Faculty Bibliography

OBJECTIVES: The objective of this study was to identify predictive factors of occult mediastinal nodal involvement on staging positron emission tomography with F-fluorodeoxyglucose in patients with non-small cell lung cancer. METHODS: We performed a retrospective review of 665 patients with suspected non-small cell lung cancer who underwent staging positron emission tomography with F-fluorodeoxyglucose from January 1, 2000 through August 31, 2010 at the Hospital of the University of Pennsylvania with clinical stage I or II disease and no evidence of N2 or N3 involvement on staging positron emission tomography (PET). A total of 201 of these patients underwent invasive pathologic staging of the mediastinum at the Hospital of the University of Pennsylvania with pathology reports available at the time of review. RESULTS: A total of 63 of the 201 patients were found to have N2 disease at the time of pathologic staging. The mean standardized uptake value (SUV) of the primary tumor for patients with occult N2 metastases was significantly higher than the node-negative patients (SUV 9.31 vs. 7.24, P=0.04). Histology, tumor location (central vs. peripheral), sex, and age were not predictive for occult N2 disease. A multivariate analysis was performed and identified primary tumor SUV>6 was the only significant predictor (P=0.02). An analysis by quartile identified a primary tumor SUV>10 to have an odds ratio of 1.72 compared with an SUV<4 of occult N2 involvement. CONCLUSIONS: Increased primary tumor SUV predicted for increased risk of mediastinal nodal disease. Tumor location was not predictive of PET-occult mediastinal nodal involvement, in contrast to previous publications. Pathologic staging of the mediastinum should be strongly considered in these patients even with a negative mediastinum on PET.

Background: Gene therapy is currently under investigation as a means of managing a variety of pulmonary diseases. Unfortunately, gene transfer to bronchial epithelium has been hampered by the lack of stable and efficient transduction. Recent studies have shown that gene vectors could be tethered to the metallic surfaces of intra-arterial stents. This approach enables efficacious and site-specific adenoviral gene delivery to the vascular endothelium. Objectives: We hypothesized that airway mesh stents impregnated with viral gene vectors could be used for local gene delivery to benign and malignant bronchial epithelium. Methods: Serotype 5 adenoviral vectors (Ad5, E1-/E3-) containing the reporter genes green fluorescent protein (Ad.GFP) or beta-galactoside/LacZ (Ad.LacZ), or a therapeutic gene, Ad.INF-beta, were coupled to either metallic mesh disks or stents via anti-Ad knob antibodies. These platforms were assessed for their ability to transfect bronchial epithelial cells from both rats and humans, as well as murine (L1C2) and human (A549) lung cancer cell lines. Gene transfer was quantified by fluorescent microscopy, scanning fluorimetry for Ad.GFP, and light microscopy studies assessing beta-galactosidase staining for Ad.LacZ. Metallic mesh and stent-mediated gene transfer was also performed in a murine flank tumor model and in a rat endotracheal tumor model in order to evaluate the therapeutic potential. Results: In these studies, murine and human non-small cell lung cancer (NSCLC) cells were successfully transfected with reporter genes in vitro. Ad.LacZ-complexed mesh successfully transfected reporter genes into established murine flank NSCLC tumors. In addition, Ad.LacZ-tethered stents could effectively transfect both tracheobronchial epithelium and submucosal glands in rats. Similar epithelial transfection was achieved in ex vivo human bronchial epithelium. Pilot in vivo experimentation provided data supporting the concept that therapeutic genes could also be delivered with this technology. In additional pilot in vivo experiments, the growth of murine flank tumors was inhibited by placement of mesh disks coupled with Ad.muINF-beta, and rats bearing endotracheal tumors demonstrated a trend towards prolonged survival with insertion of Ad.ratINF-beta-tethered stents. Conclusions: Stent-mediated gene delivery successfully enabled site-specific vector administration to target rat and human airway cells in cell culture, organ culture and in vivo. Local tracheobronchial gene delivery via stents could provide a viable clinical solution for overcoming the difficulties encountered with vector delivery within the lungs, in particular by lowering requisite vector titers and by directing desired vectors to areas of interest. This strategy may prove valuable for treating tumors involving the tracheobronchial tree, as well as other nonmalignant tracheobronchial disorders. (c) 2014 S. Karger AG, Basel.

There are limited therapies for severe emphysema. Bronchoscopic treatments of emphysema were introduced to achieve the beneficial physiological changes seen in surgical lung volume reduction; however, at the present time these treatments are mostly aimed at improving quality of life and functional status in patients with emphysema. At this time, none of these minimally invasive approaches have been approved in the United States for treatment of emphysema; however, several novel interventions have demonstrated potential in early-phase clinical trials. We performed a systematic evaluation of the relevant medical literature and present herein an evidence-based review of bronchoscopic treatments for emphysema, with a focus on the current status of this technology in the United States as compared with Europe.

BACKGROUND: Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE: We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS: BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS: One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV(1) values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS: These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting beta(2)-agonists.

Bronchoscopic tissue forceps biopsy (BBX) is a standard procedure for diagnosis of malignancy in the lung. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has proven to be a sensitive alternative to tissue biopsy for the diagnosis and staging of lung tumors. We report our institutional experience with diagnostic yield when combining BBX and EBUS-TBNA in the bronchoscopic evaluation of patients presenting with lung lesion(s). The pathology files at our institution were searched for all patients who underwent combined BBX and EBUS-TBNA procedures between 1/09 and 6/10 for the diagnosis of malignancy. The data points included biopsy site, cytologic, and histopathologic diagnoses and follow-up. We identified 115 patients who underwent BBX combined with EBUS-TBNA. About 107 (93%) of the patients received a definitive pathologic diagnosis; 93 (81%) were malignant. BBX and EBUS-TBNA of the lung lesion only were performed in 21 patients, BBX and EBUS-TBNA of lymph node(s) only in 78 patients with BBX and a combination of EBUS-TBNA of the lung lesion and lymph node(s) in 16 patients. Immunostains were performed for 71 (76%) patients and molecular testing for 11 (12%) patients. Diagnostic yield is increased when bronchoscopic technologies are combined. In a significant number of patients where BBX was negative, EBUS-TBNA provided diagnostic material, increasing diagnostic yield by 18%. In a subset of these patients the EBUS-TBNA assisted in the staging of a primary tumor. By combining these procedures, more tissue was obtained for immunohistochemistry and molecular testing, which facilitated personalized management in a minimally invasive manner.

Pleural malignancies are ideal for novel therapeutic approaches because they are invariably fatal. Intrapleural (IP) chemotherapy has only marginal benefit in pleural malignancies, but may prove efficacious with hyperthermic chemotherapy administered in combination with maximal tumor debulking. IP immunotherapies may be most effective in those patients with early-stage pleural malignancy, and may prove superior to standard pleurodesis methods in control of effusion and prolongation of survival. Immunogene therapy may be unable to successfully treat bulky tumors on its own, but success may be achieved with combination approaches that combine debulking surgery and chemotherapy with IP genetic immunotherapy.

BACKGROUND: Interventional pulmonology (IP) is an emerging subspecialty with a dedicated 12 months of additional training after traditional pulmonary and critical care fellowships with fellowships across the country. A multiple-choice question (MCQ) examination was developed to measure didactic knowledge acquired in IP fellowships. METHODS: Interventional pulmonologists from 10 academic centers developed a MCQ-based examination on a proposed curriculum for IP fellowships. The 75 multiple-choice question examination was proctored, time limited (120 min), and computer-based. The examination was administered to IP faculty, IP fellows in their last month of fellowship, graduating pulmonary and critical care fellows in their last month of training, and incoming first-year pulmonary and critical care fellows. RESULTS: The mean score for IP faculty was 87% (range, 83%-94%), 74% for IP fellows (range, 61%-81%, SD 5.09, median 76%), 62% for graduating pulmonary and critical care fellows (range 52% to 73%), and 50% for incoming pulmonary/critical care fellows (range, 35%-65%). There was a graduated increase in mean scores with level of IP training. Scores differed significantly across the four groups (P = .001). CONCLUSION: A validated MCQ examination can measure IP knowledge. There is a difference in IP knowledge based on IP training exposure.

RATIONALE: Most bronchoscopic procedures are performed using moderate sedation achieved by combining a short-acting benzodiazepine with an opioid agent. Propofol (2.6-diisopropylphenol), a short-acting hypnotic agent, has been increasingly used to provide deep sedation in the endoscopy community with an acceptable safety profile. OBJECTIVES: To compare the impact of moderate versus deep sedation on the adequacy and diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). METHODS: A retrospective review of prospectively collected data was performed at two academic institutions with interventional pulmonary fellowships using two methods of sedation during EBUS (deep vs. moderate sedation). Rapid on-site cytologic evaluation was used on all procedures in both groups. EBUS-TBNA nodal sampling was considered adequate if the aspirate yielded a specific diagnosis or lymphocytes. EBUS-TBNA was considered diagnostic if a lymph node aspirate yielded a specific diagnosis or if subsequent surgical sampling or prolonged radiographic surveillance revealed no nodal pathology. MEASUREMENTS AND MAIN RESULTS: No difference was observed in the indication for EBUS-TBNA between the two groups. More lymph nodes were sampled per patient in the deep sedation group (314 nodes from 163 patients; 2.2 nodes per patient) than in the moderate sedation group (181 lymph nodes from 146 patients; 1.4 nodes per patient; P < 0.01). The EBUS-TBNA diagnostic yield was higher for the deep sedation group (80% of patients) than for the moderate sedation group (66% of patients; P < 0.01). CONCLUSIONS: Diagnostic yield and number of lymph nodes sampled using deep sedation is superior to moderate sedation in patients undergoing EBUS-TBNA. Prospective studies accounting for other factors including patient selection and cost are needed.