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Liver transplantation (LT) offers excellent long-term outcome for certain patients with hepatocellular carcinoma (HCC), with a push to not simply rely on tumor size and number. Selection criteria should also consider tumor biology (including alpha-fetoprotein), probability of waitlist and post-LT survival (ie, transplant benefit), organ availability, and waitlist composition. These criteria may be expanded for live donor LT (LDLT) compared to deceased donor LT though this should not adversely affect the double equipoise in LDLT, namely ensuring both acceptable recipient outcomes and donor safety. HCC patients with compensated liver disease and minimal tumor burden have low urgency for LT, especially after local-regional therapy with complete response, and do not appear to derive the same benefit from LT as other waitlist candidates. These guidelines were developed to assist in selecting appropriate HCC patients for both deceased donor LT and LDLT.

The aim of this study was to investigate the impact of hypoxia and hypotension during the agonal phase of donor warm ischemia time (DWIT) on hepatic ischemia/reperfusion injury (IRI) and complications in donation after circulatory death (DCD) liver transplantation. A retrospective single-center study of 93 DCD liver transplants (Maastricht type III) was performed. DWIT was divided into 2 periods: the agonal phase (from withdrawal of treatment [WoT] until circulatory arrest) and the asystolic phase (circulatory arrest until cold perfusion). A drop to <80% in peripheral oxygenation (SpO 2 ) was considered as hypoxia in the agonal phase (SpO 2 -agonal) and a drop to <50 mm Hg as hypotension in the agonal phase (SBP-agonal). Peak postoperative aspartate transaminase level >3000 U/L was considered as severe hepatic IRI. SpO 2 dropped within 2 minutes after WoT <80%, whereas the systolic blood pressure dropped to <50 mm Hg after 9 minutes, resulting in a longer SpO 2 -agonal (13 minutes) than SBP-agonal (6 minutes). In multiple logistic regression analysis, only duration of SpO 2 -agonal was associated with severe hepatic IRI (P = 0.006) and not SBP-agonal (P = 0.32). Also, recipients with long SpO 2 -agonal (>13 minutes) had more complications with a higher Comprehensive Complication Index during hospital admission (43.0 versus 32.0; P = 0.002) and 90-day graft loss (26% versus 6%; P = 0.01), compared with recipients with a short SpO 2 -agonal (≤13 minutes). Furthermore, Cox proportional hazard modeling identified a long SpO 2 -agonal as a risk factor for longterm graft loss (hazard ratio, 3.30; 95% confidence interval, 1.15-9.48; P = 0.03). In conclusion, the onset of hypoxia during the agonal phase is related to the severity of hepatic IRI and postoperative complications. Therefore, SpO 2 <80% should be considered as the start of functional DWIT in DCD liver transplantation., (© 2018 The Authors. Liver Transplantation published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Liver transplant outcome has improved considerably as a direct result of optimized surgical and anesthesiological techniques and organ allocation programs. Because there remains a shortage of human organs, strict selection of transplant candidates remains of paramount importance. Recently, computed tomography (CT)-assessed low skeletal muscle mass (i.e. sarcopenia) was identified as a novel prognostic parameter to predict outcome in liver transplant candidates. A systematic review and meta-analysis on the impact of CT-assessed skeletal muscle mass on outcome in liver transplant candidates were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Nineteen studies, including 3803 patients in partly overlapping cohorts, fulfilled the inclusion criteria. The prevalence of sarcopenia ranged from 22.2% to 70%. An independent association between low muscle mass and posttransplantation and waiting list mortality was described in 4 of the 6 and 6 of the 11 studies, respectively. The pooled hazard ratios of sarcopenia were 1.84 (95% confidence interval 1.11-3.05, p = 0.02) and 1.72 (95% confidence interval 0.99-3.00, p = 0.05) for posttransplantation and waiting list mortality, respectively, independent of Model for End-stage Liver Disease score. Less-consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients. In conclusion, sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Transplant surgery is facing a shortage of deceased donor organs. In response, the criteria for organ donation have been extended, and an increasing number of organs from older donors are being used. For recipients, the benefits of transplantation are great, and the growing ageing population has led to increasing numbers of elderly patients being accepted for transplantation., Methods: The literature was reviewed to investigate the impact of age of donors and recipients in abdominal organ transplantation, and to highlight aspects of the fine balance in donor and recipient selection and screening, as well as allocation policies fair to young and old alike., Results: Overall, kidney and liver transplantation from older deceased donors have good outcomes, but are not as good as those from younger donors. Careful donor selection based on risk indices, and potentially biomarkers, special allocation schemes to match elderly donors with elderly recipients, and vigorous recipient selection, allows good outcomes with increasing age of both donors and recipients. The results of live kidney donation have been excellent for donor and recipient, and there is a trend towards inclusion of older donors. Future strategies, including personalized immunosuppression for older recipients as well as machine preservation and reconditioning of donor organs, are promising ways to improve the outcome of transplantation between older donors and older recipients., Conclusion: Kidney and liver transplantation in the elderly is a clinical reality. Outcomes are good, but can be optimized by using strategies that modify donor risk factors and recipient co-morbidities, and personalized approaches to organ allocation and immunosuppression., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Chronic hepatitis C virus (HCV) infection compromises long-term outcomes of liver transplantation. Although glucocorticosteroid-based immunosuppression is commonly used, discussion is ongoing on the effect of prednisolone (Pred) on HCV recurrence and response to antiviral therapy post transplantation. Recently, new drugs (direct-acting antivirals) have been approved for the treatment of HCV, however, it remains unknown whether their antiviral activity is affected by Pred. The aim of this study was to investigate the effects of Pred on the antiviral activity of asunaprevir (Asu), daclatasvir (Dac), ribavirin (RBV), and interferon-alpha (IFN-α), and on plasmacytoid dendritic cells (PDCs), the main IFN-α-producing immune cells., Methods: The effects of Pred and antiviral compounds were tested in both a subgenomic and infectious HCV replication model. Furthermore, effects were tested on human PDCs stimulated with a Toll-like receptor-7 ligand., Result: Pred did not directly affect HCV replication and did not inhibit the antiviral action of Asu, Dac, RBV, or IFN-α. Stimulated PDCs potently suppressed HCV replication. This suppression was reversed by treating PDCs with Pred. Pred significantly decreased IFN-α production by PDCs without affecting cell viability. When Asu and Dac were combined with PDCs, a significant cooperative antiviral effect was observed., Conclusion: This study shows that Pred acts on the antiviral function of PDCs. Pred does not affect the antiviral action of Asu, Dac, RBV, or IFN-α. This implies that there is no contraindication to combine antiviral therapies with Pred in the post-transplantation management of HCV recurrence., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In experimental animals inhibition of T cell co-stimulation immediately after organ transplantation effectively prevents rejection. We investigated whether the expression of co-stimulatory molecules is enhanced in cadaveric liver transplants, whether their expression is influenced by the transplantation procedure, and whether variation in expression between liver transplants is related to the occurrence of acute rejection. Expression of CD80, CD86 and the macrophage marker CD68 were determined by immunohistochemistry in biopsies from 40 clinical liver transplants obtained at different time-points during the transplantation procedure, and in normal liver tissue obtained from 10 human livers. Expression of CD80 and CD86 on Kupffer cells was graded by comparison with CD68-staining. In a subgroup CD80 and CD86 mRNA was quantified by real-time detection polymerase chain reaction. CD86 was expressed in all liver transplants and normal livers on the majority of Kupffer cells. CD80 was absent or sporadically expressed in normal liver tissue, but in 18 of 40 liver transplants at least one-quarter of Kupffer cells expressed CD80. CD80- and CD86-mRNA and protein expression in liver transplants did not change during the warm ischaemic and reperfusion phases of the transplantation procedure. CD80-expression on Kupffer cells varied strongly between individual donor livers; this variation was, however, not significantly related to the occurrence of acute rejection after transplantation. In conclusion, in nearly half of cold-preserved cadaveric liver transplants an increased proportion of Kupffer cells express CD80 at the time of transplantation in comparison with normal liver tissue. The expression was not further induced by warm ischaemia and reperfusion. However, the observed variation in CD80-expression between liver transplants is not a accurate predictive measure for acute rejection.

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intra-operative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband. Metabolic correction was initially seen in all groups, but ligation led to portal hypertension and early mortality. In the free-flow group, correction was lost after 7 days, while banding preserved correction until 6 weeks. We conclude that acute ligation can lead to portal hypertension and free-flow leads to hypoperfusion and early loss of metabolic correction. Banding divided the portal blood flow between host liver and graft and prolonged metabolic correction., (Copyright 2003 S. Karger AG, Basel)

Individuals may differ in their capacity to produce cytokines. Since cytokines play a key role in allograft rejection, we investigated whether inter-individual differences in cytokine production by in vitro stimulated PBMC are related to the occurrence of acute liver transplant rejection. Our study group comprised 49 liver transplant recipients and 30 healthy individuals. Rejection, which occurred within one month after liver transplantation, was defined in 22 patients ("rejectors") as biopsy-proven rejection, treated with high dose prednisolone. Patients who never experienced rejection episodes were termed as "nonrejectors" (n=27). PBMC of healthy individuals and of liver transplant recipients, collected late after transplantation (mean 3.5 years), were cultured in the presence and absence of Concanavalin A. The production of TNF-alpha, IFN-gamma, IL-10, and IL-13 was measured in supernatant after 1, 2, 3, 4, and 7 days of cell culture. In cell culture, stimulated PBMC of rejectors were found to produce significantly higher levels of TNF-alpha, while there was a trend towards higher production of IFN-gamma and IL-10 as compared to nonrejectors. After grouping patients into high or low cytokine producers based upon reference levels of the healthy individuals using multivariate analysis it was found that occurrence of acute liver transplant rejection correlated to high production of TNF-alpha and low production of IL-13. After stimulated cell culture PBMC of liver transplant recipients show a differential production of TNF-alpha and IL-13 which is correlated with the occurrence of acute liver transplant rejection.

Little is known about costs and cost-effectiveness of liver transplantation (LTx) for acute liver failure compared to costs and cost-effectiveness of LTx for chronic liver failure. In this study, costs of acute and of chronic LTx patients were determined in a retrospective study. Files of 100 consecutive patients who underwent LTx in 1993-1997 were studied. Costs up to 1 year after LTx were Euro 107,675 (chronic liver failure) and Euro 90,792 (acute liver failure). The difference was mainly caused by higher hospitalisation costs and higher personnel costs for chronic liver failure. Medication costs for acute liver failure were higher, due to a high administration rate of expensive anti-HBs immunoglobulin therapy in patients with viral hepatitis B. LTx for chronic liver failure is more costly and seems to be more cost-effective than LTx for acute liver failure, since 1-year survival is higher in patients who underwent transplantation for chronic liver failure.

Background: Auxiliary partial orthotopic liver transplantation (APOLT) has successfully been performed in patients with noncirrhotic metabolic diseases. It remains, however, unclear if intervention in the portal venous inflow is necessary to ensure adequate portal blood flow to graft and host liver. In this experimental study we evaluate the hepatic flow during APOLT., Methods: Left lateral/medial segmental grafts were transplanted from beagle to dalmatian dogs. Vascular structures were anastomosed end-to-end. The effect of diversion of the portal flow was studied in three groups: in the ligation group (n=3) the host portal vein was tied off, the free flow group (n=6) had random flow to both livers. In the banding group (n=11) the host portal vein was banded with a adjustable strapband to restore the pretransplantation flow distribution., Results: After reperfusion the blood flow through the common portal vein decreased from 49 to 36 ml/kg/min (P<0.03) in all animals. Flow through the left portal vein decreased from 26 to 5 ml/kg/min (P<0.0001). Banding restored the flow in the left portal vein to 12 ml/kg/min, although the flow in the free-flow group remained 4 ml/kg/min. In the ligation group the total portal flow was forced toward the graft leading to the highest perfusion: 24 ml/kg/min (P<0.005). Adverse effect of this ligation was the development of portal hypertension., Conclusions: This experimental study confirms that diversion of the portal flow is necessary for adequate graft perfusion in APOLT. Banding can restore the pretransplantation flow distribution, without compromising the flow in the common portal vein.

We reported previously that no classical features of hyperacute rejection (HAR) could be found in liver grafts in the guinea-pig (GP)-to-rat model and that recipients died shortly after transplantation of non-immunologic causes. Thus, the GP-to-rat model is not suitable for studying the mechanisms of discordant liver xenograft rejection. In the hamster to rat model, long-term survival of a liver graft is possible, but extremely low levels of xenoreactive natural antibodies are present. To mimic a discordant situation with pre-formed IgM and IgG antibodies, we sensitized rats 1 or 5 weeks before grafting. Specific anti-hamster IgM antibodies were found in recipients sensitized at week -1 but not week -5. Anti-hamster IgG was present in all recipients, albeit considerably higher in animals sensitized 5 weeks before grafting. In these two models, we examined the mechanism of HAR of liver grafts and compared this with heart xenografts. Control heart and liver grafts were rejected 4 and 7 days after transplantation respectively. Liver grafts in recipients sensitized at week -5 showed venous congestion and bleeding after reperfusion, indicating HAR, however this was not observed after sensitization at week -1. This surprising finding was confirmed by histology. Massive extravasation, edema, and acute liver cell degradation were noticed in grafts subjected to HAR. Liver grafts of recipients sensitized at week -1 showed only minimal changes. Heart grafts were rejected hyperacutely in both sensitization models. IgG antibodies could be detected on liver grafts in the group sensitized at week -5 but not in the group sensitized at week -1. Minimal IgM depositions were found on liver grafts of animals sensitized 1 week before grafting. Rejected heart grafts from similar sensitization groups showed identical antibody depositions; only IgM depositions were massive. Complement depositions were found in all groups. These results indicate that IgG, but not IgM, mediates HAR in hepatic xenografting. Such a predominance of IgG over IgM does not exist for heart grafts.

To study T-cell/macrophage interactions at the molecular level in clinical allograft rejection, we measured intragraft mRNA expression of the T-cell derived cytokine IL-2 and the macrophage derived chemokine IL-15, a novel cytokine associated with T-cell activation, in post-transplant liver biopsies (n = 33) and in non-transplanted control liver tissue by reverse transcriptase-polymerase chain reaction (RT-PCR). We analyzed biopsies without evidence of rejection (n = 12), with spontaneously resolving histological rejection (n = 10), or with histological rejection accompanied with clinical rejection (n = 11) defined by rising serum bilirubin and aspartate amino transaminase levels. IL-15 mRNA expression was present in the majority of post-transplant liver biopsies (91%, 30/33) and was significantly upregulated as compared with non-transplanted liver tissue (p = 0.005). However, the increased intragraft IL-15 mRNA level was not indicative for rejection. In contrast to intragraft IL-15 mRNA expression, IL-2 mRNA transcription was measured in the minority of the post-transplant liver biopsies (15%, 5/33) and not detectable in control specimens. In addition, IL-2 mRNA was almost specifically measured in rejection biopsies concurrent with graft dysfunction (36%, 4/11 versus 1/22 without clinical rejection; p = 0.03). No relation between intragraft IL-2 and IL-15 mRNA expression was found. The IL-15 mRNA expression levels were not higher in the IL-2 negative rejections compared with those in IL-2 positive rejections. To conclude, in contrast to IL-2, the function of IL-15 in T-cell mediated rejection remains unclear. The overall high IL-15 mRNA levels in sites of immune responses suggests that the macrophage-derived mediator IL-15 is involved in a constant flow of T-cells from the circulation into the graft.

The objective of this study was to develop an animal model to evaluate the biology of hepatocellular carcinoma (HCC) recurrence after liver transplantation. HCC was induced in Brown Norway (BN) rats (n = 45) by diet-hylnitrosamine (DEN) administered continuously through the drinking water. Starting from day 14, rats were sequentially autopsied or syngeneically transplanted according to Kamada's cuff technique. After 74 days of DEN administration, neoplastic liver lesions appeared and after a mean of 102 days (SD +/- 6) the animals died of abdominal haemorrhage from liver tumours. At this time lung metastases were present in three-fifths animals. Transplantation success was dependent on the DEN consumption and thereby the tumour stadium. After 74 days of DEN administration BN rats could no longer be transplanted because of anaesthetic problems or technical problems due to tumour adhesion to surrounding tissues. No recurrence was found in the transplants. In conclusion, we believe that timing of the operation in this HCC model is essential because the physical condition of the animals prohibits orthotopic liver transplantation in an advanced tumour stage. With a different DEN dosage scheme this problem may be solved.

Objective: Evaluation of the results of emergency liver transplantation in patients with acute liver failure., Design: Analysis of 25 patients with acute liver failure., Setting: University Hospital Rotterdam Dijkzigt., Method: Twenty-five patients with acute liver failure were admitted to the Intensive Care Unit in January 1989-May 1993. Patients were selected for emergency liver transplantation according to the Clichy criteria (presence of confusion or coma and factor V activity less than 20-30%)., Results: Liver transplantation was indicated in 17 patients and performed in 13. The 1-year survival rate in patients with a liver transplant was 85%. Four patients with an indication for liver transplantation, but who could not be transplanted died. All 8 patients without an indication for emergency liver transplantation survived., Conclusion: Survival after liver transplantation for acute hepatic failure is now about 80%; the Clichy criteria appear to be helpful in selecting patients with acute hepatic failure for liver transplantation.

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intraoperative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband. Metabolic correction was initially seen in all groups, but ligation led to portal hypertension and early mortality. In the freeflow group, correction was lost after 7 days, while banding preserved correction until 6 weeks. We conclude that acute ligation can lead to portal hypertension and freeflow leads to hypoperfusion and early loss of metabolic correction. Banding divided the portal blood flow between host liver and graft and prolonged metabolic correction. [ABSTRACT FROM AUTHOR]