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.

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.

A Novel Hybrid Approach to Management of KD: Role of Robotic Surgery.

The management of Kommerell's Diverticulum (KD) has been evolving from open repair to a hybrid of open and endovascular repair. While there is no consensus regarding the optimal strategy, the need for less invasive treatment with less morbidity early recovery, and improved quality of life is a common goal for both the patient and the provider.

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.

Esophagram should be performed to diagnose esophageal perforation before inter-hospital transfer.

Background: Early recognition of esophageal perforation may prevent morbidity and mortality, and accurate diagnostic imaging facilitates triage. Stable patients with suspected perforation may be transferred to higher levels of care before appropriate work-up and diagnosis confirmation. We reviewed patients transferred for esophageal perforation to critically analyze the diagnostic workflow. Methods: We performed a retrospective review of patients transferred to our tertiary care institution from 2015-2021 for suspected esophageal perforation. Demographics, referring site characteristics, diagnostic studies, and management were analyzed. Bivariate comparisons were performed using Wilcoxon-Mann-Whitney tests for continuous variables and chi-squared or Fisher's exact tests for categorical variables. Results: Sixty-five patients were included. Etiology of suspected perforation was spontaneous in 53.8% and iatrogenic in 33.8%. Most patients were transferred within 24 hours from time of suspected perforation (66.2%). Transferring sites included seven states and were 101-300 miles (32.3%) or >300 miles (26.2%) away. CT imaging was obtained in 96.9% before transfer, most commonly demonstrating pneumomediastinum (46.2%). Only 21.5% of patients had an esophagram before transfer. Following transfer, 36.9% (n=24) were ultimately not found to have esophageal perforation, demonstrated by negative arrival esophagram in 79.1%. In patients with confirmed perforation (n=41), 58.5% had surgery, 26.8% endoscopic intervention, and 14.6% supportive care. Conclusions: After transfer a proportion of patients were ultimately found to not have esophageal perforation, typically demonstrated by negative esophagram upon arrival. We conclude that a recommendation of performing esophagram at the presenting site, when possible, may prevent unnecessary transfers, and will likely reduce costs, conserve resources, and decrease management delays.

A comparison of short-term outcomes following robotic-assisted vs. open transthoracic diaphragm plication.

Diaphragm paralysis and eventration are rare conditions in adults. Symptomatic patients may benefit from surgical plication of the elevated hemidiaphragm. The objective of this study was to compare short-term outcomes and length of stay following robotic-assisted vs. open diaphragm plication. A multicenter retrospective study was conducted that identified patients undergoing unilateral hemidiaphragm plication from 5/2008 to 12/2020. The first RATS plication was performed in 11/2018. Electronic medical records were reviewed, and outcomes were compared between RATS and open approach. One hundred patients underwent diaphragm plication, including thirty-nine (39.0%) RATS and sixty-one (61.0%) open cases. Patients undergoing RATS diaphragm plication were older (64 years vs. 55 years, p = 0.01) and carried a higher burden of comorbidities (Charlson Comorbidity Index: 2.0 vs. 1.0, p = 0.02). The RATS group had longer median operative times (146 min vs. 99 min, p < 0.01), but shorter median hospital length of stays (3.0 days vs. 6.0 days, p < 0.01). There was a non-significant trend toward a decreased rate of 30-day postoperative complications (20.5% RATS vs. 32.8% open, p = 0.18) and 30-day unplanned readmissions (7.7% RATS vs. 9.8% open, p > 0.99). RATS is a technically feasible and safe option for performing diaphragm plications. This approach increases the surgical candidacy of older patients with a higher burden of comorbid disease without increasing complication rates, while reducing length of hospital stay.

Direct and indirect activation of the adenosine triphosphate-sensitive potassium channel to induce spinal cord ischemic metabolic tolerance.

OBJECTIVES: The mitochondrial adenosine triphosphate-sensitive potassium channel is central to pharmacologically induced tolerance to spinal cord injury. We hypothesized that both direct and nitric oxide-dependent indirect activation of the adenosine triphosphate-sensitive potassium channel contribute to the induction of ischemic metabolic tolerance. METHODS: Spinal cord injury was induced in adult male C57BL/6 mice through 7 minutes of thoracic aortic crossclamping. Pretreatment consisted of intraperitoneal injection 3 consecutive days before injury. Experimental groups were sham (no pretreatment or ischemia, n = 10), spinal cord injury control (pretreatment with normal saline, n = 27), Nicorandil 1.0 mg/kg (direct and indirect adenosine triphosphate-sensitive potassium channel opener, n = 20), Nicorandil 1 mg/kg + carboxy-PTIO 1 mg/kg (nitric oxide scavenger, n = 21), carboxy-PTIO (n = 12), diazoxide 5 mg/kg (selective direct adenosine triphosphate-sensitive potassium channel opener, n = 25), and DZ 5 mg/kg+ carboxy-PTIO 1 mg/kg, carboxy-PTIO (n = 23). Limb motor function was assessed using the Basso Mouse Score (0-9) at 12-hour intervals for 48 hours after ischemia. RESULTS: Motor function was significantly preserved at all time points after ischemia in the Nicorandil pretreatment group compared with ischemic control. The addition of carboxy-PTIO partially attenuated Nicorandil's motor-preserving effect. Motor function in the Nicorandil + carboxy-PTIO group was significantly preserved compared with the spinal cord injury control group (P < .001), but worse than in the Nicorandil group (P = .078). Motor preservation in the diazoxide group was similar to the Nicorandil + carboxy-PTIO group. There was no significant difference between the diazoxide and diazoxide + carboxy-PTIO groups. CONCLUSIONS: Both direct and nitric oxide-dependent indirect activation of the mitochondrial adenosine triphosphate-sensitive potassium channel play an important role in pharmacologically induced motor function preservation.

Effectiveness of an Electronic Medical Record-Based Recognition Tool for the Identification of Incidental Pulmonary Nodules.

BACKGROUND: Incidental pulmonary nodules (IPNs) are lung nodules detected on imaging studies performed for an unrelated reason. Approximately 1.6 million IPNs are detected in the United States every year. Unfortunately, close to 1.1 million (69%) of these IPNs are not managed with appropriate follow-up care. The goal of this study was to assess the utility of a noncommercial electronic medical record (EMR)-based IPN keyword recognition program in identifying IPNs and the ability of lung navigators to communicate these findings to patients. METHODS: This is a observational, implementation study aimed identify IPNs using an EMR-based protocol and to relay results of findings to patients. The patient population included patients 16 and older undergoing computed tomography (CT) chest, CT chest/abdomen, CT angiogram chest, CT chest/abdomen/pelvis, and chest radiography through the radiology department within a large community tertiary medical campus between June 2019 and August 2020. EPIC EMR were queried using criteria designed to find IPNs. A lung navigator reviewed these cases and sorted them into categories based on their size and risk status. After identification of risk factors, actions were taken to directly communicate results to patients. RESULTS: Seven hundred and fifty-three patients were found to have true IPNs without a history of active malignancy involving the lung. On the basis of radiographic measurements, 60% of the nodules identified were <6 mm, 17% were between 6 and 8 mm, 22% were >8 mm, and 12% were deemed nodular opacities. Lung navigators were able to contact a total of 637 (87%) individuals with IPNs and results were directly communicated. Of the 637 patients identified to have an IPN, a total of 12 (2%) cancers were diagnosed. CONCLUSION: We have here demonstrated that the development of an EMR-based keyword recognition platform for the identification of IPNs is a useful and successful tool for communication of IPN findings to patients using lung navigators.

Glypican 1 promotes proliferation and migration in esophagogastric adenocarcinoma via activating AKT/GSK/ß-catenin pathway.

Background: Glypican 1 (GPC1) is a heparan sulphate proteoglycan cell membrane protein. It is implicated in driving cancers of the breast, brain, pancreas, and prostate; however, its role in esophagogastric cancer (EGAC) remains unexplored. The aim of the study was to investigate and elucidate the molecular mechanistic of GPC1 in human EGAC. Methods: Thirty tissue and 120 microarray sections of EGAC were evaluated with Anti-GPC1 immunohistochemistry. Loss and gain of GPC1 function were performed using lentivirus transfection in EGAC cell lines. Mechanistically, AKT/GSK/ß-catenin pathway was evaluated using AKT inhibitor MK-2206 and Wnt/ß-catenin stimulant LiCl. Results: GPC1 overexpression was found in 102 cases (68%). Overexpression of GPC1 correlated with lymph node metastasis, poor differentiation and decreased overall survival. Lentivirus mediated GPC1 knockdown resulted in decreased cell proliferation, migration, invasion, and colony formation. Knockdown caused G0/G1 cell cycle arrest, increased apoptosis, and reduced epithelial mesenchymal transition (EMT). GPC1 mediated its effects by activation of AKT/GSK/ß-catenin pathway. Conclusions: This is the first descriptive study to decipher the role of GPC1 in EGAC. Our results suggest that GPC1 regulates cell proliferation and growth and may serve as an attractive oncotarget in EGAC.

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.

Optimizing Nicorandil for Spinal Cord Protection in a Murine Model of Complex Aortic Intervention.

There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 minutes before ischemia showed no neuroprotection. All nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.

Introduction of robotic surgery does not negatively affect cardiothoracic surgery resident experience.

The objective of this study was to evaluate the educational impact following the implementation of a robotic thoracic surgery program on cardiothoracic (CT) surgery trainees. We hypothesized that the introduction of a robotic thoracic surgery program would adversely affect the CT surgery resident experience, decreasing operative involvement and subsequent competency of surgical procedures. CT surgery residents and thoracic surgery attendings from a single academic institution were administered a recurring, electronic survey from September 2019 to September 2020 following each robotic thoracic surgery case. Surveys evaluated resident involvement and operative performance. This study was exempt from review by our Institutional Review Board. Attendings and residents completed surveys for 86 and 75 cases, respectively. Residents performed > 50% of the operation independently at the surgeon console in 66.2 and 73.3% of cases according to attending and resident responses, respectively. The proportion of trainees able to perform > 75% of the operation increased with each increasing year in training (p = 0.002). Based on the Global Evaluative Assessment of Robotic Skills grading tool, third-year residents averaged higher scores compared to first-year residents (22.9 versus 17.4 out of 30 possible points, p < 0.001), indicating that more extensive prior operative experience could shorten the learning curve of robotic thoracic surgery. CT surgery residents remain actively involved in an operative role during the establishment of a robotic thoracic surgery program. The transition to a robotic thoracic surgery platform appears feasible in a large academic setting without jeopardizing the educational experience of resident trainees.

Warfarin Induces Calcification of the Aortic Valve Through Extracellular Signal-regulated Kinase 1/2 and ß-catenin Signaling.

BACKGROUND: Recent clinical evidence suggests an association between warfarin use and calcification of the aortic valve. We sought to determine the effect of warfarin on aortic valve interstitial cell (AVIC) osteogenic protein expression and the signaling pathways by which this effect is mediated. METHODS: Human AVICs were isolated from normal aortic valves of patients undergoing cardiac transplantation, whereas diseased AVICs were isolated from patients undergoing aortic valve replacement for aortic stenosis. AVICs were treated with various anticoagulants, and osteogenic protein expression was evaluated using immunoblotting. Phosphorylation of lipoprotein receptor-related protein 6 (LRP6) and extracellular signal-regulated kinase 1/2 (ERK1/2) was evaluated after treatment with warfarin. AVICs were pretreated with LRP6 inhibitor dkk1 and ERK1/2 inhibitor PD98059 followed by treatment with warfarin, and osteogenic protein expression was evaluated. RESULTS: Warfarin, but not heparin or dabigatran, significantly increased Runx-2 and Osx expression in both normal and diseased human AVICs. Upregulation of ß-catenin protein expression and nuclear translocation occurred in diseased AVICs but not normal AVICs after warfarin treatment. Warfarin induced phosphorylation of LRP6 in diseased AVICs only and phosphorylation of ERK1/2 in both normal and diseased AVICs. LRP6 inhibition attenuated warfarin-induced Runx-2 expression in diseased AVICs. ERK1/2 inhibition attenuated warfarin-induced Runx-2 expression in both normal and diseased AVICs. CONCLUSIONS: Warfarin induces osteogenic activity in normal and diseased isolated human AVICs. This effect is mediated by ERK1/2 in both diseased and normal AVICs, but in diseased AVICs ß-catenin signaling also plays a role. These results implicate the role of warfarin in aortic valve calcification and highlight potential mechanisms for warfarin-induced aortic stenosis.

Expression of Adhesion Molecules in a Gastroduodenal Reflux Murine Model.

BACKGROUND: Various adhesion molecules, including intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), have been shown to play a role in inflammation as well as contribute to tumor progression and prognosis. We hypothesized that gastroduodenal reflux upregulates ICAM-1 and VCAM-1 expression in the distal esophagus, serving as possible early markers of pathologic esophageal disease. METHODS: Normal human esophageal epithelial cells (HET1A), Barrett cells (CPB), and esophageal adenocarcinoma cells (FLO1 and OE33) were treated with deoxycholic acid at increasing concentrations for 24 hours. Adhesion molecule expression was assessed using immunoblotting. A surgical mouse reflux model was generated by performing a side-to-side anastomosis between the gastroesophageal junction and the first portion of the duodenum (duodenum-gastroesophageal anastomosis). Esophageal sections were evaluated using hematoxylin and eosin staining, immunohistochemistry, and immunofluorescence. RESULTS: Deoxycholic acid induced a significant increase in ICAM-1 and VCAM-1 expression in HET1A, CPB, FLO1, and OE33 cells. Animals undergoing duodenum-gastroesophageal anastomosis demonstrated a significant increase in mucosal hyperplasia (P < .0001) and cellular proliferation (P < .0001) compared with control animals. Immunofluorescence and Western blot analysis of the lower esophagus demonstrated significant upregulation of ICAM-1 (P = .005), with no change in VCAM-1 expression (P = .82). CONCLUSIONS: Our results reveal that ICAM-1 and VCAM-1 are upregulated in response to in vitro reflux treatment of normal esophageal epithelial cells. However, our investigation using a mouse reflux model found ICAM-1 is noticeably upregulated without a concomitant increase in VCAM-1. These findings identify ICAM-1, but not VCAM-1, as a potential player in early esophageal disease developing from chronic reflux exposure.

Toll-like Receptor 4 Mediates Reflux-Induced Inflammation in a Murine Reflux Model.

Dysregulation of toll-like receptor (TLR) signaling within the gastrointestinal epithelium has been associated with uncontrolled inflammation and tumorigenesis. We sought to evaluate the role of TLR4 in the development of gastroesophageal reflux-mediated inflammation and mucosal changes of the distal esophagus. Verified human esophageal Barrett's cells with high grade dysplasia (CPB) and esophageal adenocarcinoma cells (OE33) were treated with deoxycholic acid for 24 hours. Cells were pretreated with a TLR4-specific inhibitor peptide 2 hours prior to deoxycholic acid treatment. Inflammatory markers were evaluated using immunoblotting and enzyme-linked immunosorbent assay. A surgical reflux mouse model was generated by performing a side-to-side anastomosis between the second portion of the duodenum and the gastroesophageal junction. Control animals underwent laparotomy with incision and closure of the esophagus superior to the gastroesophageal junction (sham procedure). Esophageal sections were evaluated using hematoxylin and eosin staining and immunohistochemistry. Deoxycholic acid increased expression of inflammatory markers including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin 8. Pretreatment with a TLR4 inhibitor significantly decreased deoxycholic acid-induced inflammatory marker expression. C3H/HeNCrl mice demonstrated a significant increase in mucosal hyperplasia and proliferation following DGEA compared to sham procedure. TLR4 mutant mice (C3H/HeJ) undergoing DGEA demonstrated an attenuated hyperplastic and proliferative response compared to C3H/HeNCrl mice. Inhibition of TLR4 signaling attenuates reflux-induced inflammation in vivo. These findings identify TLR4 inhibition as a potential therapeutic target to halt the progression of pathologic esophageal changes developing in the setting of chronic gastroesophageal reflux disease.

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.

Reactive Oxygen Species Mediate Nicorandil-induced Metabolic Tolerance to Spinal Cord Injury.

BACKGROUND: Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with nicorandil preserved motor function in a murine spinal cord injury model through mitochondrial adenosine triphosphate-sensitive potassium channel activation. We hypothesized that the neuroprotective effect of nicorandil is mediated by downstream generation of reactive oxygen species. METHODS: Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n = 19); nicorandil 1.0 mg/kg (n = 17); nicorandil 1.0 mg/kg plus N acetyl L-cysteine (NAC [reactive oxygen species scavenger, n = 18)]) 150 mg/kg; NAC 150 mg/kg (n = 13); and sham (n = 10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. RESULTS: Mice in the sham group showed no functional deficits after surgery. Compared with ischemic control, motor function was significantly preserved in the nicorandil pretreatment group at every timepoint after ischemia. In the nicorandil plus NAC group, the motor-preserving effect of nicorandil was completely abolished (P < .001). Viable neuron quantification showed significant neuron preservation in the nicorandil group (29.± 2.6) compared with the ischemic control group (18.5 ± 2.1, P = .024) and nicorandil plus NAC group (14 ± 8.3, P = .001); no significant difference was observed between the ischemic control group and nicorandil plus NAC group (P = 0.768). CONCLUSIONS: Reactive oxygen species generation plays a key role in the nicorandil-induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial adenosine triphosphate-sensitive potassium channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.

Impact of Radiation Dose on Postoperative Complications in Esophageal and Gastroesophageal Junction Cancers.

Introduction: The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established. Methods: We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with <50 Gy and ≥ 50 Gy, as well as to published CROSS study neoadjuvant chemoradiation group data (41.4 Gy). Results: Twenty-nine patients were treated with <50 Gy (range 39.6-46.8 Gy) and 53 patients were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Complication rates and CCI scores between our <50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS data, there was no significant difference in CCI scores between the CROSS study neoadjuvant chemoradiation, <50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS group (50%) than our <50 Gy (38%) or ≥ 50 Gy (30%) groups. Conclusions: In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50-50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.