Decreased Long-Term Severe Acute Respiratory Syndrome Coronavirus 2-Specific Humoral Immunity in Liver Transplantation Recipients 12 Months After Coronavirus Disease 2019.

Long-term humoral immunity and its protective role in liver transplantation (LT) patients have not been elucidated. We performed a prospective multicenter study to assess the persistence of immunoglobulin G (IgG) antibodies in LT recipients 12 months after coronavirus disease 2019 (COVID-19). A total of 65 LT recipients were matched with 65 nontransplanted patients by a propensity score including variables with recognized impact on COVID-19. LT recipients showed a lower prevalence of anti-nucleocapsid (27.7% versus 49.2%; P = 0.02) and anti-spike IgG antibodies (88.2% versus 100.0%; P = 0.02) at 12 months. Lower index values of anti-nucleocapsid IgG antibodies were also observed in transplantation patients 1 year after COVID-19 (median, 0.49 [interquartile range, 0.15-1.40] versus 1.36 [interquartile range, 0.53-2.91]; P < 0.001). Vaccinated LT recipients showed higher antibody levels compared with unvaccinated patients (P < 0.001); antibody levels reached after vaccination were comparable to those observed in nontransplanted individuals (P = 0.70). In LT patients, a longer interval since transplantation (odds ratio, 1.10; 95% confidence interval, 1.01-1.20) was independently associated with persistence of anti-nucleocapsid IgG antibodies 1 year after infection. In conclusion, compared with nontransplanted patients, LT recipients show a lower long-term persistence of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, SARS-CoV-2 vaccination after COVID-19 in LT patients achieves a significant increase in antibody levels, comparable to that of nontransplanted patients.

Similar Results in Liver Transplantation From Controlled Donation After Circulatory Death Donors With Normothermic Regional Perfusion and Donation After Brain Death Donors: A Case-Matched Single-Center Study.

Although good results have been reported with the use of normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation (LT), there is a lack of evidence to demonstrate similar results to donation after brain death (DBD). We present a single-center retrospective case-matched (1:2) study including 100 NRP cDCD LTs and 200 DBD LTs and a median follow-up of 36 months. Matching was done according to donor age, recipient Model for End-Stage Liver Disease score, and cold ischemia time. The following perioperative results were similar in both groups: alanine transaminase peaks of 909 U/L in the DBD group and 836 U/L in the cDCD group and early allograft disfunction percentages of 21% and 19.2%, respectively. The 1-year and 3-year overall graft survival for cDCD was 99% and 93%, respectively, versus 92% and 87%, respectively, for DBD (P = 0.04). Of note, no cases of primary nonfunction or ischemic-type biliary lesion were observed among the cDCD grafts. Our results confirm that NRP cDCD LT meets the same outcomes as those obtained with DBD LT and provides evidence to support the idea that cDCD donors per se should no longer be considered as "marginal donors" when recovered with NRP.

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients.

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case-control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17-83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03-1.36), and therapy with renin-angiotensin-aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47-34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.

Favorable Outcomes After Liver Transplantation With Normothermic Regional Perfusion From Donors After Circulatory Death: A Single-center Experience.

BACKGROUND: Controlled donation after circulatory death (cDCD) has been associated with a high incidence of ischemic cholangiopathy and other perioperative complications. In an attempt to avoid these complications, we implemented an active protocol of cDCD liver transplant (LT) with normothermic regional perfusion (NRP) preservation. METHODS: This is a descriptive analysis of data collected from a prospective date base of cDCD LT preserved with NRP from January 2015 to June 2017 with a minimum follow up of 9 months. RESULTS: Fifty-seven potential cDCD donors were connected to the NRP system. Of these, 46 livers were transplanted over a 30-month period (80% liver recovery rate). The median posttransplant peak in alanine transaminase was 1136 U/L (220-6683 U/L). Seven (15%) patients presented postreperfusion syndrome and 11 (23%) showed early allograft dysfunction. No cases of ischemic cholangiopathy were diagnosed, and no graft loss was observed over a medium follow-up period of 19 months. Of note, 13 donors were older than 65 years, achieving comparable perioperative and midterm results to younger donors. CONCLUSIONS: As far as we know, this represents the largest published series of cDCD LT with NRP preservation. Our results demonstrate that cDCD liver grafts preserved with NRP appear far superior to those obtained by the conventional rapid recovery technique.

Neutrophil-to-lymphocyte ratio predicts survival in European patients with hepatocellular carcinoma administered sorafenib.

Neutrophil-to-lymphocyte ratio (NLR) is considered a prognostic factor in patients with hepatocellular carcinoma (HCC). Our aim is to investigate the prognostic significance of NLR in patients with HCC treated with sorafenib. RESULTS: Median follow-up time was 7 months. Patients were mostly in the intermediate (27.3%) or advanced (72.7%) BCLC stages, 38.6% had vascular invasion and 27.5% extrahepatic disease. A large proportion (38.9%) had been previously treated with TACE. Liver function was preserved: 65.8% were classed as Child A. Median overall survival was 7.7 months (95% CI: 5.8-9.6). In univariate analysis, vascular invasion (P = 0.004), ECOG-PS ≥ 1 (P < 0.001), high bilirubin (P < 0.001), clinical ascites (P = 0.036), BCLC stage (P = 0.004), no previous TACE (P = 0.041) and NRL ≥ 2.3 (P = 0.005) were predictors of poor survival. Skin toxicity (P = 0.039) or hypertension (P = 0.033) during treatment were related to better survival. In multivariate analysis NLR ≥ 2.3 [HR 1.72 (95% CI: 1.03-2.71)], hyperbilirubinemia [HR 3.42 (95% CI: 1.87-6.25)] and ECOG-PS ≥ 1 [HR 1.97 (95% CI: 1.19-3.26)] were found as independent indicators of poor overall survival. Dermatologic adverse effects were an indicator of good overall survival [HR 0.59 (95% CI: 0.38-0.92)]. MATERIAL AND METHODS: One hundred and fifty-four consecutive HCC patients treated with sorafenib in four different Spanish hospitals between August 2005 and October 2013 were analysed. Clinical, laboratory, and tumour features were obtained. Survival was calculated from the moment sorafenib treatment was initiated. Log-rank and Cox regression were used to analyse the ability of NLR to predict survival. CONCLUSIONS: NLR is an independent prognostic indicator for overall survival in HCC patients treated with sorafenib.

Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation.

UNLABELLED: Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. CONCLUSION: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.

Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis.

UNLABELLED: LKB1, originally considered a tumor suppressor, plays an important role in hepatocyte proliferation and liver regeneration. Mice lacking the methionine adenosyltransferase (MAT) gene MAT1A exhibit a chronic reduction in hepatic S-adenosylmethionine (SAMe) levels, basal activation of LKB1, and spontaneous development of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These results are relevant for human health because patients with liver cirrhosis, who are at risk to develop HCC, have a marked reduction in hepatic MAT1A expression and SAMe synthesis. In this study, we isolated a cell line (SAMe-deficient [SAMe-D]) from MAT1A knockout (MAT1A-KO) mouse HCC to examine the role of LKB1 in the development of liver tumors derived from metabolic disorders. We found that LKB1 is required for cell survival in SAMe-D cells. LKB1 regulates Akt-mediated survival independent of phosphoinositide 3-kinase, adenosine monophosphate protein-activated kinase (AMPK), and mammalian target of rapamycin complex (mTORC2). In addition, LKB1 controls the apoptotic response through phosphorylation and retention of p53 in the cytoplasm and the regulation of herpesvirus-associated ubiquitin-specific protease (HAUSP) and Hu antigen R (HuR) nucleocytoplasmic shuttling. We identified HAUSP as a target of HuR. Finally, we observed cytoplasmic staining of p53 and p-LKB1(Ser428) in a NASH-HCC animal model (from MAT1A-KO mice) and in liver biopsies obtained from human HCC derived from both alcoholic steatohepatitis and NASH. CONCLUSION: The SAMe-D cell line is a relevant model of HCC derived from NASH disease in which LKB1 is the principal conductor of a new regulatory mechanism and could be a practical tool for uncovering new therapeutic strategies.