The Effect of Laparoscopic Gastric Ischemic Preconditioning Prior to Esophagectomy on Anastomotic Stricture Rate and Comparison with Esophagectomy-Alone Controls.

BACKGROUND: Benign anastomotic stricture is a recognized complication following esophagectomy. Laparoscopic gastric ischemic preconditioning (LGIP) prior to esophagectomy has been associated with decreased anastomotic leak rates; however, its effect on stricture and the need for subsequent endoscopic intervention is not well studied. METHODS: This was a case-control study at an academic medical center using consecutive patients undergoing oncologic esophagectomies (July 2012-July 2022). Our institution initiated an LGIP protocol on 1 January 2021. The primary outcome was the occurrence of stricture within 1 year of esophagectomy, while secondary outcomes were stricture severity and frequency of interventions within the 6 months following stricture. Bivariable comparisons were performed using Chi-square, Fisher's exact, or Mann-Whitney U tests. Multivariable regression controlling for confounders was performed to generate risk-adjust odds ratios and to identify the independent effect of LGIP. RESULTS: Of 253 esophagectomies, 42 (16.6%) underwent LGIP prior to esophagectomy. There were 45 (17.7%) anastomotic strictures requiring endoscopic intervention, including three patients who underwent LGIP and 42 who did not. Median time to stricture was 144 days. Those who underwent LGIP were significantly less likely to develop anastomotic stricture (7.1% vs. 19.9%; p = 0.048). After controlling for confounders, this difference was no longer significant (odds ratio 0.46, 95% confidence interval 0.14-1.82; p = 0.29). Of those who developed stricture, there was a trend toward less severe strictures and decreased need for endoscopic dilation in the LGIP group (all p < 0.20). CONCLUSION: LGIP may reduce the rate and severity of symptomatic anastomotic stricture following esophagectomy. A multi-institutional trial evaluating the effect of LGIP on stricture and other anastomotic complications is warranted.

Early Pharmacologic Therapy in Patients With Blunt Cerebrovascular Injury and TBI: Is it Safe and Effective? An EAST Multicenter Study.

BACKGROUND: Blunt cerebrovascular injury (BCVI) with concurrent traumatic brain injury (TBI) presents increased risk of both ischemic stroke and bleeding. This study investigated the safety and survival benefit of BCVI treatment (antithrombotic and/or anticoagulant therapy) in this population. We hypothesized that treatment would be associated with fewer and later strokes in patients with BCVI and TBI without increasing bleeding complications. METHODS: Patients with head AIS >0 were selected from a database of BCVI patients previously obtained for an observational trial. A Kaplan-Meier analysis compared stroke survival in patients who received BCVI treatment to those who did not. Logistic regression was used to evaluate for confounding variables. RESULTS: Of 488 patients, 347 (71.1%) received BCVI treatment and 141 (28.9%) did not. BCVI treatment was given at a median of 31 h post-admission. BCVI treatment was associated with lower stroke rate (4.9% vs 24.1%, P < .001 and longer stroke-free survival (P < .001), but also less severe systemic injury. Logistic regression identified motor GCS and BCVI treatment as the only predictors of stroke. No patients experienced worsening TBI because of treatment. DISCUSSION: Patients with BCVI and TBI who did not receive BCVI treatment had an increased rate of stroke early in their hospital stay, though this effect may be confounded by worse motor deficits and systemic injuries. BCVI treatment within 2-3 days of admission may be safe for patients with mean head AIS of 2.6. Future prospective trials are needed to confirm these findings and determine optimal timing of BCVI treatment in TBI patients with BCVI.

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.

Prospective Evaluation of a Universally Applied Laparoscopic Gastric Ischemic Preconditioning Protocol Prior to Esophagectomy with Comparison with Historical Controls.

BACKGROUND: Anastomotic leak after esophagectomy is associated with significant morbidity and mortality. Our institution began performing laparoscopic gastric ischemic preconditioning (LGIP) with ligation of the left gastric and short gastric vessels prior to esophagectomy in all patients presenting with resectable esophageal cancer. We hypothesized that LGIP may decrease the incidence and severity of anastomotic leak. METHODS: Patients were prospectively evaluated following the universal application of LGIP prior to esophagectomy protocol in January 2021 until August 2022. Outcomes were compared with patients who underwent esophagectomy without LGIP from a prospectively maintained database from 2010 to 2020. RESULTS: We compared 42 patients who underwent LGIP followed by esophagectomy with 222 who underwent esophagectomy without LGIP. Age, sex, comorbidities, and clinical stage were similar between groups. Outpatient LGIP was generally well tolerated, with one patient experiencing prolonged gastroparesis. Median time from LGIP to esophagectomy was 31 days. Mean operative time and blood loss were not significantly different between groups. Patients who underwent LGIP were significantly less likely to develop an anastomotic leak following esophagectomy (7.1% vs. 20.7%, p = 0.038). This finding persisted on multivariate analysis [odds ratio (OR) 0.17, 95% confidence interval (CI) 0.03-0.42, p = 0.029]. The occurrence of any post-esophagectomy complication was similar between groups (40.5% vs. 46.0%, p = 0.514), but patients who underwent LGIP had shorter length of stay [10 (9-11) vs. 12 (9-15), p = 0.020]. CONCLUSIONS: LGIP prior to esophagectomy is associated with a decreased risk of anastomotic leak and length of hospital stay. Further, multi-institutional studies are warranted to confirm these findings.

Long-Term Patient-Reported Symptom Improvement and Quality of Life after Transthoracic Diaphragm Plication in Adults.

BACKGROUND: Open and robotic-assisted transthoracic approaches for diaphragm plication are accepted surgical interventions for diaphragm paralysis and eventration. However, long-term patient-reported symptom improvement and quality of life (QOL) remains unclear. STUDY DESIGN: A telephone-based survey was developed focusing on postoperative symptom improvement and QOL. Patients who underwent open or robotic-assisted transthoracic diaphragm plication (2008-2020) across three institutions were invited to participate. Patients who responded and provided consent were surveyed. Likert responses on symptom severity were dichotomized and rates before and after surgery were compared using McNemar's test. RESULTS: Forty-one percent of patients participated (43 of 105 responded, mean age 61.0 years, 67.4% male, 37.2% robotic-assisted surgery), with an average time between surgery and survey of 4.1 ± 3.2 years. Patients reported significant improvement in dyspnea while lying flat (67.4% pre- vs 27.9% postoperative, p < 0.001), dyspnea at rest (55.8% pre- vs 11.6% postoperative, p < 0.001), dyspnea with activity (90.7% pre- vs 55.8% postoperative, p < 0.001), dyspnea while bending over (79.1% pre- vs 34.9% postoperative, p < 0.001), and fatigue (67.4% pre- vs 41.9% postoperative, p = 0.008). There was no statistical improvement in chronic cough. 86% of patients reported improved overall QOL, 79% had increased exercise capacity, and 86% would recommend surgery to a friend with a similar problem. Analysis comparing open and robotic-assisted approaches found no statistically significant differences in symptom improvement or QOL responses between the groups. CONCLUSIONS: Patients report significantly improved dyspneic and fatigue symptoms after transthoracic diaphragm plication, regardless of open or robotic-assisted approach. The majority of patients report improved QOL and exercise capacity.

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.

Barriers and Facilitators in Implementation of an Esophagectomy Care Pathway: a Qualitative Analysis.

INTRODUCTION: A new postoperative esophagectomy care pathway was recently implemented at our institution. Practice pattern change among provider teams can prove challenging; therefore, we sought to study the barriers and facilitators toward pathway implementation at the provider level. METHODS: This qualitative study was guided by the Theoretical Domains Framework (TDF) to study the adoption and implementation of a post-esophagectomy care pathway. Sixteen in-depth interviews were conducted with providers involved with the pathway. Matrix analysis was used to analyze the data. RESULTS: Providers included attending surgeons (n = 6), advanced practice providers (n = 8), registered dietitian (n = 1), and clinic staff (n = 1). TDF domains that were salient across our findings included knowledge, beliefs about consequences, social influences, and environmental context and resources. Identified facilitators included were electronic health record tools, such as note templates including pathway components and a pathway-specific order set, patient satisfaction, and preliminary data indicating clinical benefits such as a reduced anastomotic leak rate. The major barrier reported was a hesitance to abandon previous practice patterns, most prevalent at the attending surgeon level. CONCLUSION: The TDF enabled us to identify and understand the individuals' perceived barriers and facilitators toward adoption and implementation of a postoperative esophagectomy pathway. This analysis can help guide and improve adoption of surgical patient care pathways among providers.

Development of a Modular and Equitable Surgical Simulator.

There is a tremendous need for affordable and accessible surgical simulators in the United States and abroad. Our group developed a portable, modular, inexpensive surgical simulator designed for all levels of surgical trainees, from medical students to cardiothoracic surgery fellows, and adaptable to a variety of surgical specialties. Our goal is to provide a platform for innovative surgery simulation that applies to any learner or resource setting. We describe the development, assembly, and future directions for this simulator.

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.

Making a Painless Drain: Proof of Concept.

Chest tubes account for a large proportion of postoperative pain after cardiothoracic operations. The objective of this study was to develop a novel, cost-effective, easy-to-use, lidocaine-eluting coating to reduce pain associated with postoperative chest tubes. A lidocaine-eluting hydrogel was developed by dispersing lidocaine-loaded nanoparticles in an aqueous solution containing gelatin (5%). Glutaraldehyde (1%) was added to crosslink the gelatin into a hydrogel. The hydrogel was dehydrated, resulting in a thin, stable polymer. Sterile lidocaine hydrogel-coated silicone discs and control discs were prepared and surgically implanted in the subcutaneous space of C57B6 mice. Using von Frey filaments, mice underwent preoperative baseline pain testing, followed by pain testing on post-procedure day 1 and 3. On post-procedure day 1, mice implanted with control discs demonstrated no change in pain tolerance compared to baseline, while mice implanted with 20 mg and 80 mg lidocaine-loaded discs demonstrated a 2.4-fold (P = 0.36) and 4.7-fold (P = 0.01) increase in pain tolerance, respectively. On post-procedure day 3, mice implanted with control discs demonstrated a 0.7-fold decrease in pain tolerance compared to baseline, while mice implanted with 20 mg and 80 mg lidocaine-loaded discs demonstrated a 1.8-fold (P = 0.88) and 8.4-fold (P = 0.02) increase in pain tolerance, respectively. Our results demonstrate successful development of a lidocaine-eluting chest tube with hydrogel coating, leading to improved pain tolerance in vivo. The concept of a drug-eluting drain coating has significant importance due to its potential universal application in a variety of drain types and insertion locations.

Evaluating the risk of spinal cord ischemia in zone 2 frozen elephant trunk replacement.

BACKGROUND: The appropriate stent length in frozen elephant trunk replacements (FET) remains debated relative to the risk for paraplegia. However, landing the distal end of the stent beyond the curve of the arch facilitates distal reintervention, which is commonly beyond the 10 cm stent coverage when deployed proximal to the left subclavian artery. The aim of this study was to evaluate outcomes following the use of 15 cm stent grafts in zone 2 (z2, distal to the left common carotid). METHODS: Using our single institution-maintained database, 103 zone 2 FET performed from 2016 to 2020 were reviewed. RESULTS: Of the 103 z2, a 15 cm stent graft was used in 51 operations. The indications for FET included acute and chronic aortic dissection, arch aneurysms, and pseudoaneurysms. The incidence of SCI was 0%. Seven deaths (13.7%) occurred. CONCLUSIONS: The data demonstrates the incidence of post-operative paraplegia to be 0% with 15 cm z2 FET. The understanding of SCI in FET should not only include the stent length but also from where it begins.

Survival following lung transplantation: A population-based nested case-control study.

BACKGROUND: Lung transplantation is the mainstay of treatment for patients with end-stage respiratory failure. This study sought to evaluate survival following transplantation compared to the general population and quantify standardized mortality ratios (SMRs) using a nested case-control study design. METHODS: Control subjects were nonhospitalized inhabitants of the United States identified through the National Longitudinal Mortality Study. Case subjects were adults who underwent lung transplantation between 1990 and 2007 and identified through the Organ Procurement and Transplantation Network. Propensity-matching (5:1, nearest neighbor, caliper = 0.1) was utilized to identify suitable control subjects based on age, sex, race, and location of residency. The primary study endpoint was 10-year survival. RESULTS: About 14,977 lung transplant recipients were matched to 74,885 nonhospitalized US residents. The 10-year survival rate of lung transplant recipients was 28% (95% confidence interval [CI] = 27%-29%). The population expected mortality rate was 19 deaths/100 person-years while the observed ratio was 104 deaths/100 person-years (SMR = 5.39, 95% CI = 5.35-5.43). The largest discrepancies between observed and expected mortality rates were in females (SMR = 5.97), Hispanic (SMR = 10.70), and single lung recipients (SMR = 5.92). SMRs declined over time (1990-1995 = 5.79, 1996-2000 = 5.64, and 2001-2007 = 5.10). Standardized mortality peaks in the first year after transplant and decreases steadily over time. CONCLUSIONS: Lung transplant recipients experience a fivefold higher SMR compared to the nonhospitalized population. Long-term mortality rates have experienced consistent decline over time.

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.

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.

Factors associated with stroke formation in blunt cerebrovascular injury: An EAST multicenter study.

BACKGROUND: Stroke risk factors after blunt cerebrovascular injury (BCVI) are ill-defined. We hypothesized that factors associated with stroke for BCVI would include medical therapy (i.e., Aspirin), radiographic features, and protocolization of care. METHODS: An Eastern Association for the Surgery of Trauma-sponsored, 16-center, prospective, observational trial was undertaken. Stroke risk factors were analyzed individually for vertebral artery (VA) and internal carotid artery (ICA) BCVI. Blunt cerebrovascular injuries were graded on the standard 1 to 5 scale. Data were from the initial hospitalization only. RESULTS: Seven hundred seventy-seven BCVIs were included. Stroke rate was 8.9% for all BCVIs, with an 11.7% rate of stroke for ICA BCVI and a 6.7% rate for VA BCVI. Use of a management protocol (p = 0.01), management by the trauma service (p = 0.04), antiplatelet therapy over the hospital stay (p < 0.001), and Aspirin therapy specifically over the hospital stay (p < 0.001) were more common in ICA BCVI without stroke compared with those with stroke. Antiplatelet therapy over the hospital stay (p < 0.001) and Aspirin therapy over the hospital stay (p < 0.001) were more common in VA BCVI without stroke than with stroke. Percentage luminal stenosis was higher in both ICA BCVI (p = 0.002) and VA BCVI (p < 0.001) with stroke. Decrease in percentage luminal stenosis (p < 0.001), resolution of intraluminal thrombus (p = 0.003), and new intraluminal thrombus (p = 0.001) were more common in ICA BCVI with stroke than without, while resolution of intraluminal thrombus (p = 0.03) and new intraluminal thrombus (p = 0.01) were more common in VA BCVI with stroke than without. CONCLUSION: Protocol-driven management by the trauma service, antiplatelet therapy (specifically Aspirin), and lower percentage luminal stenosis were associated with lower stroke rates, while resolution and development of intraluminal thrombus were associated with higher stroke rates. Further research will be needed to incorporate these risk factors into lesion specific BCVI management. LEVEL OF EVIDENCE: Prognostic and Epidemiologic, Level IV.