Nicolas Kahn

Combined endoscopic-endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer.

BACKGROUND For mediastinal lymph nodes, biopsies must often be performed to accurately stage lung cancer. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) allows real-time guidance in sampling paratracheal, subcarinal, and hilar lymph nodes, and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can sample mediastinal lymph nodes located adjacent to the esophagus. Nodes can be sampled and staged more completely by combining these procedures, but to date use of two different endoscopes has been required. We examined whether both procedures could be performed with a single endobronchial ultrasound bronchoscope. METHODS Consecutive patients with a presumptive diagnosis of non-small cell lung cancer (NSCLC) underwent endoscopic staging by EBUS-TBNA and EUS-FNA through a single linear ultrasound bronchoscope. Surgical confirmation and clinical follow-up was used as the reference standard. RESULTS Among 150 evaluated patients, 139 (91%; 83 men, 56 women; mean age 57.6 years) were diagnosed with NSCLC. In these 139 patients, 619 nodes were endoscopically biopsied: 229 by EUS-FNA and 390 by EBUS-TBNA. Sensitivity was 89% for EUS-FNA and 92% for EBUS-TBNA. The combined approach had a sensitivity of 96% and a negative predictive value of 95%, values higher than either approach alone. No complications occurred. CONCLUSIONS The two procedures can easily be performed with a dedicated linear endobronchial ultrasound bronchoscope in one setting and by one operator. They are complementary and provide better diagnostic accuracy than either one alone. The combination may be able to replace more invasive methods as a primary staging method for patients with lung cancer.

Pirfenidone in Idiopathic Pulmonary Fibrosis: Real-Life Experience from a German Tertiary Referral Center for Interstitial Lung Diseases

Background: Pirfenidone is a novel antifibrotic drug for the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, adverse events may offset treatment benefits and compliance. Objectives: To assess recent course of disease, adverse events and compliance in patients who started pirfenidone. Methods: In an observational cohort study, 63 patients with mild-to-moderate IPF who started pirfenidone between May 2011 and June 2013 were reviewed. Pulmonary function, adverse events and treatment compliance were recorded at each clinic visit. Disease progression was defined as a reduction of vital capacity ≥10% and/or diffusion capacity (DLCO) ≥15%. Results: Follow-up time on pirfenidone treatment was 11 (±7) months. Sixty-six percent of the patients continued with pirfenidone monotherapy and 34% of the patients received pirfenidone combined with corticosteroids (CCS) and/or N-acetylcysteine (NAC). There was a nonsignificant reduction in mean decline of percent predicted forced vital capacity after treatment start (0.7 ± 10.9%) compared to the pretreatment period (6.6 ± 6.7%, p = 0.098). Sixty-two percent of the patients had stable disease on pirfenidone treatment. Adverse events affected 85% of the patients, leading to discontinuation of pirfenidone in 20%. Adverse events and treatment discontinuation were seen more frequently in patients with concomitant CCS and/or NAC treatment. Conclusions: Adverse events affect the majority of patients treated with pirfenidone, but are mostly manageable with supportive measures. In this heterogeneous patient group, a nonsignificant effect of pirfenidone treatment on pulmonary function was seen, underlining the need for more data on patient selection criteria and efficacy of pirfenidone, particularly in patients with coexistent emphysema and concomitant NAC/CCS treatment.

LungPoint—A New Approach to Peripheral Lesions

Introduction: Although flexible bronchoscopy is the least invasive procedure for sampling, it is limited by its inability to reach lesions in the peripheral segments of the lung. Biopsy success is further compromised if the lesion is less than 30 mm in diameter or cannot be seen on fluoroscopy. We wanted to explore whether a new bronchoscopic navigation system could help access the peripheral lung airways and enable lesion sampling. Methods: The LungPoint system produced a virtual bronchoscopic pathway indicating the bronchus into which the bronchoscope should be advanced. Virtual bronchoscopic images were displayed alongside and registered with actual bronchoscopic video. After performing broncoscopy with a standard bronchoscope for first examination, the thin bronchoscope was advanced to the target bronchus under direct visualization without fluoroscopy. A pilot study included consecutive patients at a tertiary teaching hospital with pulmonary peripheral lesions (<42 mm). Biopsies were taken later. Results: Study subjects included 25 patients (9 women and 16 men, mean age 67 years) with 25 lesions (mean size 28 mm). Using this navigation system, the bronchoscope could be advanced along the planned route in all cases. In 14 of the cases (56%), the bronchoscope could be advanced all the way to the lesion bronchus. The planning time was a median of 5 minutes, and the median examination time was 15 minutes. A definitive diagnosis was possible in 20 cases (80%). One patient experienced a small pneumothorax because of the biopsy that resolved without drainage. No other complications occurred. Conclusions: This navigation system is useful for bronchoscopy for pulmonary peripheral lesions (NCT01067755).

Endobronchial ultrasound-guided lymph node biopsy with transbronchial needle forceps: a pilot study

One limitation of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the size of the available needles, frequently yielding only cells for cytological examination. The aim of this pilot study was to evaluate the efficacy and safety of newly developed needle forceps to obtain tissue for the histological diagnosis of enlarged mediastinal lymph nodes. Patients with enlarged, positron emission tomography (PET)-positive lymph nodes were included. The transbronchial needle forceps (TBNF), a sampling instrument combining the characteristics of a needle (bevelled tip for penetrating through the bronchial wall) with forceps (two serrated jaws for grasping tissue) was used through the working channel of the EBUS-TBNA scope. Efficacy and safety was assessed. 50 patients (36 males and 14 females; mean age 51 yrs) with enlarged or PET-positive lymph nodes were included in this pilot study. In 48 (96%) patients penetration of the bronchial wall was possible and in 45 patients tissue for histological diagnosis was obtained. In three patients TBNF provided inadequate material. For patients in whom the material was adequate for a histological examination, a specific diagnosis was established in 43 (86%) out of 50 patients (nonsmall cell lung cancer: n=24; small cell lung cancer: n=7; sarcoidosis: n=4; Hodgkins lymphoma: n=4; tuberculosis: n=2; and non-Hodgkin’s lymphoma: n=2).No clinically significant procedure-related complications were encountered. This study demonstrated that EBUS-TBNF is a safe procedure and provides diagnostic histological specimens of mediastinal lymph nodes.

Hypoxic Epithelial Necrosis Triggers Neutrophilic Inflammation via IL-1 Receptor Signaling in Cystic Fibrosis Lung Disease

RATIONALE In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease. OBJECTIVES To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease. METHODS We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis. MEASUREMENTS AND MAIN RESULTS Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease. CONCLUSIONS Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.

‘Heat and Destroy’: Bronchoscopic-Guided Therapy of Peripheral Lung Lesions

Although the treatment of choice for stage I lung cancer patients is surgery, a lot of patients have a high comorbidity and are medically inoperable. Bronchoscopy, as a central technique in diagnosing lung cancer, has the potency to apply endoscopic therapy to small lung lesions in a minimally invasive way in patients with high risk for surgery. Unfortunately, bronchoscopy cannot always reach lesions in the peripheral lung, in particular the smaller lesions. Therefore, new guidance techniques like virtual bronchoscopy and electromagnetic navigation are now available and instead of using the systems as a diagnostic tool, these techniques may provide an option for therapeutic interventions to inoperable lung tumor patients. With endoscopic fiducial marker placement for robotic radiosurgery and endoluminal high-dose brachytherapy, local radiotherapy of peripheral lung tumors becomes feasible, reducing radiotherapy-induced toxicity. Radiofrequency tissue ablation through the working channel of a flexible bronchoscope may be a chance of making a diagnosis and a curative treatment in one endoscopic session. However, technical improvements of the ablation probes are currently necessary to expand the sizes of ablated areas. Even though the technologies are very attractive and pilot data are extremely encouraging, more studies establishing selection criteria and best utility are needed.

Early detection of lung cancer by molecular markers in endobronchial epithelial-lining fluid.

Introduction: Early detection of malignancies in the lung by less-invasive methods aims at achieving efficient intervention and subsequently a reduction of the high mortality rate. We investigated whether biomarker analysis in endobronchial epithelial-lining fluid (ELF) collected by bronchoscopic microsampling (BMS) may be useful for a definitive preoperative diagnosis. Methods: ELF was collected from subsegmental bronchi close to the indeterminate pulmonary nodule, which was detected by computed tomography, and from the contralateral lung. Diagnosis was confirmed by transbronchial biopsy or surgery. The study includes 142 ELF samples from 51 non–small-cell lung cancer patients and 20 benign cases. Microarray analysis was done with a patient subset (n = 15) to narrow down genes associated with a malignant phenotype. Thirteen potential biomarkers have been further analyzed by quantitative real-time polymerases chain reaction in an independent patient cohort (n = 56). Results: All patients underwent BMS without complications. Gene-expression analyses by microarrays and quantitative real-time polymerases chain reaction could be reliably applied to ELF samples, and resulted in potential biomarkers for malignant pulmonary nodules. Four genes (tenascin-C, [C-X-C motif] ligand 14, S100 calcium binding protein A9, and keratin 17) were found to be upregulated in ELF of non–small-cell lung cancer patients with adenocarcinoma or squamous cell carcinoma. Combined analysis of tenascin-C expression and the nodule size improved the prediction of malignancy in this patient cohort. Conclusions: Our study suggests that the analysis of specific biomarkers in ELF collected by BMS could be a potentially useful adjunct to other diagnostic techniques aiming at the preoperative diagnosis of malignant pulmonary nodules.

Gene expression analysis of endobronchial epithelial lining fluid in the evaluation of indeterminate pulmonary nodules

OBJECTIVE Making a definitive preoperative diagnosis in patients with indeterminate pulmonary nodules is still a challenge. Gene expression profiling may be a useful adjunctive diagnostic utility in this regard. We investigated the feasibility of bronchoscopic microsampling to collect endobronchial epithelial lining fluid to obtain RNA as a starting point for gene expression profiling. METHODS In 15 patients, epithelial lining fluid was collected in triplicate from subsegmental bronchi close to the pulmonary nodules and from contralateral lungs. Diagnosis was confirmed by transbronchial biopsy or surgery (non-small cell lung cancer, n = 11; benign or other lesions, n = 4). Total RNA was isolated from the samples and evaluated concerning quantity and quality. The complementary DNA was generated and analyzed by quantitative real-time polymerase chain reaction for potential lung cancer associated genes like matrix metalloprotinase (MMP9). RESULTS Total RNA of adequate amount (>0.8 microg) and sufficient quality was obtained in 13 (86%) of the 15 patients. In patients with lung cancer, normalized MMP9 gene expression levels in endobronchial lining fluid samples collected close to the lesions were in median 12 times higher than levels in the matching contralateral samples. MMP9 expression levels were particularly high in endobronchial lining fluid samples collected from patients with squamous cell carcinoma but not elevated in the case of benign lesions. CONCLUSIONS Our results show that quantitative gene expression analysis of endobronchial lining fluid collected by bronchoscopic microsampling is both feasible and reliable and may therefore be a useful additional diagnostic method in patients with indeterminate pulmonary nodules.

Optical coherence tomography detects structural abnormalitiesof the nasal mucosa in patients with cystic fibrosis

BACKGROUND Chronic inflammation and remodeling of the airways remain a hallmark of cystic fibrosis (CF). However, knowledge of the associated mucosal micro-anatomical changes is limited. We evaluated the potential of optical coherence tomography (OCT) for in vivo imaging of the upper airway mucosa in CF patients. METHODS A flexible OCT probe was used for cross-sectional imaging of the nasal mucosa in 25 CF patients and 25 healthy controls. RESULTS OCT images showed mucosal details including epithelium, basement membrane, lamina propria with seromucinous glands, and underlying cartilaginous structures. Mean nasal mucosa and epithelial layer thickness were increased in CF compared to controls. In CF patients, antibiotic therapy was associated with reduced nasal mucosa thickening. CONCLUSIONS OCT detected mucosal changes associated with upper airway inflammation and response to antibiotic therapy in CF patients. OCT may be a useful tool for quantitative in vivo assessment of structural changes of the airway mucosa.

Glycodelin is a potential novel follow-up biomarker for malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a short survival time arising from the mesothelial cells of the pleura. Soluble mesothelin-related peptide (SMRP), osteopontin or EFEMP1 (Fibulin-3) are well described biomarkers for malignant mesothelioma with moderate sensitivity and specificity. In this study, we characterized the expression of glycodelin, a marker for risk pregnancy, in MPM by RNA and protein analyses and investigated its potential as a MPM biomarker. We were able to detect glycodelin in the serum of MPM patients. Compared to benign lung diseases, the serum levels were significant increased. Patients with high glycodelin serum levels revealed a worse overall survival. The glycodelin serum levels correlated with the tumor response to treatment. A comparison of SMRP and glycodelin serum measurement in a large patient cohort demonstrated that the detection of both soluble factors can increase the reliable diagnostic of MPM. Glycodelin was highly expressed in MPM tumors. Analyses of a tissue micro array indicated that the immunomodulatory form glycodelin A was expressed in MPM and correlated with the survival of the patients. Altogether, glycodelin seems to be a new potential biomarker for the aggressive malignant pleural mesothelioma.