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1.  Association of body mass index and outcomes after major lung resection† 
Obesity has been thought to predispose patients to excess morbidity after lung resection because of decreased diaphragm excursion, reduced lung volumes and relative immobility. We assessed the relationship of body mass index (BMI) to acute outcomes after major lung resection.
Information from our database of lung resections was evaluated for the period 1980–2011. Univariate analysis for adverse events (pulmonary, cardiovascular, other and overall) was used to select variables for inclusion in multivariate logistic regression analyses. Missing values were imputed. BMI was categorized as underweight (<18.5), normal (18.5–24.9), overweight (25–29.9), obese (30–34.9) and very obese (≥35).
Among 1369 patients, there were 703 males (51%) and the mean age was 62 ± 11 years. Complications included the following: pulmonary 12%, cardiovascular 15%, other 16%, mortality 5% and any 29%. The incidence of complications decreased during each decade of study (40, 30, 26, 20%; P < 0.0001) and the incidence of obese/very obese increased during the same intervals (11, 22, 30, 25%; P = 0.0007). Adjusting for age, performance status, coronary artery disease, smoking status, diffusing capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and operation year, being overweight/obese/very obese did not increase the risk of postoperative complications in any category. In fact, patients in this group showed a lower rate of cardiovascular complications than those with BMI ≤ 25 (odds ratio (OR): 0.72; 95% confidence interval (CI): 0.51–1.00; P = 0.048). However, being underweight was importantly associated with an increased risk of pulmonary complications (OR: 2.5; 95% CI: 1.3–4.9; P = 0.0087) and of operative mortality (OR: 2.96; 95% CI: 1.28–6.86; P = 0.011).
Being overweight or obese does not increase the risk of complications after major lung resection. In contrast, patients who are underweight are at significantly increased risk of pulmonary complications and mortality. Knowledge of the relationship of BMI to perioperative risk for major lung resection is essential in proper risk stratification.
PMCID: PMC4402370  PMID: 24504655
Lung resection; Outcomes; Obesity; Body mass index
2.  Predicted postoperative lung function is associated with all-cause long-term mortality after major lung resection for cancer† 
Preoperative lung function is an independent predictor of long-term survival after lung resection for non-small-cell lung cancer (NSCLC). The extent of resection has an impact on operative mortality, determines postoperative lung function and may influence both overall- and cancer-specific survival. We sought to determine the impact of predicted postoperative (ppo) lung function on long-term survival after lung cancer resection.
We previously reported long-term survival analyses for patients who underwent major lung resection for NSCLC 1980–2006. For this study, we calculated ppo spirometry (forced expiratory volume in the first second, FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) in the same cohort using the functional segment technique or quantitative perfusion scans when available, and updated survival data; missing data were imputed. We assessed the relationship of ppoFEV1 and ppoDLCO to long-term survival using Cox regression.
Of 854 patients, 471 (55%) were men, the mean age was 63 years and median survival was 42 months. At the time of analysis, 70% of patients had died. On regression analysis, all-cause mortality was related to age, stage, performance status, renal function and prior myocardial infarction. Preoperative lung function was marginally associated with mortality [DLCO (10-percentage point decrease): HR (hazard ratio) 1.04, 95% confidence interval (95% CI) 1.00–1.08, P = 0.056; FEV1 (10-percentage point decrease): HR 1.04, 95% CI 1.00–1.09, P = 0.067]. In contrast, ppo lung function was strongly associated with mortality (ppoDLCO: HR 1.06, 95% CI 1.01–1.12, P = 0.024; ppoFEV1: HR 1.06, 95% CI 1.01–1.12, P = 0.031).
Ppo lung function is strongly associated with long-term survival after major lung resection and is more strongly related to survival than preoperative lung function. Surgeons struggle with challenging decisions about the appropriate extent of resection for early-stage cancer, balancing factors such as operative morbidity/mortality, local recurrence and postoperative quality of life. Ppo lung function and its relation to survival also should be taken into consideration during such deliberations.
PMCID: PMC4416119  PMID: 24052607
Lung resection; Lung cancer; Predicted postoperative function; Survival
3.  MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma 
PLoS ONE  2014;9(9):e105919.
Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.
PMCID: PMC4164360  PMID: 25221930
4.  Diffusing capacity predicts long-term survival after lung resection for cancer† 
Predictors of long-term survival for patients with lung cancer assist in individualizing treatment recommendations. Diffusing capacity (DLCO) is a predictor of complications after resection for lung cancer. We sought to determine whether DLCO is also prognostic for long-term survival after lung resection for cancer.
We assessed survival among patients in our prospective database who underwent lung resection for cancer between 1980–2006. Potential prognostic factors for all-cause mortality were evaluated by computing average annual hazard rates, and variables significantly associated with survival were included in multivariable Cox modelling. Multiple imputation was used to address missing values.
Among 854 unique patients, there were 587 deaths. The median follow-up time from surgery was 9.6 years. Predictors of survival included age, stage, performance status, body mass index, history of myocardial infarction, renal function and DLCO. On univariate analysis, the hazard ratio increased incrementally compared with those with a DLCO of ≥80% (70–79%, 1.12; 60–69%, 1.29; <60%, 1.35). On multivariable analysis, DLCO was an independent predictor of long-term survival for all patients (corrected for all other important covariates; HR 1.04 per 10-point decrement; 95% CI 1.00–1.08; P = 0.05). Its prognostic ability for long-term survival was above and beyond its influence on operative mortality.
DLCO is an independent and clinically important determinant of long-term survival after major lung resection for cancer, a finding that is not generally known. Knowledge of this may help improve selection of patients for lung resection and may help tailor the extent of resection, when possible, in order to appropriately balance operative risk with long-term outcomes.
PMCID: PMC3327864  PMID: 22368187
Lung resection; Survival; Diffusing capacity; Lung cancer
5.  Three-Dimensional Stereoscopic Volume Rendering of Malignant Pleural Mesothelioma 
International Surgery  2012;97(1):65-70.
Our objective was to investigate the application of three-dimensional (3D) stereoscopic volume rendering with perceptual colorization on preoperative imaging for malignant pleural mesothelioma. At present, we have prospectively enrolled 6 patients being considered for resection of malignant pleural mesothelioma that have undergone a multidetector-row computed tomography (CT) scan of the chest. The CT data sets were volume rendered without preprocessing. The resultant 3D rendering was displayed stereoscopically and used to provide information regarding tumor extent, morphology, and anatomic involvement. To demonstrate this technique, this information was compared with the corresponding two-dimensional CT grayscale axial images from two of these patients. Three-dimensional stereoscopic reconstructions of the CT data sets provided detailed information regarding the local extent of tumor that could be used for preoperative surgical planning. Three-dimensional stereoscopic volume rendering for malignant pleural mesothelioma is a novel approach. Combined with our innovative perceptual colorization algorithm, stereoscopic volumetric analysis potentially allows for the accurate determination of the extent of pleural mesothelioma with results difficult to duplicate using grayscale, multiplanar CT images.
PMCID: PMC3723194  PMID: 23102002
Mesothelioma; Imaging; Lung cancer; Diagnosis; Computed tomography; CAT scan; Imaging
6.  A Sphingosine 1–Phosphate 1 Receptor Agonist Modulates Brain Death–Induced Neurogenic Pulmonary Injury 
Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1–phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (∼ 50% reduction, P = 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.
PMCID: PMC3262681  PMID: 21617203
neurogenic pulmonary edema; lung injury; sphingosine 1–phosphate; sphingolipids; lung transplant donors
7.  Utilisation of a thoracic oncology database to capture radiological and pathological images for evaluation of response to chemotherapy in patients with malignant pleural mesothelioma 
BMJ Open  2012;2(5):e001620.
An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation.
We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database.
The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A.
A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0–35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data.
We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research.
The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger, more streamlined databases in the future.
PMCID: PMC3488720  PMID: 23103606
Basic Sciences
8.  Quantitative Measurement of Lung Re-Expansion in Malignant Pleural Mesothelioma Patients Undergoing Pleurectomy/Decortication 
Academic radiology  2010;18(3):294-298.
Rationale and Objectives
Malignant pleural mesothelioma (MPM) is a neoplasm that grows circumferentially along the pleura. The tumor and concurrent pleural effusion may reduce lung function by restricting or preventing lung expansion. The purpose of this study was to provide objective evidence that pleurectomy/decortication (P/D) allows trapped lung to re-expand, quantify the re-expansion based on computed tomography (CT) scans, and investigate whether the expansion persists after surgery.
Materials and Methods
A database of 12 patients demonstrating unilateral MPM was collected. Each patient underwent a pre-surgical CT scan, surgical debulking by P/D, and two post-surgical CT scans (at one and four months). The lung volume was measured in each scan using an automated algorithm and compared for each patient across time.
An increase in the ipsilateral post-surgical lung volume was observed for 10 of 12 patients (83%) one month after surgery. The median ipsilateral volume increase was 44% relative to the pre-surgical ipsilateral volume and 21% relative to the contralateral volume. A statistically significant change in ipsilateral lung volume was not observed between 1 -month and 4-month post-surgical scans, implying that the volume improvement persisted months after surgery.
Debulking of MPM with P/D substantially increased the ipsilateral lung volume relative to both the pre-surgical, ipsilateral volume and the contralateral lung volume. This improvement persisted months after surgery.
PMCID: PMC3075578  PMID: 21145765
9.  Surgical treatment of pulmonary hypertension: Lung transplantation 
Pulmonary Circulation  2011;1(3):327-333.
Pulmonary hypertension (PH) is a serious and progressive disorder that results in right ventricular dysfunction that lead to subsequent right heart failure and death. When untreated the median survival for these patients is 2.8 years. Over the past decade advances in disease specific medical therapy considerably changed the natural history. This is reflected in a threefold decrease in the number of patients undergoing lung transplantation for PH which used to be main stay of treatment. Despite the successful development of medical therapy lung transplant still remains the gold standard for patients who fail medical therapy. Referral for lung transplant is recommended when patients have a less than 2-3 years of predicted survival or in NYHA class III or IV. Both single and bilateral lung transplants have been successfully performed for PH but outcome analyses and survival comparisons generally favor a bilateral lung transplant.
PMCID: PMC3224424  PMID: 22140622
pulmonary vascular disease; surgical procedure; lung transplant
10.  Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion 
Cancer research  2008;68(1):132-142.
Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer.
PMCID: PMC2767335  PMID: 18172305
11.  Surgical Strategy of Complex Empyema Thoracis 
The optimal treatment of empyema thoracis has been widely debated. Proponents of pleural drainage alone, drainage plus fibrinolytic therapy, videoassisted thoracoscopic surgical (VATS) debridement, and open thoracotomy each champion the efficacy of their approach.
This study examines treatment of complex empyema thoracis between June 1, 1994, and April 30, 1997. Twenty-one men and 9 women underwent 30 drainage/decortication procedures (14 open thoracotomies and 16 VATS) in treatment of their disease. Effusion etiology was distributed as follows: infectious -14; neoplastic-associated - 7; traumatic - 3; other - 6.
The mean preoperative hospital stay was 14 ±8.8 days, (11.4 ± 6.5 days for VATS vs 16.8 ± 10.2 days for thoracotomy). Hospital stay from operation to discharge for thoracotomy patients was 10.0 ± 7.2 days (median 8.5 days) and for VATS patients 17.6 ± 16.8 days (median 11 days). These differences were not statistically significant. Duration of postoperative thoracostomy tube drainage was 8.3 ± 4.6 days for thoracotomy patients and 4.7 ± 2.8 days in the VATS group (p = 0.01). Operative time for the thoracotomy group was 125.0 ± 71.7 minutes, while the VATS group time was only 76.2 ± 30.7 minutes. Estimated blood loss for the thoracotomy group was 313.9 ± 254.0 milliliters and for the VATS group 131.6 ± 77.3 milliliters. Three of the 30 patients (10.0%) required prolonged ventilator support (>24 hours). Morbidity included one diaphragmatic laceration (VATS group) and one thoracic duct laceration (thoracotomy). Two VATS procedures (6.7%) required conversion to open thoracotomy for thorough decortication.
The surgical approach to empyema thoracis is evolving. In the absence of comorbid factors, the significantly lower requirement for chest tube drainage time in the VATS patients suggests that this modality is an attractive alternative to thoracotomy in the treatment of complex empyema thoracis.
PMCID: PMC3021260  PMID: 11051186
Complex empyema thoracis; Videoassisted thoracoscopic surgery (VATS)
12.  Thoracic Blastomycosis and Empyema 
Blastomycosis is endemic in river valley areas of the south-eastern and Midwestern United States. Pulmonary manifestations include chronic cough and pleuritic pain. Radiographie appearance of the infection can mimic bronchogenic lung carcinoma. Pleural effusion is rarely associated with this pulmonary infection, and empyema has not been previously reported. We report a case of pulmonary and pleural Blastomyces dermatitidis infection presenting as empyema thoracis. Diagnosis and treatment were attained with video-assisted thoracoscopic (VATS) pleural and lung biopsy and debridement.
PMCID: PMC3015345  PMID: 10323175
Video-assisted thoracoscopy (VATS); Blastomyces dermatitidis; Pleural effusion
13.  Video-Assisted Thoracoscopic Management of Post-Pneumonectomy Empyema 
Post-pneumonectomy empyema is a major therapeutic challenge in thoracic surgery. The presence or absence of a concomitant bronchopleural fistula directs treatment of this condition. When there is no bronchopleural fistula the condition is classically treated with thoracostomy drainage, irrigation and antibiotic instillation with closure. This approach is, however, associated with a significant rate of primary failure. Alternative modified techniques involve opening the thoracic cavity widely with serial debridement followed by interval closure. Multiple surgical procedures often require a protracted hospital stay.
We describe a technique in three patients utilizing video-assisted thoracoscopic surgery for debridement and closure of the pneumonectomy cavity.
Advantages of this technique include debridement under direct visualization, low morbidity, and potential for a shorter hospital stay.
PMCID: PMC3016734  PMID: 9876682
Post-pneumonectomy empyema; Video-assisted thoracoscopic surgery (VATS)

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