Circulating extracellular choline acetyltransferase regulates inflammation.

BACKGROUND: Choline acetyltransferase (ChAT) is required for the biosynthesis of acetylcholine, the molecular mediator that inhibits cytokine production in the cholinergic anti-inflammatory pathway of the vagus nerve inflammatory reflex. Abundant work has established the biology of cytoplasmic ChAT in neurons, but much less is known about the potential presence and function of ChAT in the extracellular milieu. OBJECTIVES: We evaluated the hypothesis that extracellular ChAT activity responds to inflammation and serves to inhibit cytokine release and attenuate inflammation. METHODS: After developing novel methods for quantification of ChAT activity in plasma, we determined whether ChAT activity changes in response to inflammatory challenges. RESULTS: Active ChAT circulates within the plasma compartment of mice and responds to immunological perturbations. Following the administration of bacterial endotoxin, plasma ChAT activity increases for 12-48 h, a time period that coincides with declining tumor necrosis factor (TNF) levels. Further, a direct activation of the cholinergic anti-inflammatory pathway by vagus nerve stimulation significantly increases plasma ChAT activity, whereas the administration of bioactive recombinant ChAT (r-ChAT) inhibits endotoxin-stimulated TNF production and anti-ChAT antibodies exacerbate endotoxin-induced TNF levels, results of which suggest that ChAT activity regulates endogenous TNF production. Administration of r-ChAT significantly attenuates pro-inflammatory cytokine production and disease activity in the dextran sodium sulfate preclinical model of inflammatory bowel disease. Finally, plasma ChAT levels are also elevated in humans with sepsis, with the highest levels observed in a patient who succumbed to infection. CONCLUSION: As a group, these results support further investigation of ChAT as a counter-regulator of inflammation and potential therapeutic agent.

Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice.

Deficiency of coagulation factor VIII in hemophilia A disrupts clotting and prolongs bleeding. While the current mainstay of therapy is infusion of factor VIII concentrates, inhibitor antibodies often render these ineffective. Because preclinical evidence shows electrical vagus nerve stimulation accelerates clotting to reduce hemorrhage without precipitating systemic thrombosis, we reasoned it might reduce bleeding in hemophilia A. Using two different male murine hemorrhage and thrombosis models, we show vagus nerve stimulation bypasses the factor VIII deficiency of hemophilia A to decrease bleeding and accelerate clotting. Vagus nerve stimulation targets acetylcholine-producing T lymphocytes in spleen and α7 nicotinic acetylcholine receptors (α7nAChR) on platelets to increase calcium uptake and enhance alpha granule release. Splenectomy or genetic deletion of T cells or α7nAChR abolishes vagal control of platelet activation, thrombus formation, and bleeding in male mice. Vagus nerve stimulation warrants clinical study as a therapy for coagulation disorders and surgical or traumatic bleeding.

Impact of radial margins after esophagectomy for esophageal cancer.

INTRODUCTION: The prognostic significance of radial margin (RM) involvement in esophagectomy cancer specimens is unclear. Our study investigated survival and recurrence rates between different depths of RM involvement. MATERIALS AND METHODS: We retrospectively analyzed 1103 esophagectomies at our institution from 2005 to 2019. Patients were grouped by three-tier stratification: negative RM > 1 mm away, direct RM involvement at 0 mm, and close RM between 0 mm and 1 mm. Survival, loco-regional and distant recurrences were analyzed. RESULTS: 1103 esophageal cancer patients were analyzed. 389 patients had recurrence (35.3%). Median survival (13.2 months) and recurrence rates (71%) were worst with direct RM (p < 0.001) as compared to negative RM (median survival not achieved within 5-years from surgery and 30%). Without nodal involvement, RM involvement of <1 mm was associated with decreased overall survival, and overall, loco-regional and distant recurrence-free survival compared to negative RM (log rank p-value <0.05). In those with persistent nodal disease, only direct RM was associated with decreased overall and loco-regional recurrence-free survival as compared to negative margins (p < 0.05). Direct RM tended to do worse compared to close RM in terms of median survival and trended worse for recurrence. Direct RM (baseline negative RM), but not close RM, was an independent RF in a multivariable Cox model for worse overall survival (HR 2.74; p < 0.001), recurrence-free survival (HR 1.96; p = 0.019), and loco-regional recurrence-free survival (HR 3.19; p = 0.011). CONCLUSION: RM involvement affects survival and recurrence. Tumor at 0 mm remained an independent RF for worse survival and overall and loco-regional recurrence.

Opportunities for quality improvement in the morbidity pattern of older adults undergoing pulmonary lobectomy for cancer.

BACKGROUND: There is limited information on the frequency of complications among older adults after oncological thoracic surgery in the modern era. We hypothesized that morbidity and mortality in older adults with lung cancer undergoing lobectomy is low and different than that of younger patients undergoing thoracic surgery. METHODS: All patients undergoing lobectomy at a large volume academic center between May 2016 and May 2019 were included. Patients were prospectively monitored to grade postoperative morbidity by organ system, based on the Clavien-Dindo classification. Patients were divided into two groups: Group 1 included patients 65-91 years of age, and Group 2 included those <65 years. RESULTS: Of 680 lobectomies in 673 patients, 414(61%) were older than 65 years of age (group 1). Median age at surgery was 68 years (20-91). Median hospital stay was 4 days (1-38) and longer in older adults. Older adults experienced higher rates of grade II and IV complications, mostly driven by an increased incidence of delirium, atrial fibrillation, prolonged air leak, respiratory failure and urinary retention. In this modern cohort, there was only 1 stroke (0.1%), and delirium was reduced to 7%. Patients undergoing minimally invasive (MI) surgery had a lower rate of Grade IV life-threatening complications. Older adults were more likely to be discharged to a rehabilitation facility, however this difference also disappeared with MI surgical procedures. CONCLUSIONS: Current morbidity of older adults undergoing lobectomy for cancer is low and is different than that of younger patients. Thoracotomy may be associated with postoperative complications in these patients. Our findings suggest the need to consider MI approaches and broad-based, geriatric-focused perioperative management of older adults undergoing lobectomy.

Impact of Neoadjuvant Chemoradiation on Adverse Events After Bronchial Sleeve Resection.

BACKGROUND: We analyzed the association between neoadjuvant chemoradiation in patients undergoing bronchial sleeve resection with the incidence of postoperative pulmonary and airway complications. METHODS: After instructional review board approval we performed a retrospective review of a prospectively maintained database of 136 patients who underwent sleeve resection in our institution between January 1998 and December 2016. Administration of neoadjuvant chemoradiation treatment was the studied exposure. Outcomes of interest were rates of postoperative pulmonary and airway complications. Nonparametric testing of demographic, surgical, and pathologic characteristics and morbidity was performed. Logistic regression models evaluated postoperative pulmonary complications and airway complications. Analysis was performed using Stata/IC 15. RESULTS: We analyzed 136 patients (18 underwent neoadjuvant chemoradiation), 77 (57%) of whom had non-small cell lung cancer. Postoperative pulmonary complications were observed in 44 of 136 patients (32%). Incidences of pulmonary complications were higher in the neoadjuvant chemoradiation group compared with the non-neoadjuvant radiation group (15/18 patients [83%] vs 29/118 patients [25%], respectively; P < .001). Likewise, rates of pneumonia, atelectasis, respiratory insufficiency, bronchial stenosis, prolonged air leak, bronchopleural fistula, and completion pneumonectomy (2/18 [11%]) were higher in the neoadjuvant chemoradiation group, reaching statistical significance in all cases except bronchial stenosis and prolonged air leak. Only neoadjuvant chemoradiation therapy remained significant for postoperative pulmonary and airway complications on logistic regression (both P < .05) CONCLUSIONS: Patients who undergo neoadjuvant chemoradiation before sleeve resection are at an increased risk of pulmonary and airway complications.

Analysis of Lymph Node Sampling Minimums in Early Stage Non-Small-Cell Lung Cancer.

Analyze "number of nodes" as an integer-valued variable to identify possible minimum lymph node (LN) number to sample during lung cancer resection. The National Cancer Database (NCDB) queried 2004-14 for surgically treated clinical stage I/II non-small-cell lung cancer (NSCLC). Overall survival (OS) by number of LN sampled was examined for the complete dataset, by adenocarcinoma, and by degree of resection using number of sampled LN both as integer-valued (0-30 nodes) variable and collapsed into classes. A total of 102,225 patients were analyzed. Median sampled LNs were 7. Median overall survival was 59 months if no LNs were sampled (95% confidence interval [CI]: 57.0-62.4), 74.7 months for 1 sampled LN (95% CI: 69.6-78.1), 80.2 (95% CI: 74.2-85.6) for 2 sampled LN, up to 81.5 mos. for 29 sampled LN. A Cox regression model using "0 LN" as baseline level, showed association with increased overall survival starting at 1 LN (hazard ratio [HR] 0.81, 95% CI 0.76-0.87; P <0.001). A "moving baseline" Cox regression model, showed no additional benefit when sampling additional nodes. We noticed a decreasing, linear association between OS and a number of 0-5 sampled LNs, most pronounced between 0 and 1 LN sampled, using a martingale residual plot from a null Cox model; no association was observed for more sampled LNs. For patients undergoing lobectomy, difference in OS was noted between 0 and 1LN sampled but not between 2 and 30 LN. These differences were not statistically significant until the number of 4 removed LN (respectively 3 for wedge-resections). For segmentectomies, median survival was not statistically associated with number of LN sampled. Based on NCDB data, LN sampling for lung cancer resections is recommended. Lobectomy survival is positively associated with 4 LN sampled, but ideal sampling may lie at 5LN in most cases. NCDB data does not seem to justify the quality metric of minimum 10 LNs.

Risk of Urinary Recatheterization for Thoracic Surgical Patients with Epidural Anesthesia.

BACKGROUND: Current quality guidelines recommend the removal of urinary catheters on or before postoperative day two, to prevent catheter-associated urinary tract infections (CAUTI). The goal of this study was to evaluate the impact urinary catheter removal on the need for urinary recatheterization (UR) of patients with epidural anesthesia undergoing thoracic surgery. MATERIALS AND METHODS: All patients undergoing thoracic surgery between November 4th, 2017 and January 9th, 2018 who had a urinary catheter placed at the time of intervention were prospectively evaluated. Patient characteristics including: history of benign prostatic hyperplasia (BPH), catheter related variables and rates of UR were collected through chart review and daily visits to the wards. BPH was defined as history of transurethral resection of the prostate or treatment with selective α1-adrenergic receptor antagonists. RESULTS: Over a two-month period 267 patients were included, 124 (46%) were male. Epidural catheters were placed in 88 (33%) patients. Median duration of urinary catheters for the cohort was 1 day (0 days - 18 days), and it was significantly higher in patients with epidural anesthesia (Table 1). Overall 20 (7%) patients required UR. On initial analysis, there was no statistical difference in the rate of UR among patients with and without epidural catheters [9/88 (10%) vs 11/179 (6%), p=0.23). The rate of UR was higher in males than in females (14/124 (11%) vs 6/143 (4%), p=0.03). Fifteen (12%) patients had a diagnosis of BPH. The rate of UR was three-times higher in this group than in those without BPH [4/15 (27%) vs 10/109 (9%) p=0.05]. Four (1%) patients developed a CAUTI during follow-up, and the rate of CAUTI was not different between those with and without epidural catheters. CONCLUSION: Urinary catheters in patients with thoracic epidural anesthesia can be safely removed, as evidenced by low reinsertion and infection rates. Removal of urinary catheters in patients with a history of BPH should be carefully evaluated, as over 1/4 will require urinary recatheterization in this subgroup. Further study of this group is needed to avoid unnecessary patient discomfort associated with recatheterization.

Routine surveillance for diagnosis of venous thromboembolism after pleurectomy for malignant pleural mesothelioma.

OBJECTIVE: The purpose of this study was to determine the incidence of venous thromboembolism and utility of a routine surveillance program in patients undergoing surgery for mesothelioma. METHODS: Patients undergoing pleurectomy from May 2016 to August 2018 were included. A standardized surveillance program to look for venous thromboembolism in this group included noninvasive studies every 7 days postoperatively or earlier if symptomatic. All patients received external pneumatic compression sleeves in addition to prophylactic heparin. If deep vein thrombosis or pulmonary embolus was discovered, heparin drip was initiated until conversion to therapeutic anticoagulation. RESULTS: A total of 100 patients underwent pleurectomy for mesothelioma. Seven patients were found to have preoperative deep vein thrombosis, and as such only 93 patients were included for analysis. The median age of patients at surgery was 71 years (30-85 years). During the study, 30 patients (32%) developed evidence of thrombosis; 20 patients (22%) developed only deep vein thrombosis without embolism, 3 patients (3%) developed only pulmonary embolism, and 7 patients (7%) developed both deep vein thrombosis and pulmonary embolus. Of the 27 patients who developed deep vein thrombosis, 9 (33%) were asymptomatic at the time of diagnosis, and none of these developed a pulmonary embolus or other bleeding complications. There were 2 (2%) events of major postoperative bleeding related to therapeutic anticoagulation. CONCLUSIONS: The incidence of venous thromboembolism is high (32%) among patients undergoing surveillance after pleurectomy for mesothelioma. Up to 33% of patients with deep vein thrombosis are asymptomatic at the time of diagnosis, and the incidence of complications related to anticoagulation is low. Routine surveillance may be useful to diagnose and treat deep vein thrombosis before it progresses to symptomatic or fatal pulmonary embolus.

Risk factors for delirium after esophagectomy.

INTRODUCTION: Postoperative delirium is a common complication after major surgical procedures and affects outcomes and long-term survival. We identified factors associated with postoperative delirium in patients undergoing esophagectomy. METHODS: Retrospective cohort analysis of 378 patients undergoing esophagectomy. We examined the association between postoperative delirium (DSM-V) criteria with respect to baseline variables and postoperative complications. RESULTS: Postoperative delirium was diagnosed in 64 (16.93%) patients and associated with increasing age (P < .05), chronic obstructive pulmonary disease (P = .07), pneumonia (P = .01), transfusion intraoperatively or within 72 hours of surgery (P < .001), and sepsis (P = .001). Unplanned intubation and increased length of stay (median, 14 days) were significant in patients with delirium (P = .001 and P < .001, respectively). In a secondary analysis, surgical technique and operative approach were associated with delirium. Modified McKeown (three-hole) esophagectomy was twice more likely to develop delirium compared with Ivor Lewis (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.03-4.23). The strongest association was found between delirium and open techniques (thoracotomy and laparotomy) as compared with minimally invasive techniques (thoracoscopy and laparoscopy) (OR, 2.66; 95% CI, 1.22-5.76). Survival was similar between both groups. CONCLUSIONS: Postoperative delirium is common and associated with complications following esophagectomy. Identification of predisposing factors such as age and pre-existing pulmonary diseases and proper selection of surgical treatment may reduce delirium and improve surgical outcomes.

Cumulative nonsmoking risk factors increase the probability of developing lung cancer.

BACKGROUND: It is estimated that 20% of lung cancer cases in the United States are among never smokers, yet current screening recommendations only include a small subset of high-risk patients. In this study, 2 models were used to predict the risk of developing lung cancer in subgroups of never smoking patients with additional risk variables. METHODS: The Liverpool Lung Project (LLP) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were 2 models used to calculate risk of developing lung cancer. Risk was calculated as a function of age for developing lung cancer within the next 5 to 10 years. RESULTS: PLCO estimated a peak risk of 16.20% at age 75 for 30-pack-year smokers with a first-degree relative with lung cancer. LLP estimated a peak risk of 7.3% over the next 5 years at age 79 for men with 30-pack-year and a first-degree relative with early-onset lung cancer (<60 years). Female never smokers with cumulative variables other than smoking had a peak risk of 3.40% for age 74 to 75 years. In contrast, women with only 30-pack-year smoking history and no other variable had a peak risk of 2.20% at age 74 to 75 years. CONCLUSIONS: Models such as LLP and PLCO might be used to identify risk for patients who would otherwise not receive lung cancer screening. These individual risk assessments can be used by patients and providers to assess if one is at substantial risk for developing lung cancer.

Graft-Versus-Tumor Effect in Adenocarcinoma of the Lung.

Donor T cells after allogeneic hematopoietic cell transplantation can give rise to the graft-versus-tumor (GVT) effect in hematologic malignancies. GVT effect has been reported previously to cause regression of some solid tumors. However, none have reported a documented case of GVT effect leading to complete resolution of adenocarcinoma of the lung. Here, we present the case of complete regression of a pathologically proven adenocarcinoma of the lung in a patient undergoing myeloablative-matched unrelated donor peripheral blood stem cell transplantation for the treatment of acute myelogenous leukemia.

Paraneoplastic Neuromyelitis Optica Spectrum Disorder as Presentation of Esophageal Adenocarcinoma.

Neuromyelitis optica spectrum disorders are a group of relapsing, inflammatory, demyelinating neurologic syndromes involving the central nervous system associated with antibodies against aquaporin-4. Although most commonly an idiopathic autoimmune condition, neuromyelitis optica may occur as a paraneoplastic syndrome in rare instances. We report a case of transverse myelitis caused by paraneoplastic neuromyelitis optica as the presenting clinical syndrome in a patient with esophageal adenocarcinoma.

Recent trends in surgical research of cancer treatment in the elderly, with a primary focus on lung cancer: Presentation at the 2015 annual meeting of SIOG.

Surgical research concentrating on cancer in the elderly has changed from small single institution outcome studies of carefully selected patients to larger studies that test specific aspects of surgical selection, treatment, and outcome. The purpose of this paper is to review major new trends in surgical geriatric oncology research within the last decade. Reviewing PubMed listings of the last 10years reveals several identifiable areas of particular concentration. Although we use specific studies primarily from lung cancer treatment, the generalizations can be seen across the spectrum of geriatric cancers. These trends include screening for disease that can be successfully treated, integration of operative and non-operative therapies that are changing the indications for surgery, the use of prehabilitation to allow more borderline frail patients to be treated surgically, the use of rehabilitation to facilitate rapid and complete recovery, prevention and treatment of common morbidities, with a special recent focus on delirium and cognitive impairment. New areas of surgical research include research on team building in the OR and ICU. Recent surgical research is becoming quantitative and multi-institutionally based. Overall surgical mortality has dropped over the past 25years in both academic and community hospitals. Prevention of morbidity and loss of functional status is a major focus of research. Funding for new Quality Assurance Projects for elderly patients has been awarded to the American College of Surgeons, and should provide multi-institutional quality outcome data within 5years.

Early Experience of Robot-Assisted Esophagectomy With Circular End-to-End Stapled Anastomosis.

BACKGROUND: Surgical resection is a critical element in the treatment of esophageal cancer. Esophagectomy is technically challenging and is associated with high morbidity and mortality rates. Efforts to reduce these rates have spurred the adoption of minimally invasive techniques. This study describes a single-institution experience of robot-assisted esophagectomy with circular end-to-end stapled anastomosis. METHODS: Between December 2013 and April 2015, a series of consecutive patients underwent robot-assisted Ivor Lewis esophagectomy with circular end-to-end anastomosis (RAILE-EEA) at a tertiary care center with curative intent. We retrospectively reviewed their electronic medical records using real-time prospectively collected data. The operative and postoperative outcomes were recorded. RESULTS: Twenty patients underwent RAILE-EEA during the study period. The abdominal mobilization was performed laparoscopically, and the thoracic portion was robotic. The median total operative time was 455 minutes (range, 318-765 minutes), the 90-day operative mortality was 0%, and morbidity was present in 11 of 20 patients (55%). Atrial fibrillation was the most common event and was observed in 3 patients (15%). There were no anastomotic leaks. The median estimated blood loss was 275 mL, and the conversion rate was 0%. Complete (R0) resection was achieved in all cases. The mean number of lymph nodes was 23.2 (± 2.26). The median follow-up time was 330 days (range, 108-600 days), and the overall 1-year survival was 84%. CONCLUSIONS: RAILE-EEA in our institution suggests a safe, effective, and reproducible alternative with satisfactory postoperative outcomes for the treatment of esophageal cancer. It provided good local control, adequate lymphadenectomy, low morbidity, and low 90-day operative mortality.

Thirty-Day Mortality After Lobectomy in Elderly Patients Eligible for Lung Cancer Screening.

BACKGROUND: Whether US surgeons have been able to replicate the low mortality rate of 1% after lobectomy experienced by patients treated in the National Lung Screening Trial is unknown. METHODS: To determine current operative 30-day mortality rates after lobectomy, we analyzed American College of Surgeons National Surgical Quality Improvement Program data files from 2005 to 2012. RESULTS: Of the 2,690 patients analyzed, 1,595 underwent open thoracotomy lobectomy and 1,095 underwent video-assisted thoracoscopic lobectomy. Sixty-three postoperative deaths occurred among the 2,690 patients (2.34% overall). The mortality rate for open lobectomy was 3.13% (50 cases) and that for video-assisted thoracoscopic lobectomy was 1.19% (13 cases [odds ratio 2.69, 95% confidence interval: 1.43 to 5.43, p < 0.05). Evaluation of mortality rates between surgical approaches (open versus video-assisted thoracoscopic) was performed by age group: group 1, aged 65 to 69 years (odds ratio 2.72, 95% confidence interval: 1 to 9.4, p < 0.05); group 2, aged 70 to 74 years (odds ratio 4.41, 95% confidence interval: 1.28 to 23.4, p < 0.05); and group 3, aged 75 to 80 years (no difference was found in group 3, p = 0.45). CONCLUSIONS: Among the hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program, operative mortality rates after lobectomy are comparable to the operative mortality rates in the National Lung Screening Trial.