Endobronchial ultrasound guided fine needle aspiration versus transcervical mediastinoscopy in nodal staging of non small cell lung cancer: a prospective comparison study

BACKGROUND: At present only few studies directly compare the diagnostic yield of endobronchial ultrasound guided fine needle aspiration (EBUS-FNA) and transcervical video-assisted mediastinoscopy (TM) for mediastinal lymph node staging in patients with NSCLC. If and when EBUS-FNA may replace TM as Gold Standard remains controversial. METHODS: From April 2008 to December 2009, 36 patients with mediastinal lymphadenopathy underwent simultaneous EBUS-FNA/ TM at our institution. Among them were 26 patients with confirmed or suspected NSCLC. RESULTS: A total of 133 samples were obtained by EBUS-FNA and 157 samples by TM. EBUS-FNA achieved significantly less conclusive, but more indeterminate pathological results in comparison to TM (78.7% vs. 98.6%, p < 0.001; 14.9% vs. 1.4%, p = 0.007). Less paratracheal nodes were sampled by EBUS-FNA (right: 46.2% vs. 88.5%, p = 0.003; left: 23.1% vs. 65.4%, p = 0.005), while sampling rates in the subcarinal localisation were comparable (96.2% vs. 80.8%, p = NS). Among patients with confirmed NSCLC and conclusive EBUS-FNA/ TM findings (n = 18), the prevalence of N2/N3 disease was 66.7% (n = 12) according to TM findings. Diverging nodal stages were found in five patients (27.8%). Three patients who were N2 negative in EBUS-FNA were upstaged to N2 or N3 by TM, two patients with N2 status in EBUS-FNA were upstaged to N3 by TM. CONCLUSIONS: Compared to TM, EBUS-FNA had a lower diagnostic yield and resulted in systematic mediastinal nodal understaging. At this point we suggest corroborating negative EBUS-FNA results by transcervical mediastinoscopy

Lung tumour growth kinetics in SPC-c-Raf-1-BB transgenic mice assessed by longitudinal in-vivo micro-CT quantification

<p>Abstract</p> <p>Background</p> <p>SPC-c-Raf-1-BxB transgenic mice develop genetically induced disseminated lung adenocarcinoma allowing examination of carcinogenesis and evaluation of novel treatment strategies. We report on assessment of lung tumour growth kinetics using a semiautomated region growing segmentation algorithm.</p> <p>Methods</p> <p>156 non contrast-enhanced respiratory gated micro-CT of the lungs were obtained in 12 SPC-raf transgenic (n = 9) and normal (n = 3) mice at different time points. Region-growing segmentation of the aerated lung areas was obtained as an inverse surrogate for tumour burden. Time course of segmentation volumes was assessed to demonstrate the potential of the method for follow-up studies.</p> <p>Results</p> <p>Micro-CT allowed assessment of tumour growth kinetics and semiautomated region growing enabled quantitative analysis. Significant changes of the segmented lung volumes over time could be shown (<it>p </it>= 0.009). Significant group differences could be detected between transgenic and normal animals for time points 8 to 13 months (<it>p </it>= 0.043), when marked tumour progression occurred.</p> <p>Conclusion</p> <p>The presented region-growing segmentation algorithm allows in-vivo quantification of multifocal lung adenocarcinoma in SPC-raf transgenic mice. This enables the assessment of tumour load and progress for the study of carcinogenesis and the evaluation of novel treatment strategies.</p

Qualitative and quantitative evaluation of computed tomography changes in adults with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor: a retrospective observational study

Introduction: The availability of highly effective triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination therapy with elexacaftor–tezacaftor–ivacaftor (ETI) has improved pulmonary outcomes and quality of life of people with cystic fibrosis (pwCF). The aim of this study was to assess computed tomography (CT) changes under ETI visually with the Brody score and quantitatively with dedicated software, and to correlate CT measures with parameters of clinical response.Methods: Twenty two adult pwCF with two consecutive CT scans before and after ETI treatment initiation were retrospectively included. CT was assessed visually employing the Brody score and quantitatively by YACTA, a well-evaluated scientific software computing airway dimensions and lung parenchyma with wall percentage (WP), wall thickness (WT), lumen area (LA), bronchiectasis index (BI), lung volume and mean lung density (MLD) as parameters. Changes in CT metrics were evaluated and the visual and quantitative parameters were correlated with each other and with clinical changes in sweat chloride concentration, spirometry [percent predicted of forced expiratory volume in one second (ppFEV1)] and body mass index (BMI).Results: The mean (SD) Brody score improved with ETI [55 (12) vs. 38 (15); p &lt; 0.001], incl. sub-scores for mucus plugging, peribronchial thickening, and parenchymal changes (all p &lt; 0.001), but not for bronchiectasis (p = 0.281). Quantitatve WP (p &lt; 0.001) and WT (p = 0.004) were reduced, conversely LA increased (p = 0.003), and BI improved (p = 0.012). Lung volume increased (p &lt; 0.001), and MLD decreased (p &lt; 0.001) through a reduction of ground glass opacity areas (p &lt; 0.001). Changes of the Brody score correlated with those of quantitative parameters, exemplarily WT with the sub-score for mucus plugging (r = 0.730, p &lt; 0.001) and peribronchial thickening (r = 0.552, p = 0.008). Changes of CT parameters correlated with those of clinical response parameters, in particular ppFEV1 with the Brody score (r = −0.606, p = 0.003) and with WT (r = −0.538, p = 0.010).Discussion: Morphological treatment response to ETI can be assessed using the Brody score as well as quantitative CT parameters. Changes in CT correlated with clinical improvements. The quantitative analysis with YACTA proved to be an objective, reproducible and simple method for monitoring lung disease, particularly with regard to future interventional clinical trials

Unmet needs in pneumonia research: a comprehensive approach by the CAPNETZ study group

INTRODUCTION: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The “network of excellence on Community Acquired Pneumonia” (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research. METHODS: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat. RESULTS: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications. CONCLUSION: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients’ risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP

ROSE:radiology, obstruction, symptoms and exposure - a Delphi consensus definition of the association of COPD and bronchiectasis by the EMBARC Airways Working Group

Introduction: The coexistence of chronic obstructive pulmonary disease (COPD) and bronchiectasis (BE) seems to be common and associated with a worse prognosis than for either disease individually. However, no definition of this association exists to guide researchers and clinicians. // Methods: We conducted a Delphi survey involving expert pulmonologists and radiologists from Europe, Turkey and Israel in order to define the “COPD-BE association”. A panel of 16 experts from EMBARC selected 35 statements for the survey after reviewing scientific literature. Invited participants, selected on the basis of expertise, geographical and gender distribution, were asked to express agreement on the statements. Consensus was defined as a score of ≥6 points (scale 0 to 9) in ≥70% of answers across two scoring rounds. // Results: A-hundred-and-two (72.3%) out of 141 invited experts participated the first round. Their response rate in the second round was 81%. The final consensus definition of “COPD-BE association” was: “The coexistence of (1) specific radiological findings (abnormal bronchial dilatation, airways visible within 1 cm of pleura and/or lack of tapering sign in ≥1 pulmonary segment and in >1 lobe) with (2) an obstructive pattern on spirometry (FEV1/FVC<0.7), (3) at least two characteristic symptoms (cough, expectoration, dyspnoea, fatigue, frequent infections) and (4) current or past exposure to smoke (≥10 pack-years) or other toxic agents (biomass, etc.)”. These criteria form the acronym “ROSE” (Radiology, Obstruction, Symptoms, Exposure). // Conclusions: The Delphi process formulated a European consensus definition of “COPD-BE association”. We hope this definition will have broad applicability across clinical practice and research in the future

Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis

Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic stem cell-based gene therapy. Using Csf2rb−/− mice, a model closely reflecting the human herPAP disease phenotype, we here demonstrate robust pulmonary engraftment of an alveolar macrophage population following intravenous transplantation of lentivirally corrected hematopoietic stem and progenitor cells. Engraftment was associated with marked improvement of critical herPAP disease parameters, including bronchoalveolar fluid protein, cholesterol and cytokine levels, pulmonary density on computed tomography scans, pulmonary deposition of Periodic Acid-Schiff+ material as well as respiratory mechanics. These effects were stable for at least nine months. With respect to engraftment and alveolar macrophage differentiation kinetics, we demonstrate the rapid development of CD11c+/SiglecF+ cells in the lungs from a CD11c–/SiglecF+ progenitor population within four weeks after transplantation. Based on these data, we suggest hematopoietic stem cell-based gene therapy as an effective and cause-directed treatment approach for herPAP

Imaging of bronchial pathology in antibody deficiency: Data from the European Chest CT Group

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease

Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy

Tumor-derived lactic acid inhibits T and natural killer (NK) cell function and, thereby, tumor immunosurveillance. Here, we report that melanoma patients with high expression of glycolysis-related genes show a worse progression free survival upon anti-PD1 treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers lactate secretion of tumor cells and improves anti-PD1-induced T cell killing in vitro. Surprisingly, diclofenac, but not other NSAIDs, turns out to be a potent inhibitor of the lactate transporters monocarboxylate transporter 1 and 4 and diminishes lactate efflux. Notably, T cell activation, viability, and effector functions are preserved under diclofenac treatment and in a low glucose environment in vitro. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy in vivo. Moreover, genetic suppression of glycolysis in tumor cells strongly improves checkpoint therapy. These findings support the rationale for targeting glycolysis in patients with high glycolytic tumors together with checkpoint inhibitors in clinical trials