Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

BACKGROUND: Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. METHODS: This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. RESULTS: Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. CONCLUSIONS: Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

A comparison between the effects of over-expression of miRNA-16 and miRNA-34a on cell cycle progression of mesothelioma cell lines and on their cisplatin sensitivity.

The prognosis of patients affected by malignant pleural mesothelioma (MPM) is presently poor and no therapeutic strategies have improved their survival yet. Introduction of miRNA mimics to restore their reduced or absent functionality in cancer cells is considered an important opportunity and a combination of miR's might be even more effective. In the present study, miR-16 and miR-34a were transfected, singularly and in combination, in MPM cell lines H2052 and H28, and their effects on cell proliferation and sensitivity to cisplatin are reported. Interestingly, the overexpression of both miRs, alone or combined, slows down the cell cycle progression, modulates the p53 and HMGB1 expression and increases the sensitivity of cells to cisplatin, producing a marked impairment of cell proliferation and strengthening the apoptotic effect of the drug. However, the co-overexpression of the two miRs results more effective only in the regulation of the cell cycle, but does not enhance the sensitivity of MPM cells to cisplatin. Consequently, although the potential of miR-16 and miR-34a is confirmed, we must conclude that their combination does not improve the response of MPM to chemotherapy.

Exhaled breath analysis in suspected cases of non-small-cell lung cancer: a cross-sectional study.

Lung cancer is one of the most frequently diagnosed cancers worldwide and is still the leading cause of cancer-related deaths. There is a considerable interest in finding diagnostic methods in the disease's earliest stages. A complementary approach to imaging techniques could be provided by exhaled breath gas phase and exhaled breath condensate (EBC) analysis. The aim of this study was to quantify various biomarkers in the exhaled breath gas phase and EBC in suspected cases of non-small-cell lung cancer (NSCLC). The study involved 138 subjects with suspected lung cancer, 71 of whom had a subsequent diagnosis of NSCLC. The diagnostic power of a combination of hydrogen peroxide (H2O2)-EBC, and exhaled pentane, 2-methyl pentane, hexane, ethyl benzene, heptanal, trans-2-nonenal in distinguishing NSCLC and non-NSCLC subjects was poor-to-fair (area under the curve (AUC) = 0.68), similar to that of smoking history alone (expressed as pack-years, AUC = 0.70); a further improvement was observed when smoking history was combined with exhaled compounds (AUC = 0.80). The diagnostic power was increased in those patients with little or no past smoke exposure (AUC = 0.92) or where past smoke exposure was up to 30 pack-years (AUC = 0.85). Exhaled substances had a good accuracy in discriminating suspected cancerous cases only in those subjects with a modest smoking history (≤ 30 pack-years), but the inclusion of other exhaled biomarkers may increase the overall accuracy, regardless of tobacco smoke.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Resection of giant typical carcinoid tumor with cardiopulmonary bypass support.

Carcinoids, defined as well-differentiated neuroendocrine tumors, are classified as typical or atypical based on their microscopic pathological features. Typical carcinoids have a favorable prognosis after complete resection, with 10-year survival rates of up to 90%. We present the surgical strategy used to achieve a left pneumonectomy and the indications for cardiopulmonary bypass (CPB) support in a patient with a huge typical carcinoid tumor.

A prospective, randomized, blinded comparison between continuous thoracic paravertebral and epidural infusion of 0.2% ropivacaine after lung resection surgery.

BACKGROUND: The aim of this prospective, randomized, blinded study was to compare analgesic efficacy of continuous paravertebral and epidural analgesia for post-thoracotomy pain. METHODS: Forty-two ASA physical status II-III patients undergoing lung resection surgery were randomly allocated to receive post-thoracotomy analgesia with either a thoracic epidural (group EPI, n = 21) or paravertebral (group PVB, n = 21) infusion of 0.2% ropivacaine (infusion rate: 5-10 mL h-1). The degree of pain at rest and during coughing, haemodynamic variables and blood gas analysis were recorded every 12 h for the first 48 h. RESULTS: The area under the curve of the visual analogue pain score during coughing over time was 192 (60-444) cm h-1 in group EPI and 228 (72-456) cm h-1 in group PVB (P = 0.29). Rescue morphine analgesia was required in four patients of group EPI (19%) and five patients of group PVB (23%) (P = 0.99). The PaO2/FiO2 ratio reduced significantly from baseline values in both groups without between-group differences. The median (range) percentage reduction of systolic arterial pressure from baseline was -9 (0 to -9)% in group PVB and -17 (0 to -38)% in group EPI (P = 0.02); while clinically relevant hypotension (systolic arterial pressure decrease >30% of baseline) was observed in four patients of group EPI only (19%) (P = 0.04). Patient satisfaction with the analgesia technique was 8.5 (8-9.8) cm in group EPI and 9 (7.5-10) cm in group PVB (P = 0.65). CONCLUSIONS: Continuous thoracic paravertebral analgesia is as effective as epidural blockade in controlling post-thoracotomy pain, but is associated with less haemodynamic effects.