Stent-mediated gene delivery for site-specific transgene administration to the airway epithelium and management of tracheobronchial tumors.

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 ß-galactoside/LacZ (Ad.LacZ), or a therapeutic gene, Ad.INF-ß, 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 ß-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-ß, and rats bearing endotracheal tumors demonstrated a trend towards prolonged survival with insertion of Ad.ratINF-ß-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.

Physician-directed smoking cessation using patient "opt-out" approach in the emergency department: A pilot program.

OBJECTIVE: Using a physician-directed, patient "opt-out" approach to prescriptive smoking cessation in the emergency department (ED) setting, we set out to describe patient actions as they related to smoking cessation behaviors. METHODS: A convenience sample of smokers at 2 Pennsylvania hospital EDs who met inclusion/exclusion criteria were approached to participate in a brief intervention known as screening, treatment initiation, and referral (STIR) counseling that included phone follow-up. Demographic information, current smoking status, and specific physician prescription and follow-up recommendations were collected. Approximately 3 months later, patients were contacted to determine current smoking status and actions taken since their ED visit. RESULTS: One hundred six patients were approached and 7 (6.6%) opted out of the intervention. Patients who did not opt out were evaluated for appropriate use of smoking cessation-related medications; 35 (35.4%) opted out of the prescription(s) and 6 (6.1%) were not indicated. Twenty-one (21.2%) patients opted out of ambulatory referral follow-ups with primary care and/or tobacco treatment program; one (1.0%) was not indicated for referral. Nineteen (32.8%) patients who received prescription(s) for smoking cessation-related medications initially also followed the prescription(s). Seventeen (22.1%) patients participated in referral follow-up. CONCLUSION: In this small ED pilot, using the STIR concepts in an opt-out method, few smokers opted out of the smoking cessation intervention. About one-third of the patients declined prescriptions for smoking cessation-related medications and less than one-quarter declined ambulatory referrals for follow-up. These findings support a willingness of patients to participate in STIR and the benefits of intervention in this setting.

Effectiveness of a thoracic multidisciplinary clinic in the treatment of stage III non-small-cell lung cancer.

INTRODUCTION: The Institute of Medicine, the American Society of Clinical Oncology, and the European Society of Medical Oncology promote a multidisciplinary approach for the treatment of cancer. Stage III non-small-cell lung cancer (NSCLC) represents a heterogeneous group of diseases necessitating coordination of care among medical, radiation, and surgical oncology. The optimal care of stage III NSCLC underscores the need for a multidisciplinary approach. METHODS: From tumor registry data, we identified all cases of stage III NSCLC seen at Lehigh Valley Health Network between March 2010 and March 2013. The care received by patients when seen in the thoracic multidisciplinary clinic (MDC) was compared with the care received when not seen in the thoracic MDC. RESULTS: All patients seen in the MDC, compared to <50% of patients seen outside the MDC, were evaluated by more than one physician prior to beginning the treatment. Time to initiate treatment was shorter in MDC patients than in non-MDC patients. Patients seen in the MDC had a greater concordance with clinical pathways. A greater percentage of patients seen in the thoracic MDC had pathologic staging of their mediastinum. Patients seen in the MDC were more likely to receive all of their care at Lehigh Valley Health Network. CONCLUSION: Multidisciplinary care is essential in the treatment of patients with stage III NSCLC. Greater utilization of MDCs for this complex group of patients will result in more efficient coordination of care, pretreatment evaluation, and therapy, which in turn should translate to improve patients' outcomes.

Immuno-gene therapy with interferon-beta before surgical debulking delays recurrence and improves survival in a murine model of malignant mesothelioma.

OBJECTIVES: Immuno-gene therapy of mesothelioma with an adenovirus encoding interferon-beta mediated strong antitumor responses in murine models with low but not high tumor burden. Our goals were to determine the mechanisms responsible for this loss of efficacy and to test the hypothesis that the combination of preoperative adenovirus encoding interferon-beta and surgical resection would be effective in treating bulky tumors. METHODS: Flank tumors of a mouse mesothelioma cell line were treated with adenovirus encoding interferon-beta or adenoviral vector encoding the bacterial protein beta-galactosidase. Cytotoxic T lymphocytes and tumor infiltration by T lymphocytes were measured. Tumors were surgically excised 72 hours later and tumor cells were injected in the contralateral flank to create a model of a metastatic focus. Tumor-free survival and distant metastatic disease were assessed. RESULTS: Immuno-gene therapy effectively treated small tumors (<200 mm(3)) but did not reduce the size of large (>800 mm(3)) flank tumors. Although treatment with adenovirus encoding interferon-beta resulted in the generation of tumor-neutralizing splenocytes in large tumors, the number of T cells visualized within the tumors was minimal. Tumors treated with adenovirus encoding interferon-beta (versus adenoviral vector encoding the bacterial protein beta-galactosidase or phosphate-buffered saline solution) prior to debulking increased long-term tumor-free survival and resulted in two- to sixfold smaller foci of implanted tumor cells at 2 weeks postoperatively. CONCLUSIONS: The use of adenovirus encoding interferon-beta or surgical debulking alone is ineffective in treating large tumors, but combining preoperative adenovirus encoding interferon-beta and surgical debulking significantly reduces tumor recurrence and improves long-term tumor-free survival. We postulate that adenovirus encoding interferon-beta amplifies the cytotoxic T-lymphocyte antitumor response, allowing elimination of residual tumor cells.

Clinical and financial considerations for implementing an ICU telemedicine program.

As the population in the United States increases and ages, the need to provide high-quality, safe, and cost-effective care to the most critically ill patients will be of great importance. With the projected shortage of intensivists, innovative changes to improve efficiency and increase productivity will be necessary. Telemedicine programs in the ICUs (tele-ICUs) are a successful strategy to improve intensivist access to critically ill patients. Although significant capital and maintenance costs are associated with tele-ICUs, these costs can be offset by indirect financial benefits, such as decreased length of stay. To achieve the positive clinical outcomes desired, tele-ICUs must be carefully designed and implemented. In this article, we discuss the clinical benefits of tele-ICUs. We review the financial considerations, including direct and indirect reimbursement and development and maintenance costs. Finally, we review design and implementation considerations for tele-ICUs.

Transbronchial needle injection: a systematic review of a new diagnostic and therapeutic paradigm.

BACKGROUND AND OBJECTIVE: Transbronchial needle catheters are commonly used during flexible and rigid bronchoscopy for needle aspiration. The use of these catheters can be expanded by employing the technique of transbronchial needle injection. METHODS AND RESULTS: By injecting lesions in the airways, peribronchial structures, mediastinum, or lung parenchyma, transbronchial needle injection has been applied to the treatment of lung cancer, inflammatory disorders of the airways, recurrent respiratory papillomatosis, as well as bronchopleural fistulas. Diagnostic applications have included the localization of peripheral lung nodules as well as sentinel lymph nodes. CONCLUSIONS: Our review defines this bronchoscopic technique and summarizes its various reported applications.

Endobronchial gene therapy.

Gene therapy for pulmonary disease, a field still in the experimental stage, has nonetheless progressed considerably in the past decade. There have been significant advances in pre-clinical studies, as well as important developments resulting from multiple early-phase human clinical trials for a variety of respiratory disorders. Although there are several ways of delivering therapeutic genes to the lungs, the primary delivery modality remains flexible bronchoscopy. The flexible bronchoscope, because of its unique access to both large and small airways, serves as an ideal instrument to deliver therapeutic genes to the tracheobronchial tree, even to small airways and alveoli that are beyond the reach of the bronchoscope. In addition, bronchoscopic gene delivery has the capacity to treat pulmonary vascular disorders because delivery of marker and therapeutic genes via the airways has been demonstrated to successfully transduce the pulmonary vascular endothelium. This article describes the various methods and disease targets of bronchoscopically mediated gene therapy, focusing in particular on the results of clinical studies and providing a glimpse into the future of the field.