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Background Postoperative atrial fibrillation (POAF) is a frequent adverse event after thoracic surgery with associated morbidity, mortality, and healthcare costs. It has been shown to be preventable with prophylactic amiodarone, which is only recommended in high-risk individuals due to the potential associated side effects. Risk factors for POAF have been identified and incorporated into a prediction model to identify high-risk patients. Further evaluation in the form of a multicenter clinical trial is required to assess the effectiveness of prophylaxis specifically in this high-risk population. The feasibility of such a trial first needs to be assessed. Methods The PREP-AF trial is a double-blind randomized controlled feasibility trial. Individuals undergoing major thoracic surgery who are identified to be high-risk by the POAF prediction model will be randomized 1:1 to receive a short course of amiodarone vs. placebo in the immediate postoperative period. The primary outcome is feasibility, which will be measured by the number of eligible patients identified, consented, and randomized; intervention adherence; and measurement of future outcomes of a full trial. Discussion This study will determine the feasibility of a randomized controlled trial to assess the effectiveness of prophylactic amiodarone, in high-risk patients undergoing major thoracic surgery. This will inform the development of a multi-center trial to establish if prophylactic amiodarone is safe and effective at reducing the incidence of POAF. Preventing this adverse event will not only improve outcomes for patients but also reduce the associated health resource utilization and costs. Trial registration ClinicalTrials.gov NCT04392921. Registered on 19 May 2020.

Up to 50% of patients suffer short-term postoperative adverse events (AEs) and metastatic recurrence in the long-term following curative-intent lung cancer resection. The association between AEs, particularly infectious in nature, and disease recurrence is controversial. We sought to evaluate the association of postoperative AEs on risk of developing recurrence and recurrence-free survival (RFS) following curative-intent lung resection surgery. All lung cancer resections at a single institution (January 2008–July 2015) were included, with prospective collection of AEs using the Thoracic Morbidity & Mortality System. Cox proportional hazards models were used to estimate the effect of AEs on recurrence, with results presented as hazard ratio (HR) with 95% confidence interval (CI). An a priori, clinically driven approach to predictor variable selection was used. Kaplan–Meier curves were used examine the relationship between AE and RFS. p

OBJECTIVES A prediction model developed by Passman et al. stratifies patients’ risk of postoperative atrial fibrillation (POAF) after major non-cardiac thoracic surgery using 3 simple factors (sex, age and preoperative resting heart rate). The model has neither undergone external validation nor proven to be relevant in current thoracic surgery practice. METHODS A retrospective single-centre analysis of all patients who underwent major non-cardiac thoracic surgery (2008–2017) with prospective documentation of incidence and severity of POAF was used for external validation of Passman’s derivation sample (published in 2005 with 856 patients). The model calibration was assessed by evaluating the incidence of POAF and patients’ risk scores (0–6). RESULTS A total of 2054 patients were included. Among them, POAF occurred in 164 (7.9%), compared to 147 (17.2%) in Passman’s study. Differences in our sample compared to Passman’s sample included mean heart rate (75.7 vs 73.7 bpm, P CONCLUSIONS The POAF model demonstrated good calibration in our population, despite a lower overall incidence of POAF compared to the derivation study. POAF rates were higher among patients with a higher risk score and undergoing procedures with greater intrathoracic dissection. This tool may be useful in identifying patients who are at risk of POAF when undergoing major thoracic surgery and may, therefore, benefit from targeted prophylactic therapy.

Primary biphasic tumors of the lung are rare. Lung lesions with a biphasic pattern are far more commonly primary or metastatic soft tissue tumors with entrapped native respiratory epithelium, giving the false impression of a biphasic tumor. We report a case of bilateral benign metastasizing leiomyomas in a 69-year-old female where the tumor cells diffusely entrapped native respiratory glands in a phyllodes-like pattern. The radiographic characteristics and histologic appearance were not immediately diagnostic and covered a wide differential. Reaching the final diagnosis required the use of immunohistochemical studies as well as correlation with the patient's history and radiographic findings. To the best of our knowledge, this is the first report of pulmonary benign metastasizing leiomyoma presenting in a phyllodes-like pattern. This case illustrates the importance of considering entrapment of native lung epithelium in the differential diagnosis of biphasic-appearing lung tumors.

Achalasia is a primary esophageal motility disorder in which there is incomplete relaxation of the lower esophageal sphincter and absence of peristalsis in the lower two-thirds of the esophagus. A favored treatment is with laparoscopic modified Heller myotomy with Dor fundoplication (LHMDor) with over 90% beneficial effect. The short-term outcomes of LHMDor are well documented, but stability and durability of post-operative symptom control over time is less understood. Methods Between 2004–2016, 54 patients with achalasia underwent LHMDor (single center). Using validated questionnaires, patients rated their symptoms in five domains: pain, gastroesophageal reflux disease (GERD), dysphagia, regurgitation and quality of life (QOL), rating their symptoms preoperatively, 4-weeks post-operatively, 6-months post-operatively and yearly following the operation. Results As expected, patients reported marked improvement in dysphagia, odynophagia, regurgitation, GERD and quality of life after the operation (p Conclusion These results demonstrate the durability of LHMDor in the definitive management of achalasia offering consistent symptomatic relief and significant improvement to QOL over the decade following surgery, despite some increase in GERD symptoms and antacid use.

Up to 50% of patients suffer short-term postoperative adverse events (AEs) and metastatic recurrence in the long-term following curative-intent lung cancer resection. The association between AEs, particularly infectious in nature, and disease recurrence is controversial. We sought to evaluate the association of postoperative AEs on risk of developing recurrence and recurrence-free survival (RFS) following curative-intent lung resection surgery.All lung cancer resections at a single institution (January 2008-July 2015) were included, with prospective collection of AEs using the Thoracic MorbidityMortality System. Cox proportional hazards models were used to estimate the effect of AEs on recurrence, with results presented as hazard ratio (HR) with 95% confidence interval (CI). An a priori, clinically driven approach to predictor variable selection was used. Kaplan-Meier curves were used examine the relationship between AE and RFS. p 0.05 was considered statistically significant.892 patients underwent curative-intent resection. 342 (38.3%) patients experienced an AE; 69 (7.7%) patients developed infectious AEs. 17.6% (n = 157) of patients had disease recurrence after mean follow-up of 26.5 months. Severe (Grade IV) AEs were associated with increased risk of recurrence (3.40; 95% CI 1.56-7.41) and a trend to decreased RFS. Major infectious AEs were associated with increased risk of recurrence (HR 1.71; CI 1.05-2.8) and earlier time to recurrence (no infectious AE 66 months, minor infectious 41 months, major infectious 54 months; p = 0.02).For patients undergoing curative-intent lung cancer resection, postoperative AEs associated with critical illness or major infection were associated with increased risk of oncologic recurrence.

As an innovative approach to improve quality of surgical care, we combined surgeon self-assessment and anonymized peer comparison with continuous quality improvement seminars using positive deviance (CQI/PD) to identify surgeon(s) with the lowest rates of adverse events (AEs) to guide group practice recommendations. Our objective was to quantify the impact these interventions on postoperative AEs rates after major non-cardiac chest operations. All postoperative AEs after all thoracic operations (n = 1,084, March, 2013 to February, 2016, single-center) were prospectively collected using the thoracic morbidity and mortality system, based on Clavien-Dindo schema. Online software provided surgeons (n = 6) with self-evaluation and peer comparison at all times. In addition, quarterly CQI/PD seminars (n = 8, September, 2013 to December, 2015) focused on common impactful AEs: atrial fibrillation (AFIB), prolonged alveolar air leak (PAAL), and anastomotic leak (AL). Impact was analyzed using univariate statistics 6, 9, and 12 months before and after implementation. We observed reductions of postoperative AEs after CQI/PD: a decrease (all time periods) in AFIB, greatest at 6 months (10.1% vs. 6.7%; p = .36); a decrease (all time periods) in PAAL, greatest at 12 months (18.9% vs. 11.7%; p < .05); and decrease (6 and 9 months) in AL, greatest at 6 months (11.1% vs. 8.3%; p = .82). Improvements in AE rates after individual surgeon self-evaluation and CQI/PD seminars provide encouraging results that merit further investigation.

To determine whether all grades of severity of postoperative adverse events are associated with prolonged length of stay in patients undergoing pulmonary cancer resection.This was a retrospective cohort study of all patients who underwent pulmonary resection with curative intent for malignancy at The Ottawa Hospital, Division of Thoracic Surgery (January 2008 to July 2015). Postoperative adverse events were collected prospectively with the Thoracic MorbidityMortality System, based on the Clavien-Dindo severity classification. Patient demographics, comorbidities, preoperative investigations, cardiopulmonary assessment, pathologic staging, operative characteristics, and length of stay were retrospectively reviewed. Prolonged hospital stay was defined as75th percentile for each procedure performed (wedge resection 6 days, segmentectomy 6 days, lobectomy 7 days, extended lobectomy 8 days, pneumonectomy 10 days). Univariable and multivariable logistic regression analyses were conducted to identify factors associated with prolonged hospital stay.Of 1041 patients, 579 (55.6%) were female, 610 (58.1%) were65 years old, 232 (22.3%) experienced prolonged hospital stay, and 416 (40.0%) patients had ≥1 postoperative adverse event. Multivariable analyses identified significant (P .05) factors associated with prolonged hospital stay to be (odds ratio; 95% confidence interval): lower diffusion capacity of the lung for carbon monoxide (0.99; 0.98-0.99), surgical approach: open thoracotomy (1.8; 1.3-2.5), and presence of any postoperative adverse event: Grade I (5.8; 3.3-10.2), Grade II (6.0; 4.0-8.9), Grade III (11.4; 7.0-18.7), and Grade IV (19.40; 7.1-55.18).Lower diffusion capacity of the lung for carbon monoxide, open thoracotomy approach, and the development of any postoperative adverse event, including minor events that required no additional therapy, were factors associated with prolonged hospital stay.

The viral-transforming proteins E6 and E7 make human papillomavirus–positive (HPV+) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multifunctional CD8+ T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared with mice treated with a priming vaccine alone (greater than 50 × 106 E7-specific CD8+ T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV+ murine model TC1 clears large tumors in a CD8+-dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment in vivo and exploit molecular hallmarks of HPV+ cancer, as demonstrated by marked infection of HPV+ patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV+ cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally. Cancer Immunol Res; 5(10); 847–59. ©2017 AACR.

Predictive models of prolonged air leak have relied on information not always available preoperatively (eg, extent of resection, pleural adhesions). Our objective was to construct a model to identify patients at increased risk of prolonged air leak using preoperative factors exclusively.From 2012 to 2014, data on consecutive patients undergoing pulmonary resection were collected prospectively. Prolonged air leak was defined as lasting longer than 7 days and requiring hospitalization. Factors associated with the primary outcome (p0.2) were included in a multivariate model. Regression coefficients were used to develop a weighted risk score for prolonged air leak.Of 225 patients, 8% (18/225) experienced a prolonged air leak. Male gender (p = 0.08), smoking history (p = 0.03), body mass index (BMI) 25 or below (p 0.01), Medical Research Council (MRC) dyspnea score above 1 (p = 0.06), and diffusion capacity for carbon monoxide below 80% (Dlco) (p = 0.01) were selected for inclusion in the final model. Weighted scores were male gender (1 point), BMI 25 or below (0.5 point), smoker (2 points), Dlco% below 80% (2 points), and MRC dyspnea score above 1 (1 point). The area under the receiver operating characteristic curve was 0.8 (95% confidence interval [CI] = 0.7 to 0.9]. An air leak score above 4 points offered the best combination of sensitivity (83% [95% CI = 58 to 96]) and specificity (65% [95% CI = 58 to 71]).A subgroup of lung resection patients at higher risk for a prolonged air leak can be effectively identified with the use of widely available, preoperative factors. The proposed scoring system is simple, is clinically relevant to the informed consent, and allows preoperative patient selection for interventions to reduce the risk of prolonged air leak.

Achalasia is a primary esophageal motility disorder in which there is incomplete relaxation of the lower esophageal sphincter and absence of peristalsis in the lower two thirds of the esophagus. A favored treatment is laparoscopic modified Heller myotomy with Dor fundoplication (LHMDor) with more than 90% immediate beneficial effect. The short-term outcomes of LHMDor are well documented, but stability and durability of postoperative symptom control over time is less understood.Between 2004 and 2016, 54 patients with achalasia underwent LHMDor (single center). Using validated questionnaires, patients rated their symptoms in five domains: pain, gastroesophageal reflux disease (GERD), dysphagia, regurgitation, and quality of life. Symptom ratings were done preoperatively, 4 weeks postoperatively, 6 months postoperatively, and yearly after the operation.As expected, patients reported marked improvement in dysphagia, odynophagia, regurgitation, GERD, and quality of life after the operation (P.001). From then on, the symptom control remained durable with respect to absence of pain, regurgitation, and odynophagia; however, we observed a recurrence of GERD symptoms beginning 3 to 5 years postoperatively (P = .001 and P = .04, respectively), with associated increased antireflux medication use. After initial LHMDor, 5 patients required endoscopic dilatation an average of 1.5 years postoperatively, and no patient required reoperation. Patients reported preserved improved quality of life to 11 years after the operation (P = .001).These results demonstrate the durability of LHMDor in the definitive management of achalasia, offering consistent symptomatic relief and significant improvement in quality of life over the decade after surgery, despite some increase in GERD symptoms and antireflux medication use.

Improving evidence-based chest tube removal may reduce the length of stay following surgery. Presently, most chest tube removal protocols include a fluid output threshold based on a 24-hour observation period. The purpose of this study was to evaluate if, within a 24-hour time period, fluid output measurements at 6, 8, and 12 hours could predict if the total 24-hour fluid output would comply with a predetermined volume threshold considered acceptable for safe chest tube removal. Following lung resection, pleural fluid output data were prospectively recorded by a digital drainage system and analyzed retrospectively. Twenty-four-hour fluid output was calculated from every available 6-, 8-, and 12-hour measurement and compared to set 24-hour output criteria for chest tube removal (ie, 400 mL, 250 mL, and 20% of whole-body lymphatic flow). Performance of interim fluid outputs in predicting whether 24-hour fluid output criteria were satisfied was measured. From 2015 to 2018, 150 patients had digital pleural fluid drainage data suitable for analysis. Performance of interim fluid output data in identifying which patients would satisfy 24-hour output criteria ranged from 85% (95% confidence interval [CI] = 83–86) to 94% (95% CI = 93–94) for specificity, 75% (95% CI = 73–76) to 92% (95% CI = 90–93) for positive predictive value, and 6% (95% CI = 6–7) to 15% (95% CI = 14–17) for false-positive rate. Potential time saved in duration of drainage using interim fluid output data ranged from 10 to 16 hours. Pleural fluid output measured for 6-, 8-, and 12-hour durations can accurately identify patients who will meet 24-hour fluid output threshold for safe chest tube removal.

Background: Prolonged air leak (PAL) is often the limiting factor for hospital discharge after lung surgery. Our goal was to develop a statistical model that reliably predicts pulmonary air leak resolution by applying statistical time series modeling and forecasting techniques to digital drainage data. Methods: Autoregressive Integrated Moving Average (ARIMA) modeling was used to forecast air leak flow from transplural air flow data. The results from ARIMA were retrospectively internally validated with a group of 100 patients who underwent lung resection between December 2012 and March 2017, for whom digital pleural drainage data was available for analysis and a persistent air leak was the limiting factor for chest tube removal. Results: The ARIMA model correctly identified 82% (82/100) of patients as to whether or not the last chest tube removal was appropriate. The performance characteristics of the model in properly identifying patients whose air leak would resolve and who would therefore be candidates for safe chest tube removal were: sensitivity 80% (95% CI, 69–88%), specificity 88% (95% CI, 68–97%), positive predictive value 95% (95% CI, 86–99%), and negative predictive value 59% (95% CI, 42–79%). The false positive and false negative rate was 12% (95% CI, 12–31%) and 20% (95% CI, 12–31%). Conclusions: We were able to validate a statistical model that that reliably predicted resolution of pulmonary air leak resolution over a 24-hour period. This information may improve the care of patients with chest tube by optimizing duration of pleural drainage.

Atrial fibrillation (AF) is the most common sustained arrhythmia after non-cardiac thoracic surgery and is associated with a significant increase in perioperative morbidity, intensive care unit (ICU) admission, and mortality. Practical guidance is needed to assist clinicians in managing this critical issue and direct further research. Here we aim to provide a synoptic review and analysis of the literature to distil practical recommendations for prediction, prevention and management of post-operative atrial fibrillation (POAF) suitable for clinical application and further evaluation. To predict POAF, risk factors including age, gender, elevated pre-operative heart rate and extent of surgical resection have been reproducibly identified and integrated into scoring systems. To prevent POAF, prophylactic therapy with beta-blockers, amiodarone, or magnesium have demonstrated to be effective, but need further trials in high-risk populations. To manage unstable POAF that precipitates hypotension and hypoperfusion, although rare, requires immediate electrocardioversion to restore cardiac output and adequate oxygen delivery. For hemodynamically stable patients, rate control and prevention of adverse events are the objectives. We propose an individualized approach aimed at rate control using initial incremental low dose beta-blocker or calcium channel blocker (CCB) therapy with close monitoring of a patient’s response, and continuation of the drug that they respond to, along with simultaneous identification and reduction of triggers of AF, in order for spontaneous return to sinus rhythm. For patients who persistently fail to respond to rate control therapy, rhythm control may be considered using an agent selected based on the patient’s comorbidities and the medications’ side effect profile. While controversial and requiring further study, anticoagulation therapy is recommended in patients with risk factors for thromboembolic events after 48 hours of persistent AF. We recommend continuous prospective monitoring of incidence and severity of POAF to track the impact of protocols to predict, prevent and manage POAF.

Lung cancer remains a compelling cancer problem worldwide—according to data from the International Agency for Research on Cancer, over 2 million new cases of lung cancer will be diagnosed worldwide in 2018. More sobering are the 1.7 million deaths anticipated this year as a result of lung cancer.

The original version of this article unfortunately contained a mistake in author names. The given and family names of all the authors was transposed. The author names are corrected with this correction. The original article has been corrected.

Non–small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC.

Background: Solitary fibrous tumors of the pleura (SFTP) are rare neoplasms with unpredictable behavior. Lack of unifying criteria for benign or malignant SFTP has resulted in reports of SFTP exhibiting malignant behavior years after complete surgical resection (despite benign initial diagnosis). Additionally, the role of trans-thoracic needle biopsy in initial management of SFTP is unclear. Understanding predictors of malignancy identifies patients at unacceptably high risk for non-surgical primary therapy, and for recurrence despite complete surgical resection. Objectives: The primary objectives were to identify clinicopathological predictors of malignancy & recurrence in SFTP. The secondary aim was to determine the role of trans-thoracic needle biopsy in the management decision algorithm of SFTP. Methods: Retrospective chart review was conducted (Jan. 1983-Dec. 2013) at the Ottawa Hospital for pathologically confirmed SFTP. Data were collected on biopsy-related, clinical, histopathological & immunohistochemistry (IHC) variables. Appropriate tests of statistical inference were conducted for all variables. Results: Pathologically confirmed SFTP was identified in 26 cases. Transthoracic needle biopsy was conducted in 22 (84.6%); with 16 (72.7%) biopsies diagnostic of SFTP with IHC; 3 (13.6%) being malignant. Primary management was surveillance in 3 and complete surgical resection in 23. Surgical pathology reported 15 (65.2%) benign and 8 (34.8%) malignant cases. Local recurrence occurred in 3 and distant recurrence in 1. Initial pathology was benign in 3 (75%) with recurrence. Clinicopathologic variables analyzed did not predict recurrent disease. IHC features did not differ between malignant & benign pathology significantly. Predictors of malignant pathology included: infiltrative cellular pattern (p = 0.042), nuclear crowding (p = 0.006), tumour necrosis (p 4 mitoses/ 10 high power field (p < 0.003). Conclusion: Because numerous variables analyzed did not predict recurrent disease, long-term follow-up is warranted regardless of benign or malignant initial histology. Histologic not IHC features predicted malignant pathology. Trans-thoracic needle biopsy did identify malignant SFTP; however its main use should be to differentiate SFTP from other pleural neoplasms using IHC.

Background: To determine if the maximum standardized uptake value (SUVmax) of the primary tumor as determined by preoperative (18)F-fluoro-2-deoxyglucose ((18)F-FDG) positron emission tomography (PET) is an independent predictor of overall survival, mediastinal lymph node metastasis, and stage in patients with non-small cell lung cancer (NSCLC). Methods: A retrospective review of 1033 patients with stage I-IV histologically proven NSCLC who had an (18)F-FDG PET done between 2005 and 2011 for staging before receiving therapy was performed. SUVmax of primary NSCLC was measured and correlated with tumor characteristics, lymph node involvement, cancer stage and overall survival. The patients were divided into three groups according to their SUVmax value: group I SUVmax 10. The primary outcome was survival and recurrence rate, compared using Log Rank Test. Results: The median duration of follow up was 675 days (22.5 months). The overall survival at two years for group I was 88%, group II 60% and group III 53%, significantly different among the three groups (p-value < 0.0001). Earlier stage lung cancer was found in patients with lower SUVmax values: in group I, 73% of patients had stage I cancer and only 4% had stage IV. The rate of ipsilateral mediastinal lymph node involvement (N2) in group I was 12.9% compared to 44.4% in group III (p-value < 0.0001). The overall survival was significantly different between group I and group II (Hazard Ratio (HR) 3.6; 95% C.I 2.2 - 5.7 and a p-value < 0.0001) and between group II and group III (HR 1, 4; 1.1 - 1.8 and a p-value = 0.013). Conclusion: There was a statistically significant difference in the overall survival, mediastinal lymph node metastases, and higher cancer stage with greater values of SUVmax on PET scan in patients with NSCLC.

Spontaneous pneumothorax, primary or secondary, is a common medical emergency for which specific indications for surgical intervention are well defined in selected patients. The traditional surgical approach has been by limited thoracotomy using axillary or posterolateral incision. With the advent of video-assisted minimally invasive technique in the last 20 years the traditional approach is infrequently used. The definitive operation to prevent recurrent pneumothorax by surgical approach requires bullectomy and parietal pleurectomy. The recurrence rate after the traditional open surgical approach has been low at

Anthracyclines, such as doxorubicin, are used as first-line chemotherapeutics, usually in combination therapies, for the treatment of advanced breast cancer. While these drugs have been successful therapeutic options, their use is limited due to serious drug related toxicities and acquired tumor resistance. Uncovering the molecular mechanisms that mediate doxorubicin's cytotoxic effect will lead to the identification of novel more efficacious combination therapies and allow for reduced doses of doxorubicin to be administered while maintaining efficacy. In our study, we demonstrate that activating transcription factor (ATF) 3 expression was upregulated by doxorubicin treatment in a representative panel of human breast cancer cell lines MCF7 and MDA-MB-231. We have also shown that doxorubicin treatment can induce ATF3 expression in ex vivo human breast and ovarian tumor samples. The upregulation of ATF3 in the cell lines was regulated by multiple cellular mechanisms including the activation of JNK and ATM signaling pathways. Importantly, loss of ATF3 expression resulted in reduced sensitivity to doxorubicin treatment in mouse embryonic fibroblasts. Through a 1200 FDA-approved compound library screen, we identified a number of agents whose cytotoxicity is dependent on ATF3 expression that also enhanced doxorubicin induced cytotoxicity. For example, the combination of the HDAC inhibitor vorinostat or the nucleoside analogue trifluridine could synergistically enhance doxorubicin cytotoxicity in the MCF7 cell line. Synergy in cell lines with the combination of ATF3 inducers and patients with elevated basal levels of ATF3 shows enhanced response to chemotherapy. Taken together, our results demonstrate a role for ATF3 in mediating doxorubicin cytotoxicity and provide rationale for the combination of ATF3-inducing agents with doxorubicin as a novel therapeutic approach.

Targeting the EGFR, with inhibitors such as erlotinib, represents a promising therapeutic option in advanced head and neck squamous cell carcinomas (HNSCC). However, they lack significant efficacy as single agents. Recently, we identified the ability of statins to induce synergistic cytotoxicity in HNSCC cells through targeting the activation and trafficking of the EGFR. However, in a phase I trial of rosuvastatin and erlotinib, statin-induced muscle pathology limited the usefulness of this approach. To overcome these toxicity limitations, we sought to uncover other potential combinations using a 1,200 compound screen of FDA-approved drugs. We identified monensin, a coccidial antibiotic, as synergistically enhancing the cytotoxicity of erlotinib in two cell line models of HNSCC, SCC9 and SCC25. Monensin treatment mimicked the inhibitory effects of statins on EGFR activation and downstream signaling. RNA-seq analysis of monensin-treated SCC25 cells demonstrated a wide array of cholesterol and lipid synthesis genes upregulated by this treatment similar to statin treatment. However, this pattern was not recapitulated in SCC9 cells as monensin specifically induced the expression of activation of transcription factor (ATF) 3, a key regulator of statin-induced apoptosis. This differential response was also demonstrated in monensin-treated ex vivo surgical tissues in which HMG-CoA reductase expression and ATF3 were either not induced, induced singly, or both induced together in a cohort of 10 patient samples, including four HNSCC. These results suggest the potential clinical utility of combining monensin with erlotinib in patients with HNSCC. Mol Cancer Ther; 13(11); 2559–71. ©2014 AACR.

Summary This study aimed to study the factors that are associated with urgent esophagectomy for the treatment of esophageal perforations and the impact of this therapy. A retrospective review of all esophageal perforations treated at a tertiary care hospital from January 1984 to January 2012 was performed. Compiling demographics, cause and site of perforations, time to presentation, comorbidities, radiological tests, the length of perforation, the hemodynamic status of the patient, type of treatment required, and outcomes were performed. Univariate, multivariate, and Cox regression analyses were conducted. Of 127 cases of esophageal perforation, it was spontaneous in 44 (35%), iatrogenic in 53 (44%), foreign body ingestion in 22 (17%), and traumatic perforation in 7 (6%) cases. Overall, 85 of the 127 (67%) patients were managed operatively, 35 (27.6%) patients were treated conservatively, and 7 (6.3%) patients were treated by endoscopic stent placement. Of the 85 patients who were managed operatively, 21 (16.5%) required esophagectomies, 13 (15.3%) had esophagectomy with immediate reconstruction, 5 (5.9%) patients had esophagectomy followed by delayed reconstruction, and 3 (3.5%) patients failed primary repair and required an esophagectomy as a secondary definitive procedure. Multivariate analysis revealed that esophagectomy in esophageal perforations was associated with the presence of benign or malignant esophageal stricture (P = 0.001) and a perforation >5 cm (P = 0.001). Mortality was mainly associated with the presence of a benign or malignant esophageal stricture (P = 0.04). The presence of pre-existing benign or malignant stricture or large perforation (>5 cm) is associated with the need for an urgent esophagectomy with or without immediate reconstruction. Performing esophagectomy was not found to be a significant prognosticator for mortality.

Background Postoperative adverse events (AEs), prolonged length of stay (PLOS), and patient experience are common quality measures after thoracic surgical procedures. Our objective was to investigate the relationship of postoperative AEs on patient experience and hospital length of stay (LOS) after lung cancer resection. Methods AEs (using Thoracic Morbidity and Mortality system based on Clavien-Dindo schema) and LOS were prospectively collected for all patients undergoing lung cancer resection. A 21-item questionnaire, retrospectively asking about patient experience, was mailed to patients twice (October 2015 and January 2016). The impact of AEs on experience was investigated and stratified by hospital LOS, with PLOS defined as the 75th percentile. Univariate analysis used parametric ( t test) and nonparametric (Mann-Whitney) tests according to test conditions. Results Of 288 patients who responded to the survey (70% response rate), 175 (61%) had no AEs, 113 (39%) had experienced at least one AE, and 52 (18%) had experienced PLOS. Lung cancer patients who experienced PLOS showed significantly decreased experience on several questionnaire items, including their impression of comprehensiveness of surgeons information provision during inpatient period ( p = 0.008), inpatient recovery from operation ( p = 0.001), quality of life 30 days after operation ( p = 0.032), follow-up care, ( p = 0.022), and satisfaction with outcome 1 year after operation during follow-up care ( p = 0.022). The presence of postoperative AEs led only to reduced impression about inpatient recovery from the operation ( p = 0.01). Conclusions In this cohort, postoperative AEs were minimally associated with negative patient experience. However, patients who experienced PLOS demonstrated a marked reduction in experience after thoracic surgical procedures.

Long non-coding RNAs (lncRNA) are a new class of regulatory molecules with diverse cellular functions. Recent reports have suggested that extracellular lncRNAs are detectable in human plasma and may serve as biomarkers. Here, we sought to investigate circulating lncRNAs as potential biomarkers for pulmonary arterial hypertension (PAH). Eighty-four lncRNAs, representing some of the most abundant and functionally relevant candidates identified in cellular studies, were assessed via RT-qPCR in plasma from PAH and healthy subjects. However, despite preamplification, the majority of lncRNAs were surprisingly undetectable or sporadically detectable, and showed no differential changes. Systematic characterization of plasma/RNA quality and technical performance via internal and external controls revealed no evidence of RNA degradation or RT-qPCR inhibition, and most lncRNAs were robustly detectable in pulmonary tissue. In plasma, lncRNA levels were the lowest among several different RNA species examined, and this was generalizable to other chronic and acute vascular conditions including coronary artery disease, acute coronary syndrome, and septic shock. In addition, two of three previously reported circulating lncRNA biomarker candidates were not detectable in any of the plasma samples. This study reveals new insight on the relative levels of lncRNAs in circulation, which has important implications for their potential development as biomarkers.

Minimizing adverse events after surgery is widely recognized as an important indicator of quality; yet no consensus has been reached on how to standardize the reporting of adverse events after surgical procedures. Our objectives were to develop a standardized classification system to monitor both the presence and severity of thoracic morbidity and mortality, and to evaluate its reliability and reproducibility among a national cohort of thoracic surgeons.To assess the Thoracic Morbidity and Mortality classification system (based on the Clavien-Dindo classification of adverse events), a 31-item questionnaire was sent to all members of the Canadian Association of Thoracic Surgeons in August 2009, consisting of a general description of the Thoracic Morbidity and Mortality severity grades, 20 case-based questions of postoperative adverse events to be classified, and questions regarding personal judgments. We derived descriptive and quantitative information using weighted Kappa statistics.Fifty-two (54.7%) thoracic surgeons completed the questionnaire; 41 (78.8%) of the respondents were affiliated with an academic teaching hospital. A total of 1,326 individual weighted Kappa statistics were calculated for all distinct pairs of raters, of which 1,152 (87%) were greater than 0.81, a range that is interpreted as "almost perfect agreement." A further 174 (13%) were in the range between 0.61 and 0.8, interpreted as "substantial agreement." All results were statistically significant (p0.0001). The classification system was regarded as straightforward (98% of the respondents), reproducible (94%), logical (92%), and useful (98%).The modified classification system appears to offer objective, reliable, and reproducible reporting of thoracic morbidity and mortality, and thus may assist continuous quality improvement in thoracic surgery.

OBJECTIVES: Postoperative atrial fibrillation (PAF) occurs commonly following pulmonary resection. Our aims were to quantify the incidence and severity of PAF using the Thoracic Morbidity & Mortality classification system, and identify risk factors for PAF. METHODS: All consecutive patients undergoing pulmonary resection at a single centre (January 2008 - April 2010) were enrolled. PAF was defined as postoperative, electrocardiographically documented and requiring initiation of pharmacological therapy. Univariate and multivariate analyses of risk factors associated with the development of PAF were conducted. RESULTS: The incidence of PAF was 11.8% (n = 43) of 363 pulmonary resections (open: n = 173; 47.7%; video-assisted: n = 177; 48.8%; converted: n = 13; 3.6%): sublobar (n = 93; 25.6%), lobectomy (n = 237; 65.3%), bilobectomy (n = 7; 1.9%) and pneumonectomy (n =2 4; 6.6%). Twenty-eight cases (65.1%) were uncomplicated/transient, and 15 cases (34.9%) were complicated/persistent PAF, defined as lasting for >7 days (40.0%), requiring cardioversion (13.3%), vasopressors (33.3%), in-hospital use of anticoagulants (46.7%) and/or anticoagulants on discharge (26.7%). Patients with PAF had increased mean lengths of hospital stay (10.5 days vs 6.9 days; P = 0.04). Peak onset of PAF occurred 2.5 (standard deviation (SD) ± 1.3) days after pulmonary resection, lasting for 1.8 ± 2.8 (mean, ±SD) days. Multivariate analysis identified (relative risk; 95% confidence interval): age ≥70 years (2.3; 1.1–5.1), history of angioplasty/stents/angina (4.0; 1.4–11.3), thoracotomy (3.6; 1.4–9.3), conversion to open thoracotomy (16.5; 2.2–124.0) and extent of surgery/stage (7.1; 1.0–49.4) as predictors of PAF. CONCLUSIONS: While the majority of PAF is uncomplicated and transient, one-third of cases lead to persistence or major intervention. Age, coronary artery disease and extent of surgery/stage increase the risk of PAF following pulmonary resection. Identifying patients with elevated risk may lead to targeted prophylaxis to reduce the incidence of PAF.

Monitoring surgical outcomes is critical to quality improvement; however, different data-collection methodologies can provide divergent evaluations of surgical outcomes. We compared postoperative adverse event reporting on the same patients using 2 classification systems: the retrospectively recorded American College of Surgeons (ACS) NSQIP and the prospectively collected Thoracic Morbidity and Mortality (TMM) system.Using the TMM system, complications and deaths were documented daily by fellows and reviewed weekly by staff for all thoracic surgical cases conducted at our institution (April 1, 2010 to December 31, 2011). The ACS NSQIP recording was performed 30 to 120 days after index surgery by trained surgical clinical reviewers on a systemic sampling of major cases during the same time period. Univariate analyses of the data were performed.During the study period, 1,788 thoracic procedures were performed (1,091 were designated "major," as per ACS NSQIP inclusion criteria). The ACS NSQIP evaluated 182 of these procedures, representing 21.1% and 16.7% of patients and procedures, respectively. Mortality rates were 1.4% in TMM vs 2.2% in ACS NSQIP (p = 0.42). Total patients and procedures with complications reported were 24.4% and 31.1% by TMM vs 20.2% and 39.0% by ACS NSQIP (p = 0.23 and 0.03), respectively. Rates of reported cardiac complications were higher in TMM vs ACS NSQIP (5.8% vs 1.1%; p = 0.01), and wound complications were lower (2.5% vs 6.0%; p = 0.01).Although overall rates were similar, significant differences in collection, definitions, and classification of postoperative adverse events were observed when comparing TMM and ACS NSQIP. Although both systems offer complementary value, harmonization of definitions and severity classification would enhance quality-improvement programs.

50 Background: The Ottawa Hospital, serving a population of 1.2 million across a large geographic area, redesigned its regional lung cancer diagnosis and patient intake process using a systems approach. Although having a strong record of excellent coordinated care, recent challenges had created strains on delivery metrics. Prior to the implementation of the project (October 2014), it took patients a range of 15 – 225 days to get from a referral with a suspicion of lung cancer to initial treatment, with a 90th percentile of 117 days. Methods: An innovative care platform was developed to align the people, processes and technology sides of the regional lung cancer care. It formed a basis for a “learning” system mobilizing the wider community for transformational change. We redesigned 12 main business processes facilitating accurate and timely diagnoses using the Communities of Practice approach, the Lean and Constraints methodology and the IBM business process management technology tools. In a series of rapid learning cycles, 270 technology-enabled actions were logged and resolved to support 57 process changes in workflow. The main patient value outcome was defined as improvement in the monthly proportion of patients receiving initial treatment within provincial targets and a reduction of total wait time. Results: In 14 months, the TOH Lung Cancer Transformation program yielded substantial improvement across all levels of diagnostic process including a 48% reduction in the cumulative wait times from referral to initial treatment (surgical, systemic, radiation), increased patient satisfaction with care coordination, implementation of guideline standards, efficiency gains from more intensive use of hospital resources, and sustained engagement of over 100 regional lung cancer care providers in collaborative learning and knowledge sharing across disciplinary and organizational boundaries. Conclusions: A systems approach can improve the hospital capacity to facilitate and support inter-professional and intra-professional teamwork necessary for the diagnostic process transformation.

Background Surgical resection for tissue diagnosis of lung nodules exposes patients to unnecessary risks and consumes health care resources for questionable benefit. We describe the impact of routine percutaneous lung biopsy on the management of suspicious lung nodules. Methods A retrospective review of consecutive patients referred to a regional cancer assessment center for evaluation of suspected primary or metastatic lung cancer was performed. Results From 2008 to 2010, 901 patients (male to female ratio, 0.97:1 [443 to 458]; mean age, 69.4 ± 0.3 years) underwent 1,016 percutaneous lung biopsy (fluoroscopy, 77%; computed tomography–guided, 20%). Diagnoses were non–small cell lung cancer (602 of 901; 66.8%), other malignancy (159 of 901; 17.6%), indeterminate (61 of 901; 6.8%), benign (47 of 901; 5.2%), or nondiagnostic (32 of 901; 3.6%). Of these, 393 (43.6%) were surgical candidates. Operation was avoided in 16.0% (63 of 393; benign, 36; indeterminate, 13; nondiagnostic, 14). Computed tomography follow-up in 82.5% (52 of 63) showed no change or resolution at 14.0 ± 1 months. Only 2.7% (9 of 330) underwent resection of a pathologically benign nodule. Diagnostic yield of percutaneous lung biopsy was 82.7%. Sensitivity, specificity, and positive and negative predictive values, respectively, were 100% (95% confidence interval, 98 to 100), 75% (95% confidence interval, 22 to 99), 99.7% (95% confidence interval, 98 to 100), and 100% (95% confidence interval, 31 to 100). The mean operating room time saved with this strategy was 165 ± 13.2 hours. The total cost of performing routine percutaneous biopsy ($395,500) was 44.5% of the cost of upfront wedge resection for tissue diagnosis ($888,300). Conclusions In surgical candidates, routine needle biopsy of suspicious lung nodules may lead to decreased costs, more efficient use of limited operating room resources, and a low probability of resecting pathologically benign lesions.

Objectives To assess risk factors associated with failure and bleeding in intrapleural fibrinolytic therapy (IPFT) for pleural effusions. Design Retrospective case series. Setting Two tertiary-care centres in North America. Participants We identified 237 cases that received IPFT for the treatment of pleural effusions . Data for 227 patients were compiled including demographics, investigations, radiological findings pretherapy and post-therapy and outcomes. Intervention Fibrinolytic therapy in the form of tissue plasminogen activator (t-PA) or streptokinase. Primary and secondary outcomes Success of therapy is defined as the presence of both clinical and radiological improvement leading to resolution. Failure was defined as persistence (ie, ineffective treatment) or complications requiring intervention from IPFT. Incidence of bleeding post-IPFT, identifying factors related to failure of therapy and bleeding. Results IPFT was used in 237 patients with pleural effusions; 163 with empyema/complicated parapneumonic effusions, 32 malignant effusions and 23 with haemothorax. Overall, resolution was achieved in 80% of our cases. Failure occurred in 46 (20%) cases. Multivariate analysis revealed that failure was associated with the presence of pleural thickening (>2 mm) on CT scan (p=0.0031, OR 3, 95% CI 1.46 to 6.57). Bleeding was not associated with any specific variable in our study (antiplatelet medications, p=0.08). Conclusions Pleural thickening on a CT scan was found to be associated with failure of IPFT.