Faculty Bibliography

A patient with a history of lung adenocarcinoma, which was treated with chemoradiation, presented to our interventional pulmonology clinic for suspicion of recurrent lung cancer. The patient had a PET-avid right upper-lobe mass and subcarinal lymphadenopathy. We performed a curvilinear endobronchial ultrasound (CP-EBUS) with transbronchial needle aspiration (TBNA), followed by transbronchial EBUS-guided biopsies (TBB) of the subcarinal lymph node using miniforceps. The EBUS needle sheath was inserted over the needle through the bronchial wall and advanced into the lymph node. The EBUS-guided placement of the transbronchial sheath facilitated the miniforcep insertion and the performance of multiple transbronchial biopsies. Given success with this method, we further developed this technique in a second patient with a right lower-lobe mass. In an effort to obtain adequate tissue and minimize repeated efforts at miniforcep guidance into the lesion, we inserted a radial EBUS guide sheath through the curvilinear EBUS scope and guided it into the lesion using the miniforceps. We therefore used the radial sheath as a placeholder while obtaining repeated TBB using miniforceps as described. These modifications of previously described techniques allow for maximal and expeditious sampling of target lymph nodes and masses, with sufficient material obtained for histopathologic analysis.

Abstract: Introduction:Bronchoscopic Trans-Parenchymal Nodule Access (BTPNA) is a novel approach to accessing pulmonary nodules (PN). This real-time, image-guided approach was evaluated for safety, accuracy, and yield in the healthy canine model. Methods:A novel, inorganic model of sub-centimeter pulmonary nodules (PN) was developed, consisting of 0.25 cc aliquots of calcium hydroxylapatite (Radiesse) implanted via trans-bronchial access in airways seven generations beyond the main bronchi to represent targets for evaluation of accuracy and yield. Thoracic computed tomography (CT) scans were acquired for each subject, and from these CT scans LungPoint Virtual Bronchoscopic Navigation software provided guidance to the region of interest, and novel Trans-Parenchymal Nodule Access (TPNA) software algorithms automatically generated point-of-entry (POE) recommendations, registered CT and real-time fluoroscopic images, and overlaid guidance onto live bronchoscopic and fluoroscopic video to achieve a vessel-free, straight-line path from a central airway through parenchymal tissue for access to peripheral lesions. Results:In a 9 canine cohort, the BTPNA procedure was performed to sample 31 implanted Radiesse targets, implanted to simulate PNs, via biopsy forceps through a specially designed sheath. The mean length of the 31 tunnels was 35mm (20.5 to 50.3 mm range). Mean tunnel creation time was 16:52 minutes and diagnostic yield was 90.3% (28/31). No significant adverse events were noted in any of the canine subject's status post BTPNA with no pneumothoraces and minimal bleeding (all bleeding events less than 2 milliliters in volume). Conclusion:These canine studies demonstrate that BTPNA has the potential to achieve the high yield of Transthoracic Needle Aspiration (TTNA) with the low complication profile associated with traditional bronchoscopy. These results merit further study in humans. Introduction: Bronchoscopic Trans-Parenchymal Nodule Access (BTPNA) is a novel approach to accessing pulmonary nodules (PN). This real-time, image-guided approach was evaluated for safety, accuracy, and yield in the healthy canine model. Methods: A novel, inorganic model of sub-centimeter pulmonary nodules (PN) was developed, consisting of 0.25 cc aliquots of calcium hydroxylapatite (Radiesse) implanted via trans-bronchial access in airways seven generations beyond the main bronchi to represent targets for evaluation of accuracy and yield. Thoracic computed tomography (CT) scans were acquired for each subject, and from these CT scans LungPoint Virtual Bronchoscopic Navigation software provided guidance to the region of interest, and novel Trans-Parenchymal Nodule Access (TPNA) software algorithms automatically generated point-of-entry (POE) recommendations, registered CT and real-time fluoroscopic images, and overlaid guidance onto live bronchoscopic and fluoroscopic video to achieve a vessel-free, straight-line path from a central airway through parenchymal tissue for access to peripheral lesions. Results: In a 9 canine cohort, the BTPNA procedure was performed to sample 31 implanted Radiesse targets, implanted to simulate PNs, via biopsy forceps through a specially designed sheath. The mean length of the 31 tunnels was 35mm (20.5 to 50.3 mm range). Mean tunnel creation time was 16:52 minutes and diagnostic yield was 90.3% (28/31). No significant adverse events were noted in any of the canine subject's status post BTPNA with no pneumothoraces and minimal bleeding (all bleeding events less than 2 milliliters in volume). Conclusion: These canine studies demonstrate that BTPNA has the potential to achieve the high yield of Transthoracic Needle Aspiration (TTNA) with the low complication profile associated with traditional bronchoscopy. These results merit further study in humans.

BACKGROUND: Lung volume reduction surgery improves quality of life, exercise capacity, and survival in selected patients but is accompanied by significant morbidity. Bronchoscopic approaches may provide similar benefits with less morbidity. METHODS: In a randomized, sham procedure controlled, double-blind trial, 277 subjects were enrolled at 36 centers. Patients had emphysema, airflow obstruction, hyperinflation, and severe dyspnea. The primary effectiveness measure was a significant improvement in disease-related quality of life (St. George's Respiratory Questionnaire) and changes in lobar lung volumes. The primary safety measure was a comparison of serious adverse events. RESULTS: There were 6/121 (5.0%) responders in the treatment group at 6 months, significantly >1/134 (0.7%) in the control group [Bayesian credible intervals (BCI), 0.05%, 9.21%]. Lobar volume changes were significantly different with an average decrease in the treated lobes of -224 mL compared with -17 mL for the control group (BCI, -272, -143). The proportion of responders in St. George's Respiratory Questionnaire was not greater in the treatment group. There were significantly more subjects with a serious adverse event in the treatment group (n=20 or 14.1%) compared with the control group (n=5 or 3.7%) (BCI, 4.0, 17.1), but most were neither procedure nor device related. CONCLUSIONS: This trial had technical and statistical success but partial-bilateral endobronchial valve occlusion did not obtain clinically meaningful results. Safety results were acceptable and compare favorably to lung volume reduction surgery and other bronchial valve studies. Further studies need to focus on improved patient selection and a different treatment algorithm. TRIAL REGISTRY: ClinicalTrials.gov NCT00475007.

Over 1.5 million pleural effusions occur in the United States every year as a consequence of a variety of inflammatory, infectious, and malignant conditions. Although rarely fatal in isolation, pleural effusions are often a marker of a serious underlying medical condition and contribute to significant patient morbidity, quality-of-life reduction, and mortality. Pleural effusion management centers on pleural fluid drainage to relieve symptoms and to investigate pleural fluid accumulation etiology. Many recent studies have demonstrated important advances in pleural disease management approaches for a variety of pleural fluid etiologies, including malignant pleural effusion, complicated parapneumonic effusion and empyema, and chest tube size. The last decade has seen greater implementation of real-time imaging assistance for pleural effusion management and increasing use of smaller bore percutaneous chest tubes. This article will briefly review recent pleural effusion management literature and update the latest changes in common procedural terminology billing codes as reflected in the changing landscape of imaging use and percutaneous approaches to pleural disease management.

INTRODUCTION: The presence of intrathoracic lymphadenopathy and mediastinal masses in the pediatric population often presents a diagnostic challenge. With limited minimally invasive methodologies to obtain a diagnosis, invasive sampling via mediastinoscopy or thoracotomy is often pursued. Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive, outpatient procedure that has demonstrated significant success in the adult population in the evaluation of such abnormalities. Within the pediatric literature there is limited data regarding the use of EBUS-TBNA. We report the first multicenter review of a pediatric population undergoing EBUS-TBNA procedures identifying the feasibility, safety, utility, and outcomes of this procedure. METHODS: All patients of 18 years of age or younger undergoing EBUS-TBNA at six major academic medical centers from the years 2007 through 2013 were reviewed. Data regarding procedural performance, outcomes, and complications were recorded. RESULTS: A total of 21 patients meeting the inclusion criteria were identified in six centers. The mean age of the cohort was 13.7 (+/-4.1) years. EBUS-TBNA provided adequate sampling in 20/21 (95%) of the cases with diagnostic material obtained in 10 (48%) cases. Eight patients (38%) underwent additional surgical procedures to confirm or obtain diagnostic tissue. Within our cohort, 13 patients (62%) were able to avoid invasive surgical biopsy procedures. No procedural or anesthesia related complications were identified. CONCLUSION: We report the first multicenter study to date confirming the feasibility and utility of EBUS-TBNA in the pediatric population. Due to the low overall procedural risk of EBUS-TBNA, it should be considered as a potential first line diagnostic option for children presenting with mediastinal or hilar abnormalities but further prospective studies are needed.

Recently, the gene therapy field has begun to experience clinical successes in a number of different diseases using various approaches and vectors. The workshop Gene Therapy: Charting a Future Course, sponsored by the National Institutes of Health (NIH) Office of Biotechnology Activities, brought together early and mid-career researchers to discuss the key scientific challenges and opportunities, ethical and communication issues, and NIH and foundation resources available to facilitate further clinical advances.

BACKGROUND: The current approaches for tissue diagnosis of a solitary pulmonary nodule are transthoracic needle aspiration, guided bronchoscopy, or surgical resection. The choice of procedure is driven by patient and radiographic factors, risks, and benefits. We describe a new approach to the diagnosis of a solitary pulmonary nodule, namely bronchoscopic transparenchymal nodule access (BTPNA). METHODS: In anesthetized dogs, fiducial markers were placed and thoracic CT images acquired. From the CT scan, the BTPNA software provided automatic point-of-entry prescribing of a bronchoscopic path (tunnel) through parenchymal tissue directly to the lesion. The preplanned procedure was uploaded to a virtual bronchoscopic navigation system. Bronchoscopic access was performed through the tunnels created. Proximity of the distal end of the tunnel sheath to the target was measured, and safety was recorded. RESULTS: In four canines, 13 tunnels were created. The average length of the tunnels was 32.3 mm (range, 24.7-46.7 mm). The average proximity measure was 5.7 mm (range, 0.1-12.9 mm). The distance from the pleura to the nearest point within the target was 7.4 mm (range, 0.1-15 mm). Estimated blood loss was <2 mL per case. There were no pneumothoraces. CONCLUSIONS: We describe a new approach to accessing lesions in the lung parenchyma. BTPNA allows bronchoscopic creation of a direct path with a sheath placed in proximity to the target, creating the potential to deliver biopsy tools within a lesion to acquire tissue. The technology appears safe. Further experiments are needed to assess the diagnostic yield of this procedure in animals and, if promising, to assess this technology in humans.

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.