To explore the efficacy and safety of icotinib with chemotherapy as first-line therapy for advanced lung adenocarcinoma in patients with sensitive epidermal growth factor receptor (EGFR) mutations. Methods: This prospective, randomized, controlled trial was conducted in 10 general hospitals in Shandong Province, China. Previously untreated patients with advanced lung adenocarcinoma and sensitive EGFR mutations were recruited between January 16, 2014 and December 31, 2016 and randomly allocated to the combination group (icotinib plus pemetrexed and carboplatin) or the icotinib only group. The patients were followed up until May 23, 2018. The primary endpoint was progression-free survival (PFS). Results: The efficacy analysis (intention-to-treat analysis) include 179 patients (n = 90 in the combination group and n = 89 in the icotinib only group). PFS was significantly longer in the combination group than in the icotinib only group (16.0 months vs. 10.0 months, hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.42-0.84, P = 0.003). The objective response rate and the disease control rate for the combination group were significantly higher than those for the icotinib only group (77.8% vs. 64.0%, χ 2 = 4.094, P = 0.043; 91.1% vs. 79.8%, χ 2 = 4.632, P = 0.031). However, overall survival did not differ between the two groups (36.0 months vs. 34.0 months, HR = 0.81, 95%CI 0.54-1.22, P = 0.309). The incidence rates of leukopenia and liver function damage of grades 3-4 were higher in the combination group than in the icotinib only group (12.2% vs. 0%, χ 2 = 11.086, P = 0.001; 12.2% vs. 3.5%, χ 2 = 4.488, P = 0.034). However, adverse events were resolved in most patients. Conclusion: Use of the combination of icotinib and chemotherapy as first-line therapy significantly improved the PFS of advanced lung adenocarcinoma patients with sensitive EGFR mutations. Although the combination therapy increased the incidence of leukopenia and liver function damage, the observed adverse events were tolerable and manageable.
The aim of the present study was to investigate the regulatory mechanism of nuclear factor (NF)-κB on polymorphonuclear neutrophil (PMN) accumulation and the inflammatory response in lung tissues with acute respiratory distress syndrome (ARDS), as well as the therapeutic effect of pyrrolidine dithiocarbamate (PDTC). Mouse models of ARDS were established by intraperitoneal injection of lipopolysaccharide (LPS). BALB/c mice were divided into control, LPS and PDTC + LPS groups. The expression of PMN adhesion molecules, CD11b/CD18 and intercellular adhesion molecule-1 (ICAM-1), were detected by immunohistochemistry, while the protein expression levels of NF-κB p65 in the lung tissue were analyzed by western blot analysis. In addition, flow cytometry was used to investigate the apoptosis rate of PMNs in the bronchoalveolar fluid, and the expression levels of interleukin (IL)-1β, IL-8 and tumor necrosis factor (TNF)-α and myeloperoxidase (MPO) activity were also determined. Following an intraperitoneal injection of LPS, alveolar septum rupture, pulmonary interstitial hyperemia and PMN infiltration in the alveolar was observed. The protein expression of p65 in the pulmonary cytoplasm decreased, while the expression of p65 in the nucleus increased. The levels of IL-8, IL-1β and TNF-α increased and the high expression status was maintained for 24 h. As the time increased, CD11b/CD18 and ICAM-1 expression increased, as well as MPO activity, while the apoptosis of PMNs was delayed. Compared with the LPS group, the expression of p65 in the pulmonary cytoplasm and the PMN apoptosis rate increased following PDTC intervention, while the expression of p65 in the nucleus decreased, as well as the expression levels of the cytokines and MPO activity. Therefore, PDTC reduced the production of inflammatory cytokines via the NF-κB pathway, which reduced the activation of PMNs in the lung tissue and promoted PMN apoptosis.
Mechanical loading is known to trigger proliferation of tumor cells. Periostin is a new molecule found to increase in many cancers. To determine how mechanical strain modulates tumor growth and its possible mediation by periostin through TGF-beta1, Lewis lung cancer cells were cultured on flexible-bottomed culture plates and cyclically strained using Flexercell Strain Unit. Real-time RT-PCR was used to quantify periostin and TGF-beta1 mRNA levels at 6, 12, 18, and 24 h of loading. In addition, periostin and TGF-beta1 neutralizing antibodies were added to the medium. We showed that the proliferative ability of Lewis cancer cells was significantly increased by cyclical strain. This change can be blocked by 5 microg/ml of periostin neutralizing antibody. Periostin mRNA increased by 1.1-, 3.2-, 4.7-, and 9.2-fold while TGF-beta1 mRNA increased by 5.3-, 10.3-, 7.1-, and 6.5-fold at 6, 12, 18, and 24 h, respectively. Periostin protein in medium increased after cyclical strain. Expression of periostin mRNA in response to mechanical loading was completely blocked by 2.5 microg/ml of TGF-beta1 neutralizing antibody. In addition, overexpression of periostin in Lewis cells can promote cell proliferation. Our results suggest that periostin is a potent positive regulator of tumor growth in response to mechanical loading and is possibly a downstream factor of TGF-beta1.
Background The aim of this study was to investigate the feasibility of using a combination of apatinib in the treatment of non‐small cell lung cancer. Apatinib is a tyrosine kinase inhibitor which selectivelyacts on vascular endothelial growth factor receptor 2 (VEGFR‐2) and has shown good efficacy in a variety of malignancies, but the drug resistance is fast in single drug therapy. Methods The inhibitory effect of apatinib and other drugs on lung cancer cells was determined by CCK‐8 test in vitro, and the IC50 value was determined. To establish a nude mouse xenograft model, observe the inhibitory effect of apatinib combined with other drugs on lung cancer xenografts in nude mice; immunohistochemical staining of tumor microvessel density and Ki67 expression in transplanted tumor tissues; Western blot analysis of related signaling pathways expression; immunohistochemistry was used to detect tumor microvessel density in other organs and to observe its safety. Results In this study, we found apatinib combined with pemetrexed, the first and third generation of epidermal growth factor receptor tyrosine kinase inhibitor, could synergistically inhibit the proliferation of non‐small cell lung cancer cell (NSCLC) lines, reduce the microvessel density and Ki67 protein levels of three non‐small cell lung cancer xenografts, and enhance anti‐tumor activity by synergistically inhibiting the MAPK‐ERK and PI3K‐AKT‐mTOR signaling pathway. Furthermore, there were no pathological abnormalities in the heart, brain, liver and kidney of each group. Conclusions The efficacy of apatinib combination is better than that of monotherapy, and there is no significant difference in toxicity of important organs, which suggests the feasibility of a combination of apatinib in the treatment of non‐small cell lung cancer.
BackgroundMalignant pleural effusion is a common complication of non‐small cell lung cancer (NSCLC); however, treatment options remain limited. This study evaluated the safety and efficacy of sequential intrapleural therapy with lobaplatin and erythromycin for NSCLC‐mediated malignant pleural effusion.MethodsFifty‐six patients with NSCLC complicated with malignant pleural effusion were recruited for a prospective single‐arm study from December 2014 to 2016; one patient dropped out. In addition to conventional systemic chemotherapy, lobaplatin and erythromycin were intrapleurally injected into subjects. Short and long‐term responses were analyzed. The concentration of ultrafilterable platinum in the pleural effusion and plasma were detected at different time points. Incidences of severe adverse reactions were observed.ResultsIn the 55 evaluable patients, the effective rate of pleural effusion was 81.8% after six weeks of treatment. Six and twelve months after treatment, the effective rates were 60% and 21.8%, respectively, and the one‐year survival rate was 83.6%. The concentrations of lobaplatin in pleural effusion and plasma two hours after injecting 50 mg lobaplatin into the thoracic cavity were 13.763 ± 1.523 μg/mL and 1.120 ± 0.164 μg/mL, and 17 hours later were 1.961 ± 0.351 μg/mL and 0.578 ± 0.095 μg/mL, respectively. The rate of severe adverse reactions of the first cycle of systemic chemotherapy combined with lobaplatin and erythromycin did not significantly differ from the rate in the second cycle.ConclusionIntrapleural combination therapy with lobaplatin and erythromycin is a safe and efficient treatment for patients with NSCLC‐mediated malignant pleural effusion.
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