Anatomic Lung Resection Outcomes After Implementation of a Universal Thoracic ERAS Protocol Across a Diverse Health Care System.

OBJECTIVE: We sought to evaluate how implementing a thoracic enhanced recovery after surgery (ERAS) protocol impacted surgical outcomes after elective anatomic lung resection. BACKGROUND: The effect of implementing the ERAS Society/European Society of Thoracic Surgery thoracic ERAS protocol on postoperative outcomes throughout an entire health care system has not yet been reported. METHODS: This was a prospective cohort study within one health care system (January 2019-March, 2023). A thoracic ERAS protocol was implemented on May 1, 2021 for elective anatomic lung resections, and postoperative outcomes were tracked using the electronic health record and Vizient data. The primary outcome was overall morbidity; secondary outcomes included individual complications, length of stay, opioid use, chest tube duration, and total cost. Patients were grouped into pre-ERAS and post-ERAS cohorts. Bivariable comparisons were performed using independent t -test, χ 2 , or Fisher exact tests, and multivariable logistic regression was performed to control for confounders. RESULTS: There were 1007 patients in the cohort; 450 (44.7%) were in the post-ERAS group. Mean age was 66.2 years; most patients were female (65.1%), white (83.8%), had a body mass index between 18.5 and 29.9 (69.7%), and were ASA class 3 (80.6%). Patients in the postimplementation group had lower risk-adjusted rates of any morbidity, respiratory complication, pneumonia, surgical site infection, arrhythmias, infections, opioid usage, ICU use, and shorter postoperative length of stay (all P <0.05). CONCLUSIONS: Postoperative outcomes were improved after the implementation of an evidence-based thoracic ERAS protocol throughout the health care system. This study validates the ERAS Society/European Society of Thoracic Surgery guidelines and demonstrates that simultaneous multihospital implementation can be feasible and effective.

Simvastatin Inhibits Histologic Changes Associated with Gastroduodenal Reflux in a Murine Model.

BACKGROUND: Observational studies demonstrate a protective effect of statins on the development and progression of esophageal adenocarcinoma. The role of statins in the prevention of reflux-induced esophageal changes remains unknown. AIMS: Using a mixed gastroduodenal reflux mouse model, we hypothesized that oral administration of simvastatin would attenuate reflux-induced mucosal changes of the distal esophagus. METHODS: Human Barrett's (CPB) and esophageal adenocarcinoma (FLO1 and OE19) cells were treated with simvastatin. Cell proliferation and apoptosis were evaluated using the MTS proliferation and annexin V apoptosis assays, respectively. A reflux mouse model was generated by performing a side-to-side anastomosis between the gastroesophageal junction and first portion of the duodenum (duodeno-gastroesophageal anastomosis, DGEA). DGEA mice were fed a standard or simvastatin-containing diet following surgery. Mice were euthanized 6 weeks post-operatively. RESULTS: Simvastatin significantly decreased proliferation and increased apoptosis in all cell lines. Compared to control animals, mice undergoing DGEA who were fed a standard diet demonstrated a fourfold increase in mucosal thickness and significant increase in proliferating cells (p < 0.0001). DGEA mice fed a simvastatin-containing diet had an attenuated response to reflux, with a significant reduction in mucosal hyperplasia and proliferation (p < 0.0001). DGEA mice fed a simvastatin-containing diet demonstrated significant upregulation of procaspase-3 (p = 0.009) and cleaved caspase-3 (p = 0.034) in the distal esophagus. CONCLUSIONS: We demonstrate for the first time a reduction in reflux-induced histologic changes of the distal esophagus following oral administration of simvastatin in vivo. These findings identify simvastatin as a potential preventative agent to inhibit the development and progression of reflux-induced esophageal injury.

Induction Chemotherapy Plus Neoadjuvant Chemoradiation for Esophageal and Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy with concurrent radiotherapy (nCRT) is an accepted treatment regimen for patients with potentially curable esophageal and gastroesophageal junction (GEJ) adenocarcinoma. The purpose of this study is to evaluate whether induction chemotherapy (IC) before nCRT is associated with improved pathologic complete response (pCR) and overall survival (OS) when compared with patients who received nCRT alone for esophageal and GEJ adenocarcinoma. METHODS: Using the National Cancer Database (NCDB), patients who received nCRT and curative-intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006 to 2015 were included. Chemotherapy and radiation therapy start dates were used to define cohorts who received IC before nCRT (IC + nCRT) versus those who only received concurrent nCRT before surgery. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. RESULTS: 12,460 patients met inclusion criteria, of whom 11,880 (95%) received nCRT and 580 (5%) received IC + nCRT. Following propensity weighting, OS was significantly improved among patients who received IC + nCRT versus nCRT (HR 0.82; 95% CI 0.74-0.92; p < 0.001) with median OS for the IC + nCRT cohort of 3.38 years versus 2.45 years for nCRT. For patients diagnosed from 2013 to 2015, IC + nCRT was also associated with higher odds of pCR compared with nCRT (OR 1.59; 95% CI 1.14-2.21; p = 0.007). CONCLUSION: IC + nCRT was associated with a significant OS benefit as well as higher pCR rate in the more modern patient cohort. These results merit consideration of a sufficiently powered prospective multiinstitutional trial to further evaluate these observed differences.

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 Inhibition Attenuates Adhesive Properties of Esophageal Barrett's Cells.

BACKGROUND: Gastroesophageal reflux and Barrett's esophagus are significant risk factors for the development of esophageal adenocarcinoma. Group IIa secretory phospholipase A2 (sPLA2) catalyzes the production of various proinflammatory metabolites and plays a critical role in promoting reflux-induced inflammatory changes within the distal esophagus. We hypothesized that inhibition of sPLA2 in human Barrett's cells would attenuate adhesion molecule expression via decreased activation of nuclear factor kappa B (NF-κB) and decrease cell proliferation, possibly mitigating the invasive potential of Barrett's esophagus. MATERIALS AND METHODS: Normal human esophageal epithelial cells (HET1A) and Barrett's cells (CPB) were assayed for baseline sPLA2 expression. CPB cells were treated with a specific inhibitor of sPLA2 followed by tumor necrosis factor-α. Protein expression was evaluated using immunoblotting. Cell proliferation was assessed using an MTS cell proliferation assay kit. Statistical analysis was performed using the Student's t-test or analysis of variance, where appropriate. RESULTS: CPB cells demonstrated higher baseline sPLA2 expression than HET1A cells (P = 0.0005). Treatment with 30 µM sPLA2 inhibitor significantly attenuated intercellular adhesion molecule-1 (P = 0.004) and vascular cell adhesion molecule-1 (P < 0.0001) expression as well as decreased NF-κB activation (P = 0.002). sPLA2 inhibition decreased cell proliferation in a dose-dependent manner (P < 0.001 for 15, 20, and 30 µM doses). CONCLUSIONS: sPLA2 inhibition in human Barrett's cells decreases cellular adhesive properties and NF-κB activation as well as decreases cell proliferation, signifying downregulation of the inflammatory response and possible attenuation of cellular malignant potential. These findings identify sPLA2 inhibition as a potential chemopreventive target for premalignant lesions of the esophagus.

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.

Conversion to open surgery during minimally invasive esophagectomy portends worse short-term outcomes: an analysis of the National Cancer Database.

OBJECTIVE: The objectives were to determine factors associated with conversion to open surgery in patients with esophageal cancer who underwent minimally invasive esophagectomy (MIE, including laparo-thoracoscopic and robotic) and the impact of conversion to open surgery on patient outcomes. METHODS: We included patients from the National Cancer Database with esophageal and gastroesophageal junction cancer who underwent MIE from 2010 to 2015. Patient-, tumor-, and facility-related characteristics as well as short-term and oncologic outcomes were compared between patients who were converted to open surgery and those who underwent successful MIE without conversion to open surgery. Multivariable logistic regression models were used to analyze risk factors for conversion to open surgery from attempted MIE. RESULTS: 7306 patients underwent attempted MIE. Of these patients, 82 of 1487 (5.2%) robotic-assisted esophagectomies were converted to open, compared to 691 of 5737 (12.0%) laparo-thoracoscopic esophagectomies (p < 0.001). Conversion rates decreased significantly over the study period (ptrend = 0.010). Patient age, tumor size, and nodal involvement were independently associated with conversion. Facility minimally invasive cumulative volume and robotic approach were associated with decreased conversion rates. Patients whose MIEs were converted had increased 90-day mortality [Odds Ratio (OR) 1.49; 95% Confidence Interval (CI) 1.10, 2.02], prolonged hospital stay (OR 1.39; 95% CI 1.17, 1.66), and higher rates of unplanned readmission (OR 1.67; 95% CI 1.27, 2.20). No significant differences were found in surgical margins or number of lymph nodes harvested. CONCLUSION: Patients undergoing attempted MIE requiring conversion to open surgery had significantly worse short-term outcomes including postoperative mortality. Patient factors and hospital experience contribute to conversion rates. These findings should inform surgeons and patients considering esophagectomy for cancer.

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.

Synergetic Induction of NGF With Diazoxide and Erythropoietin Attenuates Spinal Cord Ischemic Injury.

BACKGROUND: Paraplegia remains a significant complication of thoracoabdominal aortic intervention. We previously reported that diazoxide (DZ), enhances the neuroprotective efficacy of erythropoietin (EPO). We hypothesized that DZ and EPO combined treatment attenuates spinal cord ischemic injury through upregulation of nerve growth factor (NGF). METHODS: DZ (pretreatment) was given to adult male C57/BL6 mice by oral gavage and EPO (before surgery) was intraperitoneally injected 32 h after administration of DZ. Spinal cords were harvested 0, 2, 4, and 6 h after injection of EPO. NGF expression was analyzed by western blot. After determining the optimal time, NGF expression was compared between DZ (pretreatment) + EPO (before surgery), DZ + PBS, PBS + EPO, and PBS + PBS (ischemic control). Four groups were studied to compare the motor function after ischemia: DZ + EPO (n = 11), ischemic control (n = 9), DZ + EPO + tropomyosin receptor kinase A receptor inhibitor (n = 9), and sham (without cross-clamp, n = 4). Spinal cord ischemia was induced by a 4-min thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-h intervals until 48 h, and spinal cords were harvested for evaluation of NGF expression and histological changes. RESULTS: NGF expression was significantly upregulated 4 h after administration of EPO. At 4 h after injection of EPO, NGF expression in the DZ + EPO group was significantly higher than that in the other groups. DZ + EPO significantly preserved motor function compared with all other groups. At 48 h after reperfusion, the level of NGF expression in the DZ + EPO group, was significantly higher than in all other groups. CONCLUSIONS: DZ + EPO attenuates spinal cord ischemic injury through upregulation of NGF. Better understanding of this mechanism may serve to further prevent ischemic complications for aortic intervention.

Simvastatin reduces the TLR4-induced inflammatory response in human aortic valve interstitial cells.

BACKGROUND: Calcific aortic stenosis is a chronic inflammatory disease. Proinflammatory stimulation via toll-like receptor 4 (TLR4) causes the aortic valve interstitial cell (AVIC) to undergo phenotypic change. The AVIC first assumes an inflammatory phenotype characterized by the production of inflammatory mediators such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). This change has been linked with an osteogenic phenotypic response. Statins have recently been shown to have anti-inflammatory properties. We therefore hypothesized that statins may have an anti-inflammatory effect on human AVICs by downregulation of TLR4-stimulated inflammatory responses. Our purposes were (1) to determine the effect of simvastatin on TLR4-induced expression of inflammatory mediators in human AVICs and (2) to determine the mechanism(s) through which simvastatin exert this effect. MATERIALS AND METHODS: Human AVICs were isolated from the explanted hearts of four patients undergoing cardiac transplantation. Cells were treated with simvastatin (50 µM) for 1 h before stimulation with TLR4 agonist lipopolysaccharide (LPS, 0.2 µg/mL). Immunoblotting (IB) was used to analyze cell lysates for ICAM-1 expression, and enzyme-linked immunosorbent assay was used to detect IL-8 and MCP-1 in cell culture media. Likewise, lysates were analyzed for TLR4 and nuclear factor-kappa B activation (IB). After simvastatin treatment, lysates were analyzed for TLR4 levels (IB). Statistics were by analysis of variance (P < 0.05). RESULTS: Simvastatin reduced TLR4-induced ICAM-1, IL-8, and MCP-1 expression in AVICs. Simvastatin down-regulated TLR4 levels and suppressed TLR4-induced phosphorylation of nuclear factor-kappa B. CONCLUSIONS: These data demonstrate the potential of a medical therapy (simvastatin) to impact the pathogenesis of aortic stenosis.

Is Chemical Pyloroplasty Necessary for Minimally Invasive Esophagectomy?

BACKGROUND: Many centers use botulinum toxin for chemical pyloroplasty in minimally invasive esophagectomies as prophylaxis against delayed gastric emptying. No previous studies have compared botulinum toxin injection with no pyloric intervention for patients treated with a combined laparoscopic and thoracoscopic approach. The authors hypothesized that chemical pyloroplasty does not improve outcomes for these patients. METHODS: The study investigated patients undergoing minimally invasive esophagectomies from September 2009 to June 2015. Delayed gastric emptying was defined as inability to tolerate a soft diet by postoperative day 10, as corroborated by esophagram, upper endoscopy, or both. Data were compared using Student's t test, χ 2 analysis, and Mann-Whitney U test where appropriate. RESULTS: The study identified 71 patients treated with minimally invasive esophagectomy: 35 patients with chemical pyloroplasty treated from September 2009 to January 2014 and 36 patients without pyloric intervention from February 2014 to June 2015. The groups were statistically similar in age, gender distribution, T stage, percentage of patients receiving neoadjuvant therapy, body mass index, preoperative weight loss, preoperative serum albumin, and preoperative placement of feeding tubes (all p > 0.05). The overall incidence of delayed gastric emptying was low in both groups: 8.6% (3/35) of the patients with chemical pyloroplasty versus 5.6% (2/36) of the patients with no pyloric intervention (p = 0.62). The two groups also did not differ significantly in the development of aspiration pneumonia or the need for pyloric intervention. CONCLUSIONS: In a well-matched cohort study with a historical control group, use of botulinum toxin for chemical pyloroplasty in minimally invasive esophagectomies was not associated with improved outcomes related to the pylorus versus no pyloric intervention. Although preliminary, these data suggest that chemical pyloroplasty is not necessary in minimally invasive esophagectomy.

Matrix Gla protein regulates calcification of the aortic valve.

BACKGROUND: The aortic valve interstitial cell (AVIC) has been implicated in the pathogenesis of aortic stenosis. In response to proinflammatory stimulation, the AVIC undergoes a phenotypic change from that of a myofibroblast phenotype to that of osteoblast-like cell. Matrix Gla-protein (MGP) has been identified as an important inhibitor of vascular calcification. We therefore hypothesized that MGP expression is reduced in diseased AVICs, and loss of this protective protein contributes to calcification of the aortic valve. Our purpose was to compare MGP expression in normal versus diseased AVICs. MATERIALS AND METHODS: Human AVICs were isolated from normal aortic valves from explanted hearts (n = 6) at the time of heart transplantation. AVICs were also isolated from calcified, diseased valves of patients (n = 6) undergoing aortic valve replacement. AVICs were grown in culture until they reached passages 2-6 before experimentation. Immunofluorescent staining, reverse transcriptase-polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay were used to compare levels of MGP in normal and diseased AVICs. Statistics were performed using the Mann-Whitney U test (P < 0.05). RESULTS: MGP expression was significantly decreased in diseased AVICs relative to normal AVICs by immunofluorescent staining, reverse transcriptase-polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay. CONCLUSIONS: An important anti-calcification defense mechanism is deficient in calcified aortic valves. MGP expression is significantly lower in diseased relative to normal AVICs. Lack of this important "anti-calcification" protein may contribute to calcification of the aortic valve.

Alpha-2 agonist attenuates ischemic injury in spinal cord neurons.

BACKGROUND: Paraplegia secondary to spinal cord ischemia-reperfusion injury remains a devastating complication of thoracoabdominal aortic intervention. The complex interactions between injured neurons and activated leukocytes have limited the understanding of neuron-specific injury. We hypothesize that spinal cord neuron cell cultures subjected to oxygen-glucose deprivation (OGD) would simulate ischemia-reperfusion injury, which could be attenuated by specific alpha-2a agonism in an Akt-dependent fashion. MATERIALS AND METHODS: Spinal cords from perinatal mice were harvested, and neurons cultured in vitro for 7-10 d. Cells were pretreated with 1 µM dexmedetomidine (Dex) and subjected to OGD in an anoxic chamber. Viability was determined by MTT assay. Deoxyuridine-triphosphate nick-end labeling staining and lactate dehydrogenase (LDH) assay were used for apoptosis and necrosis identification, respectively. Western blot was used for protein analysis. RESULTS: Vehicle control cells were only 59% viable after 1 h of OGD. Pretreatment with Dex significantly preserves neuronal viability with 88% viable (P < 0.05). Dex significantly decreased apoptotic cells compared with that of vehicle control cells by 50% (P < 0.05). Necrosis was not significantly different between treatment groups. Mechanistically, Dex treatment significantly increased phosphorylated Akt (P < 0.05), but protective effects of Dex were eliminated by an alpha-2a antagonist or Akt inhibitor (P < 0.05). CONCLUSIONS: Using a novel spinal cord neuron cell culture, OGD mimics neuronal metabolic derangement responsible for paraplegia after aortic surgery. Dex preserves neuronal viability and decreases apoptosis in an Akt-dependent fashion. Dex demonstrates clinical promise for reducing the risk of paraplegia after high-risk aortic surgery.

Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury.

BACKGROUND: Paraplegia continues to complicate thoracoabdominal aortic interventions. The elusive mechanism of spinal cord ischemia-reperfusion injury has delayed the development of pharmacological adjuncts. Microglia, the resident macrophages of the central nervous system, can have pathological responses after a variety of insults. This can occur through toll-like receptor 4 (TLR-4) in stroke models. We hypothesize that spinal cord ischemia-reperfusion injury after aortic occlusion results from TLR-4-mediated microglial activation in mice. METHODS AND RESULTS: TLR-4 mutant and wild-type mice underwent aortic occlusion for 5 minutes, followed by 60 hours of reperfusion when spinal cords were removed for analysis. Spinal cord cytokine production and microglial activation were assessed at 6 and 36 hours after surgery. Isolated microglia from mutant and wild-type mice were subjected to oxygen and glucose deprivation for 24 hours, after which the expression of TLR-4 and proinflammatory cytokines was analyzed. Mice without functional TLR-4 demonstrated decreased microglial activation and cytokine production and had preserved functional outcomes and neuronal viability after thoracic aortic occlusion. After oxygen and glucose deprivation, wild-type microglia had increased TLR-4 expression and production of proinflammatory cytokines. CONCLUSIONS: The absence of functional TLR-4 attenuated neuronal injury and microglial activation after thoracic aortic occlusion in mice. Furthermore, microglial upregulation of TLR-4 occurred after oxygen and glucose deprivation, and the absence of functional TLR-4 significantly attenuated the production of proinflammatory cytokines. In conclusion, TLR-4-mediated microglia activation in the spinal cord after aortic occlusion is critical in the mechanism of paraplegia after aortic cross-clamping and may provide targets for pharmacological intervention.

Aortic valve calcification is mediated by a differential response of aortic valve interstitial cells to inflammation.

BACKGROUND: Although calcific aortic stenosis is common, calcification of the other three heart valves is not. The aortic valve interstitial cell (VIC) has been implicated in the pathogenesis of aortic stenosis. Proinflammatory stimulation of aortic VICs induces an osteogenic and inflammatory phenotypic change. We hypothesized that the VICs of the other heart valves do not undergo these changes. Using isolated human VICs from normal aortic, mitral, pulmonary, and tricuspid valves, our purpose was to compare the osteogenic response to proinflammatory stimulation via toll-like receptor 4 (TLR-4). MATERIALS AND METHODS: Aortic, pulmonic, mitral, and tricuspid (n=4 for each valve type) VICs were isolated from hearts valves explanted from patients undergoing cardiac transplantation. Cells were cultured and grown to confluence in passage 2-6 before treatment with Lipopolysaccharide (LPS) (100-200 ng/mL) for 24 or 48 h. Cells were characterized by immunofluorescent staining. TLR-4 expression was analyzed (immunoblotting, flow cytometry). Bone morphogenetic protein 2 and intercellular adhesion molecule 1 production were determined (immunoblotting). Monocyte chemoattractant protein 1 levels were determined by enzyme-linked immunosorbent assay. Statistics were by Mann-Whitney U test. RESULTS: TLR-4 stimulation induced bone morphogenetic protein 2 production only in aortic VICs (P<0.05). Intra-cellular adhesion molecule 1 production and monocyte chemoattractant protein 1 secretion increased in a similar fashion among TLR-4-stimulated VICs from all four valves. CONCLUSIONS: Proinflammatory stimulation induces an osteogenic phenotype in aortic VICs but not mitral, pulmonic, or tricuspid VICs. We conclude that this differential osteogenic response of aortic VICs contributes to the pathogenesis of calcific aortic stenosis.

Notch1 promotes the pro-osteogenic response of human aortic valve interstitial cells via modulation of ERK1/2 and nuclear factor-κB activation.

OBJECTIVE: Calcific aortic valve disease is a leading cardiovascular disease in the elderly, and progressive calcification results in the failure of valvular function. Aortic valve interstitial cells (AVICs) from stenotic valves express higher levels of bone morphogenetic protein-2 in response to Toll-like receptor 4 stimulation. We recently found that Toll-like receptor 4 interacts with Notch1 in human AVICs. This study tests the hypothesis that Notch1 promotes the pro-osteogenic response of human AVICs. APPROACH AND RESULTS: AVICs isolated from diseased human valves expressed higher levels of bone morphogenetic protein-2 and alkaline phosphatase after lipopolysaccharide stimulation. The augmented pro-osteogenic response is associated with elevated cellular levels of Notch1 and enhanced Notch1 cleavage in response to lipopolysaccharide stimulation. Inhibition or silencing of Notch1 suppressed the pro-osteogenic response in diseased cells, and the Notch 1 ligand, Jagged1, enhanced the response in AVICs isolated from normal human valves. Interestingly, extracellular signal-regulated protein kinases 1/2 (ERK1/2) and nuclear factor-κB phosphorylation induced by lipopolysaccharide was markedly reduced by inhibition or silencing of Notch1 and enhanced by Jagged1. Inhibition of ERK1/2 or nuclear factor-κB also reduced bone morphogenetic protein-2 and alkaline phosphatase expression induced by lipopolysaccharide. CONCLUSIONS: Notch1 mediates the pro-osteogenic response to Toll-like receptor 4 stimulation in human AVICs. Elevated Notch1 levels and enhanced Notch1 activation play a major role in augmentation of the pro-osteogenic response of AVICs of stenotic valves through modulation of ERK1/2 and nuclear factor-κB activation. These pathways could be potential therapeutic targets for prevention of the progression of calcific aortic valve disease.

Safety of Home Discharge With a Chest Tube After Bronchoscopic Lung Volume Reduction Complicated by Persistent Airleak.

BACKGROUND: The incidence of pneumothorax after bronchoscopic lung volume reduction (BLVR) using Zephyr (Pulmonx Corporation) endobronchial valves is ~26%. Many patients who develop a postprocedural pneumothorax require chest tube placement. If a persistent airleak is present, patients tolerating waterseal can be discharged home with a mini-atrium with a low risk of empyema. METHODS: Data were collected on patients from the Epic (Epic System Corporation) electronic medical record between July 2019 and November 2022. Our retrospective study reviewed a total of 102 BLVR procedures. Twenty-six of these procedures were complicated by a pneumothorax post-BLVR (25%). After 24 procedures, patients were discharged home with a chest tube after a persistent airleak. The primary endpoint of the study was the incidence of intrapleural infection in this population. The secondary endpoint was the average length of time the chest tube was in place until outpatient removal. RESULTS: Out of the 24 discharge events, 2 events (8.3%) were complicated by an intrapleural infection before chest tube removal. The average number of days requiring a chest tube until outpatient removal was 16.9 days, which is similar to the duration observed in patients discharged home with a chest tube after lung volume reduction surgery. CONCLUSION: Discharging patients home with a chest tube after BLVR therapy is safe and may reduce hospital length of stay. Our study shows the incidence of intrapleural infection after home discharge with a chest tube after BLVR is low.

Implementation of an Electronic Medical Record Alert Significantly Increases Lung Cancer Screening Uptake.

INTRODUCTION: Lung cancer survival is significantly improved with early detection. However, lung cancer screening (LCS) uptake remains low despite national recommendations. Our aim was to determine whether implementation of an electronic medical record (EMR) alert and order set would increase LCS uptake. STUDY DESIGN: A query of current and former smokers identified 62,630 patients aged 50 and above in the primary care setting between January 1, 2021 and May 5, 2022. We randomly reviewed 3704 charts for LCS eligibility and recorded who received LCS in the form of low-dose computed tomography amongst the eligible patients. We collected demographic information including gender, race, primary language, ethnicity, zip code, and insurance. Data analysis was performed utilizing 2-proportional z tests. RESULTS: We identified 461 patients who were LCS eligible. Our overall LCS uptake was 19.9% (92/461). Three-time frames were analyzed: (1) prior to EMR alert implementation, (2) after implementation of EMR alert (January 7, 2021), and (3) after implementation of EMR alert and order set (March 3, 2021). Screening uptake was significantly improved with initiation of EMR alert (1/46 [2.2%] to 23/109 [21.1%]; P = .003). LCS uptake remained similarly high after subsequent order set implementation (23/109 [21.1%] and 68/306 [22.2%]; P = .72). Amongst the different demographics, age was significantly associated with screening uptake, with age ≥65 demonstrating statistically significant increased rates of screening (15.6% [41/263] for <65 vs 25.8% [51/198] for ≥65; P = .007). CONCLUSION: Implementation of EMR alerts significantly improves LCS uptake in the primary care setting. Such efforts should be considered in other hospital settings to improve LCS uptake.

The association between patient preoperative disposition and outcomes after diagnostic lung biopsy.

Background: Surgical diagnostic lung biopsy (DLB) is performed to guide the management of pulmonary disease with unclear etiology. However, the utilization of surgical DLB in critically ill patients remains unclear. The purpose of this study was to determine if patient preoperative disposition impacts complication rates after DLB. Methods: This was retrospective cohort study using electronic health record (EHR) data at one academic institution [2013-2021]. Patients who underwent DLB were identified using current procedural terminology (CPT) codes and cohorted based on preoperative disposition. The primary outcome was 30-day mortality; secondary outcomes were overall morbidity, individual complications, and changes to medical therapy. Complication rates were compared using chi-squared tests, Fisher's exact tests, or analysis of variance (ANOVA). Multivariable logistic regression was performed to generate risk-adjusted odds ratios (ORs) for each complication. Results: Of 285 patients, 238 (83.5%) presented from home, 26 (9.1%) from inpatient floor units, and 21 (7.4%) from intensive care units (ICUs). Patients requiring ICU had the highest 30-day rates of mortality, overall morbidity, and all individual complications (all P<0.05). After risk adjustment, non-ICU inpatients had higher odds of postoperative ventilator use, prolonged ventilation, and ICU need than outpatients (all P<0.05). Preoperative ICU disposition was associated with increased OR of 30-day mortality [OR, 70.92; 95% confidence interval (CI): 5.55-906.32] and overall morbidity (OR, 7.27; 95% CI: 1.93-27.42) compared to patients with other preoperative dispositions. There were no differences in changes to medical therapy between the cohorts. Conclusions: Patients requiring ICU before DLB had significantly higher risk-adjusted rates of mortality and postoperative complications than outpatients and other inpatients. A clear benefit from tissue diagnosis should be defined prior to performing DLB on critically ill patients.

Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial.

OBJECTIVE: Donation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. METHODS: This was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. RESULTS: The DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. CONCLUSIONS: Although DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.