NEDD9 Restrains dsDNA Damage Response during Non-Small Cell Lung Cancer (NSCLC) Progression.

DNA damaging modalities are the backbone of treatments for non-small cell lung cancer (NSCLC). Alterations in DNA damage response (DDR) in tumor cells commonly contribute to emerging resistance to platinating agents, other targeted therapies, and radiation. The goal of this study is to identify the previously unreported role of NEDD9 scaffolding protein in controlling DDR processes and sensitivity to DNA damaging therapies. Using a siRNA-mediated approach to deplete NEDD9 in a group of human and murine KRAS/TP53-mutant NSCLC cell lines, coupled with a set of cell viability and clonogenic assays, flow cytometry analysis, and Western blotting, we evaluated the effects of NEDD9 silencing on cellular proliferation, DDR and epithelial-to-mesenchymal transition (EMT) signaling, cell cycle, and sensitivity to cisplatin and UV irradiation. Using publicly available NSCLC datasets (TCGA) and an independent cohort of primary NSCLC tumors, subsequent in silico and immunohistochemical (IHC) analyses were performed to assess relevant changes in NEDD9 RNA and protein expression across different stages of NSCLC. The results of our study demonstrate that NEDD9 depletion is associated with the increased tumorigenic capacity of NSCLC cells. These phenotypes were accompanied by significantly upregulated ATM-CHK2 signaling, shifting towards a more mesenchymal phenotype in NEDD9 depleted cells and elevated sensitivity to UV-irradiation. IHC analyses revealed an association between reduced NEDD9 protein expression and a decrease in overall (OS) and progression-free survival (PFS) of the NSCLC patients. These data, for the first time, identified NEDD9 as a negative regulator of ATM kinase activity and related DDR signaling in numerous KRAS/TP53 mutated NSCLC, with its effects on the regulation of DDR-dependent EMT signaling, sensitivity to DNA damaging modalities in tumor cells, and the survival of the patients.

Surgical resection of Masaoka stage III thymic epithelial tumours with great vessels involvement: a retrospective multicentric analysis from the European Society of Thoracic Surgeons thymic database.

OBJECTIVES: The aim of this study was to analyse the outcomes of an international cohort of patients affected by Masaoka stage III thymic epithelial tumours with vascular involvement and treated by surgery. METHODS: Study design was the observational multicentre retrospective cohort study. Data were extracted from the European Society of Thoracic Surgeons thymic database; additional variables were collected. Inclusion criteria were as follows: stage III (Masaoka-Koga) thymic epithelial tumours; surgery with radical intention; clinical or pathological great vessels involvement; and radiologically suspected or diagnosed intraoperatively. Outcome items were analysed. RESULTS: Sixty-five patients submitted to surgery from 2001 to 2017 fulfilled inclusion criteria. Thymoma and thymic carcinoma patients did not differ for demographics and clinical characteristics. The majority of great vessel treated were superior vena cava or innominate veins (72.3%). Eleven patients (16.9%) had postoperative cardiopulmonary complications; vascular stenosis was observed in 3 patients (4.6%). The multivariable Cox analysis for disease-free survival showed an increased hazard of recurrence for thymic carcinoma (hazard ratio = 3.59; 95% confidence interval: 1.66-7.78, P = 0.001). The 1-, 3-, 5- and 10-year overall survival rates were 0.86, 0.84, 0.81, and 0.53, respectively. There was no significant difference in overall survival according to resection status or between thymoma and thimic carcinoma. The univariable Cox regression model did not show an increased hazard of death for myasthenic patients considering all resection status and for patients who received neoadjuvant therapy. CONCLUSIONS: We observed that clinical outcomes of patients treated for stage III thymic epithelial tumours with vascular involvement are satisfactory suggesting to increase the confidence in dealing with these complex surgeries. Complete resection should be achieved, even though extensive vascular reconstructions are required.

An original device for intraoperative detection of small indeterminate nodules†.

OBJECTIVES: The purpose of this study was to evaluate the efficiency of our newly designed tactile mechanoreceptor in detection of pulmonary lesions during thoracoscopy. METHODS: Twenty-seven patients with peripheral undetermined subpleural solitary pulmonary lesions detected on computed tomography were included in a prospective non-randomized trial. All nodules from 7 to 18 mm in diameter were located deep in the lung parenchyma (≥ 10 mm from the lung surface). All patients underwent thoracoscopic exploration with diagnostic intent. Instrumental palpation with lung forceps was performed first, followed by thorough inspection of lung tissue with the tactile mechanoreceptor. This device is a metal tube 10 mm in diameter, which can be inserted into the pleural cavity via a standard 10-mm port. There is an elastic membrane on its working end, which deforms greatly if the palpated tissue has greater density. Intraoperatively, the surgeon pushed the targeted region of pulmonary tissue with the mechanoreceptor and carried out the measurement. The density of tissue characteristics was displayed with special software using colour change in real time. After detection of a pulmonary nodule, it was resected with endostaplers. RESULTS: Instrumental palpation was successful in detection of pulmonary lesions in 10 (37%) patients and was confirmed with the tactile mechanoreceptor. In 12 (44%) patients, instrumental palpation failed to locate an intrapulmonary nodule, while the tactile mechanoreceptor facilitated finding the lesion and performing thoracoscopic lung resection in all these patients. Intraoperative histological examination confirmed benign disease in 8, metastatic lesion in 12 and primary lung cancer in 7 patients requiring thoracoscopic lobectomy. In 5 (19%) patients, neither forceps nor the tactile mechanoreceptor was able to detect any pulmonary lesion, necessitating mini-thoracotomy for finger palpation. The overall efficacy of the tactile mechanoreceptor in detection of pulmonary lesions was 81%, and of impalpable nodes 71%. CONCLUSIONS: The tactile mechanoreceptor is an effective tool for detection of impalpable pulmonary lesions during thoracoscopy.