Mycobacterium abscessus (Mabs) drives life-shortening mortality in cystic fibrosis (CF) patients, primarily because of its resistance to chemotherapeutic agents. Both our knowledge on and models to investigate the host and bacterial determinants that drive Mabs pathology in CF patients remain rudimentary. Here, we evaluated whether the lung organoid technology from CF patients is appropriate for modelling Mabs infection and whether antioxidant treatment is a candidate therapeutic approach in the context of CF disease. We derived airway organoids (AOs) from lung biopsy of a CF patient and characterized these AO by assessing CF transmembrane conductance regulator (CFTR) function, mucus and reactive oxygen species (ROS) production, lipid peroxidation, and cell death. We microinjected smooth (S-) or rough (R-)Mabs in the lumen of AOs to evaluate its fitness, responses of AOs to infection, and treatment efficacy by colony forming unit assay, qPCR and microscopy. We show that CF patient-derived AOs exhibited low residual CFTR function, enhanced mucus accumulation, and increased oxidative stress, lipid peroxidation, and cell death at basal state. While in AOs, S Mabs formed biofilm, R Mabs formed cord serpentines and displayed a higher virulence. S and R Mabs replicated more efficiently in CF AOs than in AOs derived from healthy lung. Pharmacological activation of antioxidant pathways resulted in better control of Mabs growth. In conclusion, we have established CF patient-derived AOs as a suitable human system to decipher mechanisms of CF-enhanced respiratory infection by Mabs and confirmed antioxidant approaches as a potential host-directed strategy to improve Mabs infection control.
OBJECTIVES We described patients with microscopic residual disease (R1) operated on for non-small-cell lung cancer (NSCLC) and investigated predictive factors for R1. We also examined prognostic factors for overall survival in these patients. METHODS From June 2003 to December 2019, a total of 2595 patients benefited from an anatomical resection operation for NSCLC in our department. All preoperative data were prospectively collected in Epithor, the French thoracic surgery national database. All pre-, per- and postoperative care followed the current recommendations. Tumours were classified by experienced pathologists according to the TNM classification and the resection status R. Survival information was collected retrospectively using the French national death register. RESULTS A total of 94 R1 patients (3.6%) and 2255 R0 patients (86.9%) were identified. R1 patients showed significant differences: They were older (p = 0.02), with a high rate of pneumonectomy(p < 0.001), more squamous cell carcinomas (p < 0.001) and more cases of advanced-stage disease (p < 0.001). We proved that incomplete resection was a poor and independent prognostic factor whereas complete resection had a significant impact on overall survival (HR: 4.66 [3.46–6.27]). Thus, we identified high clinical T status (odds ratio [OR]: 8.82 [5.00–15.56]), high clinical N status (OR: 3.54 [2.13–5.87), squamous cell carcinoma (OR: 3.86 [2.33–6.42]), obesity (OR 1.91 [1.04–3.52]) and low forced expiratory volume in 1 s (OR: 3.62 [1.70–7.68]) as risk factors for R1. No statistical differences were found according to the location of positive resection margin or treatment, whether adjuvant or neoadjuvant. CONCLUSIONS Incomplete resection was a poor prognostic factor for overall survival of patients operated on for NSCLC, particularly in the advanced stages of the disease. Identification of different predictive factors should help to avoid this situation. subj collection: 152
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