Immune evasion before tumour invasion in early lung squamous carcinogenesis.

Early detection and treatment are critical for improving the outcome of patients with cancer1. Understanding the largely uncharted biology of carcinogenesis requires deciphering molecular processes in premalignant lesions, and revealing the determinants of the intralesional immune reaction during cancer development. The adaptive immune response within tumours has previously been shown to be strongest at the earliest stage of carcinoma2,3. Here we show that immune activation and immune escape occur before tumour invasion, and reveal the relevant immune biomarkers of the pre-invasive stages of carcinogenesis in the lung. We used gene-expression profiling and multispectral imaging to analyse a dataset of 9 morphological stages of the development of lung squamous cell carcinoma, which includes 122 well-annotated biopsies from 77 patients. We identified evolutionary trajectories of cancer and immune pathways that comprise (1) a linear increase in proliferation and DNA repair from normal to cancerous tissue; (2) a transitory increase of metabolism and early immune sensing, through the activation of resident immune cells, in low-grade pre-invasive lesions; (3) the activation of immune responses and immune escape through immune checkpoints and suppressive interleukins from high-grade pre-invasive lesions; and, ultimately, (4) the activation of the epithelial-mesenchymal transition in the invasive stage of cancer. We propose that carcinogenesis in the lung involves a dynamic co-evolution of pre-invasive bronchial cells and the immune response. These findings highlight the need to develop immune biomarkers for early detection as well as immunotherapy-based chemopreventive approaches for individuals who are at high risk of developing lung cancer.

Eosinophils and Lung Cancer: From Bench to Bedside.

Eosinophils are rare, multifunctional granulocytes. Their growth, survival, and tissue migration mainly depend on interleukin (IL)-5 in physiological conditions and on IL-5 and IL-33 in inflammatory conditions. Preclinical evidence supports an immunological role for eosinophils as innate immune cells and as agents of the adaptive immune response. In addition to these data, several reports show a link between the outcomes of patients treated with immune checkpoint inhibitors (ICI) for advanced cancers and blood eosinophilia. In this review, we present, in the context of non-small cell lung cancer (NSCLC), the biological properties of eosinophils and their roles in homeostatic and pathological conditions, with a focus on their pro- and anti-tumorigenic effects. We examine the possible explanations for blood eosinophilia during NSCLC treatment with ICI. In particular, we discuss the value of eosinophils as a potential prognostic and predictive biomarker, highlighting the need for stronger clinical data. Finally, we conclude with perspectives on clinical and translational research topics on this subject.

Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 3-year outcomes.

BACKGROUND: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up. METHODS: TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life. RESULTS: Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed. CONCLUSION: TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.

Severe asthma: oral corticosteroid alternatives and the need for optimal referral pathways.

OBJECTIVE: Patients with severe asthma require high-dose inhaled corticosteroids, with or without add-on treatments, to maintain asthma control. Because symptom control remains unsatisfactory in some patients despite these therapies, maintenance therapy with oral corticosteroids (OCS) remains considered a treatment option by physicians. Besides physician-diagnosed exacerbations, many patients intermittently self-medicate with OCS during episodes of worsening symptoms or as a prevention of such episodes. However, long-term OCS use is associated with several comorbidities that may decrease health-related quality of life, worsen prognosis, and should ideally require monitoring and management. In this review, we discuss the adverse effects of OCS use, the OCS-sparing effect of biologics in severe asthma, and the need for optimal referral pathways to ensure the best outcomes for those at-risk asthma patients. DATA SOURCES: PubMed. STUDY SELECTION: Studies with results on the OCS-sparing effect of biologics in adult severe asthma were selected. RESULTS: Chronic and intermittent OCS use in asthma is associated with considerable adverse effects in asthma. Omalizumab, mepolizumab, benralizumab, and dupilumab reduce the need for OCS in severe asthma, while also reducing the exacerbation rate and improving several patient-related outcomes. CONCLUSION: Targeted biologic therapies have revolutionized the treatment of uncontrolled severe asthma by reducing or even eliminating the need for OCS and improving other major outcomes. Novel agents are now rapidly increasing the therapeutic armamentarium, but additional efforts are needed to optimize referral pathways in order to ensure sustainable access to these therapies.

Azithromycin during Acute Chronic Obstructive Pulmonary Disease Exacerbations Requiring Hospitalization (BACE). A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: Azithromycin prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPDs); however, its value in the treatment of an AECOPD requiring hospitalization remains to be defined.Objectives: We investigated whether a 3-month intervention with low-dose azithromycin could decrease treatment failure (TF) when initiated at hospital admission and added to standard care.Methods: In an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, patients who had been hospitalized for an AECOPD and had a smoking history of ≥10 pack-years and one or more exacerbations in the previous year were randomized (1:1) within 48 hours of hospital admission to azithromycin or placebo. The study drug (500 mg/d for 3 d) was administered on top of a standardized acute treatment of systemic corticosteroids and antibiotics, and subsequently continued for 3 months (250 mg/2 d). The patients were followed for 6 months thereafter. Time-to-first-event analyses evaluated the TF rate within 3 months as a novel primary endpoint in the intention-to-treat population, with TF defined as the composite of treatment intensification with systemic corticosteroids and/or antibiotics, a step-up in hospital care or readmission for respiratory reasons, or all-cause mortality.Measurements and Main Results: A total of 301 patients were randomized to azithromycin (n = 147) or placebo (n = 154). The TF rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53-1.01; P = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% (P = 0.0272), 13% versus 28% (P = 0.0024), and 2% versus 4% (P = 0.5075) in the azithromycin and placebo groups, respectively. Clinical benefits were lost 6 months after withdrawal.Conclusions: Three months of azithromycin for an infectious AECOPD requiring hospitalization may significantly reduce TF during the highest-risk period. Prolonged treatment seems to be necessary to maintain clinical benefits.

Artificial intelligence outperforms pulmonologists in the interpretation of pulmonary function tests.

The interpretation of pulmonary function tests (PFTs) to diagnose respiratory diseases is built on expert opinion that relies on the recognition of patterns and the clinical context for detection of specific diseases. In this study, we aimed to explore the accuracy and interrater variability of pulmonologists when interpreting PFTs compared with artificial intelligence (AI)-based software that was developed and validated in more than 1500 historical patient cases.120 pulmonologists from 16 European hospitals evaluated 50 cases with PFT and clinical information, resulting in 6000 independent interpretations. The AI software examined the same data. American Thoracic Society/European Respiratory Society guidelines were used as the gold standard for PFT pattern interpretation. The gold standard for diagnosis was derived from clinical history, PFT and all additional tests.The pattern recognition of PFTs by pulmonologists (senior 73%, junior 27%) matched the guidelines in 74.4±5.9% of the cases (range 56-88%). The interrater variability of κ=0.67 pointed to a common agreement. Pulmonologists made correct diagnoses in 44.6±8.7% of the cases (range 24-62%) with a large interrater variability (κ=0.35). The AI-based software perfectly matched the PFT pattern interpretations (100%) and assigned a correct diagnosis in 82% of all cases (p<0.0001 for both measures).The interpretation of PFTs by pulmonologists leads to marked variations and errors. AI-based software provides more accurate interpretations and may serve as a powerful decision support tool to improve clinical practice.

Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo - a post-hoc analysis of the BACE randomized controlled trial.

BACKGROUND: In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality. OBJECTIVES: (1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions. METHODS: Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time. RESULTS: Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/µL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses. CONCLUSIONS: This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy. TRIAL REGISTRATION: ClinicalTrials.gov number. NCT02135354 .

Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

RATIONALE: Targeted lung denervation (TLD) is a novel bronchoscopic treatment for the disruption of parasympathetic innervation of the lungs. OBJECTIVES: To assess safety, feasibility, and dosing of TLD in patients with moderate to severe COPD using a novel device design. METHODS: Thirty patients with COPD (forced expiratory volume in 1 s 30-60%) were 1:1 randomized in a double-blinded fashion to receive TLD with either 29 or 32 W. Primary endpoint was the rate of TLD-associated adverse airway effects that required treatment through 3 months. Assessments of lung function, quality of life, dyspnea, and exercise capacity were performed at baseline and 1-year follow-up. An additional 16 patients were enrolled in an open-label confirmation phase study to confirm safety improvements after procedural enhancements following gastrointestinal adverse events during the randomized part of the trial. RESULTS: Procedural success, defined as device success without an in-hospital serious adverse event, was 96.7% (29/30). The rate of TLD-associated adverse airway effects requiring intervention was 3/15 in the 32 W versus 1/15 in the 29 W group, p = 0.6. Five patients early in the randomized phase experienced serious gastric events. The study was stopped and procedural changes made that reduced both gastrointestinal and airway events in the subsequent phase of the randomized trial and follow-up confirmation study. Improvements in lung function and quality of life were observed compared to baseline values for both doses but were not statistically different. CONCLUSIONS: The results demonstrate acceptable safety and feasibility of TLD in patients with COPD, with improvements in adverse event rates after procedural enhancements.

Success rate of medical thoracoscopy and talc pleurodesis in malignant pleurisy: A single-centre experience.

BACKGROUND AND OBJECTIVE: Malignant pleurisy is associated with advanced oncological disease and dyspnoea is the most common presenting symptom. Pleurodesis is the preferred palliative and supportive treatment option, targeting symptom relief. The identification of clinical and endoscopic features that determine the success of talc pleurodesis in malignant pleurisy could guide clinical decision-making. METHODS: All symptomatic patients with malignant pleurisy subjected to talc pleurodesis through medical thoracoscopy between January 2012 and December 2015 were included. Univariate and multivariate analyses were performed to identify factors associated with successful pleurodesis. RESULTS: Of the 155 patients, 122 (78%) were classified as having a successful pleurodesis based on clinical and radiological criteria. Factors associated with unsuccessful pleurodesis (univariate analysis) were the presence of pleural adhesions (odds ratio (OR): 0.43 (95% CI: 0.19-0.96); P = 0.04), extensive spread of pleural lesions (OR: 0.17 (95% CI: 0.05-0.59); P = 0.001), the use of systemic corticosteroids (OR: 0.28 (95% CI: 0.10-0.83); P = 0.02) and a prolonged time period between the clinical diagnosis of the pleural effusion and the moment of pleurodesis (OR: 0.14 (95% CI: 0.06-0.32); P < 0.0001). The latter being associated with failure of pleurodesis in a multivariate analysis (OR: 0.08 (95% CI: 0.01-0.25); P < 0.0001). Chest ultrasound prior to pleurodesis showed a sensitivity of 91% and a specificity of 88% in predicting the success of pleurodesis. CONCLUSION: The success rate of pleurodesis in malignant pleurisy could potentially be enhanced by correct patient selection and early referral for pleurodesis. Ultrasonic assessment of pleural adhesions and potential lung expansion prior to pleurodesis is useful in clinical decision-making.

Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial.

BACKGROUND: Dual bronchodilation combining a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The once-daily (q.d.) fixed-dose combination (FDC) of LABA, indacaterol 110 µg and LAMA, glycopyrronium 50 µg (IND/GLY 110/50 µg q.d.) demonstrated superior improvements in lung function, dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid (ICS) in more than 11,000 patients with moderate-to-severe COPD in several randomised controlled clinical trials. METHODS: The CRYSTAL study was the first, 12-week, randomised, open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 µg q.d. on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year. Patients were divided into 2 groups according to their background therapy and symptom scores and were randomised (3:1) to IND/GLY or to continue with their previous treatments. RESULTS: The study included 4389 randomised patients, of whom 2160 were in groups switched to IND/GLY (intention-to-treat population). The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s (FEV1; treatment difference, Δ = +71 mL) and transition dyspnoea index (TDI; [Δ = 1.09 units]), and to LABA or LAMA on trough FEV1 (Δ = +101 mL) and a TDI (Δ = 1.26 units). Improvements in health status and lower rescue medication use were also observed with IND/GLY. The safety profile of the study medication was similar to that observed in previous studies. CONCLUSIONS: IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01985334 .

Relationship between the sensation of activity limitation and the results of functional assessment in asthma patients.

OBJECTIVE: In asthma patients, the assessment of activity limitation is based on questions evaluating how limited the patient feels in their activities. However, the lack of functional data complicates the interpretation of the answers. We aimed to evaluate the intensity of relationships between the patient's perception of activity limitation and the results of several functional tests. METHODS: Twenty patients complaining of asthma exacerbation were invited to complete three scores (Chronic Respiratory Disease questionnaire, Asthma Control Questionnaire, Hospital Anxiety and Depression scale). They also underwent lung function measurements, a 6-minute walk test and a cardio-pulmonary exercise test. In addition, physical activity was studied by actigraphy. Spearman's rank correlation coefficients between the patient's perception of activity limitation and each of the other parameters were analysed. RESULTS: Five parameters were significantly correlated with the perception of activity limitation: ACQ question 4, related to dyspnea (rs 0.74, p < 0.001); Emotion domain of the Chronic Respiratory Disease questionnaire (rs -0.57, p = 0.02); HAD anxiety (rs 0.48, p = 0.032); HAD depression (rs 0.46, p = 0.041); ACQ question 6, related to reliever use (rs 0.46, p = 0.046). No parameters from the lung function test, 6MWT, CPET or actigraphy, were significantly correlated with the perception of activity limitation. CONCLUSIONS: In response to questions about limitation of activity, patients do not specifically answer mentioning physical limitation but rather the psychological burden associated with this constraint.

Interfascial Spread of Injectate After Adductor Canal Injection in Fresh Human Cadavers.

The adductor canal block has become a common analgesic technique in patients undergoing knee arthroplasty. Dispersion of local anesthetic outside the adductor canal through interfascial layers and blockade of smaller nerves that confer innervation to the knee could contribute to the analgesic efficacy of the adductor canal block. We studied the diffusion of local anesthetic mixed with dye after injection into the adductor canal in fresh human cadavers. In all 8 legs, injectate was found in the popliteal fossa in contact with the sciatic nerve and/or popliteal blood vessels. Interfascial spread patterns were identified.

The Feasibility of Tracheal Oxygen Supplementation during Flexible Bronchoscopy.

BACKGROUND: Hypoxemia is a frequent adverse event occurring during flexible bronchoscopy and is usually prevented by close monitoring and, if needed, oxygen supplementation by nasal cannula. OBJECTIVE: We aim to demonstrate that tracheal oxygen supplementation during flexible bronchoscopy is a feasible, safe and effective method to restore oxygen saturation levels after oxygen desaturation. METHODS: In a first phase, we compare oxygen supplementation by the tracheal or nasal route in a single blinded cross-over design in healthy volunteers. In a second phase, we study patients referred for diagnostic flexible bronchoscopy, who desaturate despite oxygen supplementation by nasal cannula, in order to assess the ability to correct hypoxemia through tracheal oxygen supplementation. RESULTS: In the first phase, the mean capillary partial pressure of oxygen was 181 mm Hg when oxygen at a flow rate of 4 liters/min was administered by the tracheal route, compared to 125 mm Hg by the nasal route (p < 0.001). The capillary partial pressure of carbon dioxide was not significantly different. During 950 bronchoscopic procedures in the second phase of the trial, 30 patients desaturated below 90% despite oxygen supplementation by nasal cannula. In 22 out of these 30 patients, switching to the tracheal route resulted in a correction of the saturation within 120 s. In the remaining 8 patients, saturation levels were corrected after increasing the oxygen flow rate to 4 liters/min. After restoring saturation levels, the bronchoscopy could be completed in 25 of 30 patients. CONCLUSIONS: Tracheal oxygen supplementation is safe, feasible and an effective way to restore oxygen saturation levels during flexible bronchoscopy.

Chronic Obstructive Pulmonary Disease: CT Quantification of Airway Dimensions, Numbers of Airways to Measure, and Effect of Bronchodilation.

PURPOSE: To determine the effect of bronchodilation on airway indexes reflecting airway disease in patients with chronic obstructive pulmonary disease (COPD) and to determine the minimum number of segmental and subsegmental airways required. MATERIALS AND METHODS: This study was approved by the local ethical committee, and written informed consent was obtained from all subjects. Twenty patients with COPD who had undergone pre- and postbronchodilator pulmonary function tests and computed tomographic (CT) examinations were prospectively included. Eight healthy volunteers underwent two CT examinations. Luminal area and wall thickness (WT) of third- and fourth-generation airways were measured twice by three readers. The percentage of total airway area occupied by the wall and the square root of wall area at an internal perimeter of 10 mm (√WAPi10) were calculated. The effects of pathologic status, session, reader, bronchodilation, and CT examination were assessed by using mixed linear model analyses. The number of airways to measure for a definite percentage error of √WAPi10 was computed by using a bootstrap method. RESULTS: There were no significant session, reader, or bronchodilation effects on WT in third-generation airways and √WAPi10 in patients with COPD (P values ranging from .187 to >.999). WT in third-generation airways and √WAPi10 were significantly different in patients with COPD and control subjects (P = .018 and <.001, respectively). Measuring 12 third- or fourth-generation airways ensured a maximal 10% error of √WAPi10. CONCLUSION: WT in third-generation airways and √WAPi10 are not significantly different before and after bronchodilation and are different in patients with COPD and control subjects. Twelve is the minimum number of third- or fourth-generation airways required to ensure a maximal 10% error of √WAPi10. (©) RSNA, 2015 Clinical trial registration no. NCT01142531 Online supplemental material is available for this article.

Bronchial valve treatment for pulmonary air leak after anatomical lung resection for cancer.

A persistent post-operative pulmonary expiratory air leak after an anatomical pulmonary resection is usually managed conservatively, but can be associated with significant morbidity and increased costs. The use of bronchial valves is a minimally invasive method that may be an effective and safe treatment in this setting. In a prospective study, the clinical efficacy of intrabronchial valve treatment in patients with a prolonged persistent pulmonary air leak after anatomical surgical resection for cancer was investigated. 10 out of 277 patients with anatomical pulmonary resection for cancer were included, and 90% were scheduled for valve treatment. We demonstrated an air leak cessation at a median of 2 days after valve placement, which resulted in chest tube removal at a median of 4 days after valve placement. Elective removal of the intrabronchial valves could be safely planned 3 weeks after valve implantation. Lung function alteration associated with airway occlusion by valves was limited. Intrabronchial valve treatment with the aid of a digital thoracic drainage system is an effective and safe therapy for patients with a prolonged pulmonary air leak after anatomical lung resection for cancer.

Suitability of small bronchoscopic tumour specimens for lung cancer genotyping.

BACKGROUND: Biomarker-driven clinical trials in advanced non-small cell lung cancer (NSCLC) usually accept biopsy specimens only, as cytology specimens are supposed to be more challenging due to low neoplastic cell content and suboptimal DNA quantity. OBJECTIVES: We aimed to evaluate 2 aspects of bronchoscopic biopsy and cytology specimens: (1) the proportion of neoplastic cells and quantity of DNA extracted, and (2) the detection limit of the Scorpion amplification refractory mutation system on endoscopic samples obtained in daily clinical practice. METHODS: We screened 679 patients with advanced-stage NSCLC for the presence of an activating EGFR mutation according to the guidelines of the European Society of Medical Oncology. Their diagnostic tumour tissue samples were characterized. A dilution experiment was performed to determine the minimal proportion of neoplastic cells for a reliable test result. RESULTS: Surgical biopsies, bronchoscopic forceps biopsy samples and needle aspiration cytology specimens exhibited a median tumour cell proportion of 70 versus 30 versus 20% and a DNA quantity of 2,500 versus 1,610 versus 1,440 ng, respectively. The overall EGFR mutation rate was 11%, with no differences between different sample types. Dilution experiments showed that the detection limit depends on the type of mutation. A neoplastic cell content of at least 10 and 25% for exon 19 deletions and exon 21 L858R point mutation, respectively, was required for a true negative result. CONCLUSIONS: Bronchoscopic forceps biopsy and needle aspiration cytology specimens are suitable for accurate EGFR mutation analysis using single-gene quantitative real-time polymerase chain reaction. Technologies with a better analytical sensitivity are evolving and should consider these endoscopic tumour specimens.

Multicentre European study for the treatment of advanced emphysema with bronchial valves.

This multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bronchial valve therapy using a bilateral upper lobe treatment approach without the goal of lobar atelectasis. Patients with upper lobe predominant severe emphysema were randomised to bronchoscopy with (n = 37) or without (n = 36) IBV Valves for a 3-month blinded phase. A positive responder was defined as having both a ≥ 4-point improvement in St George's Respiratory Questionnaire (SGRQ) and a lobar volume shift as measured by quantitative computed tomography. At 3 months, there were eight (24%) positive responders in the treated group versus none (0%) in the control group (p = 0.002). Also, there was a significant shift in volume in the treated group from the upper lobes (mean ± SD -7.3 ± 9.0%) to the non-treated lobes (6.7 ± 14.5%), with minimal change in the control group (p<0.05). Mean SGRQ total score improved in both groups (treatment: -4.3 ± 16.2; control: -3.6 ± 10.7). The procedure and devices were well tolerated and there were no differences in adverse events reported in the treatment and control groups. Treatment with bronchial valves without complete lobar occlusion in both upper lobes was safe, but not effective in the majority of patients.