Transbronchial cryobiopsy followed by as-needed surgical lung biopsy versus immediate surgical lung biopsy for diagnosing interstitial lung disease (the COLD study): a randomised controlled trial.

BACKGROUND: An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB. METHODS: The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed. FINDINGS: Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy. INTERPRETATION: In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers.

Systematic endoscopic staging of mediastinum to guide radiotherapy planning in patients with locally advanced non-small-cell lung cancer (SEISMIC): an international, multicentre, single-arm, clinical trial.

BACKGROUND: Systematic mediastinal lymph node staging by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) improves accuracy of staging in patients with early-stage non-small-cell lung cancer (NSCLC). However, patients with locally advanced NSCLC commonly undergo only selective lymph node sampling. This study aimed to determine the proportion of patients with locally advanced NSCLC in whom systematic endoscopic mediastinal staging identified PET-occult lymph node metastases, and to describe the consequences of PET-occult disease on radiotherapy planning. METHODS: This prospective, international, multicentre, single-arm, international study was conducted at seven tertiary lung cancer centres in four countries (Australia, Canada, the Netherlands, and the USA). Patients aged 18 years or older with suspected or known locally advanced NSCLC underwent systematic endoscopic mediastinal lymph node staging before combination chemoradiotherapy or high-dose palliative radiotherapy. The primary endpoint was the proportion of participants with PET-occult mediastinal lymph node metastases shown following systematic endoscopic staging. The study was prospectively registered with Australian New Zealand Clinical Trials Registry, ACTRN12617000333314. FINDINGS: From Jan 30, 2018, to March 23, 2022, 155 patients underwent systematic endoscopic mediastinal lymph node staging and were eligible for analysis. 58 (37%) of patients were female and 97 (63%) were male. Discrepancy in extent of mediastinal disease identified by PET and EBUS-TBNA was observed in 57 (37% [95% CI 29-44]) patients. PET-occult lymph node metastases were identified in 18 (12% [7-17]) participants, including 16 (13% [7-19]) of 123 participants with clinical stage IIIA or cN2 NSCLC. Contralateral PET-occult N3 disease was identified in nine (7% [2-12]) of 128 participants staged cN0, cN1, or cN2. Identification of PET-occult disease resulted in clinically significant changes to treatment in all 18 patients. In silico dosimetry studies showed the median volume of PET-occult lymph nodes receiving the prescription dose of 60 Gy was only 10·1% (IQR 0·1-52·3). No serious adverse events following endoscopic staging were reported. INTERPRETATION: Our findings suggests that systematic endoscopic mediastinal staging in patients with locally advanced or unresectable NSCLC is more accurate than PET alone in defining extent of mediastinal involvement. Standard guideline-recommended PET-based radiotherapy planning results in suboptimal tumour coverage. Our findings indicate that systematic endoscopic staging should be routinely performed in patients with locally advanced NSCLC being considered for radiotherapy to accurately inform radiation planning and treatment decision making in patients with locally advanced NSCLC. FUNDING: None.

Exhaled breath analyses for bronchial thermoplasty in severe asthma patients.

BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma. Although multiple trials have demonstrated clinical improvement after BT, optimal patient selection remains a challenge and the mechanism of action is incompletely understood. The aim of this study was to examine whether exhaled breath analysis can contribute to discriminate between BT-responders and non-responders at baseline and to explore pathophysiological insights of BT. METHODS: Exhaled breath was collected from patients at baseline and six months post-BT. Patients were defined as responders or non-responders based on a half point increase in asthma quality of life questionnaire scores. Gas chromatography-mass spectrometry was used for volatile organic compounds (VOCs) detection and analyses. Analytical workflow consisted of: 1) detection of VOCs that differentiate between responders and non-responders and those that differ between baseline and six months post-BT, 2) identification of VOCs of interest and 3) explore correlations between clinical biomarkers and VOCs. RESULTS: Data was available from 14 patients. Nonanal, 2-ethylhexanol and 3-thujol showed a significant difference in intensity between responders and non-responders at baseline (p = 0.04, p = 0.01 and p = 0.03, respectively). After BT, no difference was found in the compound intensity of these VOCs. A negative correlation was observed between nonanal and IgE and BALF eosinophils (r = -0.68, p < 0.01 and r = -0.61, p = 0.02 respectively) and 3-thujol with BALF neutrophils (r = -0.54, p = 0.04). CONCLUSIONS: This explorative study identified discriminative VOCs in exhaled breath between BT responders and non-responders at baseline. Additionally, correlations were found between VOC's and inflammatory BALF cells. Once validated, these findings encourage research in breath analysis as a non-invasive easy to apply technique for identifying airway inflammatory profiles and eligibility for BT or immunotherapies in severe asthma.

Airway smooth muscle and long-term clinical efficacy following bronchial thermoplasty in severe asthma.

The mechanism of action of bronchial thermoplasty (BT) treatment for patients with severe asthma is incompletely understood. This study investigated the 2.5-year impact of BT on airway smooth muscle (ASM) mass and clinical parameters by paired data analysis in 22 patients. Our findings demonstrate the persistence of ASM mass reduction of >50% after 2.5 years. Furthermore, sustained improvement in asthma control, quality of life and exacerbation rates was found, which is in line with previous reports. An association was found between the remaining ASM and both the exacerbation rate (r=0.61, p=0.04 for desmin, r=0.85, p<0.01 for alpha smooth muscle actin (SMA)) and post-bronchodilator forced expiratory volume in 1 s predicted percentage (r=-0.69, p=0.03 for desmin, r=-0.58, p=0.08 for alpha SMA). This study provides new insight into the long-term impact of BT.

ERS International Congress 2023: highlights from the Clinical Techniques, Imaging and Endoscopy Assembly.

The Clinical Techniques, Imaging and Endoscopy Assembly is involved in the diagnosis and treatment of several pulmonary diseases, as demonstrated at the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. From interventional pulmonology, the congress included several exciting results for the use of bronchoscopy in lung cancer, including augmented fluoroscopy, robotic-assisted bronchoscopy and cryobiopsies. In obstructive lung disease, the latest results on bronchoscopic treatment of emphysema with hyperinflation and chronic bronchitis were presented. Research on using cryobiopsies to diagnose interstitial lung disease was further explored, with the aims of elevating diagnostic yield and minimising risk. For imaging, the latest updates in using artificial intelligence to overcome the increased workload of radiologists were of great interest. Novel imaging in sarcoidosis explored the use of magnetic resonance imaging, photon-counting computed tomography and positron emission tomography/computed tomography in the diagnostic work-up. Lung cancer screening is still a hot topic and new results were presented regarding incorporation of biomarkers, identifying knowledge gaps and improving screening programmes. The use of ultrasound in respiratory medicine is an expanding field, which was demonstrated by the large variety in studies presented at the 2023 ERS Congress. Ultrasound of the diaphragm in patients with amyotrophic lateral sclerosis and myasthenia gravis was used to assess movements and predict respiratory fatigue. Furthermore, studies using ultrasound to diagnose or monitor pulmonary disease were presented. The congress also included studies regarding the training and assessment of competencies as an important part of implementing ultrasound in clinical practice.

Correlation between Serum Biomarkers and Lung Ultrasound in COVID-19: An Observational Study.

Serum biomarkers and lung ultrasound are important measures for prognostication and treatment allocation in patients with COVID-19. Currently, there is a paucity of studies investigating relationships between serum biomarkers and ultrasonographic biomarkers derived from lung ultrasound. This study aims to assess correlations between serum biomarkers and lung ultrasound findings. This study is a secondary analysis of four prospective observational studies in adult patients with COVID-19. Serum biomarkers included markers of epithelial injury, endothelial dysfunction and immune activation. The primary outcome was the correlation between biomarker concentrations and lung ultrasound score assessed with Pearson's (r) or Spearman's (rs) correlations. Forty-four patients (67 [41-88] years old, 25% female, 52% ICU patients) were included. GAS6 (rs = 0.39), CRP (rs = 0.42) and SP-D (rs = 0.36) were correlated with lung ultrasound scores. ANG-1 (rs = -0.39) was inversely correlated with lung ultrasound scores. No correlations were found between lung ultrasound score and several other serum biomarkers. In patients with COVID-19, several serum biomarkers of epithelial injury, endothelial dysfunction and immune activation correlated with lung ultrasound findings. The lack of correlations with certain biomarkers could offer opportunities for precise prognostication and targeted therapeutic interventions by integrating these unlinked biomarkers.

Airway wall extracellular matrix changes induced by bronchial thermoplasty in severe asthma.

BACKGROUND: Airway remodeling is a prominent feature of asthma, which involves increased airway smooth muscle mass and altered extracellular matrix composition. Bronchial thermoplasty (BT), a bronchoscopic treatment for severe asthma, targets airway remodeling. OBJECTIVE: We sought to investigate the effect of BT on extracellular matrix composition and its association with clinical outcomes. METHODS: This is a substudy of the TASMA trial. Thirty patients with severe asthma were BT-treated, of whom 13 patients were treated for 6 months with standard therapy (control group) before BT. Demographic data, clinical data including pulmonary function, and bronchial biopsies were collected. Biopsies at BT-treated and nontreated locations were analyzed by histological and immunohistochemical staining. Associations between histology and clinical outcomes were explored. RESULTS: Six months after treatment, it was found that the reticular basement membrane thickness was reduced from 7.28 µm to 5.74 µm (21% relative reduction) and the percentage area of tissue positive for collagen increased from 26.3% to 29.8% (13% relative increase). Collagen structure analysis revealed a reduction in the curvature frequency of fibers. The percentage area positive for fibulin-1 and fibronectin increased by 2.5% and 5.9%, respectively (relative increase of 124% and 15%). No changes were found for elastin. The changes in collagen and fibulin-1 negatively associated with changes in FEV1 reversibility. CONCLUSIONS: Besides reduction of airway smooth muscle mass, BT has an impact on reticular basement membrane thickness and the extracellular matrix arrangement characterized by an increase in tissue area occupied by collagen with a less dense fiber organization. Both collagen and fibulin-1 are negatively associated with the change in FEV1 reversibility.

Performance of EUS-FNA and EUS-B-FNA for the diagnosis of left adrenal glands metastases in patients with lung cancer: A systematic review and meta-analysis.

OBJECTIVES: For diagnosing left adrenal gland metastasis in lung cancer, clinical guidelines recommend to perform EUS, but EUS-B (EUS using an EBUS-scope) is increasingly being used. We evaluated the diagnostic performance of both procedures. MATERIALS AND METHODS: We did a systematic review (PROSPERO, CRD42023416205) and searched MEDLINE and EMBASE on 04-July-2023 for studies evaluating EUS and/or EUS-B in diagnosing left adrenal gland metastases in adults with (suspected) lung cancer. Outcomes were: (1) ability to visualize the left adrenal gland, (2) ability to sample (in those with successful visualization and in whom sampling was attempted), (3) ability to obtain adequate material (in those with successful sampling), (4) malignancy detection rate (in those with successful sampling), and (5) remaining risk of malignancy (in those with a negative EUS(-B)-FNA and undergoing a reference standard). We performed random-effects meta-analyses. RESULTS: We included 19 studies (EUS: n = 11, EUS-B: n = 6, both: n = 2), covering 1712 patients. All studies had high (n = 18) or unclear (n = 1) risk of bias (QUADAS-2). Average ability to visualize the left adrenal gland was 0.94 (95 %CI 0.82-0.98; n = 7 studies). Average ability to sample was 1.00 (95 %CI 0.99-1.00; n = 9). Average ability to obtain adequate material was 0.96 (95 %CI 0.93-0.98; n = 18). Average malignancy detection rate was 0.42 (95 %CI 0.34-0.49; n = 18). Remaining risk of malignancy was 0.07 (95 %CI 0.04-0.12; n = 8). Ability to visualize was slightly higher for EUS (0.99; 95 %CI 0.90-1.00) than EUS-B (0.84; 95 %CI 0.70-0.92; p = 0.025), but the other performance characteristics were similar. No major complications were reported. CONCLUSION: Both EUS and EUS-B have good performance and are safe for left adrenal gland analysis in patients with lung cancer, but the number of high-quality studies is limited and further well-constructed prospective studies are needed.

Endobronchial ultrasound in diagnosing and staging of lung cancer by Acquire 22G TBNB versus regular 22G TBNA needles: A randomized clinical trial.

OBJECTIVES: Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) has an important role in the diagnosis and staging of lung cancer. Evaluation of programmed death ligand 1 (PD-L1) expression and molecular profiling has become standard of care but cytological samples frequently contain insufficient tumor cells. The 22G Acquire needle with Franseen needle tip was developed to perform transbronchial needle biopsy (TBNB) with improved tissue specimens. This study evaluated if the 22G Acquire TBNB needle results in enhanced PD-L1 suitability rate compared to the regular Expect 22G TBNA needle. METHODS: in this multi-center randomized clinical trial (Netherlands Trial Register NL7701), patients with suspected (N)SCLC and an indication for mediastinal/hilar staging or lung tumor diagnosis were recruited in five university and general hospitals in the Netherlands, Poland, Italy and Czech Republic. Patients were randomized (1:1) between the two needles. Two blinded reference pathologists evaluated the samples. The primary outcome was PD-L1 suitability rate in patients with a final diagnosis of lung cancer. In case no malignancy was diagnosed, the reference standard was surgical verification or 6 month follow-up. RESULTS: 154 patients were randomized (n = 76 Acquire TBNB; n = 78 Expect TBNA) of which 92.9% (n = 143) had a final malignant diagnosis. Suitability for PD-L1 analysis was 80.0% (n = 56/70; 95 %CI 0.68-0.94) with the Acquire needle and 76.7% (n = 56/73; 95 %CI 0.65-0.85) with the Expect needle (p = 0.633). Acquire TBNB needle specimens provided more frequent superior quality (65.3% (95 %CI 0.57-0.73) vs 49.4% (95 %CI 0.41-0.57, p = 0.005) and contained more tissue cores (72.0% (95 %CI 0.60-0.81) vs 41.0% (95 %CI 0.31-0.54, p < 0.01). There were no statistically significant differences in tissue adequacy, suitability for molecular analysis and sensitivity for malignancy and N2/N3 disease. CONCLUSION: The 22G Acquire TBNB needle procured improved quality tissue specimens compared to the Expect TBNA needle but this did not result in an improved the suitability rate for PD-L1 analysis.

In vivo polarisation sensitive optical coherence tomography for fibrosis assessment in interstitial lung disease: a prospective, exploratory, observational study.

INTRODUCTION: Endobronchial polarisation sensitive optical coherence tomography (EB-PS-OCT) is a bronchoscopic imaging technique exceeding resolution of high-resolution CT (HRCT) by 50-fold. It detects collagen birefringence, enabling identification and quantification of fibrosis. STUDY AIM: To assess pulmonary fibrosis in interstitial lung diseases (ILD) patients with in vivo EB-PS-OCT using histology as reference standard. PRIMARY OBJECTIVE: Visualisation and quantification of pulmonary fibrosis by EB-PS-OCT. SECONDARY OBJECTIVES: Comparison of EB-PS-OCT and HRCT detected fibrosis with histology, identification of ILD histological features in EB-PS-OCT images and comparison of ex vivo PS-OCT results with histology. METHODS: Observational prospective exploratory study. Patients with ILD scheduled for transbronchial cryobiopsy or surgical lung biopsy underwent in vivo EB-PS-OCT imaging prior to tissue acquisition. Asthma patients were included as non-fibrotic controls. Per imaged lung segment, fibrosis was automatically quantified assessing the birefringent area in EB-PS-OCT images. Fibrotic extent in corresponding HRCT areas and biopsies were compared with EB-PS-OCT detected fibrosis. Microscopic ILD features were identified on EB-PS-OCT images and matched with biopsies from the same segment. RESULTS: 19 patients were included (16 ILD; 3 asthma). In 49 in vivo imaged airway segments the parenchymal birefringent area was successfully quantified and ranged from 2.54% (no to minimal fibrosis) to 21.01% (extensive fibrosis). Increased EB-PS-OCT detected birefringent area corresponded to increased histologically confirmed fibrosis, with better predictive value than HRCT. Microscopic ILD features were identified on both in vivo and ex vivo PS-OCT images. CONCLUSIONS: EB-PS-OCT enables pulmonary fibrosis quantification, thereby has potential to serve as an add-on bronchoscopic imaging technique to diagnose and detect (early) fibrosis in ILD.

Needle-based confocal laser endomicroscopy for real-time granuloma detection.

BACKGROUND AND OBJECTIVE: Needle-based confocal laser endomicroscopy (nCLE) allows real-time microscopic imaging at the needle tip. nCLE malignancy criteria are used for tool-in-lesion confirmation during bronchoscopic lung nodule analysis. However, to date, nCLE criteria for granulomas are lacking. The aim was to identify and validate nCLE granuloma criteria and assess if blinded raters can distinguish malignant from granulomatous nCLE videos. METHODS: In patients with suspected sarcoidosis, nCLE-imaging of mediastinal lymph nodes was performed during endoscopic ultrasound procedures, followed by needle aspiration. nCLE granuloma criteria were identified by comparison with pathology and final diagnoses. Additionally, nCLE-videos of granulomatous lung nodules part of prospective trials and clinical care were compared to the proposed nCLE granuloma criteria. Blinded raters validated nCLE videos of sarcoid and reactive mediastinal lymph nodes and malignant and granulomatous lung nodules twice. RESULTS: Granuloma criteria were identified (brighter-toned, homogeneous and well-demarcated lesions) based on nCLE-imaging in 14 sarcoidosis patients. Raters evaluated 26 nCLE-videos obtained in lymph nodes (n = 15 sarcoidosis; n = 11 reactive and total of 260 ratings). Granuloma criteria were recognized with 88% accuracy. The inter-observer (κ = 0.63, 95% CI 0.54-0.72) and intra-observer reliability (κ = 0.70 ± 0.06) were substantial. Based on 12 nCLE-videos obtained in lung nodules (n = 4 granulomas, n = 6 malignancy, n = 2 malignancy + granulomas and total of 120 ratings) granuloma and malignancy criteria were recognized with 92% and 75% accuracy. CONCLUSION: nCLE imaging facilitates real-time granuloma visualization. Blinded raters accurately and consistently recognized granulomas on nCLE-imaging and distinguished nCLE granuloma criteria from malignancy. Our data show the potential of nCLE as a real-time bronchoscopic guidance tool for lung nodule analysis.

Diagnostic yield and safety of navigation bronchoscopy: A systematic review and meta-analysis.

BACKGROUND: Navigation bronchoscopy has seen rapid development in the past decade in terms of new navigation techniques and multi-modality approaches utilizing different techniques and tools. This systematic review analyses the diagnostic yield and safety of navigation bronchoscopy for the diagnosis of peripheral pulmonary nodules suspected of lung cancer. METHODS: An extensive search was performed in Embase, Medline and Cochrane CENTRAL in May 2022. Eligible studies used cone-beam CT-guided navigation (CBCT), electromagnetic navigation (EMN), robotic navigation (RB) or virtual bronchoscopy (VB) as the primary navigation technique. Primary outcomes were diagnostic yield and adverse events. Quality of studies was assessed using QUADAS-2. Random effects meta-analysis was performed, with subgroup analyses for different navigation techniques, newer versus older techniques, nodule size, publication year, and strictness of diagnostic yield definition. Explorative analyses of subgroups reported by studies was performed for nodule size and bronchus sign. RESULTS: A total of 95 studies (n = 10,381 patients; n = 10,682 nodules) were included. The majority (n = 63; 66.3%) had high risk of bias or applicability concerns in at least one QUADAS-2 domain. Summary diagnostic yield was 70.9% (95%-CI 68.4%-73.2%). Overall pneumothorax rate was 2.5%. Newer navigation techniques using advanced imaging and/or robotics(CBCT, RB, tomosynthesis guided EMN; n = 24 studies) had a statistically significant higher diagnostic yield compared to longer established techniques (EMN, VB; n = 82 studies): 77.5% (95%-CI 74.7%-80.1%) vs 68.8% (95%-CI 65.9%-71.6%) (p < 0.001).Explorative subgroup analyses showed that larger nodule size and bronchus sign presence were associated with a statistically significant higher diagnostic yield. Other subgroup analyses showed no significant differences. CONCLUSION: Navigation bronchoscopy is a safe procedure, with the potential for high diagnostic yield, in particular using newer techniques such as RB, CBCT and tomosynthesis-guided EMN. Studies showed a large amount of heterogeneity, making comparisons difficult. Standardized definitions for outcomes with relevant clinical context will improve future comparability.

Effectiveness of Flexible Bronchoscopy Simulation-Based Training: A Systematic Review.

BACKGROUND: The implementation of simulation-based training (SBT) to teach flexible bronchoscopy (FB) skills to novice trainees has increased during the last decade. However, it is unknown whether SBT is effective to teach FB to novices and which instructional features contribute to training effectiveness. RESEARCH QUESTION: How effective is FB SBT and which instructional features contribute to training effectiveness? STUDY DESIGN AND METHODS: We searched Embase, PubMed, Scopus, and Web of Science for articles on FB SBT for novice trainees, considering all available literature until November 10, 2022. We assessed methodological quality of included studies using a modified version of the Medical Education Research Study Quality Instrument, evaluated risk of bias with relevant tools depending on study design, assessed instructional features, and intended to correlate instructional features to outcome measures. RESULTS: We identified 14 studies from an initial pool of 544 studies. Eleven studies reported positive effects of FB SBT on most of their outcome measures. However, risk of bias was moderate or high in eight studies, and only six studies were of high quality (modified Medical Education Research Study Quality Instrument score ≥ 12.5). Moreover, instructional features and outcome measures varied highly across studies, and only four studies evaluated intervention effects on behavioral outcome measures in the patient setting. All of the simulation training programs in studies with the highest methodological quality and most relevant outcome measures included curriculum integration and a range in task difficulty. INTERPRETATION: Although most studies reported positive effects of simulation training programs on their outcome measures, definitive conclusions regarding training effectiveness on actual bronchoscopy performance in patients could not be made because of heterogeneity of training features and the sparse evidence of training effectiveness on validated behavioral outcome measures in a patient setting. TRIAL REGISTRATION: PROSPERO; No.: CRD42021262853; URL: https://www.crd.york.ac.uk/prospero/.

Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer: A Randomized Clinical Trial.

PURPOSE: Resectable non-small-cell lung cancer (NSCLC) with a high probability of mediastinal nodal involvement requires mediastinal staging by endosonography and, in the absence of nodal metastases, confirmatory mediastinoscopy according to current guidelines. However, randomized data regarding immediate lung tumor resection after systematic endosonography versus additional confirmatory mediastinoscopy before resection are lacking. METHODS: Patients with (suspected) resectable NSCLC and an indication for mediastinal staging after negative systematic endosonography were randomly assigned to immediate lung tumor resection or confirmatory mediastinoscopy followed by tumor resection. The primary outcome in this noninferiority trial (noninferiority margin of 8% that previously showed to not compromise survival, Pnoninferior < .0250) was the presence of unforeseen N2 disease after tumor resection with lymph node dissection. Secondary outcomes were 30-day major morbidity and mortality. RESULTS: Between July 17, 2017, and October 5, 2020, 360 patients were randomly assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to confirmatory mediastinoscopy first (seven dropouts before and six after mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI, 4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%) was noninferior compared with mediastinoscopy first (7.7%) in both intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior = .0144) and per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior = .0157). Major morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4% after mediastinoscopy first (P = .4940). CONCLUSION: On the basis of our chosen noninferiority margin in the rate of unforeseen N2, confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging.

High-Definition Videobronchoscopy for the Diagnosis of Airway Involvement in Sarcoidosis: The Enhance Sarcoidosis Multicenter Study.

BACKGROUND: The ability of high-definition (HD) videobronchoscopy to detect airway involvement in sarcoidosis has not been evaluated previously. RESEARCH QUESTION: What is the role of HD videobronchoscopy in the identification of sarcoidosis-associated airway abnormalities (AAs)? What are the patterns of AAs more commonly observed and more frequently associated with the detection of granulomas in endobronchial biopsy (EBB)? STUDY DESIGN AND METHODS: In this prospective international multicenter cohort study, consecutive patients with suspected sarcoidosis underwent airway inspection with an HD videobronchoscope and EBB using a standardized workflow. AAs were classified according to six patterns defined a priori: nodularity, cobblestoning, thickening, plaque, increased vascularity, and miscellaneous. We assessed diagnostic yield of EBB, prevalence of AAs, and interobserver agreement for different patterns of AAs. RESULTS: AAs were identified in 64 of 134 patients with sarcoidosis (47.8%), with nodularity (n = 23 [17.2%]), plaque (n = 19 [14.2%]), and increased vascularity (n = 19 [14.2%]) being the most prevalent. The diagnostic yield of EBB was 36.6%. AAs were significantly more prevalent in patients with than in those without nonnecrotizing granulomas on EBB (67.4% vs 36.5%; P = .001). Likewise, parenchymal disease on CT scan imaging was significantly more common in patients with than in those without nonnecrotizing granulomas on EBB (79.6% vs 54.1%; P = .003). On a per-lesion analysis, nonnecrotizing granulomas were seen especially in EBB samples obtained from areas of cobblestoning (9/10 [90%]) and nodularity (17/29 [58.6%]). The overall diagnostic yield of random EBB was low (31/134 [23.1%]). The interobserver agreement for the different patterns of AA was fair (Fleiss κ = 0.34). INTERPRETATION: In a population with a large prevalence of White Europeans, HD videobronchoscopy detected AAs in approximately one-half of patients with sarcoidosis. The diagnostic yield of EBB was higher in patients with parenchymal involvement on CT scan imaging and in those with AAs, especially if manifesting as cobblestoning and nodularity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT4743596; URL: www. CLINICALTRIALS: gov.

Robotic bronchoscopic needle-based confocal laser endomicroscopy to diagnose peripheral lung nodules.

BACKGROUND AND OBJECTIVE: Robotic bronchoscopy has demonstrated high navigational success in small peripheral lung nodules but the diagnostic yield is discrepantly lower. Needle based confocal laser endomicroscopy (nCLE) enables real-time microscopic imaging at the needle tip. We aim to assess feasibility, safety and needle repositioning based on real-time nCLE-guidance during robotic bronchoscopy in small peripheral lung nodules. METHODS: Patients with suspected peripheral lung cancer underwent fluoroscopy and radial EBUS assisted robotic bronchoscopy. After radial EBUS nodule identification, nCLE-imaging of the target area was performed. nCLE-malignancy and airway/lung parenchyma criteria were used to identify the optimal sampling location. In case airway was visualized, repositioning of the biopsy needle was performed. After nCLE tool-in-nodule confirmation, needle passes and biopsies were performed at the same location. MEASUREMENTS AND MAIN RESULTS: Twenty patients were included (final diagnosis n = 17 (lung) cancer) with a median lung nodule size of 14.5 mm (range 8-28 mm). No complications occurred. In 19/20 patients, good quality nCLE-videos were obtained. In 9 patients (45%), real-time nCLE-imaging revealed inadequate positioning of the needle and repositioning was performed. After repositioning, nCLE-imaging provided tool-in-nodule-confirmation in 19/20 patients. Subsequent ROSE demonstrated representative material in 9/20 patients (45%) and overall diagnostic yield was 80% (16/20). Of the three patients with malignant nCLE-imaging but inadequate pathology, two were diagnosed with malignancy during follow-up. CONCLUSION: Robotic bronchoscopic nCLE-imaging is feasible and safe. nCLE-imaging in small, difficult-to-access lung nodules provided additional real-time feedback on the correct needle positioning with the potential to optimize the sampling location and diagnostic yield.

Advances in bronchoscopic optical coherence tomography and confocal laser endomicroscopy in pulmonary diseases.

PURPOSE OF REVIEW: Imaging techniques play a crucial role in the diagnostic work-up of pulmonary diseases but generally lack detailed information on a microscopic level. Optical coherence tomography (OCT) and confocal laser endomicroscopy (CLE) are imaging techniques which provide microscopic images in vivo during bronchoscopy. The purpose of this review is to describe recent advancements in the use of bronchoscopic OCT- and CLE-imaging in pulmonary medicine. RECENT FINDINGS: In recent years, OCT- and CLE-imaging have been evaluated in a wide variety of pulmonary diseases and demonstrated to be complementary to bronchoscopy for real-time, near-histological imaging. Several pulmonary compartments were visualized and characteristic patterns for disease were identified. In thoracic malignancy, OCT- and CLE-imaging can provide characterization of malignant tissue with the ability to identify the optimal sampling area. In interstitial lung disease (ILD), fibrotic patterns were detected by both (PS-) OCT and CLE, complementary to current HRCT-imaging. For obstructive lung diseases, (PS-) OCT enables to detect airway wall structures and remodelling, including changes in the airway smooth muscle and extracellular matrix. SUMMARY: Bronchoscopic OCT- and CLE-imaging allow high resolution imaging of airways, lung parenchyma, pleura, lung tumours and mediastinal lymph nodes. Although investigational at the moment, promising clinical applications are on the horizon.