Prevalence and time-course of diaphragmatic dysfunction following lung resection: A repeated ultrasonic assessment.

PURPOSE: Ultrasound (US) allows non-invasive repeated assessments of diaphragmatic excursion (DE) and thickening fraction (DTF) at the bedside, reflecting diaphragmatic dysfunction (DD). We aimed at determining the prevalence and time-course of DD following elective thoracic surgery and the association with postoperative complications. MATERIAL AND METHODS: Prospective, single-centre, observational study with consecutive patients undergoing thoracic surgery. DE/DTF were measured by two observers blinded to each other at 3 different time-points: prior to surgery, immediately after extubation and on postoperative day 3. The changes in DE/DTF of both hemi-diaphragms over time were compared according to the side (operated/non-operated) using a two-way-ANOVA. The association with postoperative complications was assessed using logistic regression. RESULTS: Fifty patients, 60% males, aged 60 ± 15 years were included. Surgical procedures included lobectomy (n = 30), wedge-resection (n = 17) or pneumonectomy (n = 3). On the operated side, we observed a decrease in DE/DTF at D0 (-0.71 ± 0.12 mm, P < 0.05; -44 ± 30%, P < 0.05) and D3 (-0.82 ± 0.19 mm, P < 0.05; -39 ± 19%, P < 0.05) with respect to preoperative and non-operated side values over the study period. Persistent DD on the operated side was associated with an increased risk of lung infection (OR: 9.0, 95% CI [1.92-65.93], P = 0.001), ICU-admission (OR: 3.9, 95% CI [1.10-15.53], P = 0.04) according to univariate analysis and a prolonged length in hospital (OR: 1.3, 95% CI [1.1-1.7], P = 0.016) according to multivariate analysis. CONCLUSIONS: Thoracic surgery generates DD mainly observed on the operated side, which persists at least up to postoperative D3 and is associated with an increase in hospital stay.

Clinical assessment of the miR-34, miR-200, ZEB1 and SNAIL EMT regulation hub underlines the differential prognostic value of EMT miRs to drive mesenchymal transition and prognosis in resected NSCLC.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) receiving curative surgery have a risk of relapse, and adjuvant treatments only translate into a 5% increase in 5-year survival. We assessed the clinical significance of epithelial-mesenchymal transition (EMT) and explored its association with the [SNAIL/miR-34]:[ZEB/miR-200] regulation hub to refine prognostic information. METHODS: We validated a 7-gene EMT score using a consecutive series of 176 resected NSCLC. We quantified EMT transcription factors, microRNAs (miRs) of the miR-200, miR-34 families and miR-200 promoter hypermethylation to identify outcome predictors. RESULTS: Most tumours presented with an EMT-hybrid state and the EMT score was not predictive of outcome. Individually, all miR-200 were inversely associated with the EMT score, but only chromosome-1 miRs, miR-200a, b, 429, were associated with disease-free survival (p = 0.08, 0.05 and 0.025) and overall survival (p = 0.013, 0.003 and 0.006). We validated these associations on The Cancer Genome Atlas data. Tumour unsupervised clustering based on miR expression identified two good prognostic groups, unrelated to the EMT score, suggesting that miR profiling may have an important clinical value. CONCLUSION: miR-200 family members do not have similar predictive value. Core EMT-miR, regulators and not EMT itself, identify NSCLC patients with a low risk of relapse after surgery.

Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma.

OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive tumor with limited therapeutic options, requiring the development of efficient targeted therapies based on molecular phenotype of the tumor and to identify predictive biomarkers of the response. MATERIALS AND METHODS: The effect of inhibitors was investigated by cell viability assessment on primary MPM cell lines established in our laboratory from patient tumors, well characterized at the molecular level. Effects on apoptosis, cell proliferation and viability on MPM growing in multicellular spheroid were also assessed for verteporfin. Gene and protein expression, and gene knockdown by RNA interference were used to define mechanism of inhibition and specific predictive biomarkers. RESULTS: Anti-tumor effect of eight major signaling pathways inhibitors involved in mesothelial carcinogenesis was investigated. Three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor. Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors. CONCLUSION: Our study shows that drug screening on well-characterized MPM cells allows for the identification of novel potential therapeutic strategies and defining specific biomarkers predictive of the drug response.