Publications by authors named "Jouke T Annema"

101 Publications

Compact portable multiphoton microscopy reveals histopathological hallmarks of unprocessed lung tumor tissue in real time.

Transl Biophotonics 2020 Nov 21;2(4):e202000009. Epub 2020 Aug 21.

Faculty of Science, Department of Physics, LaserLab Vrije Universiteit Amsterdam Amsterdam Netherlands.

During lung cancer operations a rapid and reliable assessment of tumor tissue can reduce operation time and potentially improve patient outcomes. We show that third harmonic generation (THG), second harmonic generation (SHG) and two-photon excited autofluorescence (2PEF) microscopy reveals relevant, histopathological information within seconds in fresh unprocessed human lung samples. We used a compact, portable microscope and recorded images within 1 to 3 seconds using a power of 5 mW. The generated THG/SHG/2PEF images of tumorous and nontumorous tissues are compared with the corresponding standard histology images, to identify alveolar structures and histopathological hallmarks. Cellular structures (tumor cells, macrophages and lymphocytes) (THG), collagen (SHG) and elastin (2PEF) are differentiated and allowed for rapid identification of carcinoid with solid growth pattern, minimally enlarged monomorphic cell nuclei with salt-and-pepper chromatin pattern, and adenocarcinoma with lipidic and micropapillary growth patterns. THG/SHG/2PEF imaging is thus a promising tool for clinical intraoperative assessment of lung tumor tissue.
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http://dx.doi.org/10.1002/tbio.202000009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311669PMC
November 2020

Bronchoscopic needle-based confocal laser endomicroscopy (nCLE) as a real-time detection tool for peripheral lung cancer.

Thorax 2021 Jun 25. Epub 2021 Jun 25.

Respiratory Medicine, Amsterdam University Medical Centers, Amsterdam, Noord-Holland, The Netherlands

Introduction: Diagnosing peripheral lung cancer with the bronchoscope is challenging with near miss of the target lesion as major obstacle. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic tumour visualisation at the needle tip (smart needle).

Aim: To investigate feasibility and safety of bronchoscopic nCLE imaging of suspected peripheral lung cancer and to assess whether nCLE imaging allows real-time discrimination between malignancy and airway/lung parenchyma.

Methods: Patients with suspected peripheral lung cancer based on (positron emission tomography-)CT scan underwent radial endobronchial ultrasound (rEBUS) and fluoroscopy-guided flexible bronchoscopy. After rEBUS lesion detection, an 18G needle loaded with the CLE probe was inserted in the selected airway under fluoroscopic guidance. The nCLE videos were obtained at the needle tip, followed by aspirates and biopsies. The nCLE videos were reviewed and compared with the cytopathology of the corresponding puncture and final diagnosis. Five blinded raters validated nCLE videos of lung tumours and airway/lung parenchyma twice.

Results: The nCLE imaging was performed in 26 patients. No adverse events occurred. In 24 patients (92%) good to high quality videos were obtained (final diagnosis; lung cancer n=23 and organising pneumonia n=1). The nCLE imaging detected malignancy in 22 out of 23 patients with lung cancer. Blinded raters differentiated nCLE videos of malignancy from airway/lung parenchyma (280 ratings) with a 95% accuracy. The inter-observer agreement was substantial (κ=0.78, 95% CI 0.70 to 0.86) and intra-observer reliability excellent (mean±SD κ=0.81±0.05).

Conclusion: Bronchoscopic nCLE imaging of peripheral lung lesions is feasible, safe and allows real-time lung cancer detection. Blinded raters accurately distinguished nCLE videos of lung cancer from airway/lung parenchyma, showing the potential of nCLE imaging as real-time guidance tool.
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http://dx.doi.org/10.1136/thoraxjnl-2021-216885DOI Listing
June 2021

Intracardiac EUS-B-Guided FNA for Diagnosing Cardiac Tumors.

Respiration 2021 Jun 24:1-5. Epub 2021 Jun 24.

Department of Respiratory Medicine, Location Academic Medical Center (AMC), Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Primary cardiac tumors are extremely rare. Obtaining a tissue diagnosis is difficult and commonly requires open-heart surgery with associated morbidity. Esophageal endoscopic ultrasound (EUS) and EUS with the EBUS scope (EUS-B) provide real-time sampling of centrally located lung tumors and mediastinal lymph nodes. They also provide an excellent view of the left atrium, since it is located adjacent to the esophagus. To date, left atrium tumor diagnostics by endosonography is poorly explored. We describe 2 exceptional diagnostic cases of left atrium tumors in which cardiac surgery was hazardous due to the clinical condition or previous surgical interventions. During EUS-B-guided fine-needle aspiration (FNA), the left atrial masses were successfully and safely sampled, revealing a Burkitt lymphoma and a synovial sarcoma. FNA including cell block analysis enabled specific tumor diagnosis and molecular subtyping. Our findings suggest that in selected cases, linear endosonography qualifies as a minimally invasive technique for intracardiac tumor diagnostics.
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http://dx.doi.org/10.1159/000516504DOI Listing
June 2021

Endobronchial ultrasound for T4 staging in patients with resectable NSCLC.

Lung Cancer 2021 08 28;158:18-24. Epub 2021 May 28.

Department of Respiratory Medicine, Amsterdam University Medical Centers, Location Academic Medical Center (AMC), Amsterdam, the Netherlands. Electronic address:

Background: In lung cancer patients, accurate assessment of mediastinal and vascular tumor invasion (stage T4) is crucial for optimal treatment allocation and to prevent unnecessary thoracotomies. We assessed the diagnostic accuracy of linear endobronchial ultrasound (EBUS) for T4-status in patients with centrally located lung cancer.

Methods: This is a retrospective study among consecutive patients who underwent EBUS for diagnosis and staging of lung cancer in four hospitals in The Netherlands (Amsterdam, Leiden), Italy (Bologna) and Poland (Zakopane) between 04-2012 and 04-2019. Patients were included if the primary tumor was detected by EBUS and subsequent surgical-pathological staging was performed, which served as the reference standard. T4-status was extracted from EBUS and pathology reports. Chest CT's were re-reviewed for T4-status.

Results: 104 patients with lung cancer in whom EBUS detected the primary tumour, and who underwent subsequent surgical-pathological staging were included. 36 patients (35 %) had T4-status, based on vascular (n = 17), mediastinal (n = 15), both vascular and mediastinal (n = 3), or oesophageal invasion (n = 1). For EBUS, sensitivity, specificity, PPV and NPV for T4-status were (n = 104): 63.9 % (95 %CI 46.2-79.2 %), 92.6 % (83.7-97.6 %), 82.1 % (65.6-91.7 %), and 82.9 % (75.7-88.2 %), respectively. For chest CT (n = 72): 61.5 % (95 %CI 40.6-79.8 %), 37.0 % (23.2-52.5 %), 35.6 % (27.5-44.6 %), and 63.0 % (47.9-75.9 %), respectively. When combining CT and EBUS with concordant T4 status (n = 33): 90.9 % (95 %CI 58.7-99.8 %), 77.3 % (54.6-92.20 %), 66.7 % (47.5-81.6 %), and 94.4 % (721-99.1%), respectively.

Conclusion: Both EBUS and CT alone are inaccurate for assessing T4-status as standalone test. However, combining a negative EBUS with a negative CT may rule out T4-status with high certainty.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.032DOI Listing
August 2021

Assessment of Lung Reaeration at 2 Levels of Positive End-expiratory Pressure in Patients With Early and Late COVID-19-related Acute Respiratory Distress Syndrome.

J Thorac Imaging 2021 Jun 3. Epub 2021 Jun 3.

Departments of Intensive Care Radiology and Nuclear Medicine Respiratory Medicine Anesthesiology, Amsterdam UMC, location AMC, Amsterdam, The Netherlands Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Purpose: Patients with novel coronavirus disease (COVID-19) frequently develop acute respiratory distress syndrome (ARDS) and need invasive ventilation. The potential to reaerate consolidated lung tissue in COVID-19-related ARDS is heavily debated. This study assessed the potential to reaerate lung consolidations in patients with COVID-19-related ARDS under invasive ventilation.

Materials And Methods: This was a retrospective analysis of patients with COVID-19-related ARDS who underwent chest computed tomography (CT) at low positive end-expiratory pressure (PEEP) and after a recruitment maneuver at high PEEP of 20 cm H2O. Lung reaeration, volume, and weight were calculated using both CT scans. CT scans were performed after intubation and start of ventilation (early CT), or after several days of intensive care unit admission (late CT).

Results: Twenty-eight patients were analyzed. The median percentages of reaerated and nonaerated lung tissue were 19% [interquartile range, IQR: 10 to 33] and 11% [IQR: 4 to 15] for patients with early and late CT scans, respectively (P=0.049). End-expiratory lung volume showed a median increase of 663 mL [IQR: 483 to 865] and 574 mL [IQR: 292 to 670] after recruitment for patients with early and late CT scans, respectively (P=0.43). The median decrease in lung weight attributed to nonaerated lung tissue was 229 g [IQR: 165 to 376] and 171 g [IQR: 81 to 229] after recruitment for patients with early and late CT scans, respectively (P=0.16).

Conclusions: The majority of patients with COVID-19-related ARDS undergoing invasive ventilation had substantial reaeration of lung consolidations after recruitment and ventilation at high PEEP. Higher PEEP can be considered in patients with reaerated lung consolidations when accompanied by improvement in compliance and gas exchange.
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http://dx.doi.org/10.1097/RTI.0000000000000600DOI Listing
June 2021

MEDIASTinal staging of non-small cell lung cancer by endobronchial and endoscopic ultrasonography with or without additional surgical mediastinoscopy (MEDIASTrial): a statistical analysis plan.

Trials 2021 Feb 27;22(1):168. Epub 2021 Feb 27.

Department of Surgery, Máxima MC, Veldhoven, PO BOX 7777, 5500 MB, Veldhoven, The Netherlands.

Background: Invasive mediastinal nodal staging is recommended by guidelines in selected patients with resectable non-small cell lung cancer (NSCLC). Endosonography is recommended as initial staging technique, followed by confirmatory mediastinoscopy in case of negative N2 or N3 cytology after endosonography. Confirmatory mediastinoscopy however is under debate owing its limited additional diagnostic value, its associated morbidity and its delay in the start of lung cancer treatment. The MEDIASTrial examines whether confirmatory mediastinoscopy can be safely omitted after negative endosonography in mediastinal nodal staging of NSCLC. The present work is the proposed statistical analysis plan of the clinical consequences of omitting mediastinoscopy, which is submitted before closure of the MEDIASTrial and before knowledge of any results was done to enhance transparency of scientific behaviour.

Methods: The primary outcome measure of this non-inferiority trial will be unforeseen N2 disease resulting from lobe-specific mediastinal lymph node dissection. For non-inferiority, the upper limit of the 95% confidence interval of the unforeseen N2 rate in the group without mediastinoscopy should not exceed 14.3% in order to probably have no negative impact on survival. Since this is a non-inferiority trial, both an intention to treat (ITT) and a per protocol (PP) analyses will be done. The ITT and the PP analyses should both indicate non-inferiority before the diagnostic strategy omitting mediastinoscopy will be interpreted as non-inferior to the strategy with mediastinoscopy. Secondary outcome measures include 30-day major morbidity and mortality, the total number of days of hospital care, overall and disease free 2-year survival, generic and disease-specific health related quality of life and cost-effectiveness and cost-utility of staging strategies with and without mediastinoscopy.

Discussion: The MEDIASTrial will determine if confirmatory mediastinoscopy can be omitted after tumour negative systematic endosonography in invasive mediastinal staging of patients with resectable NSCLC.

Trial Registration: Netherlands Trial Register NL6344/NTR6528 . Registered on 2017 July 06.
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http://dx.doi.org/10.1186/s13063-021-05127-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913384PMC
February 2021

Metabolic differences between bronchial epithelium from healthy individuals and patients with asthma and the effect of bronchial thermoplasty.

J Allergy Clin Immunol 2021 Feb 6. Epub 2021 Feb 6.

Department of Respiratory Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Background: Asthma is a heterogeneous disease with differences in onset, severity, and inflammation. Bronchial epithelial cells (BECs) contribute to asthma pathophysiology.

Objective: We determined whether transcriptomes of BECs reflect heterogeneity in inflammation and severity in asthma, and whether this was affected in BECs from patients with severe asthma after their regeneration by bronchial thermoplasty.

Methods: RNA sequencing was performed on BECs obtained by bronchoscopy from healthy controls (n = 16), patients with mild asthma (n = 17), patients with moderate asthma (n = 5), and patients with severe asthma (n = 17), as well as on BECs from treated and untreated airways of the latter (also 6 months after bronchial thermoplasty) (n = 23). Lipidome and metabolome analyses were performed on cultured BECs from healthy controls (n = 7); patients with severe asthma (n = 9); and, for comparison, patients with chronic obstructive pulmonary disease (n = 7).

Results: Transcriptome analysis of BECs from patients showed a reduced expression of oxidative phosphorylation (OXPHOS) genes, most profoundly in patients with severe asthma but less profoundly and more heterogeneously in patients with mild asthma. Genes related to fatty acid metabolism were significantly upregulated in asthma. Lipidomics revealed enhanced levels of lipid species (phosphatidylcholines, lysophosphatidylcholines. and bis(monoacylglycerol)phosphate), whereas levels of OXPHOS metabolites were reduced in BECs from patients with severe asthma. BECs from patients with mild asthma characterized by hyperresponsive production of mediators implicated in neutrophilic inflammation had decreased expression of OXPHOS genes compared with that in BECs from patients with mild asthma with normoresponsive production. BECs obtained after thermoplasty had significantly increased expression of OXPHOS genes and decreased expression of fatty acid metabolism genes compared with BECs obtained from untreated airways.

Conclusion: BECs in patients with asthma are metabolically different from those in healthy individuals. These differences are linked with inflammation and asthma severity, and they can be reversed by bronchial thermoplasty.
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http://dx.doi.org/10.1016/j.jaci.2020.12.653DOI Listing
February 2021

Trends in mediastinal nodal staging and its impact on unforeseen N2 and survival in lung cancer.

Eur Respir J 2021 04 1;57(4). Epub 2021 Apr 1.

Dept of Surgery, Máxima MC, Veldhoven, The Netherlands

Introduction: Guidelines for invasive mediastinal nodal staging in resectable nonsmall cell lung cancer (NSCLC) have changed over the years. The aims of this study were to describe trends in invasive staging and unforeseen N2 (uN2) and to assess a potential effect on overall survival.

Methods: A nationwide Dutch cohort study included all clinical stage IA-IIIB NSCLC patients primarily treated by surgical resection between 2005 and 2017 (n=22 555). We assessed trends in invasive nodal staging (mediastinoscopy 2005-2017; endosonography 2011-2017), uN2 and overall survival and compared outcomes in the entire group and in clinical nodal stage (cN)1-3 patients with or without invasive staging.

Results: An overall increase in invasive nodal staging from 26% in 2005 to 40% in 2017 was found (p<0.01). Endosonography increased from 19% in 2011 to 32% in 2017 (p<0.01), while mediastinoscopy decreased from 24% in 2011 to 21% in 2017 (p=0.08). Despite these changes, uN2 was stable over the years at 8.7%. 5-year overall survival rate was 41% for pN1 compared to 37% in single node uN2 (p=0.18) and 26% with more than one node uN2 (p<0.01). 5-year overall survival rate of patients with cN1-3 with invasive staging was 44% 39% in patients without invasive staging (p=0.12).

Conclusion: A significant increase in invasive mediastinal nodal staging in patients with resectable NSCLC was found between 2011 and 2017 in the Netherlands. Increasing use of less invasive endosonography prior to (or as a substitute for) surgical staging did not lead to more cases of uN2. Performance of invasive staging indicated a possible overall survival benefit in patients with cN1-3 disease.
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http://dx.doi.org/10.1183/13993003.01549-2020DOI Listing
April 2021

Reply to Svenningsen : Eosinophilia and Response to Bronchial Thermoplasty.

Am J Respir Crit Care Med 2021 01;203(1):148-149

University of Amsterdam Amsterdam, the Netherlands.

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http://dx.doi.org/10.1164/rccm.202008-3353LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781123PMC
January 2021

Pulmonary adenocarcinoma with psammoma bodies is associated with a specific endobronchial ultrasound pattern and a high prevalence of actionable driver mutations.

Lung Cancer 2020 09 26;147:204-208. Epub 2020 Jul 26.

Medical Oncology Unit, Azienda Ospedaliero Universitaria Policlinico S. Orsola, Università di Bologna, Bologna, Italy.

Introduction: Pulmonary adenocarcinoma with psammoma bodies (PAPBs) is a rare histological variant whose association with a high prevalence of targetable mutations has been suggested by scant literature reports describing small series. We aim to describe the endobronchial ultrasound (EBUS) pattern and the molecular profile by next-generation sequencing of an Italian series of patients with PAPBs.

Material And Methods: Over a 8-year period (2012-2019), we identified 15 patients with a very uncommon endobronchial ultrasound (EBUS) heterogeneity pattern characterized by the presence of multiple to countless, punctate non-shadowing foci ("starry sky" sign) which were not evident at CT and corresponded to psammoma bodies at pathological examination. The clinical, radiological, pathological and molecular findings of these patients were retrieved and analyzed.

Results: Pathological examination of the EBUS-TBNA specimens revealed malignancy (12 pulmonary adenocarcinoma, 2 breast carcinoma, 1 colonic carcinoma) and showed the presence of psammoma bodies in all of the 15 patients with the starry sky sign. Among the 12 patients with pulmonary adenocarcinoma with psammoma bodies, female sex (8/12, 66.7 %) and never-smoking habit (6/12, 50 %) were prevalent. Molecular tumor profiling using the Oncomine™ Focus DNA and RNA fusion panels was successfully performed in 11/12 patients and revealed 10 genetic alterations (BRAF mutation, 4; EGFR mutation, 2; ALK rearrangement, RET rearrangement, PIK3CA mutation, CDK4 amplification 1) in 7 patients (63.6 %).

Conclusion: The present series suggests that pulmonary adenocarcinoma with psammoma bodies is associated with a readily identifiable EBUS pattern and with a high prevalence of different, often uncommon and actionable, driver mutations.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.025DOI Listing
September 2020

Bronchial Thermoplasty Induced Airway Smooth Muscle Reduction and Clinical Response in Severe Asthma. The TASMA Randomized Trial.

Am J Respir Crit Care Med 2021 01;203(2):175-184

Department of Respiratory Medicine and.

Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma targeting airway smooth muscle (ASM). Observational studies have shown ASM mass reduction after BT, but appropriate control groups are lacking. Furthermore, as treatment response is variable, identifying optimal candidates for BT treatment is important. First, to assess the effect of BT on ASM mass, and second, to identify patient characteristics that correlate with BT response. Patients with severe asthma ( = 40) were randomized to immediate ( = 20) or delayed ( = 20) BT treatment. Before randomization, clinical, functional, blood, and airway biopsy data were collected. In the delayed control group, reassessment, including biopsies, was performed after 6 months of standard clinical care, followed by BT. In both groups, post-BT data including biopsies were obtained after 6 months. ASM mass (% positive desmin or α-smooth muscle actin area in the total biopsy) was calculated with automated digital analysis software. Associations between baseline characteristics and Asthma Control Questionnaire and Asthma Quality of Life Questionnaire (AQLQ) improvement were explored. Median ASM mass decreased by >50% in the immediate BT group ( = 17) versus no change in the delayed control group ( = 19) ( = 0.0004). In the immediate group, Asthma Control Questionnaire scores improved with -0.79 (interquartile range [IQR], -1.61 to 0.02) compared with 0.09 (IQR, -0.25 to 1.17) in the delayed group ( = 0.006). AQLQ scores improved with 0.83 (IQR, -0.15 to 1.69) versus -0.02 (IQR, -0.77 to 0.75) ( = 0.04). Treatment response in the total group ( = 35) was positively associated with serum IgE and eosinophils but not with baseline ASM mass. ASM mass significantly decreases after BT when compared with a randomized non-BT-treated control group. Treatment response was associated with serum IgE and eosinophil levels but not with ASM mass.
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http://dx.doi.org/10.1164/rccm.201911-2298OCDOI Listing
January 2021

Predictive Value of Endobronchial Ultrasound Strain Elastography in Mediastinal Lymph Node Staging: The E-Predict Multicenter Study Results.

Respiration 2020;99(6):484-492. Epub 2020 Jun 3.

Department of Pulmonology, Radboudumc, Nijmegen, The Netherlands,

Background: Systematic assessment of lymph node status by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is indicated in (suspected) lung cancer. Sampling is herein guided by nodal size and FDG-PET characteristics. Ultrasound strain elastography (SE) might further improve risk stratification. By imaging tissue deformation over time, SE computes relative tissue strain. In several tissues, a lower strain (deformation) has been associated with a higher likelihood of malignancy.

Objectives: To assess if EBUS-SE can independently help predict malignancy, and when combined with size and FDG uptake information.

Methods: This multicenter (n = 5 centers) prospective trial included patients with suspected or proven lung cancer using a standardized measurement protocol. Cytopathology combined with surgery or follow-up imaging (>6 months) were used as reference standard.

Results: Between June 2016 and July 2018, 327 patients and 525 lymph nodes were included (mean size 12.3 mm, malignancy prevalence 0.48). EBUS-SE had an overall AUC of 0.77. A mean strain <115 (range 0-255) showed 90% sensitivity, 43% specificity, 60% positive predictive value, and 82% negative predictive value. Combining EBUS-SE (<115) with size (<8 mm) and FDG-PET information into a risk stratification algorithm increased the accuracy. Combining size and SE showed that the 48% a priori chance of malignancy changed to 11 and 70% in double negative or positive nodes, respectively. In the subset where FDG-PET was available (n = 370), triple negative and positive nodes went from a 42% a priori chance of malignancy to 9 and 73%, respectively.

Conclusions: EBUS-SE can help predict lymph node malignancy and may be useful for risk stratification when combined with size and PET information.
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http://dx.doi.org/10.1159/000507592DOI Listing
June 2020

Adherence to the mediastinal staging guideline and unforeseen N2 disease in patients with resectable non-small cell lung cancer: Nationwide results from the Dutch Lung Cancer Audit - Surgery.

Lung Cancer 2020 04 15;142:51-58. Epub 2020 Feb 15.

Department of Surgery, Máxima MC, Veldhoven, PO BOX 7777, 5500 MB, Veldhoven, the Netherlands. Electronic address:

Objectives: Invasive mediastinal staging is advised by guidelines in patients with resectable non-small cell lung cancer (NSCLC) and suspicious lymph nodes (cN1-3) or for central, FDG-non-avid or peripheral tumours >3 cm. Our objective was to assess current guideline adherence and consequent unforeseen N2 disease (uN2) in NSCLC patients having various indications for mediastinal staging.

Materials And Methods: We analysed the Dutch Lung Cancer Audit - Surgery data of all patients who underwent a primary lung resection with lymph node dissection for NSCLC in 2017-2018. Based on the 2015 ESTS-ERS-ESGE guideline we assessed the use of initial endosonography and confirmatory mediastinoscopy as well as uN2 rates.

Results: A total of 2238 patients were analysed. 43 % (95 %-CI: 41-45) underwent initial endosonography followed by a confirmatory mediastinoscopy in 44 % (95 %-CI:40-47) of them, resulting in a 19 % (95 %-CI: 17-20) rate of properly staged patient according to the guidelines. uN2 was demonstrated in 12.5 % (95 %-CI: 9.7-16.0) of correctly staged patients compared to 10.9 % (95 %-CI: 9.6-12.4) who were not (p = .36). The highest uN2 rate was found in cN1-3 patients who were not staged (23.0 %, 95 %-CI: 16.4-31.2) compared to 13.0 % (95 %-CI: 9.7-17.1) who were (p = .01).

Conclusion: Guideline adherence in Dutch NSCLC patients with an indication for invasive mediastinal staging is poor. The highest uN2 rate was found in unstaged cN1-3 patients, suggesting that this subgroup may benefit from an appropriate staging conform guidelines.
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http://dx.doi.org/10.1016/j.lungcan.2020.02.008DOI Listing
April 2020

Resistance of the respiratory system measured with forced oscillation technique (FOT) correlates with bronchial thermoplasty response.

Respir Res 2020 Feb 12;21(1):52. Epub 2020 Feb 12.

Department of Respiratory Medicine. F5-144, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Background: Bronchial Thermoplasty (BT) is an endoscopic treatment for severe asthma using radiofrequency energy to target airway remodeling including smooth muscle. The correlation of pulmonary function tests and BT response are largely unknown. Forced Oscillation Technique (FOT) is an effort-independent technique to assess respiratory resistance (Rrs) by using pressure oscillations including small airways.

Aim: To investigate the effect of BT on pulmonary function, assessed by spirometry, bodyplethysmography and FOT and explore associations between pulmonary function parameters and BT treatment response.

Methods: Severe asthma patients recruited to the TASMA trial were analyzed in this observational cohort study. Spirometry, bodyplethysmography and FOT measurements were performed before and 6 months after BT. Asthma questionnaires (AQLQ/ACQ-6) were used to assess treatment response.

Results: Twenty-four patients were analyzed. AQLQ and ACQ improved significantly 6 months after BT (AQLQ 4.15 (±0.96) to 4.90 (±1.14) and ACQ 2.64 (±0.60) to 2.11 (±1.04), p = 0.004 and p = 0.02 respectively). Pulmonary function parameters remained stable. Improvement in FEV correlated with AQLQ change (r = 0.45 p = 0.03). Lower respiratory resistance (Rrs) at baseline (both 5 Hz and 19 Hz) significantly correlated to AQLQ improvement (r = - 0.52 and r = - 0.53 respectively, p = 0.01 (both)). Borderline significant correlations with ACQ improvement were found (r = 0.30 p = 0.16 for 5 Hz and r = 0.41 p = 0.05 for 19 Hz).

Conclusion: Pulmonary function remained stable after BT. Improvement in FEV correlated with asthma questionnaires improvement including AQLQ. Lower FOT-measured respiratory resistance at baseline was associated with favorable BT response, which might reflect targeting of larger airways with BT.

Trial Registration: ClinicalTrials.gov Identifier: NCT02225392; Registered 26 August 2014.
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http://dx.doi.org/10.1186/s12931-020-1313-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017531PMC
February 2020

Endobronchial Ultrasound for the Diagnosis of Centrally Located Lung Tumors: A Systematic Review and Meta-Analysis.

Respiration 2020;99(5):441-450. Epub 2019 Nov 15.

Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands,

Introduction: Obtaining a tissue diagnosis of centrally located lung tumors in patients presenting without endobronchial abnormalities is challenging, and therefore a considerable diagnostic problem.

Objective: The objective of this study was to evaluate the performance of linear endobronchial ultrasound guided-transbronchial-needle aspiration (EBUS-TBNA) for the diagnosis of centrally located lung tumors.

Methods: We performed a systematic review (PROSPERO, CRD42017080968) and searched MEDLINE, Embase, BIOSIS Previews, and Web of Science till November 18, 2018 for studies that evaluated the yield and/or sensitivity of EBUS-TBNA for diagnosing centrally located lung tumors. We assessed the study quality using QUADAS-2 and performed random-effects meta-analysis.

Results: A total of 5,657 manuscripts were identified; of these 14 were considered for the study, including 1,175 patients who underwent EBUS-TBNA for diagnosing an intrapulmonary tumor. All studies had a high risk of bias or applicability concerns, predominately regarding patient selection. The average yield of EBUS-TBNA for diagnosing centrally located lung tumors was 0.89 (95% CI 0.84-0.92) and average sensitivity for diagnosing malignant tumors was 0.91 (95% CI 0.88-0.94). Among studies reporting this information, EBUS-related complications occurred in 5.4% of patients (42/721).

Conclusion: EBUS-TBNA has a high yield and sensitivity for diagnosing centrally located lung tumors and is safe in selected patients. Prospective studies are recommended to evaluate the routine use of this procedure for diagnosing intrapulmonary tumors.
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http://dx.doi.org/10.1159/000500363DOI Listing
April 2021

Distribution of lymph node metastases in esophageal carcinoma [TIGER study]: study protocol of a multinational observational study.

BMC Cancer 2019 Jul 4;19(1):662. Epub 2019 Jul 4.

The Royal Marsden, London, UK.

Background: An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients.

Methods: The TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival.

Discussion: The TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics.

Trial Registration: NCT03222895 , date of registration: July 19th, 2017.
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http://dx.doi.org/10.1186/s12885-019-5761-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610993PMC
July 2019

multifunctional optical coherence tomography at the periphery of the lungs.

Biomed Opt Express 2019 Jun 30;10(6):3070-3091. Epub 2019 May 30.

LaserLaB Amsterdam and Department of Physics and Astronomy, VU University Amsterdam, de Boelelaan 1081, 1081HV, Amsterdam, the Netherlands.

Remodeling of tissue, such as airway smooth muscle (ASM) and extracellular matrix, is considered a key feature of airways disease. No clinically accepted diagnostic method is currently available to assess airway remodeling or the effect of treatment modalities such as bronchial thermoplasty in asthma, other than invasive airway biopsies. Optical coherence tomography (OCT) generates cross-sectional, near-histological images of airway segments and enables identification and quantification of airway wall layers based on light scattering properties only. In this study, we used a custom motorized OCT probe that combines standard and polarization sensitive OCT (PS-OCT) to visualize birefringent tissue in the airway wall of a patient with severe asthma in a minimally invasive manner. We used optic axis uniformity (OAxU) to highlight the presence of uniformly arranged fiber-like tissue, helping visualizing the abundance of ASM and connective tissue structures. Attenuation coefficient images of the airways are presented for the first time, showing superior architectural contrast compared to standard OCT images. A novel segmentation algorithm was developed to detect the surface of the endoscope sheath and the surface of the tissue. PS-OCT is an innovative imaging technique that holds promise to assess airway remodeling including ASM and connective tissue in a minimally invasive, real-time manner.
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http://dx.doi.org/10.1364/BOE.10.003070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583343PMC
June 2019

Confocal Laser Endomicroscopy as a Guidance Tool for Pleural Biopsies in Malignant Pleural Mesothelioma.

Chest 2019 10 7;156(4):754-763. Epub 2019 May 7.

Department of Respiratory Medicine, Amsterdam University Medical Centers, Amsterdam. Electronic address:

Background: Pleural biopsies in patients with suspected malignant pleural mesothelioma (MPM) are often inconclusive resulting in repeat diagnostic procedures. Confocal laser endomicroscopy (CLE) enables real-time imaging on a cellular level. We investigated pleural CLE imaging as a biopsy guidance technique to distinguish malignant from benign pleural disease.

Methods: Prospective, multicenter study in patients with (suspected) MPM based on PET-CT imaging who were scheduled for pleural biopsies. Patients received 2.5 mL fluorescein intravenously preceding the procedure. In vivo through-the-needle CLE imaging of the pleura and ex vivo CLE imaging of the biopsies were correlated with histology. CLE characteristics for various pleural entities were identified, and their interpretability was tested by CLE video scoring by multiple blinded raters.

Results: CLE imaging was successfully obtained in 19 of 20 diagnostic pleural biopsy procedures (thoracoscopy: n = 4, surgical excision: n = 3, CT scan: n = 3, ultrasound: n = 9, esophageal ultrasound guided: n = 1) in 15 patients. CLE videos (n = 89) and corresponding pleural biopsies (n = 105) were obtained. No study-related adverse events occurred. Tumor deposits of MPM were distinguished from areas with pleural fibrosis based on CLE imaging and recognized by raters (n = 3) (interobserver agreement, 0.56; 95% CI, 0.49-0.64).

Conclusions: CLE imaging was feasible and safe regardless of the biopsy method. Real-time visualization of pleural abnormalities in epithelial and sarcomatoid MPM could be distinguished from pleural fibrosis. Therefore, CLE has potential as a guidance biopsy tool to reduce the current substantial rate of repeat biopsy procedures by identification of areas with malignant cells in vivo (smart needle).

Trial Registry: ClinicalTrials.gov; No.: NCT02689050; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2019.04.090DOI Listing
October 2019

Needle-based confocal laser endomicroscopy for real-time diagnosing and staging of lung cancer.

Eur Respir J 2019 06 20;53(6). Epub 2019 Jun 20.

Dept of Respiratory Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands

Diagnosing lung cancer in the absence of endobronchial abnormalities is challenging. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic imaging of cells. We assessed the feasibility and safety of using nCLE for real-time identification of lung cancer.In patients with suspected or proven lung cancer scheduled for endoscopic ultrasound (EUS), lung tumours and mediastinal lymph nodes were imaged with nCLE before fine-needle aspiration (FNA) was performed. nCLE lung cancer characteristics were identified by comparison with pathology. Multiple blinded raters validated CLE videos of lung tumours and mediastinal nodes twice.EUS-nCLE-FNA was performed in 22 patients with suspected or proven lung cancer in whom 27 lesions (six tumours, 21 mediastinal nodes) were evaluated without complications. Three nCLE lung cancer criteria (dark enlarged pleomorphic cells, dark clumps and directional streaming) were identified. The accuracy of nCLE imaging for detecting malignancy was 90% in tumours and 89% in metastatic lymph nodes. Both inter-observer agreement (mean κ=0.68, 95% CI 0.66-0.70) and intra-observer agreement (mean±sd κ=0.70±0.15) were substantial.Real-time lung cancer detection by endosonography-guided nCLE was feasible and safe. Lung cancer characteristics were accurately recognised.
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http://dx.doi.org/10.1183/13993003.01520-2018DOI Listing
June 2019

Unforeseen N2 Disease after Negative Endosonography Findings with or without Confirmatory Mediastinoscopy in Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

J Thorac Oncol 2019 06 21;14(6):979-992. Epub 2019 Mar 21.

Department of Surgery, Máxima Medical Center, Veldhoven, The Netherlands. Electronic address:

Introduction: Confirmatory mediastinoscopy after negative endosonography findings is advised by the guidelines on patients with resectable NSCLC and suspected intrathoracic nodes on fludeoxyglucose F 18 positron emission tomography-computed tomography. Its role however is under debate owing to its limited nodal metastasis detection rate, morbidity, associated treatment delay, and unknown impact on survival.

Methods: Systematic review and meta-analysis of studies on invasive mediastinal staging in patients with (suspected) NSCLC. The Medline, Embase, and Cochrane databases were searched until September 19, 2018, without year or language restrictions. The Quality Assessment Tool for Diagnostic Accuracy Studies, version 2, was used to evaluate the risk of bias and applicability of the included studies. Rates of unforeseen N2 disease were assessed for endobronchial ultrasound and/or endoscopic ultrasound staging strategies with or without confirmatory mediastinoscopy. Additionally, the complication rates of cervical video mediastinoscopy for mediastinal staging of NSCLC were investigated.

Results: A total of 5073 articles were found, of which 42 studies or subgroups (covering a total of 3248 patients undergoing the surgical reference standard of treatment) were considered in the analysis. Random effects meta-analysis of endosonography with or without confirmatory mediastinoscopy showed rates of unforeseen N2 disease of 9.6% (95% confidence interval [CI]: 7.8%-11.7%, I = 30%) versus 9.9% (95% CI: 6.3%-15.2%, I = 73%), respectively. Random effects meta-analysis of mediastinoscopy (eight studies [1245 patients in total]) showed a complication rate of 6.0% (95% CI: 4.8%-7.5%), with laryngeal recurrent nerve palsy accounting for 2.8% (95% CI: 2.0%-4.0%).

Conclusion: The rate of unforeseen N2 disease after negative endosonography findings was similar in patients undergoing immediate lung tumor resection to those undergoing confirmatory mediastinoscopy first, at the cost of 6.0% rate of complications by mediastinoscopy.
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http://dx.doi.org/10.1016/j.jtho.2019.02.032DOI Listing
June 2019

Airway smooth muscle reduction after bronchial thermoplasty in severe asthma correlates with FEV.

Clin Exp Allergy 2019 04 20;49(4):541-544. Epub 2019 Feb 20.

Department of Pulmonology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/cea.13365DOI Listing
April 2019

Systematic and combined endosonographic staging of lung cancer (SCORE study).

Eur Respir J 2019 02 7;53(2). Epub 2019 Feb 7.

Dept of Respiratory Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Guidelines recommend endosonography for mediastinal nodal staging in patients with resectable nonsmall cell lung cancer (NSCLC). We hypothesise that a systematic endobronchial ultrasound (EBUS) evaluation combined with an oesophageal investigation using the same EBUS bronchoscope (EUS-B) improves mediastinal nodal staging the current practice of targeted positron emission tomography (PET)-computed tomography (CT)-guided EBUS staging alone.A prospective, multicentre, international study (NCT02014324) was conducted in consecutive patients with (suspected) resectable NSCLC. After PET-CT, patients underwent systematic EBUS and EUS-B. Node(s) suspicious on CT, PET, EBUS and/or EUS-B imaging and station 4R, 4L and 7 (short axis ≥8 mm) were sampled. For patients without N2/N3 disease determined on endosonography, surgical-pathological staging was the reference standard.229 patients were included in this study. The prevalence of N2/N3 disease was 103 out of 229 patients (45%). A PET-CT-guided targeted approach by EBUS identified 75 patients with N2/N3 disease (sensitivity 73%, 95% CI 63-81%; negative predictive value (NPV) 81%, 95% CI 74-87%). Four additional patients with N2/N3 disease were found by systematic EBUS (sensitivity 77%, 95% CI 67-84%; NPV 84%, 95% CI 76-89%) and five more by EUS-B (84 patients total; sensitivity 82%, 95% CI 72-88%; NPV 87%, 95% CI 80-91%). Additional clinical relevant staging information was obtained in 23 out of 229 patients (10%).Systematic EBUS followed by EUS-B increased sensitivity for the detection of N2/N3 disease by 9% compared to PET-CT-targeted EBUS alone.
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http://dx.doi.org/10.1183/13993003.00800-2018DOI Listing
February 2019

Confocal Laser Endomicroscopy as a Guidance Tool for Transbronchial Lung Cryobiopsies in Interstitial Lung Disorder.

Respiration 2019;97(3):259-263. Epub 2018 Nov 14.

Department of Respiratory Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands,

Background: Transbronchial cryobiopsy (TBCB) of the lung parenchyma is a minimally invasive alternative for surgical lung biopsy in interstitial lung disease (ILD) patients. Drawbacks are the nondiagnostic rate and complication risk of pneumothorax and bleeding. Fluoroscopy is the current guidance tool for TBCB, which is limited by 2D imaging and a radiation dose for the patient. Confocal laser endomicroscopy (CLE) is a high-resolution imaging technique that provides immediate feedback during bronchoscopy about the elastin fiber network of peripheral lung areas. Both the visceral pleura and fibrotic lung areas consist of elastin fibers and are therefore potentially detectable with CLE.

Objectives: To investigate whether CLE is capable of (1) distinguishing fibrotic from normal alveolar areas and (2) identifying the pleura.

Methods: In and ex vivo CLE imaging obtained during bronchoscopy was compared with histology of lung biopsies in 14 ILD patients.

Results: CLE imaging of the alveolar compartment was feasible in all patients without adverse events. Based on CLE imaging, key characteristics that influence both diagnostic yield (dense fibrotic areas) and complication rate (pleura and subpleural space) were visualized.

Conclusions: CLE seems a promising alternative to fluoroscopy as a guidance tool for TBCB procedures.
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http://dx.doi.org/10.1159/000493271DOI Listing
April 2020

Bronchial Thermoplasty-Induced Acute Airway Effects Assessed with Optical Coherence Tomography in Severe Asthma.

Respiration 2018;96(6):564-570. Epub 2018 Aug 15.

Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The

Background: Bronchial thermoplasty (BT) is an endoscopic treatment for severe asthma targeting airway smooth muscle (ASM) with radiofrequent energy. Although implemented worldwide, the effect of BT treatment on the airways is unclear. Optical coherence tomography (OCT) is a novel imaging technique, based on near-infrared light, that generates high-resolution cross-sectional airway wall images.

Objective: To assess the safety and feasibility of OCT in severe asthma patients and determine acute airway effects of BT by OCT and compare these to the untreated right middle lobe (RML).

Methods: Severe asthma patients were treated with BT (TASMA trial). During the third BT procedure, OCT imaging was performed immediately following BT in the airways of the upper lobes, the right lower lobe treated 6 weeks prior, and the untreated RML.

Results: 57 airways were imaged in 15 patients. No adverse events occurred. Three distinct OCT patterns were discriminated: low-intensity scattering pattern of (1) bronchial and (2) peribronchial edema and (3) high-intensity scattering pattern of epithelial sloughing. (Peri)bronchial edema was seen in all BT-treated airways, and less pronounced in only 1/3 of the RML airways. These effects extended beyond the ASM layer and more distal than the directly BT-treated areas and were reduced, but not resolved, after 6 weeks. Epithelial sloughing occurred in 11/14 of the BT-treated airways and was absent in untreated RML airways.

Conclusions: Acute BT effects can be safely assessed with OCT and 3 distinct patterns were identified. The acute effects extended beyond the targeted ASM layer and distal of directly BT-treated airway areas, suggesting that BT might also target smaller distal airways.
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http://dx.doi.org/10.1159/000491676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390463PMC
October 2019

Concurrent Daily Cisplatin and High-Dose Radiation Therapy in Patients With Stage III Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2018 11 25;102(3):543-551. Epub 2018 Jul 25.

Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.

Purpose: The purpose of this study was to determine survival, local and distant control, toxicity, and prognostic factors in patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy (CCRT).

Methods And Materials: Consecutive patients with stage IIIA and IIIB NSCLC (N = 154) staged with F-fluorodeoxyglucose positron emission tomography/computed tomography were retrospectively selected (2005-2015). CCRT consisted of daily low-dose cisplatin (6 mg/m) combined with 24 fractions of 2.75 Gy to a total dose of 66 Gy.

Results: During a median follow-up period of 22 months (range, 1-92 months) the median overall survival was 36 months. The 1-, 2-, 3-, and 5-year survival rates were 79% (95% confidence interval [CI], 73%-86%), 61% (95% CI, 54%-70%), 52% (95% CI, 43%-60%), and 40% (95% CI, 31%-51%), respectively. The local relapse-free survival at 5 years was 55% (95% CI, 44%-69%). Metastasis-free survival at 5 years was 53% (95% CI, 44%-65%). The incidence of severe gastrointestinal disorders (grade 3-5) was 11%, among which grade 3 radiation esophagitis was 8.4%. The incidence of severe respiratory, thoracic, and mediastinal disorders (grade 3-5) was 8.4%, among which grade 3 radiation pneumonitis was 1.3%. Predictors of overall survival were lymph node gross tumor volume (GTV) (hazard ratio [HR], 1.007; 95% CI, 1.000-1.012) and sex (HR, 0.500; 95% CI, 0.320-0.870) in favor of women. Although lymph node GTV was a predictor of treatment toxicity (HR, 1.010; 95% CI, 1.000-1.013), tumor GTV was the predictor for distant metastasis during follow-up (HR, 1.002; 95% CI, 1.001-1.003).

Conclusions: CCRT with daily low-dose cisplatin for locally advanced stage III NSCLC resulted in promising overall survival (3-year survival rate of 52% and 5-year survival rate of 40%) with low toxicity. Lymph node GTV, tumor GTV, and sex were predictors of overall survival, treatment toxicity, and distant metastasis.
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http://dx.doi.org/10.1016/j.ijrobp.2018.07.188DOI Listing
November 2018

MEDIASTinal staging of non-small cell lung cancer by endobronchial and endoscopic ultrasonography with or without additional surgical mediastinoscopy (MEDIASTrial): study protocol of a multicenter randomised controlled trial.

BMC Surg 2018 May 18;18(1):27. Epub 2018 May 18.

Department of Surgery, Máxima Medical Center, PO BOX 7777, 5500 MB, Veldhoven, the Netherlands.

Background: In case of suspicious lymph nodes on computed tomography (CT) or fluorodeoxyglucose positron emission tomography (FDG-PET), advanced tumour size or central tumour location in patients with suspected non-small cell lung cancer (NSCLC), Dutch and European guidelines recommend mediastinal staging by endosonography (endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS)) with sampling of mediastinal lymph nodes. If biopsy results from endosonography turn out negative, additional surgical staging of the mediastinum by mediastinoscopy is advised to prevent unnecessary lung resection due to false negative endosonography findings. We hypothesize that omitting mediastinoscopy after negative endosonography in mediastinal staging of NSCLC does not result in an unacceptable percentage of unforeseen N2 disease at surgical resection. In addition, omitting mediastinoscopy comprises no extra waiting time until definite surgery, omits one extra general anaesthesia and hospital admission, and may be associated with lower morbidity and comparable survival. Therefore, this strategy may reduce health care costs and increase quality of life. The aim of this study is to compare the cost-effectiveness and cost-utility of mediastinal staging strategies including and excluding mediastinoscopy.

Methods/design: This study is a multicenter parallel randomized non-inferiority trial comparing two diagnostic strategies (with or without mediastinoscopy) for mediastinal staging in 360 patients with suspected resectable NSCLC. Patients are eligible for inclusion when they underwent systematic endosonography to evaluate mediastinal lymph nodes including tissue sampling with negative endosonography results. Patients will not be eligible for inclusion when PET/CT demonstrates 'bulky N2-N3' disease or the combination of a highly suspicious as well as irresectable mediastinal lymph node. Primary outcome measure for non-inferiority is the proportion of patients with unforeseen N2 disease at surgery. Secondary outcome measures are hospitalization, morbidity, overall 2-year survival, quality of life, cost-effectiveness and cost-utility. Patients will be followed up 2 years after start of treatment.

Discussion: Results of the MEDIASTrial will have immediate impact on national and international guidelines, which are accessible to public, possibly reducing mediastinoscopy as a commonly performed invasive procedure for NSCLC staging and diminishing variation in clinical practice.

Trial Registration: The trial is registered at the Netherlands Trial Register on July 6th, 2017 ( NTR 6528 ).
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http://dx.doi.org/10.1186/s12893-018-0359-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960166PMC
May 2018

Bronchial Thermoplasty in Severe Asthma: Best Practice Recommendations from an Expert Panel.

Respiration 2018;95(5):289-300. Epub 2018 Apr 17.

MAHSC, University of Manchester and Manchester Foundation Trust, Manchester, United Kingdom.

Bronchial thermoplasty (BT) is a bronchoscopic treatment for patients with severe asthma who remain symptomatic despite optimal medical therapy. In this "expert best practice" paper, the background and practical aspects of BT are highlighted. Randomized, controlled clinical trials have shown BT to be safe and effective in reducing severe exacerbations, improving quality of life, and decreasing emergency department visits. Five-year follow-up studies have provided evidence of the functional stability of BT-treated patients with persistence of a clinical benefit. The Global Initiative for Asthma (GINA) guidelines state that BT can be considered as a treatment option for adult asthma patients at step 5. Patient selection for BT requires close collaboration between interventional pulmonologists and severe asthma specialists. Key patient selection criteria for BT will be reviewed. BT therapy is delivered in 3 separate bronchoscopy sessions at least 3 weeks apart, covering different regions of the lung separately. Patients are treated with 50 mg/day of prednisolone or equivalent for 5 days, starting treatment 3 days prior to the procedure. The procedure is performed under moderate-to-deep sedation or general anesthesia. At bronchos-copy a single-use catheter with a basket design is inserted through the instrument channel and the energy is delivered by a radiofrequency (RF) generator (AlairTM Bronchial Thermoplasty System). BT uses temperature-controlled RF energy to impact airway remodeling, including a reduction of excessive airway smooth muscle within the airway wall, which has been recognized as a predominant feature of asthma. The treatment should be performed in a systemic manner, starting at the most distal part of the (sub)segmental airway, then moving proximally to the main bronchi, ensuring that the majority of the airways are treated. In general, 40-70 RF activations are provided in the lower lobes, and between 50 and 100 activations in the upper lobes combined. The main periprocedural adverse events are exacerbation of asthma symptoms and increased cough and sputum production. Occasionally, atelectasis has been observed following the procedure. The long-term safety of BT is excellent. An optimized BT responder profile - i.e., which specific asthma phenotype benefits most - is a topic of current research.
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http://dx.doi.org/10.1159/000488291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492603PMC
October 2018
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