Sustained Clinical Benefits of Spiration Valve System in Patients with Severe Emphysema: 24-Month Follow-Up of EMPROVE.

Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

High risk lung nodule: A multidisciplinary approach to diagnosis and management.

Pulmonary nodules are often discovered incidentally during CT scans performed for other reasons. While the vast majority of nodules are benign, a small percentage may represent early-stage lung cancer with the potential for curative treatments. With the growing use of CT for both clinical purposes and lung cancer screening, the number of pulmonary nodules detected is expected to increase substantially. Despite well-established guidelines, many nodules do not receive proper evaluation due to a variety of factors, including inadequate coordination of care and financial and social barriers. To address this quality gap, novel approaches such as multidisciplinary nodule clinics and multidisciplinary boards may be necessary. As pulmonary nodules may indicate early-stage lung cancer, it is crucial to adopt a risk-stratified approach to identify potential lung cancers at an early stage, while minimizing the risk of harm and expense associated with over investigation of low-risk nodules. This article, authored by multiple specialists involved in nodule management, delves into the diagnostic approach to lung nodules. It covers the process of determining whether a patient requires tissue sampling or continued surveillance. Additionally, the article provides an in-depth examination of the various biopsy and therapeutic options available for malignant lung nodules. The article also emphasizes the significance of early detection in reducing lung cancer mortality, especially among high-risk populations. Furthermore, it addresses the creation of a comprehensive lung nodule program, which involves smoking cessation, lung cancer screening, and systematic evaluation and follow-up of both incidental and screen-detected nodules.

Therapeutic bronchoscopy for malignant central airway obstruction: impact on quality of life and risk-benefit analysis.

PURPOSE OF REVIEW: Malignant central airway obstruction (CAO) is a common complication in cancer and confers significant symptom burden and reduction in quality of life. Multiple bronchoscopic interventions exist for malignant CAO. In this review, we discuss the role of therapeutic bronchoscopy in the management of malignant CAO, emphasizing its impact on symptom control and quality of life while balancing the risks and benefits of intervention. RECENT FINDINGS: Significant practice variations exist among practitioners of therapeutic bronchoscopy, and limited data exist to guide real-time clinical decision-making. Recent analyses demonstrate that therapeutic bronchoscopy is effective for symptoms associated with malignant CAO with infrequent complications. These studies also show that many of the improvements in symptoms and quality of life are sustained after intervention and are associated with improved overall survival in patients with malignant CAO. Recent data have also shown that the improvement in symptoms associated with therapeutic bronchoscopy may enable more definitive cancer treatment, further improving patient outcomes. SUMMARY: Therapeutic bronchoscopy is safe and effective at improving patient-centered outcomes in malignant CAO. Research is ongoing to better understand its optimal role in this setting, refine decision-making regarding advanced bronchoscopic interventions, and further improve patient outcomes.

Update on the diagnosis and management of malignant pleural effusions.

Roughly 150,000 malignant pleural effusions (MPE) are diagnosed in the United States each year. The majority of cases are caused by lung and breast cancer, and since MPE represents advanced disease, the prognosis is generally poor. In this article we review the pathophysiology, epidemiology, and prognosis of MPE. We then discuss the approach to diagnosis of MPE including the role of imaging, pleural fluid analysis, and medical thoracoscopy. Current management strategies for symptomatic MPE include repeated thoracentesis for patients with very limited life expectancy as well as more definitive procedures such as chemical pleurodesis, tunneled indwelling pleural catheters, and novel combined approaches. The choice of intervention is guided by the efficacy, local expertise, and risk, as well as patient factors and preferences.

Predicting Lymph Node Metastasis in Non-small Cell Lung Cancer: Prospective External and Temporal Validation of the HAL and HOMER Models.

BACKGROUND: Two models, the Help with the Assessment of Adenopathy in Lung cancer (HAL) and Help with Oncologic Mediastinal Evaluation for Radiation (HOMER), were recently developed to estimate the probability of nodal disease in patients with non-small cell lung cancer (NSCLC) as determined by endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). The objective of this study was to prospectively externally validate both models at multiple centers. RESEARCH QUESTION: Are the HAL and HOMER models valid across multiple centers? STUDY DESIGN AND METHODS: This multicenter prospective observational cohort study enrolled consecutive patients with PET-CT clinical-radiographic stages T1-3, N0-3, M0 NSCLC undergoing EBUS-TBNA staging. HOMER was used to predict the probability of N0 vs N1 vs N2 or N3 (N2|3) disease, and HAL was used to predict the probability of N2|3 (vs N0 or N1) disease. Model discrimination was assessed using the area under the receiver operating characteristics curve (ROC-AUC), and calibration was assessed using the Brier score, calibration plots, and the Hosmer-Lemeshow test. RESULTS: Thirteen centers enrolled 1,799 patients. HAL and HOMER demonstrated good discrimination: HAL ROC-AUC = 0.873 (95%CI, 0.856-0.891) and HOMER ROC-AUC = 0.837 (95%CI, 0.814-0.859) for predicting N1 disease or higher (N1|2|3) and 0.876 (95%CI, 0.855-0.897) for predicting N2|3 disease. Brier scores were 0.117 and 0.349, respectively. Calibration plots demonstrated good calibration for both models. For HAL, the difference between forecast and observed probability of N2|3 disease was +0.012; for HOMER, the difference for N1|2|3 was -0.018 and for N2|3 was +0.002. The Hosmer-Lemeshow test was significant for both models (P = .034 and .002), indicating a small but statistically significant calibration error. INTERPRETATION: HAL and HOMER demonstrated good discrimination and calibration in multiple centers. Although calibration error was present, the magnitude of the error is small, such that the models are informative.

Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial.

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema.Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Lung Cancer Heterogeneity in Modulation of Th17/IL17A Responses.

The interplay between tumors and their immune microenvironment is critical for cancer development and progression. The discovery of tumor heterogeneity has provided a window into a complex interplay between tumors, their secreted products, and host immune responses at the cellular and molecular levels. Tumor heterogeneity can also act as a driving force in promoting treatment resistance and correlates with distinct tumor-mediated acquired immune responses. A prevailing question is how genetic aberrations in solid tumors can shape the immune landscape, resulting in pro-tumor or anti-tumor activities. Here we review evidence for clinical and pathophysiological mechanisms that underlie different types of non-small cell lung cancer (NSCLC) and provide new insights for future immunomodulatory-based therapies. Some of the more common driver mutations in NSCLC heterogeneity includes the opposing immune responses in oncogenic mutations in K-ras vs. non-K-ras models and their pro-inflammatory cytokines such as interleukin (IL)17A. We will discuss possible molecular and metabolic mechanisms that may govern the opposing immune responses observed in distinct genetic models of NSCLCs. A deeper understanding of how tumor heterogeneity modulates immune response can improve current therapeutic strategies and provide precise treatment to individual lung cancer patients.

Air Leak Management Program With Digital Drainage Reduces Length of Stay After Lobectomy.

BACKGROUND: Air leaks can impede recovery from lung resection. To help prevent and manage air leaks, we developed a comprehensive program that includes using precompression of lung staple lines, sealant, fissureless video-assisted thoracoscopic (VATS) lobectomy, a digital drainage system, and endobronchial valve placement for prolonged air leak. We assessed the effectiveness of this program on air leak duration, hospital length of stay (LOS), and chest tube duration in our high-risk veteran population. METHODS: Using a prospectively maintained database, we retrospectively analyzed data from 226 patients who underwent lung resection for cancer by VATS lobectomy in a Veterans Affairs center. Patients were divided into two groups. Group A (n = 134; historical controls) underwent lobectomy from July 2009 through October 2013; group B (n = 92; intervention group) underwent lobectomy from November 2013 through July 2016 and received care per the comprehensive program. RESULTS: The median hospital LOS was significantly shorter in group B than in group A patients (5 days versus 6 days, respectively; p = 0.0001). Group B had a shorter median chest tube duration (2 days versus 3 days, p = 0.027). Prolonged air leak (more than 5 days) occurred in 5.4% of group B and 9.7% of group A patients (p = 0.24). Prolonged LOS (more than 14 days) was less frequent in group B (1.1%) than in group A (8.2%, p = 0.030). Multivariable analysis showed that predictors of decreased air leak duration, chest tube duration, and LOS included undergoing surgery in the later period (group B). CONCLUSIONS: Our comprehensive program was associated with reduced chest tube days and hospital LOS.

IL17A Regulates Tumor Latency and Metastasis in Lung Adeno and Squamous SQ.2b and AD.1 Cancer.

Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non-small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 (Pts4d/d ) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4d/d mice globally lacking in IL17a (Pts4d/dIl17a-/- ) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103+ dendritic cells, and adoptive transfer of IL17a-sufficient CD4+ T cells reversed early tumor development and metastasis in Pts4d/dIl17a-/- mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 6(6); 645-57. ©2018 AACR.

Flexible Bronchoscopy.

Flexible bronchoscopy has changed the course of pulmonary medicine. As technology advances, the role of the flexible bronchoscope for both diagnostic and therapeutic indications is continually expanding. This article reviews the historical development of the flexible bronchoscopy, fundamental uses of the flexible bronchoscope as a tool to examine the central airways and obtain diagnostic tissue, and the indications, complications, and contraindications to flexible bronchoscopy.

Persistent air leaks: a review with an emphasis on bronchoscopic management.

Persistent air leak (PAL) is a cause of significant morbidity in patients who have undergone lung surgery and those with significant parenchymal lung disease suffering from a pneumothorax. Its management can be complex and challenging. Although conservative treatment with chest drain and observation is usually effective, other invasive techniques are needed when conservative treatment fails. Surgical management and medical pleurodesis have long been the usual treatments for PAL. More recently numerous bronchoscopic procedures have been introduced to treat PAL in those patients who are poor candidates for surgery or who decline surgery. These techniques include bronchoscopic use of sealants, sclerosants, and various types of implanted devices. Recently, removable one-way valves have been developed that are able to be placed bronchoscopically in the affected airways, ameliorating air-leaks in patients who are not candidates for surgery. Future comparative trials are needed to refine our understanding of the indications, effectiveness, and complications of bronchoscopic techniques for treating PAL. The following article will review the basic principles of management of PAL particularly focusing on bronchoscopic techniques.

Safety and feasibility of prolonged bronchoscopy involving diagnosis of lung cancer, systematic nodal staging, and fiducial marker placement in a high-risk population.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is considered the standard treatment for medically inoperable early stage lung cancer. Bronchoscopy has shown to be effective in obtaining diagnosis of peripheral lung tumors, staging the mediastinum (with endobronchial ultrasound- EBUS-), and placing fiducial markers (FMs). However, the combination of these 3 procedures in a single bronchoscopy has not been studied. The aim of this study is to describe safety and feasibility of performing diagnosis, systematic nodal staging, and placement of FMs in a single bronchoscopic procedure. METHODS: Retrospective review of patients who underwent bronchoscopy with diagnosis of peripheral lung cancer, EBUS for nodal staging, and FM placement in a single procedure at Michael E. DeBakey VA Medical Center between January 2011 and July 2015. RESULTS: Twenty-one patients met our criteria, one having 2 synchronous tumors. 95% of patients had an ASA score of at least 3. Twenty-two tumors were diagnosed with a size of 2.72±1.06 cm. Distance from pleura was 1.33±1.42 cm. Median duration of bronchoscopy was 96 minutes (range, 75 to 136 minutes). Guided-bronchoscopy provided diagnosis of lung cancer in all cases. Fluoroscopy and RP-EBUS were utilized in 21 patients, "hybrid" scope in 14, and electromagnetic navigational bronchoscopy in 3. A total of 100 lymph nodes (LN) were sampled with EBUS-TBNA, with 95% of the patients having at least 4 LN sampled. A total of 71 FM were placed for 22 tumors. All markers were retained and allowed for successful SBRT. There were no pneumothoraces and no major complications. CONCLUSIONS: Although it results in lengthy procedures, a single bronchoscopy obtaining diagnosis of peripheral lung nodules, systematic nodal staging, and FM placement can be safely performed in high-risk patients. Our "all-in-one" strategy could potentially expedite treatment, decrease complications, and reduce costs. Further prospective studies are needed to corroborate our findings.