Association of tumor location with economic outcomes and air leak complications in thoracic lobectomies: results from a national hospital billing dataset.

Purpose: To assess whether tumor location during thoracic lobectomies affects economic outcomes or air leak complications. Patients and methods: Retrospective, observational study using Premier Healthcare Database. The study included patients aged ≥18 years who underwent elective inpatient thoracic lobectomy for lung cancer between 2012 and 2014 (first qualifying=index admission). Three mutually exclusive tumor location groups were formed: upper lobe, middle lobe, and lower lobe. Primary outcomes were index admission's length of stay (LOS), total hospital costs, and operating room time; in-hospital air leak complications (composite of air leak/pneumothorax) served as an exploratory outcome. Multivariable models were used to examine the association between tumor location and the study outcomes, accounting for covariates and hospital-level clustering. Results: 8,750 thoracic lobectomies were identified: upper lobe (n=5,284), middle lobe (n=512), and lower lobe (n=2,954). Compared with the upper lobe, the middle and lower lobe groups had statistically significant (p<0.05): shorter adjusted LOS (7.0 days upper vs 5.8 days middle, 6.6 days lower), lower adjusted mean total hospital costs ($26,177 upper vs $23,109 middle, $24,557 lower), and lower adjusted odds of air leak complications (odds ratio middle vs upper=0.81, 95% CI=0.74-0.89; odds ratio lower vs upper=0.60, 95% CI=0.46-0.78). Findings were similar but varied in statistical significance when stratified by open and video-assisted thoracoscopic surgery approach. Conclusion: Among patients undergoing elective thoracic lobectomy for lung cancer in real-world clinical practice, upper lobe tumors were significantly associated with increased in-hospital resource use and air leak complications as compared with lower or middle lobe tumors.

Preclinical quantification of air leaks in a physiologic lung model: effects of ventilation modality and staple design.

PURPOSE: Thoracic air leaks are a common complication following pulmonary resections. Limitations in clinical studies and preclinical models have hindered efforts to understand the pathophysiology of air leaks. With an emphasis on staple-line specific air leaks, we hypothesize that ventilation modality - intraoperative positive pressure vs postoperative negative pressure - and stapler design may play a role in air leaks. METHODS: Using a novel physiologic lung model, air leaks associated with graduated and uniform staple designs were evaluated under positive and negative pressure ventilation, simulating perioperative breathing in porcine lungs. Air leak incidence, air leak volume, and air leak rate were captured along with ventilation pressure and tidal volume. RESULTS: In all cases, negative pressure ventilation was associated with a higher occurrence of leaks when compared to positive pressure ventilation. Lungs leaked more air and at a faster rate under negative pressure ventilation compared to positive pressure ventilation. Graduated staple designs were associated with higher occurrence of leaks as well as larger leak rates when compared to uniform staples. Tissue thickness was not associated with differences in air leaks when tested with appropriate staple heights. CONCLUSION: Using a novel lung model to investigate the pathophysiology of air leaks, we have identified breathing modality and staple design as two important variables that may impact air leaks. This work will help guide device design and drive future studies in human tissue, and it may help inform clinical practice to ultimately improve patient outcomes.

Impact of Powered and Tissue-Specific Endoscopic Stapling Technology on Clinical and Economic Outcomes of Video-Assisted Thoracic Surgery Lobectomy Procedures: A Retrospective, Observational Study.

INTRODUCTION: Video-assisted thoracic surgery (VATS) lung resections are complex procedures with a critical role played by endoscopic staplers in the transection of vessels, bronchi, and lung tissue. This retrospective, observational study compared hospital resource use, costs, and complications of VATS lobectomy procedures for whom powered versus manual endoscopic surgical staplers were used. METHODS: Patients ≥ 18 years of age undergoing elective VATS lobectomy during an inpatient admission from January 1, 2012 to September 30, 2016 were identified from the Premier Healthcare Database (first admission = index admission). Use of either powered or manual endoscopic staplers during the index admission was identified from hospital administrative records. Multivariable regression analyses adjusting for patient, hospital, and provider characteristics and hospital-level clustering were carried out to compare the following outcomes between the powered and manual stapler groups: hospital length of stay (LOS), operating room time (ORT), hospital costs, complications (bleeding and/or transfusions, air leak complications, pneumonia, and infection), discharge status, and 30-, 60-, and 90-day all-cause readmissions. RESULTS: The powered and manual stapler groups comprised 659 patients (mean age 66.1 years; 53.6% female) and 3100 patients (mean age 66.7 years; 54.8% female), respectively. In the multivariable analyses, the powered stapler group had shorter LOS (4.9 vs. 5.9 days, P < 0.001), lower total hospital costs ($23,841 vs. $26,052, P = 0.009), and lower rates of combined hemostasis complications (bleeding and/or transfusions; 8.5% vs. 16.0%, P < 0.001) and transfusions (5.4% vs. 10.9%, P = 0.002), compared with the manual stapler group. Other outcomes did not differ significantly between the study groups. Similar trends were observed in subanalyses comparing devices across predominant manufacturers in each group, and in subanalyses of patients with comorbid chronic obstructive pulmonary disease. CONCLUSION: In this analysis of VATS lobectomy procedures, powered staplers were associated with significant benefits with respect to selected types of hospital resource use, costs, and clinical outcomes when compared with manual staplers. FUNDING: Johnson & Johnson.

Burden of air leak complications in thoracic surgery estimated using a national hospital billing database.

BACKGROUND: One of the most common outcomes of lung resections are parenchymal air leaks. These air leaks are most often self-limited and spontaneously resolve several days after surgery. Historically, only prolonged air leaks have been considered to have a significant effect on patient outcomes. This study aims to evaluate the impact of any air leak complications (aALCs) on resource utilization and mortality. METHODS: The Premier Perspective® database was used to identify all elective primary lobectomy, segmentectomy, and wedge resections performed from 2012 to 2014; aALC was defined as a composite of air leak and pneumothorax. Generalized estimating equation models were used to estimate the impact of aALCs on length of stay (LOS), operating room time (ORT), hospital costs, and mortality during index hospitalization. RESULTS: A total of 21,150 patients undergoing lung resection surgery were included in the analysis: lobectomy (n=10,946), segmentectomy (n=1,788), and wedge resection (n=8,416). The overall incidence of aALCs was 24.26% (95% CI [23.68, 24.83]). Identified risk factors included resection type, surgical approach, male gender, and presence of COPD. Patients with aALCs had a significantly higher economic burden (adjusted mean [standard error of mean, SE]: LOS=7.24 [SE=0.12] days; ORT=214.9 [SE=6.4] min; and hospital costs=$26,070 [SE=$1404]) compared to those without aALCs (adjusted mean [SE]: LOS=4.75 [SE=0.07] days; ORT=201.7 [SE=3.9] min; and hospital costs=$19,558 [SE=$399]). aALC was also associated with increased overall index hospitalization mortality (odds ratio=1.90, 95% CI [1.42, 2.55]). CONCLUSION: This analysis showed that aALCs are not only frequent but also associated with significantly higher resource utilization and mortality.

A multi-center evaluation of a powered surgical stapler in video-assisted thoracoscopic lung resection procedures in China.

BACKGROUND: Lung cancer is one of the most prevalent malignancies worldwide. The number of anatomic lung cancer resections performed via video-assisted thoracoscopic surgery (VATS) is growing rapidly. Staplers are widely used in VATS procedures, but there is limited clinical data regarding how they might affect performance and postoperative outcomes, including air leak. This clinical trial assessed the use of a powered stapler in VATS lung resection, with a primary study endpoint being occurrence and duration of air leak and prolonged air leak (PAL). METHODS: Data was collected from a single arm, multi-center study in Chinese patients receiving VATS wedge resection or lobectomy. Intra-operative data included surgery duration; cartridge selection for ligation/transection of bronchus, major vessels, and lung parenchyma; staple line interventions; blood loss; and device usage. Post-operative data included air leak assessments, chest tube duration, length of hospital stay, and adverse events (AEs). RESULTS: A total of 94 procedures across four institutions in China were included in the final analysis: 15 wedge resections, 74 lobectomies, and five wedge resections followed by lobectomies. Post-operative air leak occurred in five (5.3%) patients who had lobectomy procedures, with PAL in one (1.1%) patient. Sites were generally consistent relative to cartridge use by tissue type. The incidence of stapler firings requiring surgical interventions was seven out of 550 (1.3%). Surgeons participating in the study were satisfied with the articulation and overall usability of the stapler. CONCLUSIONS: The powered staplers make the VATS procedure easier for the surgeons and have achieved intra- and post-operative patient outcomes comparable to those previously reported.

Predictors of anastomotic leak after esophagectomy: an analysis of the society of thoracic surgeons general thoracic database.

BACKGROUND: Anastomotic leak is an important cause of morbidity and mortality after esophagectomy. Few studies have targeted risk factors for the development of leak after esophagectomy. The purpose of this study is to use The Society of Thoracic Surgeons Database to identify variables associated with leak after esophagectomy. METHODS: The Society of Thoracic Surgeons Database was queried for patients treated with esophagectomy for esophageal cancer between 2001 and 2011. Univariate and multivariate analysis of variables associated with an increased risk anastomotic leak was performed. RESULTS: There were 7,595 esophagectomies, with 804 (10.6%) leaks. Thirty-day mortality and length of stay were higher for patients with anastomotic leak. Mortality in patients requiring surgical management was 11.6% (38 of 327) compared with 4.4% (20 of 458) in medically managed leaks (p < 0.001). The leak rate was higher in patients with cervical anastomosis compared with those with intrathoracic anastomoses, 12.3% versus 9.3%, respectively (p = 0.006). There was no difference in leak-associated mortality between the two approaches. Factors associated with leak on univariate analysis include obesity, heart failure, coronary disease, vascular disease, hypertension, steroids, diabetes, renal insufficiency, tobacco use, procedure duration greater than 5 hours, and type of procedure (p < 0.05). Multivariable regression analysis associated heart failure, hypertension, renal insufficiency, and type of procedure as risk factors for the development of leak (p < 0.05). CONCLUSIONS: Anastomotic leak after esophagectomy is an important cause of postoperative mortality and increased length of stay. We have identified important risk factors for the development of esophageal anastomotic leak after esophagectomy. Further studies aimed at risk reduction are warranted.

Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer.

MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.

Fusion positron emission/computed tomography underestimates the presence of hilar nodal metastases in patients with resected non-small cell lung cancer.

BACKGROUND: The 5-year survival for patients with resected stage II (N1) non-small cell lung cancer ranges from 40% to 55%. No data exist addressing the benefit of neoadjuvant therapy for patients with stage II disease. This is largely in part due to the lack of a reliable, minimally invasive method to assess hilar nodes. This study is aimed at determining the ability of fusion positron emission/computed tomography (PET/CT) to identify hilar metastases in patients with resected non-small cell lung cancer. METHODS: A retrospective review of surgically resected patients with fusion PET/CT within 30 days of resection was performed. The sensitivity, specificity, positive predictive value, and negative predictive value for PET/CT in detecting hilar nodal metastases was calculated for a range of maximum standardized uptake values (SUVmax). Hilar nodes from patients with falsely positive PET/CT scans were analyzed for the presence of histoplasmosis. Additionally, the impact of hilar node size greater than 1 centimeter on the calculated values was assessed. RESULTS: There were 119 patients evaluated. The number of lymph nodes resected ranged from 1 to 12 (X=2.98). There was decreased sensitivity and increased specificity with higher SUVmax cutoff values. At the standard SUVmax value of 2.5, the sensitivity and specificity were only 48.5% and 80.2%. The addition of size of hilar node by CT led to a modest improvement in sensitivity at all SUVmax cutoff values. CONCLUSIONS: Fusion PET/CT lacks sensitivity and specificity in identifying hilar nodal metastasis in patients with resected non-small cell lung cancer. Further prospective studies assessing the utility of PET/CT versus alternative sampling techniques are warranted.

Giant asymptomatic primary esophageal schwannoma.

Primary esophageal schwannomas are uncommon. We describe a case of a large asymptomatic primary esophageal schwannoma in a 65-year-old patient. Computed tomography and positron emission tomography revealed an (18)F-fluorodeoxyglucose-avid 11-cm mass arising from the esophagus. A preoperative diagnosis was made via endoscopic ultrasound. The patient underwent a three-field esophagogastrectomy with cervical esophagogastric anastomosis. He remains well and free of recurrence 10 months after treatment.

Left atrial myxoma embolus to the renal artery: should a nephrectomy be advised?

Cardiac myxoma represents the most common primary cardiac tumor, which accounts for 75% of all benign cardiac tumors. Embolization is a well-known hazard of myxoma and can be a presenting feature. Resection is generally recommended for cardiac myxomata; once identified but less understood is what to do with systemic emboli. Although extremely uncommon, the literature contains a number of examples of metastatic myxomata with active growth at the site of embolic implantation, with most cases being cerebral. We present an unusual case of embolic occlusion of the right renal artery from a left ventricular myxoma. Excision of the tumor required cardiac autotransplantation and mitral valve replacement. Subsequent right nephrectomy revealed renal artery occlusion with pathologically viable myxoma tissue.

Application of the revised lung cancer staging system (IASLC Staging Project) to a cancer center population.

OBJECTIVE: The International Association for the Study of Lung Cancer (IASLC) proposed a revision to the Union Internationale Contre le Cancer (UICC-6) staging system for non-small cell lung cancer. The goal of our study was to compare these systems in patients undergoing surgery for non-small cell lung cancer to determine whether one system is superior in staging operable disease. METHODS: Pathologic stages in 1154 patients undergoing complete resection over a 9-year period were analyzed. Patients were assigned a stage based on both IASLC and UICC-6 systems. We tested for statistically meaningful differences between the two staging systems using the Wilcoxon signed rank test and the permutation test. RESULTS: The IASLC system is more effective than the UICC-6 system at ordering and differentiating patients (P = .009). Application of the IASLC system resulted in 202 (17.5%) patients being reassigned to a different stage (P = .012), with the most common shifts occurring from IB to IIA and IIIB to IIIA. The 5-year and median survivals of the IASLC IIIA patients including those shifted from the UICC-6 IIIB were 37% and 35 months, respectively. Reclassifying UICC-6 IIIB to IASLC IIIA did not reduce survival for the newly characterized IIIA cohort. CONCLUSION: Our data confirm that the proposed IASLC staging system is more effective at differentiating stage than the UICC-6 system. Reclassifying patients from UICC-6 IIIB to IASLC IIIA will shift some patients from a stage previously considered unresectable to a stage frequently offered surgical resection. Further study and validation of the IASLC system are warranted.

Defining N2 disease in non-small cell lung cancer.

In summary, patients with N2 disease constitute a heterogeneous population with differing treatments and prognoses. Subtleties in the presentation, method of diagnosis, extent of nodal involvement, and patterns of nodal involvement must be taken into consideration to determine prognosis and optimal therapy. Is the patient with an incidental, pathologically identified, single focus of mediastinal disease the same as the patient with clinically identified multilevel bulky unresectable disease? Clearly not, although both patients share a similar stage, grouping the data presented here clearly demonstrate that these patients differ considerable in their prognosis and in their treatment. The current staging system attempts at assigning a single unifying definition of N2 fails to take into account the numerous subtleties inherent in this patient population. Although it is unlikely that N2 disease will be subclassified to any significant extent, some of these factors may eventually find themselves into a modern revision of our current staging system. For now, the upcoming IASLC revisions to the Union Internationale Contre le Cancer (UICC) staging system will not alter the definitions of nodal disease or add distinct subsets. Therefore, it is imperative that physicians evaluating and treating patients with N2 disease recognize and appreciate the influence of these subtle differences in presentation. Decision making surrounding the treatment of N2-positive patients will continue to remain complex as long as the definition of the disease remains heterogeneous.

Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells.

OBJECTIVE: DNA methyltransferase (DNMT)1, DNMT3b, or both, facilitate malignant transformation through chromatin remodeling mechanisms. The present study was undertaken to examine the effects of antisense-mediated inhibition of DNMT expression in cultured thoracic malignancies. METHODS: CALU-6 and A549 lung cancer, SKGT5 and BIC esophageal adenocarcinoma, and H2373 and H2052 malignant pleural mesothelioma (MPM) cells, as well as normal human bronchial epithelial (NHBE) cells, were transfected with phosphorothioate-modified antisense oligos targeting DNMT1, DNMT3b, or both, or mismatch oligos. Quantitative reverse transcription-polymerase chain reaction, Western blotting, trypan blue exclusion, and ApoBrdU techniques were used to evaluate DNMT expression, proliferation, and apoptosis after antisense oligo transfections. Gene expression profiles were assessed by using long-oligo array techniques. RESULTS: Antisense oligos mediated specific and dose-dependent depletion of DNMT1 and DNMT3b, resulting in pronounced inhibition of proliferation of all thoracic cancer lines, but not NHBE cells. Depletion of DNMT1 or DNMT3b coincided with dramatic, caspase-dependent, p53-independent apoptosis in 4 of the 6 thoracic cancer lines. The antiproliferative effects of the antisense oligos were not attributable to induction of RASSF1A, p16, or p21 tumor suppressor genes, and did not coincide with demethylation of genes encoding cancer-testis antigens. DNA methyltransferase knockdown mediated induction of numerous genes regulating response to genotoxic stress. Gene expression profiles after DNMT1, DNMT3b, or combined DNMT1/3b depletion were remarkably similar, yet distinctly different from expression profiles mediated by 5 aza 2' deoxycytidine. CONCLUSIONS: Antisense oligos targeting DNMT1 and DNMT3b induce genomic stress, and mediate potent growth inhibition in lung and esophageal cancer and MPM cells. These findings support further evaluation of DNMT knockdown strategies for cancer therapy.

Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells.

cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2'-deoxycytidine (DAC)/depsipeptide FK228 (DP) exposure in order to identify translational end points for clinical trials evaluating these agents. In both cell lines, sequential DAC/DP treatment induced expression of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signal transduction known to diminish the malignant phenotype of cancer cells. TFPI-2 expression was diminished or absent in 16 of 32 cell lines established from thoracic malignancies. Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state. Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines. TFPI-2 promoter methylation was observed in one of five pulmonary adenocarcinomas, and seven of seven esophageal adenocarcinomas, but not corresponding normal tissues. DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells. DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation. In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin. Induction of TFPI-2 by distinct, yet cooperative mechanisms involving chromatin remodeling and PKC signaling strengthens the preclinical rationale for sequential administration of DNA demethylating agents and HDAC inhibitors in cancer patients. Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment response in individuals receiving sequential DAC/DP infusions.