Liver Transplantation for Severe Hepatic Trauma: a multicenter analysis from the UNOS dataset.

BACKGROUND: Orthotopic liver transplantation (OLT) is rarely indicated after hepatic trauma but it can be the only therapeutic option in some patients. There are scarce data analyzing the surgical outcomes of OLT after trauma. METHODS: We used the UNOS dataset to identify patients who underwent OLT for trauma from 1987 to 2022, and compared them to a cohort of patients transplanted for other indications. Cox proportional hazard and multivariable logistic regression analyses were performed to assess predictors of graft and patient survival. RESULTS: 72 patients underwent OLT for trauma during the study period. Patients with trauma were more frequently on mechanical ventilation at the time of transplantation (26.4% vs. 7.6%, p < 0.001) and had a greater incidence of pre-transplant portal vein thrombosis (PVT) (12.5% vs. 4%, p = 0.002). Our 4:1 matched analysis showed that trauma patients had significantly shorter wait times, higher incidence of pre-transplant PVT and prolonged length of stay (LOS). Trauma was associated with decreased overall graft survival (HR = 1.42, 95% CI = 1.01-1.98), and increased LOS (p = 0.048). There were no significant differences in long term patient survival. CONCLUSION: Unique physiological and vascular challenges after severe hepatic trauma might be associated with decreased graft survival in patients requiring liver transplantation. LEVEL OF EVIDENCE: Retrospective cohort study, III.

Metabolic Disruption Induced by mTOR Signaling Pathway Inhibition in Regulatory T-Cell Expansion for Clinical Application.

BACKGROUND: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess the efficacy of the mTORC1/C2 inhibitor, AZD8055, in the manufacturing of clinically competent Treg cells and compare the effects with those induced by rapamycin (RAPA), another mTOR inhibitor commonly used in Treg expansion protocols. METHODS: Primary human Treg cells were isolated from leukapheresis product. Cell viability, expansion rates, suppressive function, autophagy, mitochondrial unfolded protein response (mitoUPR), and cell metabolic profile were assessed. RESULTS: We observed a stronger inhibition of the mTORC2 signaling pathway and downstream events triggered by Interleukin 2 (IL2)-receptor in AZD8055-treated cells compared with those treated with RAPA. AZD8055 induced progressive metabolic changes in mitochondrial respiration and glycolytic pathways that disrupted the long-term expansion and suppressive function of Tregs. Unlike RAPA, AZD8055 treatment impaired autophagy and enhanced the mitoUPR cell stress response pathway. CONCLUSIONS: A distinct pattern of mTOR inhibition by AZD, compared with RAPA, induced mitochondrial stress response and dysfunction, impaired autophagy, and disrupted cellular bioenergetics, resulting in the loss of proliferative potential and suppressive function of Treg cells.

Liver transplantation for biliary cysts: perioperative and long-term outcomes.

BACKGROUND: Biliary cysts (BC) is a rare indication for orthotopic liver transplantation (OLT). METHODS: We queried the UNOS dataset to identify patients who underwent OLT for Caroli's disease (CD) and choledochal cysts (CC). All patients with BC (CD + CC) were compared to a cohort of patients transplanted for other indications. Patients with CC were also compared to those with CD. Cox proportional hazard model was performed to assess predictors of graft and patient survival. RESULTS: 261 patients underwent OLT for BC. Patients with BC had better pre-operative liver function compared to those transplanted for other indications. 5-year graft and patient survival were 72% and 81%, respectively, similar to those transplanted for other indications after matching. Patients with CC were younger and had increased preoperative cholestasis compared to those with CD. Donor age, race, and gender were predictors of poor graft and patient survival in patients transplanted for CC. CONCLUSIONS: Patients with BC have similar outcomes to those transplanted for other indications and more frequently require MELD score exception. In patients transplanted for choledochal cysts, female gender, donor age, and African-American race were independent predictors of poor survival. Pediatric patients transplanted for Caroli's disease had better survival compared to adults.

Predictors of Liver Failure in Non-Cirrhotic Patients Undergoing Hepatectomy.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is associated with high mortality following liver resection. There have been limited studies evaluating predictors of PHLF and clinically significant PHLF in non-cirrhotic patients. METHODS: This was a retrospective cohort study using the National Surgical Quality Improvement Program database (NSQIP) to evaluate 8,093 non-cirrhotic patients undergoing hepatectomy from 2014 to 2018. Primary endpoints were PHLF and clinically significant PHLF (PHLF grade B or C). RESULTS: Among all patients, 4.74% (n = 383) developed PHLF and 2.5% clinically significant PHLF (n = 203). The overall 30-day mortality was 1.35% (n = 109), 11.5% (n = 44) in patients with PHLF, and 19.2% in those with clinically significant PHLF. Factors associated with PHLF were: metastatic liver disease (OR = 1.84, CI = 1.14-2.98), trisectionectomy (OR = 3.71, CI = 2.59-5.32), right total lobectomy (OR = 4.17, CI = 3.06-5.68), transfusions (OR = 1.99, CI = 1.52-2.62), organ/space SSI (OR = 2.84, CI = 2.02-3.98), post-operative pneumonia (OR = 2.43, CI = 1.57-3.76), sepsis (OR = 2.27, CI = 1.47-3.51), and septic shock (OR = 5.67, CI = 3.43-9.36). Patients who developed PHLF or clinically significant PHLF had 2-threefold increased risk of perioperative mortality. Post-hepatectomy renal failure (OR = 8.47, CI = 3.96-18.1), older age (OR = 1.04, CI = 1.014-1.063), male sex (OR = 1.83, CI = 1.07-3.14), sepsis (OR = 2.96, CI = 1.22-7.2), and septic shock (OR = 3.92, CI = 1.61-9.58) were independently associated with 30-mortality in patients with clinically significant PHLF. CONCLUSION: PHLF in non-cirrhotic patients increased the risk of perioperative mortality and is associated with the extent of hepatectomy and infectious complications. Careful evaluation of the liver remnant, antibiotic prophylaxis, nutritional assessment, and timely management of post-operative infections could decrease major morbidity and mortality following hepatectomy.

Outcomes in Elderly Patients Undergoing Liver Transplantation Compared with Liver-Directed Ablative Therapy in Early-Stage Hepatocellular Carcinoma.

BACKGROUND: Orthotopic liver transplantation (OLT) is the accepted treatment in patients with unresectable, early-stage hepatocellular carcinoma (HCC) in the setting of cirrhosis. Due to increasing waitlist demand for OLT, determining optimal groups for transplant is critical. Elderly patients are known to have poorer postoperative outcomes. Considering the effectiveness of liver-directed therapies for HCC, we sought to determine whether elderly patients received survival benefit from OLT over liver-directed therapy alone. STUDY DESIGN: The National Cancer Database participant use file was used to analyze data between 2004 and 2017. Only patients ≥70 years of age who received OLT or liver-directed therapy alone were included. Patients with alpha-fetoprotein >500 ng/mL or missing alpha-fetoprotein values were excluded. Baseline demographic variables, model for end-stage liver disease score, and overall survival from time of diagnosis were collected. Descriptive statistics, Kaplan-Meier survival, Cox proportional hazards model, and propensity score matching were used. RESULTS: A total of 2,377 patients received ablative therapy alone, and 214 patients received OLT. Multivariable analysis and Kaplan-Meier showed that OLT conferred a significant survival benefit compared to liver-directed therapy alone. Age was also associated with a yearly 3% increase in risk of mortality. Propensity-matched analysis adjusting also demonstrated a significant survival benefit for elderly patients receiving OLT compared to liver-directed therapy alone. CONCLUSION: Despite increased age and associated comorbidities being factors associated with poor outcomes, OLT confers a survival advantage compared to liver-directed ablative therapies alone in selected elderly patients with HCC. OLT should be offered in medically appropriate elderly patients with HCC.

Hepatic Steatosis is Associated with an Increased Risk of Postoperative Infections and Perioperative Transfusion Requirements in Patients Undergoing Hepatectomy.

BACKGROUND: To determine the impact of hepatic steatosis on perioperative outcomes of patients undergoing hepatectomy. METHODS: We analyzed all hepatectomy patients with normal and fatty liver texture, between 2014 and 2018 using NSQIP. Main endpoints included perioperative transfusions (within 72 h) and infectious complications. RESULTS: A total of 8,237 patients underwent hepatectomy during the study period. The overall rate of fatty liver texture (FLG) was 31% (2,557). Operative duration was significantly longer; inflow occlusion was more common (Pringle maneuver), and the need of transfusions was significantly higher in the FLG compared to the normal liver group (NLG) (p = < 0.001). On multivariate analysis, patients in the FLG had increased risk of developing infectious complications (OR 1.22 [95%IC 1.05-1.41]) and transfusion requirements within 72 h after hepatectomy (OR 1.43 [95% CI 1.24-1.63]). CONCLUSIONS: Hepatic steatosis is an independent risk factor for the development of infectious complications and increased perioperative transfusion requirements in patients undergoing hepatectomy. Those requiring transfusions within 72 h had also an increased risk of infections after hepatectomy.

Perioperative Challenges in Patients Transplanted with Livers from Extreme Obese Donors.

The combination of rising rates of obesity and the shortage of deceased donor livers have forced the consideration of marginal liver donors in terms of body mass index (BMI) for liver transplantation (LT). To date, there are still conflicting data on the impact of donor obesity on post-LT outcomes. We analyzed all patients undergoing LT alone in the United States (US) from October 2005 through December 2019 using the United Network of Organ Sharing (UNOS) data set. We categorized donor BMI >40 kg/m2 as extremely obese (EO). Primary endpoints included 30-day perioperative mortality and early graft loss (EGL) within 7 days. A subgroup analysis was performed for the EO donor group to assess how macrovesicular steatosis (MaS) >30% affects 30-day mortality and EGL within 7 days. A total of 72,616 patients underwent LT during the study period. The 30-day perioperative mortality was significantly higher in the EO donor group (P = 0.02). On multivariate analysis, recipients undergoing LT with EO donors had a 38% higher 30-day mortality risk (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.21-1.69) and 53% increased risk of EGL (OR, 1.53; 95% CI, 1.22-1.90). MaS >30% was independently associated with a 2-fold increased risk of 30-day mortality (P = 0.003) and 3.5-fold increased risk of EGL within 7 days (P < 0.001). The impact of MaS >30% in EGL was 2-fold for all patients transplanted during the study period compared with 3.5-fold in the EO donor group. There is an increased risk of EGL and 30-day perioperative mortality in recipients transplanted with EO donors. Future studies are warranted in morbid and super obese donors to assess the possible effect of obesity-related proinflammatory factors in EGL.

Identification of a therapeutic dose of continuously delivered erythropoietin in the eye using an inducible promoter system.

Erythropoietin (EPO) can protect the retina from acute damage, but long-term systemic treatment induces polycythemia. Intraocular gene delivery of EPO is not protective despite producing high levels of EPO likely due to its bellshaped dose curve. The goal of this study was to identify a therapeutic dose of continuously produced EPO in the eye. We packaged a mutated form of EPO (EPOR76E) that has equivalent neuroprotective activity as wild-type EPO and attenuated erythropoietic activity into a recombinant adeno-associated viral vector under the control of the tetracycline inducible promoter. This vector was injected into the subretinal space of homozygous postnatal 5-7 day retinal degeneration slow mice, that express the tetracycline transactivators from a retinal pigment epithelium specific promoter. At weaning, mice received a single intraperitoneal injection of doxycycline and were then maintained on water with or without doxycycline until postnatal day 60. Intraocular EPO levels and outer nuclear layer thickness were quantified and correlated. Control eyes contained 6.1 ± 0.1 (SEM) mU/ml EPO. The eyes of mice that received an intraperitoneal injection of doxycycline contained 11.8 ± 2.0 (SEM) mU/ml EPO-R76E. Treatment with doxycycline water induced production of 35.9 ± 2.4 (SEM) mU/ml EPO-R76E in the eye. The outer nuclear layer was approximately 8 µm thicker in eyes of mice that received doxycycline water as compared to the control groups. Our data indicates that drug delivery systems should be optimized to deliver at least 36 mU/ml EPO into the eye since this dose was effective for the treatment of a progressive retinal degeneration.