Influence of Biopsy Technique on Molecular Genetic Tumor Characterization in Non-Small Cell Lung Cancer-The Prospective, Randomized, Single-Blinded, Multicenter PROFILER Study Protocol.

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient's progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival.

Use of 3-D navigation to target the site of autologous blood installation for lung volume reduction in bullous emphysema.

Bronchoscopic lung volume reduction (BLVR) using intrabullous autologous blood instillation has been reported in single cases where other techniques are not possible. We present the use of three-dimensional navigation to instill autologous blood into emphysematous bullae for BLVR. A 62-year-old man presented with increasing dyspnea, due to emphysema with a conglomerate of giant bullae with two particularly large bullae. Surgical treatment was refused, so bronchoscopic autologous blood instillation into the bronchial segment leading to the large bullae was attempted, but was unsuccessful; blood failed to penetrate into the bullous cavity. Dyspnea worsened over the following year. We therefore performed another bronchoscopy and punctured a large bulla with a needle and created a tunnel from the central airways. Puncture position and direction were determined using a prototype of an electromagnetic navigation system. Under fluoroscopic guidance, a catheter was placed via the tunnel into the bulla and blood was instilled. This resulted in an almost complete shrinkage of the bullae, reduction of residual volume, and marked improvement in dyspnea within 4 months. To our knowledge, this is the first reported case of successful BLVR by navigated bronchoscopy with transbronchial puncture, dilatation, and autologous blood instillation into a giant bulla.

Cryobiopsy increases the EGFR detection rate in non-small cell lung cancer.

OBJECTIVES: Detection of activating epidermal growth factor receptor (EGFR) mutation is crucial for individualized treatment of advanced non-small-cell lung cancer (NSCLC). However little is known about how biopsy technique affects the detection rate of EGFR mutations. This retrospective, single center study evaluated the detection rate of EGFR mutations in tissue obtained by bronchoscopic cryobiopsy and compared this to other standard tissue sampling techniques. MATERIALS AND METHODS: We retrospectively analyzed 414 patients with histologically confirmed NSCLC and known EGFR mutation status between 3/2008-7/2014. Tumor specimens obtained by tissue preserving bronchoscopic cryobiopsy were compared to those obtained by other techniques. RESULTS AND CONCLUSION: Analysis of bronchoscopic cryobiopsy tissue detected 29 activating EGFR mutations in 27 (21.6 %) out of 125 patients, while analysis of tissue obtained by non-cryobiopsy techniques (bronchoscopic forceps biopsies, fine needle aspiration, imaging guided transthoracical and surgical procedures) detected 42 EGFR mutations in 40 (13.8 %) out of 298 patients (p < 0.05). Cryobiopsy increased detection rate of EGFR mutations in central tumors compared with forceps biopsy (19.6 % versus 6.5 %, p < 0.05), while an insignificant trend was detected also for peripheral tumors (33.3 % versus 26.9 %). Bronchosopic cryobiopsy increases the detection rate of activating EGFR mutations in NSCLC in comparison to other tissue sampling techniques. This will help to optimize individualized treatment of patients with advanced tumors. Because of the retrospective nature of this analysis, a prospective trial is mandatory for final assessment.

Bleeding risk of transbronchial cryobiopsy compared to transbronchial forceps biopsy in interstitial lung disease - a prospective, randomized, multicentre cross-over trial.

BACKGROUND: Bronchoscopic cryobiopsy is a new method of bronchoscopic tissue sampling in interstitial lung disease. In case of transbronchial biopsies, the resultant tissue samples are of high quality, and the lung parenchyma seen in the samples is adequate for a histological diagnosis in most cases. Bleeding after transbronchial biopsy is the most important procedure- associated complication and may be life threatening. This study addresses the risk of bleeding of transbronchial cryobiopsy. METHODS: In this prospective, randomized, controlled multicentre study 359 patients with interstitial lung disease requiring diagnostic bronchoscopic tissue sampling were included. Both conventional transbronchial forceps biopsy and transbronchial cryobiopsy were undertaken in each patient. The sequence of the procedures was randomized. Bleeding severity was evaluated semi-quantitatively as "no bleeding", "mild" (suction alone), "moderate" (additional intervention) or "severe" (prolonged monitoring necessary or fatal outcome), for each intervention. RESULTS: In 359 patients atotal of 1160 cryobiopsies and 1302 forceps biopsies were performed. Bleeding was observed after forceps biopsy in 173 patients (48.2%) and after cryobiopsy in 261 patients (72.7%). Bleeding was significantly greater in the cryobiopsy group (cryobiopsy/forceps biopsy: no bleeding 27.3%/51.8%; mild 56.5%/44.0%; moderate 15.0%/4.2%; severe 1.2%/0%; p < 0.001). The rate of clinically relevant bleeding (moderate or severe) was higher after the cryobiopsy procedures compared to the forceps biopsies (16.2% vs. 4.2%, p < 0.05). No fatal bleeding complications occurred. CONCLUSIONS: Compared to transbronchial forceps biopsy, transbronchial cryobiopsy was associated with an increased risk of bleeding which is of clinical relevance. Therefore training and additional precautions for bleeding control should be considered. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov ( NCT01894113 ).

A new functional method to choose the target lobe for lung volume reduction in emphysema - comparison with the conventional densitometric method.

BACKGROUND: Lung volume reduction (LVR) improves breathing mechanics by reducing hyperinflation. Lobar selection usually focuses on choosing the most destroyed emphysematous lobes as seen on an inspiratory CT scan. However, it has never been shown to what extent these densitometric CT parameters predict the least deflation of an individual lobe during expiration. The addition of expiratory CT analysis allows measurement of the extent of lobar air trapping and could therefore provide additional functional information for choice of potential treatment targets. OBJECTIVES: To determine lobar vital capacity/lobar total capacity (LVC/LTC) as a functional parameter for lobar air trapping using on an inspiratory and expiratory CT scan. To compare lobar selection by LVC/LTC with the established morphological CT density parameters. METHODS: 36 patients referred for endoscopic LVR were studied. LVC/LTC, defined as delta volume over maximum volume of a lobe, was calculated using inspiratory and expiratory CT scans. The CT morphological parameters of mean lung density (MLD), low attenuation volume (LAV), and 15th percentile of Hounsfield units (15%P) were determined on an inspiratory CT scan for each lobe. We compared and correlated LVC/LTC with MLD, LAV, and 15%P. RESULTS: There was a weak correlation between the functional parameter LVC/LTC and all inspiratory densitometric parameters. Target lobe selection using lowest lobar deflation (lowest LVC/LTC) correlated with target lobe selection based on lowest MLD in 18 patients (50.0%), with the highest LAV in 13 patients (36.1%), and with the lowest 15%P in 12 patients (33.3%). CONCLUSION: CT-based measurement of deflation (LVC/LTC) as a functional parameter correlates weakly with all densitometric CT parameters on a lobar level. Therefore, morphological criteria based on inspiratory CT densitometry partially reflect the deflation of particular lung lobes, and may be of limited value as a sole predictor for target lobe selection in LVR.

Incidental lung volume reduction following fulminant pulmonary hemorrhage in a patient with severe emphysema.

Endoscopic lung volume reduction is an emerging technique meant to improve lung function parameters, quality of life, and exercise tolerance in patients with severe lung emphysema. This is the first report of lung volume reduction by autologous blood in a patient with non-bullous lung emphysema. A 74-year-old woman with heterogeneous lung emphysema developed accidentally diffuse lobar bleeding immediately after valve placement. Due to persistent hemorrhage, the valves had to be removed shortly thereafter. Despite extraction of the valves, respiratory function of the patient improved rapidly indicated also by a drop in the COPD assessment test questionnaire, 3 months later. This was consistent with both improvement of lung function tests and six-minute walking test.