Endothelin-1 Induces Mesothelial Mesenchymal Transition and Correlates with Pleural Fibrosis in Tuberculous Pleural Effusions.

Endothelin (ET)-1 is involved in various fibrotic diseases. However, its implication in pleural fibrosis remains unknown. We aimed to study the profibrotic role of ET-1 in tuberculous pleural effusion (TBPE). The pleural effusion ET-1 levels were measured among 68 patients including transudative pleural effusion (TPE, n = 12), parapneumonic pleural effusion (PPE, n = 20), and TBPE (n = 36) groups. Pleural fibrosis, defined as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Additionally, the effect of ET-1 on mesothelial mesenchymal transition (MMT) and extracellular matrix (ECM) producion in human pleural mesothelial cells (PMCs) was assessed. Our findings revealed that effusion ET-1 levels were significantly higher in TBPE than in TPE and PPE, and were markedly higher in TBPE patients with RPT >10 mm than those with RPT ≤10 mm. ET-1 levels correlated substantially with residual pleural shadowing and independently predicted RPT >10 mm in TBPE. In PMCs, ET-1 time-dependently induced MMT with upregulation of α-smooth muscle actin and downregulation of E-cadherin, and stimulated ECM production; furthermore, ET receptor antagonists effectively abrogated these effects. In conclusion, ET-1 induces MMT and ECM synthesis in human PMCs and correlates with pleural fibrosis in TBPE. This study confers a novel insight into the pathogenesis and potential therapies for fibrotic pleural diseases.

Distinct clinical outcomes of non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors: non-responders versus responders.

INTRODUCTION: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been associated with favorable progression free survival (PFS) in patients with non-small cell lung cancers (NSCLC) harboring EGFR mutations. However, a subset of this population doesn't respond to EGFR-TKI treatment. Therefore, the present study aimed to elucidate survival outcome in NSCLC EGFR-mutant patients who were treated with EGFR TKIs. METHODS: Among the 580 consecutive NSCLC patients who were treated at our facility between 2008 and 2012, a total of 124 treatment-naïve, advanced NSCLC, EGFR-mutant patients treated with EGFR TKIs were identified and grouped into non-responders and responders for analyses. RESULTS: Of 124 patients, 104 (84%) responded to treatment, and 20 (16%) did not; and the overall median PFS was 9.0 months. Notably, the PFS, overall survival (OS) and survival rates were significantly unfavorable in non-responders (1.8 vs. 10.3 months, hazard ratio (HR) = 29.2, 95% confidence interval (CI), 13.48-63.26, P<0.0001; 9.4 vs. 17.3 months, HR = 2.74, 95% CI, 1.52-4.94, P = 0.0008; and 58% vs. 82% in 6, 37% vs. 60% in 12, and 19 vs. 40% at 24 months, respectively). In multivariate analysis, treatment efficacy strongly affected PFS and OS, independent of covariates (HR = 47.22, 95% CI, 17.88-124.73, P<0.001 and HR = 2.74, 95% CI, 1.43-5.24, P = 0.002, respectively). However, none of the covariates except of the presence of EGFR exon 19 deletion in the tumors was significantly associated with better treatment efficacy. CONCLUSIONS: A subset of NSCLC EGFR-mutant patients displayed unfavorable survival despite EGFR TKI administration. This observation reinforces the urgent need for biomarkers effectively predicting the non-responders and for drug development overcoming primary resistance to EGFR TKIs. In addition, optimal therapeutic strategies to prolong the survival of non-responders need to be investigated.

Suitability of computed tomography-guided biopsy specimens for subtyping and genotyping of non-small-cell lung cancer.

INTRODUCTION: Recent advances in the treatment of NSCLC highlight the importance of distinguishing NSCLC subtypes and genotypes. We aimed to determine whether histological specimens obtained from computed tomography (CT)-guided biopsy are suitable for specific subtyping and epidermal growth factor receptor (EGFR) analyses of NSCLC. PATIENTS AND METHODS: The clinicohistological data of 332 consecutive patients undergoing 352 CT-guided biopsies for lung lesions between January 2007 and December 2011 were retrospectively analyzed. Additionally, NSCLC specimens were examined for the suitability of EGFR mutational testing. RESULTS: Of 209 specimens diagnosed as NSCLC, 197 (94.3%) were specifically subtyped into adenocarcinoma (n = 164; 78.5%), squamous cell carcinoma (n = 27; 12.9%) and other subtypes (n = 6; 2.9%). The rate of NSCLC not otherwise specified (NOS) was 5.7%, and the diagnosis of NSCLC-NOS was significantly associated with the poor differentiation of cancer (adjusted odds ratio, 6.17; 95% confidence interval, 1.62-23.55; P = .008). Of 134 histological tumor specimens submitted for EGFR molecular testing, 132 (98.5%) were suitable for analyses, and 130 of them (98.5%) showed conclusive results, revealing 59.8% (n = 79) with EGFR exon mutation(s). The sensitivity, specificity, and positive and negative predictive values of CT-guided biopsy in patients with malignancy were 92.2%, 100%, 100%, and 74.1%, respectively. Six percent (n = 21) of total lung biopsies led to pneumothorax requiring chest drainage, and no procedure-related fatality was observed. CONCLUSION: Small tumor specimens obtained with CT-guided needle lung biopsy are suitable for specific subtyping and EGFR analyses of NSCLC, thus providing critical information for personalized therapy.