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.

Anti-neoplastic sulfonamides alter the metabolic homeostasis and disrupt the suppressor activity of regulatory T cells.

Regulatory T cells (Tregs) are essential to maintain self-tolerance and immune homeostasis but, as components of the tumor microenvironment (TME), are also a major barrier to effective cancer immunosurveillance and immunotherapy. FH535 and its derivative Y3 are two N-aryl-benzene-sulfonamides (NABs) that inhibit HCC cell proliferation and tumor progression. However, the impact of NABs on the immune cells in the TME is not yet known. Analyses of explanted livers from patients with hepatocellular carcinoma (HCC) showed that high levels of tumor-infiltrating Tregs were associated with poor tumor differentiation. These results lead us to investigate the immunomodulatory effects of NABs in regulatory and effector T cells. Exposure of primary human Tregs to NABs induced a rapid but temporary increase of cell expansion, a gradual disruption of suppressor activity, and concomitant bioenergetics and autophagic flux dysregulations. In contrast to Tregs, no gross effects were observed in effector T cells. Addition of Rapamycin prevented the functional decay of Tregs and restored their metabolic profile, suggesting that NAB effects require the integrity of the mTOR pathway. This study revealed the immunomodulatory properties of NABs with a preferential impact on Treg activity and provided novel insights into the anti-tumor potential of sulfonamides.

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.

Untangling the Knots of Regulatory T Cell Therapy in Solid Organ Transplantation.

Numerous preclinical studies have provided solid evidence supporting adoptive transfer of regulatory T cells (Tregs) to induce organ tolerance. As a result, there are 7 currently active Treg cell-based clinical trials in solid organ transplantation worldwide, all of which are early phase I or phase I/II trials. Although the results of these trials are optimistic and support both safety and feasibility, many experimental and clinical unanswered questions are slowing the progression of this new therapeutic alternative. In this review, we bring to the forefront the major challenges that Treg cell transplant investigators are currently facing, including the phenotypic and functional diversity of Treg cells, lineage stability, non-standardized ex vivo Treg cell manufacturing process, adequacy of administration route, inability of monitoring and tracking infused cells, and lack of biomarkers or validated surrogate endpoints of efficacy in clinical trials. With this plethora of interrogation marks, we are at a challenging and exciting crossroad where properly addressing these questions will determine the successful implementation of Treg cell-based immunotherapy in clinical transplantation.

The Role of Alterations in Alpha-Klotho and FGF-23 in Kidney Transplantation and Kidney Donation.

Cardiovascular disease and mineral bone disorders are major contributors to morbidity and mortality among patients with chronic kidney disease and often persist after renal transplantation. Ongoing hormonal imbalances after kidney transplant (KT) are associated with loss of graft function and poor outcomes. Fibroblast growth factor 23 (FGF-23) and its co-receptor, α-Klotho, are key factors in the underlying mechanisms that integrate accelerated atherosclerosis, vascular calcification, mineral disorders, and osteodystrophy. On the other hand, kidney donation is also associated with endocrine and metabolic adaptations that include transient increases in circulating FGF-23 and decreases in α-Klotho levels. However, the long-term impact of these alterations and their clinical relevance have not yet been determined. This manuscript aims to review and summarize current data on the role of FGF-23 and α-Klotho in the endocrine response to KT and living kidney donation, and importantly, underscore specific areas of research that may enhance diagnostics and therapeutics in the growing population of KT recipients and kidney donors.

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.

The Unity Council at 40: a pioneering community development and service organization (1967-2007).

The Spanish Speaking Unity Council (Unity Council) is a community development nonprofit organization that was established in 1964, during the civil rights movement, by a group of community members who wanted to ensure the political representation of the Latino community. Over its 45-year history, the Unity Council has grown into a $12 million community development organization that delivers a range of programming, including social services and employment training as well as facilitating the development and support of local businesses, low-income housing, and neighborhood improvement activities. The history of the agency presents the multiple challenges and rewards associated with development in an underserved community and an example of the important role that leadership plays in the growth of a nonprofit.