant human erythropoietin or their combination. Ischemia was achieved by clamping the aorta and ovarian arteries for 60 min, following 120 min of reperfusion and tissue sampling. For sham animals, clamping was omitted during surgery. There were no differences in tissue histological score, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, myeloperoxidase (MPO) and TUNEL-positive cell count between all sham-operated rats. Pretreatment with RLX preserved normal tissue morphology, reduced MDA levels, MPO and TUNEL-positive cell count, preserved SOD activity and upregulated NICD and HES1 gene expression when compared to the control group. Pretreatment with EPO reduced MDA levels. In conclusion, pretreatment with RLX, EPO or a combination of both EPO and RLX significantly alleviates uterine tissue damage caused by IRI. [ABSTRACT FROM AUTHOR]

Background: Due to a tremendous organ shortage, livers from donors with extended criteria are increasingly considered for transplantation. Pathologists are more and more requested to evaluate these livers histopathologically using frozen sections at high urgency for acceptability. Methods: This article reviews the current knowledge on pre-transplant histology in liver transplantation. Prerequisites and conditions for proper pre-transplant evaluation of donor liver tissue are discussed as well as frozen section evaluation and reporting. Data sources include the relevant medical literature, web sites specialized in organ transplantation, and the authors' experiences in liver transplant centers. Conclusions: Pre-transplant histopathological evaluation is a time-effective, accurate, and reliable tool to assess liver quality from candidate deceased donors. Pre-transplant biopsies are of value in the selection of donor livers for transplantation, especially in case of extended criteria donors, and should be performed more frequently in order to avoid unnecessary loss of organs suitable for transplantation and transplantation of inappropriate organs. Correlation of histopathological findings with clinical conditions is essential and requires excellent communication between pathologists, surgeons, and the other members of the transplant team. [ABSTRACT FROM AUTHOR]

This manuscript reports the results of a nationwide survey of transplant surgeons in Germany, including the demographics, training, position, individual case loads, center volumes, program structure, professional practice, grade of specialization, workload, work hours, salary, and career expectations. We contacted all 32 German transplant centers that perform liver, kidney, and pancreas transplantation. Surgeons engaged in transplantation were asked to reply to the survey. Eighty-five surgeons responded, with a mean age of 44 ± 8 years, 13% of whom were female. The median transplant frequency per active transplant surgeon was relatively low, with 16 liver transplants, 15 kidney transplants, and three pancreas transplants. The median reported center volumes were 45 liver transplants, 90 kidney transplants, and five pancreas transplants per year. Most of the surgeons reported a primary focus on hepato-pancreato-biliary surgery, and only 10% of effective work time was actually dedicated to perform transplant surgeries. The majority of respondents estimated their weekly work hours to be between 55 and 66 h. When asked about their career satisfaction and expectations, most respondents characterized their salaries as inappropriately low and their career prospects as inadequate. This survey provides a first impression of the transplant surgery work force in Germany. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury (IRI) is encountered in various stages during solid organ transplantation (SOT). IRI is known to be a multifactorial inflammatory condition involving hypoxia, metabolic stress, leukocyte extravasation, cellular death (including apoptosis, necrosis and necroptosis) and an activation of immune response. Although the cycle of sterile inflammation during IRI is consistent among different organs, the underlying mechanisms are poorly understood. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be crucial in the implementation of necroptosis. Moreover, apart from "silent" apoptotic death, necrosis also causes sterile inflammation—necroinflammation, which is triggered by various damage-associated molecular patterns (DAMPs). Those DAMPs activate the innate immune system, causing local and systemic inflammatory responses, which can result in graft failure. In this overview we summarize knowledge on mechanisms of sterile inflammation processes during SOT with special focus on necroptosis and IRI and discuss protective strategies. [ABSTRACT FROM AUTHOR]

Cell transplantation is a treatment option for diabetes, metabolic liver disease in children, and leukemia. Except for the latter indication, solid organ transplantation is one of the available therapies but can be replaced by cell transplantation. However, due to the limited amount of cells that can be transplanted and due to rejection, results of cell transplants are still inferior to solid organ transplantation; there is a general shortage of donor organs, and cell isolation is limited to organs which cannot be transplanted as a whole for anatomic reasons. Therefore, alternatives to islets and beta cells are needed. There are some cells which can be generated from the recipient and would not be rejected; still, immunosuppression would be required to prevent reoccurrence of type I diabetes unless durable tolerance to beta cells could be induced. Generating beta cells for transplant from the recipient would help to overcome the lack of available organs. Moreover, understanding the underlying mechanisms of differentiation of these cells into beta-like cells would deepen our understanding of both pathophysiology and development of diabetes mellitus type I. This article examines embryonal stem cells, induced pluripotent cells, mesenchymal stromal cells, and hepatocytes as potential alternatives to beta-cell transplantation. [ABSTRACT FROM AUTHOR]

Although extended donor criteria grafts bear a higher risk of complications such as graft dysfunction, the exceeding demand requires to extent the pool of potential donors. The risk of complications is highly associated with ischemia-reperfusion injury, a condition characterized by high loads of oxidative stress exceeding antioxidative defense mechanisms. The antioxidative properties, along with other beneficial effects like anti-inflammatory, antiapoptotic or antiarrhythmic effects of several micronutrients and natural compounds, have recently emerged increasing research interest resulting in various preclinical and clinical studies. Preclinical studies reported about ameliorated oxidative stress and inflammatory status, resulting in improved graft survival. Although the majority of clinical studies confirmed these results, reporting about improved recovery and superior organ function, others failed to do so. Yet, only a limited number of micronutrients and natural compounds have been investigated in a (large) clinical trial. Despite some ambiguous clinical results and modest clinical data availability, the vast majority of convincing animal and in vitro data, along with low cost and easy availability, encourage the conductance of future clinical trials. These should implement insights gained from animal data. [ABSTRACT FROM AUTHOR]

Background: Health-related quality of life (HrQoL) and workability are related parameters to measure success of therapy. Both have been insufficiently explored in patients after liver transplantation (LT). Particularly little is known about patients' attitude to return to work, employment status before LT, and how frequently there is any employment at any time after LT. Methods: This is a single-center retrospective cohort study including 150 adult outpatients after LT. Liver transplantations had been performed between 1993 and 2018. The study was carried out from February to July 2018. The exclusion criteria were combined transplantations, positive screening for current alcohol abuse, and anxiety or depression. To evaluate HrQoL and fitness to work, the patients were tested using the Short Form 36, the Chronic Liver Disease Questionnaire, and the Work Ability Index. Key results: The return rate of sufficiently filled-in questionnaires was 46.8% (66 patients). The mean age of patients was 59.9 years (SD=10.8), ranging from 25 to 78 years old. HrQoL was partly comparable to the normal population. Workability sum scores with a mean value of 31.61 (SD 9.79) suggested moderate workability at present. While only 28.8% of respondents were ever employed after LT, 45.5% currently wished to work or would have wished to work. Conclusions: HRQL seems to be partly similar to population data, and subjective workability seems to be moderate in patients after LT. Despite a positive attitude to return to work in almost half of respondents, a lower rate of actual return to work was found in this study. [ABSTRACT FROM AUTHOR]

In recent decades, solid organ transplantation (SOT) has increased the survival and quality of life for patients with end-stage organ failure by providing a potentially long-term treatment option. Although the availability of organs for transplantation has increased throughout the years, the demand greatly outweighs the supply. One possible solution for this problem is to extend the potential donor pool by using extended criteria donors. However, organs from such donors are more prone to ischemia reperfusion injury (IRI) resulting in higher rates of delayed graft function, acute and chronic graft rejection and worse overall SOT outcomes. This can be overcome by further investigating donor preconditioning strategies, graft perfusion and storage and by finding novel therapeutic agents that could reduce IRI. relaxin (RLX) is a peptide hormone with antifibrotic, antioxidant, anti-inflammatory and cytoprotective properties. The main research until now focused on heart failure; however, several preclinical studies showed its potentials for reducing IRI in SOT. The aim of this comprehensive review is to overview currently available literature on the possible role of RLX in reducing IRI and its positive impact on SOT [ABSTRACT FROM AUTHOR]

Background: Organ preservation before transplantation is still a challenge. Both the University of Wisconsin and Bretschneider's histidine-tryptophan-ketoglutarate (HTK; Custodiol®) solution are standard for liver, kidney and pancreas preservation. Organ preservation with both solutions is comparable; recently, however, Custodiol® solution has been modified to Custodiol-N according to the needs of today. Thus, our study was defined to study its effect in clinical transplantation.Methods: Patients undergoing kidney transplantation (n = 412) (including approximately 30 combined kidney-pancreas) or liver transplantation (n = 202) receive grafts that have been cold stored in either Custodiol® or Custodiol-N to demonstrate noninferiority of Custodiol-N regarding both graft function and graft injury after transplantation.Discussion: Preclinical data have clearly shown that Custodiol-N is superior to Custodiol® in cold static organ preservation via mechanisms including inhibition of hypoxic cell injury, cold-induced cell injury and avoidance of adverse effects during warm exposure to the solution. Further clinical safety data on Custodiol-N for cardioplegia are available. Thus, this study was designed to compare Custodiol® with Custodiol-N for the first time in a prospective, randomized, single-blinded, multicentre, phase III clinical transplantation trial.Trial Registration: Eudra-CT, 2017-002198-20. Registered on 28 November 2018. [ABSTRACT FROM AUTHOR]

The perinatal management of newborns with giant omphaloceles requires careful suspicion concerning 'unexpected' associated malformations. We describe a newborn with a combination of incomplete Pentalogy of Cantrell consisting of giant omphalocele, anterior congenital diaphragmatic hernia (CDH) and pericardial absence complicated by a hepatic rapidly involuting congenital hemangioma (RICH). A giant omphalocele was detected prenatally. Postnatally, staged closure of the omphalocele was planned. A mass of the liver was noted and (mis-)taken for a hematoma. In the further course, the baby developed cardiorespiratory insufficiency due to a central CDH which was excised. Subsequently, staged closure of the omphalocele became impossible. Specific workup revealed a mass in the left liver lobe. The mass was resected and the abdominal wall defect repaired. Histology confirmed the diagnosis of an RICH. The surgical treatment of newborns with giant omphaloceles requires a multidisciplinary neonatal support and an elaborate pediatric surgical armamentarium to cope with additional malformations. [ABSTRACT FROM AUTHOR]

Donor preconditioning with glycine prevents Kupffer cell-dependent reperfusion injury to liver grafts. Partial liver grafts need to regenerate and grow in size after transplantation; however, glycine inactivates Kupffer cells, which are important for hepatic regeneration. Thus, this study was designed to evaluate the impact of donor preconditioning with glycine after partial liver transplantation (pLTx). PLTx was performed in 28 female Sprague–Dawley rats. Glycine (1.5 ml, 300 mM; i.v.) was given to 14 live donors before organ procurement. Liver enzymes and histology were investigated 8 h after reperfusion to index liver injury and leukocyte infiltration. Hepatic microperfusion and leukocyte–endothelium interaction were assessed using the in vivo fluorescence microscopy method. Ki-67 and TNF-α were detected by immunohistochemistry for regeneration and Kupffer cell activation. Glycine significantly increased survival from 0% in controls to 40%, while both liver enzyme levels and necrosis were decreased to about 50% of controls (p < 0.05). Sinusoidal blood flow increased by 40–80%, while leukocyte–endothelium interaction decreased to 30% of control values (p < 0.05). While Kupffer cell-derived TNF-α decreased to 70% of controls, there was no difference between groups in Ki-67 expression. Data presented here clearly demonstrate that glycine protects partial liver grafts from reperfusion injury without effects on regeneration. [ABSTRACT FROM AUTHOR]

Background: Experimental pneumoperitoneum induces ischemia/reperfusion injury (IRI) in the liver, most likely via Kupffer cell (KC)-dependent mechanisms. Glycine has been shown to ameliorate IRI in various animal models. Thus, this study was performed to assess the effects of glycine on the liver after pneumoperitoneum. Materials and Methods: Sprague-Dawley rats (220–250 g in weight) underwent CO2 pneumoperitoneum (12 mm Hg) for 90 min. Some rats received i.v. glycine (1.5 mL, 300 mM) 10 min before pneumoperitoneum. Controls were given the same volume of Ringer’s solution. Transaminases, hepatic microcirculation, and phagocytosis of latex beads indexing both liver injury and KC activation were examined following pneumoperitoneum. Analysis of variance (ANOVA), plus a subsequent t test or χ2 test (or Fisher’s exact test) were carried out as appropriate. Results are presented as mean ± SEM. Results: Glycine significantly decreased lactate dehydrogenase at 1 h and both aspartate aminotransferase and alanine aminotransferase at 2 h after pneumoperitoneum from 477 ± 43, 154 ± 17, and 60 ± 6 U/L in controls to 348 ± 25, 101 ± 11, and 34 ± 3 U/L, respectively (p < 0.05). In parallel, glycine significantly decreased both the rate of permanent adherence of leukocytes to the endothelium by up to 35% and the rate of phagocytosis by > 50% compared to the control group. Conclusion: Glycine decreased IRI after pneumoperitoneum, most likely via KC-dependent mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Liver grafts are allocated based on both urgency and utility. Due to a tremendous shortage of suitable organs for liver transplantation (LT), a careful selection of suitable recipients is of utmost importance. While the sickest first principle for organ allocation based on MELD score goes along with poor utility, other parameters reflecting the general health condition like frailty and sarcopenia might be essential to detect suitable patients for the waiting list. Thus, this study was designed to evaluate both frailty and sarcopenia in LT. A systematic review of the literature on sarcopenia and frailty measurements in liver transplant recipients was performed. Thirteen of 238 studies were selected for full paper review. Six of the studies investigating the impact of frailty on waitlist mortality were subjected to a meta‐analysis. Despite the different methodologies to assess sarcopenia, reports showed that sarcopenia was highly related to waitlist mortality with a sum of all that highly favored negative outcome in case of sarcopenia. The existing literature clearly underlines that frailty and sarcopenia are important to determine in LT candidates. One unique index for transplant candidates reflecting frailty should be developed and be used as a standard in all transplant centers to facilitate comparability. [ABSTRACT FROM AUTHOR]

Melatonin has been shown to exert anticancer activity on hepatocellular carcinoma ( HCC) through its antiproliferative and pro-apoptotic effect in both experimental and clinical studies, and sorafenib is the only approved drug for the systemic treatment of HCC. Thus, this study was designed to investigate the combined effect of melatonin and sorafenib on proliferation, apoptosis, and its possible mechanism in human HCC. Here, we found that both melatonin and sorafenib resulted in a dose-dependent growth inhibition of HuH-7 cells after 48 hours treatment, and the combination of them enhanced the growth inhibition in a synergistic manner. Colony formation assay indicated that co-treatment of HuH-7 cells with melatonin and sorafenib significantly decreased the clonogenicity compared to the treatment with single agent. Furthermore, FACS and TUNEL assay confirmed that melatonin synergistically augmented the sorafenib-induced apoptosis after 48 hours incubation, which was in accordance with the activation of caspase-3 and the JNK/c-jun pathway. Inhibition of JNK/c-jun pathway with its inhibitor SP600125 reversed the phosphorylation of c-jun and the activation of caspase-3 induced by co-treatment of HuH-7 cells with melatonin and sorafenib in a dose-dependent manner. Furthermore, SP600125 exhibited protective effect against apoptosis induced by the combination of melatonin and sorafenib. This study demonstrates that melatonin in combination with sorafenib synergistically inhibits proliferation and induces apoptosis in human HCC cells; therefore, supplementation of sorafenib with melatonin may serve as a potential therapeutic choice for advanced HCC. [ABSTRACT FROM AUTHOR]

Summary Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Neo-angiogenesis is important for tumor growth. Glycine is a non-toxic amino acid with suspected anti-angiogenic effects. This study was designed to evaluate anti-angiogenic effects of glycine in colorectal cancer. Glycine was added to cultures of human and rat colorectal cancer cells (CRC), and endothelial cells (HUVEC). Glycine's direct impact was monitored using MTT assays. Angiogenesis in HUVEC was monitored using 3D sprouting and migration assays. VEGF and CRC-conditioned media were used to stimulate angiogenesis. The glycine receptor (GlyR) was detected using Western blotting and inhibited using strychnine. The WAG-Rij/CC-531 model of metastatic CRC was used to evaluate glycine's impact in vivo. Tumor growth and vessel density were monitored in rats fed with or without 5 % glycine for 14 days. VEGF and conditioned media significantly increased proliferation, migration, and capillary formation to up to 267 %. Glycine completely neutralized this effect and strychnine completely blunted glycine's effect. GlyR was detected in HUVEC. Tumor volume, weight, and vessel density decreased by 35 % ( p = 0.02), 34 % ( p = 0.03), and 55 % ( p = 0.04) in glycine-fed animals. Glycine inhibits angiogenic signaling of endothelial cells and tumor growth. Glycine would be a promising additive to standard and targeted cancer therapies. [ABSTRACT FROM AUTHOR]

Background Therapeutic options to treat progression of end-stage liver disease (ESLD) or improve long-term survival after liver transplantation remain scarce. We investigated the impact of coffee consumption under these conditions. Methods We recorded coffee consumption habits of 379 patients with ESLD awaiting liver transplantation and 260 patients after liver transplantation. Survival was analyzed based on coffee intake. Results One hundred ninety-five patients with ESLD consumed coffee on a daily basis, while 184 patients did not. Actuarial survival was impaired ( P = 0.041) in non-coffee drinkers (40.4 ± 4.3 months, 95% confidence interval [CI]: 32.0-48.9) compared with coffee drinkers (54.9 ± 5.5 months, 95% CI: 44.0-65.7). In subgroup analysis, the survival of patients with alcoholic liver disease (ALD; P = 0.020) and primary sclerosing cholangitis (PSC; P = 0.017) was increased with coffee intake while unaffected in patients with chronic viral hepatitis ( P = 0.517) or other liver disease entities ( P = 0.652). Multivariate analysis showed that coffee consumption of PSC and ALD patients retained as an independent risk factor (odds ratio [OR]: 1.94; 95% CI: 1.15-3.28; P = 0.013) along with MELD score (OR: 1.13; 95% CI: 1.09-1.17; P = 0.000). Following liver transplantation, long-term survival was longer in coffee drinkers (coffee: 61.8 ± 2.0 months, 95% CI: 57.9-65.8) than non-drinkers (52.3 ± 3.5 months, 95% CI: 45.4-59.3; P = 0.001). Conclusions Coffee consumption delayed disease progression in ALD and PSC patients with ESLD and increased long-term survival after liver transplantation. We conclude that regular coffee intake might be recommended for these patients. [ABSTRACT FROM AUTHOR]

Background The 12-month (M) PROTECT study showed that de novo liver transplant recipients ( LTxR) who switched from a calcineurin inhibitor ( CNI)-based immunosuppression to a CNI-free everolimus ( EVR)-based regimen showed numerically better renal function. Here, we present the five-yr follow-up data. Methods PROTECT was a randomized controlled study in which LTxR received basiliximab and CNI-based immunosuppression ± corticosteroids. Patients were randomized 1:1 to receive EVR or continue CNI. Patients completing the core study could enter the extension study on their randomized treatment. Results A total of 81 patients entered the extension study (41, EVR; 40, CNI). At M59 post-randomization, the adjusted mean eGFR was significantly higher in the EVR group, with a benefit of 12.4 mL/min using Cockcroft-Gault (95% CI: 1.2; 23.6; p = 0.0301). Also, there was a significant benefit for adjusted and unadjusted eGFR using the four-variable Modification of Diet in Renal Disease ( MDRD4) or Nankivell formula. During the extension period, treatment failure rates were similar. SAEs occurred in 26 (63.4%) and 28 (70.0%) of the patients in EVR and CNI groups, respectively. Conclusion Compared with the CNI-based treatment, EVR-based CNI-free immunosuppression resulted in significantly better renal function and comparable patient and graft outcomes after five-yr follow-up. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal malignancies and resistance to chemotherapy prevents the therapeutic outcome. MicroRNAs provide a novel therapeutic strategy. Here, the established and primary human PDA cell lines PANC-1, AsPC-1, MIA-PaCa2, AsanPaCa, BxPC-3 and three gemcitabine-resistant subclones were examined. A gene expression profiling revealed that the ribonucleotide reductase M1 (RRM1) was upregulated in gemcitabine-resistant cells, which was confirmed by qRT-PCR, Western blot analysis and immunostaining. Inhibition of RRM1 by lipotransfection of siRNA reduced its expression and reversed gemcitabine resistance. The expression of RRM1 correlated to gemcitabine resistance in vitro and was higher in malignant patient pancreas tissue compared to non-malignant pancreas tissue. By microRNA expression profiling, we identified microRNA-101-3p as top-downregulated candidate. Lipotransfection of microRNA-101-3p mimics inhibited the expression of RRM1, reduced the luciferase activity of its 3'UTR and sensitized for gemcitabine-induced cytotoxicity. These results underline the relevance of microRNA-101-3p-driven regulation of RRM1 in drug resistance and suggest the co-delivery of microRNA-101-3p and gemcitabine for more effective therapy outcome. [ABSTRACT FROM AUTHOR]

Graft rinse prior reperfusion in liver transplantation ( LT) is believed to reduce the incidence of postreperfusion syndrome and improve clinical outcome. A MEDLINE search was performed to obtain a comprehensive review of the published literature dealing with graft rinse in LT. Moreover, all thirty-four LT centers in the Eurotransplant ( ET) region were invited to participate in an online survey to whether or not graft rinse is performed and whether further research in the field is needed. Seventeen reports have been found to investigate graft rinse protocols in 1894 LT recipients. Eighteen of the thirty centers that participated in the online survey performed graft rinse prior reperfusion in LT. The most commonly used rinse solution was albumin. Nineteen centers stated interest in participating in a multicenter RCT in the field. The published literature does not provide concluding appraisal of the benefit of graft rinse in LT. Graft rinse protocols are not standardized and are based on personal experience. Appropriately designed clinical trials addressing the topic are demanded. The online survey appears to be a helpful tool for the evaluation of clinical practice and future research topics in the transplant community. [ABSTRACT FROM AUTHOR]

Background Benign liver tumours represent a challenge in clinical management. There is considerable controversy with respect to the indications for surgery as the evidence for surgical treatment is variable. The aim of this retrospective study was to analyse the indication and outcome after resection of benign, solid liver lesions. Methods Data of 79 patients, who underwent liver resection between 2001 and 2012, were analysed for demographic and outcome parameters. Results Thirty-eight patients with focal nodular hyperplasia (48%), 23 patients with haemangioma (29%) and 18 patients with hepatocellular adenoma (23%) underwent a hepatic resection. A major hepatic resection was performed in 23 patients (29%) and a minor resection in 56 patients (71%). The post-operative mortality rate was zero and the 30-day morbidity rate 13.9%. After a median follow-up of 64 months, 75 patients (95%) were alive, and no patient had developed recurrent disease. Fifty-four patients (68%) were pre-operatively symptomatic, of which, 87% had complete or partial relief of symptoms after a liver resection. The incidence of symptoms increased with the lesions' size. Discussion The management of benign liver lesions necessitates an individualized therapy within a multidisciplinary, evidence-based, treatment algorithm. Resection of benign liver lesions can be performed safely in well-selected patients without mortality and low post-operative morbidity. [ABSTRACT FROM AUTHOR]

Purpose: Zinc is an important trace element with catalytic and defensive functions. We assessed the impact of zinc deficiency in patients with end-stage liver disease awaiting liver transplantation. Methods: Serum zinc levels were measured at the time of evaluation for liver transplantation ( n = 368). Patients were dichotomized in two groups based on low and normal zinc serum levels. Results: Serum zinc levels are tightly associated with liver function as patients with low zinc levels ( n = 226) had a higher Model for End-Stage Liver Disease (MELD) score (15.0 [5.0-40.0]) than patients with normal zinc ( n = 142) levels (9.0 [6.0-34.0]; p < 0.00). Multivariate analysis demonstrated that serum zinc levels function as an independent predictor of hepatic decompensation (hydropic decompensation: odds ratio [OR] 0.82; 95 % confidence interval [CI] 0.70-0.96; p = 0.015; hepatic encephalopathy: OR 0.80; 95 % CI 0.71-0.90; p = 0.000; spontaneous bacterial peritonitis: OR 0.85; 95 % CI 0.72-1.00; p = 0.047; hepatorenal syndrome: OR 0.83; 95 % CI 0.72-0.95; p = 0.011). Actuarial survival free of liver transplantation was reduced for low-zinc patients (26.7 ± 4.0 months; 95 % CI 18.8-34.6) compared to patients with normal zinc levels (30.9 ± 3.0 months; 95 % CI 24.9-36.9; p = 0.008). Reduction of zinc levels for patients on the transplantation list resulted in a 28.3-fold increased risk of death/liver transplantation (95 % CI 3.2-244.8, p < 0.001). Conclusions: Serum zinc levels are associated with reduced survival in end-stage liver disease patients. Whether or not zinc supplementation might be beneficial for patients on a liver transplantation list requires further study. [ABSTRACT FROM AUTHOR]