Statins Inhibit Toll-Like Receptor 4-Mediated Growth of Human Esophageal Adenocarcinoma Cells.

BACKGROUND: Esophageal adenocarcinoma (EAC) is a lethal malignancy with poor prognosis. Pharmacologic inhibitors of inflammation, such as statins, have been shown to decrease the risk of development and progression of esophageal cancer, but the mechanism of this protection is unclear. The objective of this study was to elucidate the effect of statins on toll-like receptor 4-mediated-proliferation of human EAC cells and identify the mechanism responsible for these observed effects. METHODS: Human EAC cells (OE33 and FLO1) were treated with simvastatin or atorvastatin for increasing doses and time periods. Toll-like receptor 4 (TLR4) expression was assessed. Cells were pretreated with statin followed by lipopolysaccharide (LPS). Cell proliferation and expression of signaling proteins were evaluated. FLO1 cells were injected into the flank of nude mice. Mice received intraperitoneal injections of simvastatin, atorvastatin, or control solution and tumor volume was measured. RESULTS: OE33 and FLO1 cells demonstrated decreased TLR4 expression after treatment with simvastatin or atorvastatin for 8 h (P < 0.05). LPS increased proliferation, whereas pretreatment with statin abolished this response (P < 0.05). Statins decreased expression and activation of LPS-induced signaling proteins, including MyD88, TRAF6, Akt, and NF-κB (P < 0.05). Mice receiving daily statin injections demonstrated smaller tumors than control mice (P < 0.001 at day 33). CONCLUSIONS: Treatment of EAC cells with simvastatin or atorvastatin decreases TLR4-mediated proliferation and in vivo tumor growth. Decreased TLR4 expression and subsequent reduction in MyD88-dependent signaling could be a mechanism by which statins act to reduce tumor growth rates.

Secretory Phospholipase A2 IIa Mediates Expression of Growth Factor Receptors in Esophageal Adenocarcinoma.

BACKGROUND: Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling. AIMS: We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC. METHODS: Normal human esophageal epithelium, Barrett's esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers. RESULTS: sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls. CONCLUSIONS: sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition's ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.

Postoperative Complications Are Not Elevated in Well-Compensated ESRD Patients Undergoing Cardiac Surgery: End-Stage Renal Disease Cardiac Surgery Outcomes.

BACKGROUND: Patients with end-stage renal disease (ESRD) are at high risk for cardiac disease requiring surgery, and have been shown to have increased surgical risks. There have been significant improvements in ESRD management, surgical techniques, and patient selection over the past 10 y. We evaluated rates of serious postoperative outcomes in stable, well-dialyzed patients with ESRD undergoing nonemergent cardiac surgery compared to the general cardiac surgery population. METHODS: In this propensity-score matched study, we evaluated 1451 adult patients who underwent nonemergent cardiac surgery at the University of Colorado Hospital (UCH) between 2011 and 2016. Patients with ESRD were compared to nonESRD patients. The primary outcome was a composite endpoint, including 30-d mortality, stroke, postoperative infection, and prolonged intensive care unit (ICU) length of stay (LOS). RESULTS: A total of 35 patients with ESRD met inclusion criteria. These select patients were younger with few comorbidities than the nonESRD population. There were no statistically significant differences in the composite outcome between ESRD and nonESRD patients in the propensity-matched analysis (OR 0.70, CI 0.29-1.72, P = 0.44). There were no significant differences or trends for in-hospital mortality, postoperative stroke, infection, ICU LOS, or hospital LOS between the patients with and without ESRD. CONCLUSIONS: Stable ESRD patients undergoing nonemergent surgery are not at increased risk of major postoperative complications when compared to those without ESRD. Well-compensated ESRD patients should not be excluded from surgical consideration.

Clinical predictors of in-hospital mortality in venoarterial extracorporeal membrane oxygenation.

INTRODUCTION: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is utilized as a life-saving procedure and bridge to myocardial recovery for patients in refractory cardiogenic shock. Despite technical advancements, VA-ECMO retains high mortality. This study aims to identify the clinical predictors of in-hospital mortality after VA-ECMO to improve risk stratification for this tenuous patient population. METHODS: The REgistry for Cardiogenic Shock: Utility and Efficacy of Device Therapy database is a multicenter, observational registry of ECMO patients. From 2013 to 2018, 789 patients underwent VA-ECMO. Bivariate analysis was performed on more than 300 variables regarding their association with in-hospital mortality. Logistic regression analyses were performed with variables chosen based upon clinical and statistical significance in the bivariate analysis. Tests were considered significant at a two-sided P < .05. RESULTS: Although 63.5% patients were successfully weaned from VA-ECMO, in-hospital mortality was 57.9%. Nonsurvivors were older (P < .0001), had higher body mass index (P = .01), higher rates of hypertension (P = .02), coronary artery disease (P = .02), chronic obstructive pulmonary disease (P = .02), chronic liver disease (P = .008), percutaneous coronary intervention (P = .02), and surgical revascularization (P = .02). Multivariate predictors for in-hospital mortality include older age (odds ratio [OR], 1.019; P = .007), cardiac arrest (OR, 2.76; P = .006), chronic liver disease (OR, 8.87; P = .04), elevated total bilirubin (OR, 1.093; P < .0001), and the presence of a left ventricular vent (OR, 2.018; P = .03). Pre-ECMO sinus rhythm was protective (OR, 0.374; P = .006). CONCLUSIONS: In a large study of recent VA-ECMO patients, in-hospital mortality remains significant, but acceptable given the severe pathology manifested in this population. Identification of pre-ECMO predictors of mortality helps stratify high-risk patients when deciding on ECMO placement, prolonged support, and prognosis.

Inhibition of secretory phospholipase A2 IIa attenuates prostaglandin E2-induced invasiveness in lung adenocarcinoma.

Secretory phospholipase A2 IIa (sPLA2 IIa) catalyzes the production of multiple inflammatory mediators that influence the development of lung and other cancers. The most potent of these carcinogenic mediators is prostaglandin E2 (PGE2). We hypothesize that sPLA2 IIa inhibition modulates the production of PGE2, and sPLA2 IIa inhibition exerts its antineoplastic effects via downregulation of PGE2 production. We aim to evaluate these relationships via analysis of PGE2-mediated growth regulation pathways. A549 and H1650 lung adenocarcinoma cells were assayed for PGE2 production in the presence of sPLA2 IIa inhibitor. A549 and H1650 cells were treated with PGE2 and immune blotting was performed to assess ICAM-1 expression and STAT-3 activity. PGE2-induced ICAM-1 expression was measured via immunofluorescence. A549 and H1650 cells were treated with PGE2 in the presence of STAT3 inhibitor and assayed for ICAM-1 expression. A549 cells were treated with PGE2 in the presence ICAM-1 blocking antibody and assayed for invasion. PGE2 stimulation significantly increased the invasiveness and proliferation of lung adenocarcinoma (invasion p < 0.05, proliferation p < 0.05 A549 cells, p < 0.005 H1650 cells). sPLA2 IIa inhibition reduced PGE2 secretion (p < 0.05). PGE2 stimulation significantly upregulated the expression of cell adhesion molecule ICAM-1 and the phosphorylation of anti-apoptotic transcription factor STAT3 (p < 0.05). STAT3 inhibition attenuated ICAM-1 expression demonstrating the dependence of ICAM-1 on the STAT3 pathway (p < 0.05). ICAM-1 blockade attenuated the pro-invasive effects of PGE2 (p < 0.05). sPLA2 IIa inhibition attenuates the potent effects of PGE2-induced invasiveness. This is mediated by decreasing pro-inflammatory and invasion-promoting ICAM-1via the STAT-3 pathway. These data further describe how sPLA2 IIa inhibition mechanistically exerts its anticancer effects and support its use as an antineoplastic agent.

Aortic Arch Repair Using Open and Hybrid Techniques: A Systematic Review.

Early surgical intervention is critical for treatment of aortic arch aneurysms and dissections, but limited comprehensive data exist to define the optimal approach for surgical management with respect to postoperative outcomes. We conducted a systematic review of the 2 most common surgical approaches-total arch replacement and hybrid arch repair. We referenced the electronic PubMed database reporting on outcomes for these surgical approaches from inception to June 2022. Our initial search query returned a total of 2,517 records. All records were independently screened for adherence to our inclusion criteria and a total of 12 retrospective cohort studies were identified as appropriate for inclusion. Across the included studies, a total of 618 patients underwent hybrid repair, as compared to 2,104 patients who underwent total arch replacement. We found that most of the literature supported the findings of similar rates of permanent neurologic dysfunction, acute kidney injury, and short-term mortality between approaches and higher postoperative reintervention rates following hybrid repair. Reported outcomes of studies included in this review often conflicted regarding midterm and long-term survival, as well as hospital and intensive care unit length of stay following open and hybrid repair. Future studies should address midterm and long-term survival with a prospective study design.

Activation of Toll-Like Receptor 2 Promotes Proliferation of Human Lung Adenocarcinoma Cells.

BACKGROUND/AIM: The aim of this study was to evaluate the role of toll-like receptor 2 (TLR2) in the proliferation of human lung cancer cells and identify the signaling pathway that mediates this effect. MATERIALS AND METHODS: Adenocarcinoma (A549 and H1650) and adenosquamous (H125) cells were treated with increasing doses of Pam3CSK4, a TLR2 agonist. Cell proliferation and NF-ĸB activation were evaluated. NF-ĸB was inhibited prior to treatment with Pam3CSK4 and proliferation was assessed. RESULTS: TLR2 expression was significantly higher in A549 and H1650 cells compared to H125 cells (p<0.001). TLR2 stimulation induced proliferation in adenocarcinoma cells only and led to a corresponding increase in NF-ĸB activity (p<0.05). Inhibition of NF-ĸB prior to treatment with Pam3CSK4 attenuated this proliferative response. CONCLUSION: TLR2 activation induced proliferation of lung adenocarcinoma cells through activation of NF-ĸB. Thus, the TLR2 signaling pathway may be a potential therapeutic target in lung adenocarcinoma.

Toll-Like Receptor-4 Is a Mediator of Proliferation in Esophageal Adenocarcinoma.

BACKGROUND: Chronic inflammation from reflux disease has been implicated as part of the development of esophageal adenocarcinoma. Toll-like receptors (TLRs), a component of the innate immune system, have been implicated in mediating hyperplasia and metaplasia in response to inflammatory stimuli. Increased TLR4 in human esophageal cancer has been correlated with its carcinogenesis. We hypothesized that TLR4 mediates proliferation of human esophageal adenocarcinoma cells. METHODS: Normal human esophageal (HET1A) and adenocarcinoma (OE33, FLO-1) cell lines were cultured using standard techniques. TLR4 was measured at baseline and in response to reflux stimuli. All cell lines were treated with the TLR4 agonist lipopolysaccharide for 48 hours, and growth response was measured. Changes in myeloid differentiation primary response 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), and nuclear factor-κB (NF-κB) activity were measured during lipopolysaccharide treatment. All cell lines had NF-κB inhibited, and growth rate response was measured. RESULTS: TLR4 was expressed in all cell lines, with increased baseline expression in adenocarcinoma cell lines (p < 0.05). Reflux stimuli increased TLR4 expression (p < 0.01) in normal esophageal cells. After treatment with lipopolysaccharide, all cell lines showed significant increases in proliferation (p < 0.05) due to the NF-κB pathway, and their growth rate was reduced with NF-κB inhibition (p < 0.05). CONCLUSIONS: TLR4 is consistently detectable in esophageal cell lines and most highly expressed in adenocarcinoma. TLR4 expression increases in an inflammatory model of reflux disease. TLR4 activation results in increased proliferation due to the TLR4-MyD88-TRAF6-NF-κB signaling pathway, and inhibition of NF-κB leads to decreased esophageal cell growth. These findings suggest TLR4 may be a target to suppress esophageal cancer growth.

Improved Mortality Associated With the Use of Extracorporeal Membrane Oxygenation.

BACKGROUND: Our objective was to evaluate the association of bridge to transplant (BTT) extracorporeal membrane oxygenation (ECMO) on survival after lung transplantation (LTx) and determine the degree to which transplant center volume affects this relationship. METHODS: Using the United Network for Organ Sharing database, we performed a retrospective cohort study evaluating the survival of patients undergoing LTx between 2005 and 2017. On the basis of previous literature, LTx centers were classified into 3 groups using their average annual LTx volume over the preceding 5 years: less than 25, 25 to 49, and more than 50. Survival of BTT ECMO and non-ECMO patients was analyzed using a log-rank test. Propensity scores for BTT ECMO were calculated, and a weighted proportional hazards model was used to compare BTT ECMO and non-ECMO patients by center volume. RESULTS: There were 20,976 patients who met inclusion criteria, with 611 (2.9%) undergoing BTT ECMO. Overall, BTT ECMO was associated with increased posttransplantation hazard of mortality (hazard ratio, 1.37; 95% confidence interval, 1.14 to 1.64). Kaplan-Meier plots by center volume suggest that BTT ECMO-associated mortality may be mitigated at high-volume LTx centers. In the propensity score-weighted proportional hazards model, we determined that when centers perform more than 35 LTxs per year, the increased hazard of BTT ECMO on mortality is no longer observed. CONCLUSIONS: BTT ECMO can be performed as a bridge to LTx without significantly increasing patient mortality in high-volume centers. Patients undergoing BTT ECMO at LTx centers that perform more than 35 LTxs annually have equivalent mortality to those who do not require ECMO before transplantation.