Kurt G. Tournoy

Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial.

CONTEXT Mediastinal nodal staging is recommended for patients with resectable non-small cell lung cancer (NSCLC). Surgical staging has limitations, which results in the performance of unnecessary thoracotomies. Current guidelines acknowledge minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging. OBJECTIVE To compare the 2 recommended lung cancer staging strategies. DESIGN, SETTING, AND PATIENTS Randomized controlled multicenter trial (Ghent, Leiden, Leuven, Papworth) conducted between February 2007 and April 2009 in 241 patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on computed or positron emission tomography. INTERVENTION Either surgical staging or endosonography (combined transesophageal and endobronchial ultrasound [EUS-FNA and EBUS-TBNA]) followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread. MAIN OUTCOME MEASURES The primary outcome was sensitivity for mediastinal nodal (N2/N3) metastases. The reference standard was surgical pathological staging. Secondary outcomes were rates of unnecessary thoracotomy and complications. RESULTS Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%; 95% confidence interval [CI], 27%-44%) by surgical staging vs 56 patients (46%; 95% CI, 37%-54%) by endosonography (P = .11) and in 62 patients (50%; 95% CI, 42%-59%) by endosonography followed by surgical staging (P = .02). This corresponded to sensitivities of 79% (41/52; 95% CI, 66%-88%) vs 85% (56/66; 95% CI, 74%-92%) (P = .47) and 94% (62/66; 95% CI, 85%-98%) (P = .02). Thoracotomy was unnecessary in 21 patients (18%; 95% CI, 12%-26%) in the mediastinoscopy group vs 9 (7%; 95% CI, 4%-13%) in the endosonography group (P = .02). The complication rate was similar in both groups. CONCLUSIONS Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00432640.

Airway eosinophilia is not a requirement for allergen-induced airway hyperresponsiveness.

House dust mites (HDMs) are the major source of perennial allergens causing human allergic asthma. Animal models mimicking as closely as possible the allergic features observed in human asthma are therefore interesting tools for studying the immunological and pathophysiological mechanisms involved. Especially the role of eosinophils and allergen‐specific immunoglobulin (Ig) E in the pathophysiology of airway hyperresponsiveness (AHR) remains a subject of intense debate.

Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation.

We investigated the specific role of matrix metalloproteinase (MMP)-9 in allergic asthma using a murine model of allergen-induced airway inflammation and airway hyperresponsiveness in MMP-9(-/-) mice and their corresponding wild-type (WT) littermates. After a single intraperitoneal sensitization to ovalbumin, the mice were exposed daily either to ovalbumin (1%) or phosphate-buffered saline aerosols from days 14 to 21. Significantly less peribronchial mononuclear cell infiltration of the airways and less lymphocytes in the bronchoalveolar lavage fluid were detected in challenged MMP-9(-/-) as compared to WT mice. In contrast, comparable numbers of bronchoalveolar lavage fluid eosinophils were observed in both genotypes. After allergen exposure, the WT mice developed a significant airway hyperresponsiveness to carbachol whereas the MMP-9(-/-) mice failed to do so. Allergen exposure induced an increase of MMP-9-related gelatinolytic activity in WT lung extracts. Quantitative reverse transcriptase-polymerase chain reaction showed increased mRNA levels of MMP-12, MMP-14, and urokinase-type plasminogen activator after allergen exposure in the lung extracts of WT mice but not in MMP-9-deficient mice. In contrast, the expression of tissue inhibitor of metalloproteinases-1 was enhanced after allergen exposure in both groups. We conclude that MMP-9 plays a key role in the development of airway inflammation after allergen exposure.

Matrix metalloproteinase-9-mediated dendritic cell recruitment into the airways is a critical step in a mouse model of asthma

Dendritic cells (DCs) appear to be strategically implicated in allergic diseases, including asthma. Matrix metalloproteinase (MMP)-9 mediates transmigration of inflammatory leukocytes across basement membranes. This study investigated the role of MMP-9 in airway DC trafficking during allergen-induced airway inflammation. MMP-9 gene deletion affected the trafficking of pulmonary DCs in a specific way: only the inflammatory transmigration of DCs into the airway lumen was impaired, whereas DC-mediated transport of airway Ag to the thoracic lymph nodes remained unaffected. In parallel, the local production of the Th2-attracting chemokine CC chemokine ligand 17/thymus and activation-regulated chemokine, which was highly concentrated in purified lung DCs, fell short in the airways of allergen-exposed MMP-9−/− mice. This was accompanied by markedly reduced peribronchial eosinophilic infiltrates and impaired allergen-specific IgE production. We conclude that the specific absence of MMP-9 activity inhibits the development of allergic airway inflammation by impairing the recruitment of DCs into the airways and the local production of DC-derived proallergic chemokines.

EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy

BACKGROUND Obtaining a tissue diagnosis of malignancy is challenging in patients with suspected lung cancer presenting with centrally located intrapulmonary masses. OBJECTIVE (1) To evaluate the yield of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing centrally located lesions after a non-diagnostic conventional bronchoscopy. (2) To assess the impact of EBUS-TBNA on patient management for this indication. STUDY DESIGN AND PATIENTS A retrospective analysis of a series of patients with a central parenchymal lung lesion suspected to be lung cancer who had been referred to three university hospitals for EBUS-TBNA to obtain a tissue diagnosis was undertaken. If EBUS-TBNA did not result in a formal pathological diagnosis of malignancy, patients were subsequently referred for a transthoracic needle aspiration biopsy or a surgical diagnostic procedure. RESULTS Sixty patients were investigated with EBUS-TBNA. The majority (82%) had a prior (non-diagnostic) flexible bronchoscopy. EBUS-TBNA was performed in an out-patient setting in 97%. With ultrasound, the primary lung lesion was observed in all cases. EBUS-TBNA confirmed lung cancer in 46 (77%). A final reference pathology diagnosis was available in 59 (98%) cases. The sensitivity of EBUS-TBNA for diagnosing lung cancer was 82% (95% confidence intervals (CI) 69-91%) with a negative predictive value of 23% (95%CI 5-53%). Based on the EBUS-TBNA findings, transthoracic needle aspiration biopsy or a surgical diagnostic procedure was cancelled in 47% and 30% of patients, respectively. No serious procedure-related complications were reported. CONCLUSION EBUS-TBNA is a sensitive tool for the diagnosis of centrally located primary lung cancer not visible at conventional bronchoscopy. Therefore, EBUS-TBNA can impact on patient management in this setting. However, the low negative predictive value indicates that a negative EBUS-TBNA result should be confirmed by other methods. IMPLICATION EBUS-TBNA can be considered as a diagnostic test in patients with a centrally located lung lesion after a previous non-diagnostic conventional bronchoscopy.

Decreased FOXP3 protein expression in patients with asthma.

Background:  T‐regulatory cells (Treg) are important in balancing immune responses and maintaining peripheral tolerance. Current evidence suggests that asthma is characterized by a relative deficiency in Treg, allowing T helper 2 cells to expand. In this study, we aimed to evaluate circulating Treg, defined by the protein FOXP3, in both control subjects and patients with stable asthma.

Endogenous interleukin-10 suppresses allergen-induced airway inflammation and nonspecific airway responsiveness.

The airway inflammation observed in asthma is orchestrated by activated Th‐2 lymphocytes relevant for the induction of altered airway responsiveness. An increasing body of evidence is accumulating that not only the pro‐inflammatory cytokines interleukin (IL)‐4 and IL‐5 but also the immunomodulating cytokines IL‐12 and possibly IL‐10 are crucial for regulating the allergic airway inflammation.

Integrated FDG-PET/CT does not make invasive staging of the intrathoracic lymph nodes in non-small cell lung cancer redundant: a prospective study

Background: Staging of non-small cell lung cancer (NSCLC) is important for determining choice of treatment and prognosis. The accuracy of FDG-PET scans for staging of lymph nodes is too low to replace invasive nodal staging. It is unknown whether the accuracy of integrated FDG-PET/CT scanning makes invasive staging redundant. Methods: In a prospective study, the mediastinal and/or hilar lymph nodes in patients with proven NSCLC were investigated with integrated FDG-PET/CT scanning. Pathological confirmation of all suspect lymph nodes was obtained to calculate the accuracy of the fusion images. In addition, the use of the standardised uptake value (SUV) in the staging of intrathoracic lymph nodes was analysed. Results: 105 intrathoracic lymph node stations from 52 patients with NSCLC were characterised. The prevalence of malignancy in the lymph nodes was 36%. The sensitivity of the integrated FDG-PET/CT scan to detect malignant lymph nodes was 84% and its specificity was 85% (positive likelihood ratio 5.64, negative likelihood ratio 0.19). SUVmax, SUVmean and the SUVmax/SUVliver ratio were all significantly higher in malignant than in benign lymph nodes. The area under the receiver operating curve did not differ between these three quantitative variables, but the highest accuracy was found with the SUVmax/SUVliver ratio. At a cut-off value of 1.5 for the SUVmax/SUVliver ratio, the sensitivity and specificity to detect malignant lymph node invasion were 82% and 93%, respectively. Conclusion: The accuracy of integrated FDG-PET/CT scanning is too low to replace invasive intrathoracic lymph node staging in patients with NSCLC. The visual interpretation of the fusion images of the integrated FDG-PET/CT scan can be replaced by the quantitative variable SUVmax/SUVliver without loss of accuracy for intrathoracic lymph node staging.

Endosonography vs Conventional Bronchoscopy for the Diagnosis of Sarcoidosis: The GRANULOMA Randomized Clinical Trial

IMPORTANCE Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis. Bronchoscopy with transbronchial lung biopsies, the current diagnostic standard, has moderate sensitivity in assessing granulomas. Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique. OBJECTIVE To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis. DESIGN, SETTING, AND PATIENTS Randomized clinical multicenter trial (14 centers in 6 countries) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis (stage I/II) in whom tissue confirmation of noncaseating granulomas was indicated. INTERVENTIONS Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography (esophageal or endobronchial ultrasonography) with aspiration of intrathoracic lymph nodes. All patients also underwent bronchoalveolar lavage. MAIN OUTCOMES AND MEASURES The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis. The diagnosis was based on final clinical judgment by the treating physician, according to all available information (including findings from initial bronchoscopy or endosonography). Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis. RESULTS A total of 149 patients were randomized to bronchoscopy and 155 to endosonography. Significantly more granulomas were detected at endosonography vs bronchoscopy (114 vs 72 patients; 74% vs 48%; P < .001). Diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73%-86%); for bronchoscopy, 53% (95% CI, 45%-61%) (P < .001). Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group; all patients recovered completely. Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54% (95% CI, 46%-62%) for flow cytometry and 24% (95% CI, 16%-34%) for cytospin analysis. CONCLUSION AND RELEVANCE Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in greater diagnostic yield. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00872612.

Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production.

ObjectiveAnimal models of asthma mimic major features of human disease. Since the genetic background of experimental animals might affect hyperresponsiveness and inflammation, we studied its potential influence and the mechanisms leading to differences in strains.MethodsWe applied a mouse model of allergic asthma to BALB/c and C57BL/6 mice.ResultsBALB/c mice displayed greater levels of airway reactivity to methacholine than C57BL/6 mice. Moreover, BALB/c mice exhibited higher numbers of mast cells in lung tissue when compared to C57BL/6. On the contrary, eosinophil and neutrophil counts in bronchoalveolar lavage fluid (BALF) as well as peribronchial eosinophilia were greater in C57BL/6. IL (Interleukin)-4, IL-5, IL-13, and CCL11 levels measured in whole-lung extracts were higher in BALB/c, while, in sharp contrast, CCL11 and CCL5 levels were higher in BALF of C57BL/6 mice.ConclusionsWe observed phenotypic differences between C57BL/6 and BALB/c mice in an asthma model with different distributions of pro-inflammatory cytokines and inflammatory cells.