The Risk of Incarceration During Nonoperative Management of Incisional Hernias: A Population-based Analysis of 30,998 Patients.

OBJECTIVE: The aim of the study was to quantify the risk of incarceration of incisional hernias. BACKGROUND: Operative repair is the definitive treatment for incisional ventral hernias but is often deferred if the perceived risk of elective operation is elevated secondary to comorbid conditions. The risk of incarceration during nonoperative management (NOM) factors into shared decision making by patient and surgeon; however, the incidence of acute incarceration remains largely unknown. METHODS: A retrospective analysis of adult patients with an International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis of incisional hernia was conducted from 2010 to 2017 in 15 hospitals of a single healthcare system. The primary outcome was incarceration necessitating emergent operation. The secondary outcome was 30-, 90-, and 365-day mortality. Univariate and multivariate analyses were used to determine independent predictors of incarceration. RESULTS: Among 30,998 patients with an incisional hernia (mean age 58.1 ±â€Š15.9 years; 52.7% female), 23,022 (78.1%) underwent NOM of whom 540 (2.3%) experienced incarceration, yielding a 1- and 5-year cumulative incidence of 1.24% and 2.59%, respectively. Independent variables associated with incarceration included: age older than 40 years, female sex, current smoker, body mass index 30 or greater, and a hernia-related inpatient admission. All-cause mortality rates at 30, 90, and 365 days were significantly higher in the incarceration group at 7.2%, 10%, and 14% versus 1.1%, 2.3%, and 5.3% in patients undergoing successful NOM, respectively. CONCLUSIONS: Incarceration is an uncommon complication of NOM but is associated with a significant risk of death. Tailored decision making for elective repair and considering the aforementioned risk factors for incarceration provides an initial step toward mitigating the excess morbidity and mortality of an incarceration event.

Ex Vivo Expanded Donor Alloreactive Regulatory T Cells Lose Immunoregulatory, Proliferation, and Antiapoptotic Markers After Infusion Into ATG-lymphodepleted, Nonhuman Primate Heart Allograft Recipients.

BACKGROUND: Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. METHODS: darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. RESULTS: darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. CONCLUSIONS: Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.

Improved Understanding of Acute Incisional Hernia Incarceration: Implications for Addressing the Excess Mortality of Emergent Repair.

BACKGROUND: Incisional hernia develops in up to 20% of patients undergoing abdominal operations. We sought to identify characteristics associated with poor outcomes after acute incisional hernia incarceration. STUDY DESIGN: We performed a retrospective cohort study of adult patients with incisional hernias undergoing elective repair or with acute incarceration between 2010 and 2017. The primary end point was 30-day mortality. Logistic regression was used to determine adjusted odds associated with 30-day mortality. The American College of Surgeons Surgical Risk Calculator was used to estimate outcomes had these patients undergone elective repair. RESULTS: A total of 483 patients experienced acute incarceration; 30-day mortality was 9.52%. Increasing age (adjusted odds ratio 1.05; 95% CI, 1.02 to 1.08) and bowel resection (adjusted odds ratio 3.18; 95% CI, 1.45 to 6.95) were associated with mortality. Among those with acute incarceration, 231 patients (47.9%) had no documentation of an earlier surgical evaluation and 252 (52.2%) had been evaluated but had not undergone elective repair. Among patients 80 years and older, 30-day mortality after emergent repair was high (22.9%) compared with estimated 30-day mortality for elective repair (0.73%), based on the American College of Surgeons Surgical Risk Calculator. Estimated mortality was comparable with observed elective repair mortality (0.82%) in an age-matched cohort. Similar mortality trends were noted for patients younger than 60 years and aged 60 to 79 years. CONCLUSIONS: Comparison of predicted elective repair and observed emergent repair mortality in patients with acute incarceration suggests that acceptable outcomes could have been achieved with elective repair. Almost one-half of acute incarceration patients had no earlier surgical evaluation, therefore, targeted interventions to address surgical referral can potentially result in fewer incarceration-related deaths.

Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high-fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4-/- ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. CONCLUSION: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).

Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction.

The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and up-regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC-1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC-1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine-induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll-like receptor-9. This binding leads to activation of p38 and subsequent phosphorylation of PGC-1α, with resultant up-regulation of mitochondrial biogenesis. CONCLUSION: Taken together, our findings suggest that during hypoxia HMGB1 up-regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017;66:182-197).