[Show abstract][Hide abstract] ABSTRACT: STK11 is commonly mutated in lung cancer. In light of recent experimental data showing that specific STK11 mutants could acquire oncogenic activities due to the synthesis of a short STK11 isoform, we investigated whether this new classification of STK11 mutants could help refine its role as a prognostic marker. We conducted a retrospective high-throughput genotyping study in 567 resected non-squamous non-small-cell lung cancer (NSCLC) patients. STK11 exons 1 or 2 mutations (STK11ex1-2) with potential oncogenic activity were analyzed separately from exons 3 to 9 (STK11ex3-9). STK11ex1-2 and STK11ex3-9 mutations occurred in 5% and 14% of NSCLC. STK11 mutated patients were younger (P = .01) and smokers (P< .0001). STK11 mutations were significantly associated with KRAS and inversely with EGFR mutations. After a median follow-up of 7.2 years (95%CI 6.8-.4), patients with STK11ex1-2 mutation had a median OS of 24 months (95%CI 15-57) as compared to 69 months (95%CI 56-93) for wild-type (log-rank, P = .005) and to 91 months (95%CI 57-unreached) for STK11ex3-9 mutations (P = .003). In multivariate analysis, STK11ex1-2 mutations remained associated with a poor prognosis (P = .002). Results were validated in two public datasets. Western blots showed that STK11ex1-2 mutatedtumors expressed short STK11 isoforms. Finally using mRNAseq data from the TCGA cohort, we showed that a stroma-derived poor prognosis signature was enriched in STK11ex1-2 mutated tumors. All together our results show that STK11ex1-2 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES To determine contemporary early outcomes associated with bilobectomy for lung cancer and to identify their predictors using
a nationally representative general thoracic surgery database.
Full-text · Article · Aug 2015 · European Journal of Cardio-Thoracic Surgery
[Show abstract][Hide abstract] ABSTRACT: Background Osseous metaplasia is an extremely rare histological variation of thymus tumors. Despite intratumoral calcifications are described ossification is exceptional. Case report A 27-year-old woman with no relevant medical history was referred to our department for the treatment of a full-calcified anterior mediastinal tumor. It was detected on a spinal X-ray performed for chronic back pain and confirmed by a chest X-ray. On the computed tomography, a bulky anterior mediastinal tumor containing heterogeneous calcification was confirmed. The patient underwent a posterolateral thoracotomy. Intraoperatively there was a large hard stony mass in the anterior mediastinum extending to the right hemi thorax. Complete excision of the mass including thymectomy was done. The patient underwent uneventful recovery. Histopathology reported a thymoma type B1 with osseous metaplasia according to the World Health Organization classification and Masaoka I stage according to intraoperative findings. Results To our knowledge it is the third case published in all literature of a thymus tumor with complete osseous metaplasia in an adult and the first case that tumor is almost entirely ossified. Conclusion The mechanism of osseous metaplasia is unknown. Several theories have been given. Certain cell mediators would stimulate and influence connective tissue to be replaced by heterotopic bone. Further cases of osseous metaplasia will be necessary to figure out pathogenesis, prognosis and treatments outcomes of these particular types of thymomas.
No preview · Article · Jun 2015 · European Surgery
[Show abstract][Hide abstract] ABSTRACT: Objectives: Non-small cell lung carcinoma (NSCLC) with N1 involvement is associated with 5-year survival rates ranging from 7% to 55%. Numerous factors have been independently reported to explain this heterogeneous prognosis, but their relative weight on long-term survival is unknown. Methods: Patients who underwent surgical resection for NSCLC in two French centers from 1993 to 2010 were prospectively recorded and retrospectively reviewed. The overall survival (OS) of patients undergoing first-line surgery for pN1 disease was analyzed according to the type of extension, number of metastatic LN, number and anatomic location of metastatic stations. Results: The study group included 450 patients (male 80.2%, mean age 63.3 ± 9.9 years, 5-year overall survival 46%). The number of metastatic station was 1 in 340 (75.6%, single-station disease) and ≥2 in 110 patients (24.4%, multi-station disease). The number of metastatic stations was correlated with the number of metastatic LN ( p < .001), and associated with adverse OS ( p = .0014). The presence of intralobar metastatic LN (station 12-13-14) was associated with a mechanism of direct extension ( p < .001), but did not impact OS ( p = .71). The location of metastatic stations was of prognostic significance only in case of multi-station disease, with hilar (station 10) involvement being associated with adverse OS ( p = .005). The 110 patients with multi-station pN1 disease and the 134 patients operated on for single-station pN0N2 (skip-N2) disease during the study period yield comparable outcome ( p = .52). Conclusions: In patients with resected pN1 NSCLC, the number of metastatic stations and their location in case of multi-station disease have a prognostic value.
Full-text · Article · May 2015 · European Journal of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Background
Tobacco-induced pulmonary vascular disease is partly driven by endothelial dysfunction. The bioavailability of the potent vasodilator nitric oxide (NO) depends on competition between NO synthase-3 (NOS3) and arginases for their common substrate (L-arginine). We tested the hypothesis whereby tobacco smoking impairs pulmonary endothelial function via upregulation of the arginase pathway.
Endothelium-dependent vasodilation in response to acetylcholine (Ach) was compared ex vivo for pulmonary vascular rings from 29 smokers and 10 never-smokers. The results were expressed as a percentage of the contraction with phenylephrine. We tested the effects of L-arginine supplementation, arginase inhibition (by N(omega)-hydroxy-nor-l-arginine, NorNOHA) and NOS3 induction (by genistein) on vasodilation. Protein levels of NOS3 and arginases I and II in the pulmonary arteries were quantified by Western blotting.
Overall, vasodilation was impaired in smokers (relative to controls; p < 0.01). Eleven of the 29 smokers (the ED+ subgroup) displayed endothelial dysfunction (defined as the absence of a relaxant response to Ach), whereas 18 (the ED− subgroup) had normal vasodilation. The mean responses to 10−4 M Ach were −23 ± 10% and 31 ± 4% in the ED+ and ED− subgroups, respectively (p < 0.01). Supplementation with L- arginine improved endothelial function in the ED+ subgroup (−4 ± 10% vs. -32 ± 10% in the presence and absence of L- arginine, respectively; p = 0.006), as did arginase inhibition (18 ± 9% vs. -1 ± 9%, respectively; p = 0.0002). Arginase I protein was overexpressed in ED+ samples, whereas ED+ and ED− samples did not differ significantly in terms of NOS3 expression. Treatment with genistein did not significantly improve endothelial function in ED+ samples.
Overexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction.
Full-text · Article · Mar 2015 · Respiratory Research
[Show abstract][Hide abstract] ABSTRACT: Le traitement chirurgical des aspergillomes pulmonaires permet de contrôler les symptômes, de prévenir les complications et d’améliorer la survie. Dans les formes accessibles à la chirurgie, l’impact d’un traitement antifongique demeure controversé. L’objectif de cette étude est d’analyser l’impact d’un traitement antifongique sur la morbidité postopératoire et la survie globale des patients opérés pour un aspergillome pulmonaire.
Full-text · Article · Nov 2014 · Revue de Pneumologie Clinique