Influence of VEGFR2 gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy-refractory extensive-stage SCLC: a real-world retrospective study.

PURPOSE: Great individual differences were observed regarding the efficacy of apatinib clinically. The aim of present study was to investigate the influence of vascular endothelial growth factor receptor2 (VEGFR2) gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy-refractory extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 128 patients with chemotherapy-refractory ES-SCLC who were treated with apatinib at an initial dosage of 250 or 500 mg were included in this study. The change of target lesions was assessed. Overall response rate (ORR) was evaluated. Prognosis was carried out and safety profile was documented. Additionally, peripheral blood and biopsy cancer tissue specimens of the patients with SCLC were collected for the analysis of polymorphism and VEGFR2 gene mRNA expression, respectively. The association between genotype status and baseline characteristics was performed. Univariate analysis of genotype status and prognosis was carried out using Kaplan-Meier survival analysis and multivariate analysis were adjusted by Cox regression analysis. RESULTS: Efficacy of apatinib included partial response (PR) in 15 patients, stable disease (SD) in 86 patients, progressive disease (PD) in 27 patients. Therefore, ORR of the 128 patients with ES-SCLC was 11.7%, and disease control rate (DCR) was 78.9%. Prognosis suggested that the median progression-free survival (PFS) and overall survival (OS) of the 128 patients with ES-SCLC was 4.2 months and 8.2 months, respectively. The polymorphism analysis focusing on VEGFR2 gene indicated that one single nucleotide polymorphism 889C>T was of clinical significance. Prevalence of 889C>T among the 128 patients with SCLC were as follows: CC genotype 87 cases (68.0%), CT genotype 38 cases (29.7%) and TT genotype 3 cases (2.3%), the minor allele frequency of 889C>T was 0.17, which was in accordance with Hardy-Weinberg Equilibrium (P = 0.628). Patients with CT and TT genotypes were merged in the subsequent analysis. Prognosis analysis exhibited that the median PFS of patients with CT/TT genotype and CC genotype was 3.3 and 5.0 months, respectively (P = 0.02). Furthermore, the median OS of patients was 5.5 and 9.0 months, respectively (P = 0.008). Additionally, multivariate Cox regression analysis of OS demonstrated that CT/TT genotype was an independent factor for OS [Hazard ratio (HR) = 0.64, P = 0.019]. However, the safety profile according to genotype status of 889C>T failed to show significant difference. Interestingly, mRNA expression analysis suggested that the mRNA expression of VEGFR2 in cancer tissues were significantly different according to CC and CT/TT genotypes (P < 0.001). CONCLUSION: The administration with apatinib for patients with chemotherapy-refractory ES-SCLC was of potential clinical significance. The clinical outcomes of patients with ES-SCLC who were treated with apatinib could be impacted by VEGFR2 889C>T polymorphism through mediating the VEGFR2 mRNA expression.

The role of autoantibody detection in the diagnosis and staging of lung cancer.

BACKGROUND: Previously, the clinical value of seven autoantibodies (p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGEA1, and CAGE) has been surveyed in our pilot observation and other published studies. Herein, we aimed to further investigate the role of these autoantibodies in the diagnosis and staging of LC. METHODS: We included a total of 135 individuals, who were divided into a Lung cancer (LC) group and a control group according to the final diagnosis. Seven autoantibody detection kits were used (ELISA method) for the expression measurement. The patients' demographics information (e.g., age, gender, and smoking history) were also documented. RESULTS: Among the seven types of autoantibodies, only P53 and GBU4-5 were significantly increased in the LC group compared to the controls. Also, the P53 autoantibody was markedly different among the various subtype groups. Meanwhile, the GBU4-5 level was significantly higher in the small cell lung cancer (SCLC) patients compared to patients with adenocarcinoma (ADC). Autoantibodies against PGP9.5, SOX2, GBU4-5, and CAGE were found to be associated with stages. Their expressions were notably higher in the advanced stage (IV) versus early stages (I-II). Using logistic regression, the outcomes of LC prediction and stage prediction showed that the area under curve (AUCs) of the receiver operating characteristic (ROC) curves were 0.743 and 0.798, respectively. CONCLUSIONS: In summary, our study confirmed the diagnostic value of tumor-associated autoantibodies, which may be useful as latent tumor markers to facilitate the detection of early LC. Single autoantibody testing is not yet sufficient in LC cancer screening, and the combined detection of autoantibodies can improve the sensitivity of detection compared with single antibody detection, especially for P53, PGP9.5, SOX2, GBU4-5, and CAGE autoantibodies.

Icotinib as Adjuvant Treatment for Stage II-IIIA Lung Adenocarcinoma Patients with EGFR Mutation (ICWIP Study): Study Protocol for a Randomised Controlled Trial.

The efficacy and possible role of epidermal growth factor receptor tyrosine kinase inhibitors in treating early-stage non-small-cell lung cancer have yet to be established. Therefore, we aimed to explore the efficacy and safety of icotinib in completely resected EGFR-mutant stage II-IIIA lung adenocarcinoma patients who underwent standard chemotherapy. This is a randomised, double-blinded, placebo-controlled, multicentre, Phase III trial. A total of 124 patients aged 18-75 years who qualified the inclusion criteria were recruited. These patients were randomised (1:1) to receive either icotinib (125 mg 3 times per day) or placebo (the same dosage and frequency) for 36 months, followed by a further 36 months of observational window. The primary endpoint is disease-free survival (DFS), while the secondary endpoints are overall survival, 3-year and 5-year DFS, safety and tolerability of the medication, and health-related quality-of-life. Analyses will be conducted in a full analysis set and a per-protocol set as well. To our knowledge, the present study is the first randomised, double-blinded, placebo-controlled, multicenter trial designed to explore efficacy and safety of icotonib in this population. The results obtained in the near future may provide potential guidance in clinical practice. Trial Registration: This trial was registered on www.ClinicalTrail.gov as NCT02125240.

MicroRNA­145 inhibits migration and induces apoptosis in human non­small cell lung cancer cells through regulation of the EGFR/PI3K/AKT signaling pathway.

In the present study, the therapeutic effects and the underlying molecular mechanisms of microRNA (miR)­145 were investigated in non­small cell lung cancer (NSCLC) cells. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was performed to examine miR­145 expression. An MTT assay and flow cytometry were used to investigate cell proliferation and apoptosis, respectively. The protein expression of Bax, epidermal growth factor receptor (EGFR), phosphatidylinositol 3­kinase (PI3K) and phosphorylated­protein kinase B (AKT) was examined by western blot analysis. miR­145 expression was downregulated in patients with NSCLC who were treated with chemotherapy. The downregulation of miR­145 in A549 cells reduced lactate dehydrogenase (LDH) expression, apoptosis, caspase­3/-9 levels and Bax protein expression, while it increased cell proliferation. Upregulation of miR­145 in A459 cells increased LDH, apoptosis, caspase­3/-9 levels and Bax protein expression, while it inhibited cell proliferation. The EGFR/PI3K/AKT signaling pathway was suppressed by miR­145 upregulation in A549 cells and induced by miR­145 downregulation. The EGFR inhibitor suppressed the EGFR/PI3K/AKT signaling pathway and increased the anticancer effects of miR­145 upregulation in A549 cells. The PI3K inhibitor suppressed the PI3K/AKT signaling pathway and reversed the anticancer effects of miR­145 upregulation in A549 cells. In conclusion, the present study demonstrated that miR­145 regulates the EGFR/PI3K/AKT signaling pathway in patients with NSCLC.

Over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced non-small cell lung cancer cells through PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR.

The present study determined the anticancer activity and its mechanism of microRNA­133b on cell proliferation of cisplatin-induced non-small cell lung cancer cells. The expression of microRNA-133b cisplatin­induced non-small cell lung cancer (NSCLC) tissue was lower than that of para-carcinoma tissue in patients. Overall survival of higher expression in cisplatin-induced NSCLC patients was higher than that of lower expression in cisplatin­induced NSCLC patients. Over-regulation of microRNA-133b inhibited cell proliferation and LDH activity, induced apoptosis and caspase-3 activity, suppressed the protein expression of EGFR, PI3K, p-Akt, p-JAK2 and p-STAT3, decreased cyclin D1 and increased Bax protein expression in cisplatin­induced A549 cells. EGFR inhibitor (lapatinib) suppressed EGFR protein expression, inhibited cell proliferation and LDH activity, and induced apoptosis and caspase-3 activity in cisplatin-induced A549 cells by over-regulation of microRNA-133b. When EGFR protein expression was suppressed, PI3K, p-Akt, p-JAK2 and p-STAT3, decreased cyclin D1 and increased Bax protein expression in cisplatin-induced A549 cells by over-regulation of microRNA-133b. Altogether, our results indicated that over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced NSCLC by PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR.

MicroRNA-148b is down-regulated in non-small cell lung cancer and associated with poor survival.

BACKGROUND: The aim of this study was to clarify the clinicopathological significance of miRNA-148b (miR-148b) expression in NSCLC, and to explore the correlation between miR-148b level and the prognosis of patients with NSCLC. METHODS: 151 patients diagnosed with NSCLC between May 2007 and April 2012 were included in the present study. Real-time RT-PCR method was used to assess the expression levels of miR-148b. The differences between two groups were assessed using Student's t -test, and the Kaplan-Meier method was used to estimate overall survival. RESULTS: The expression of miR-148b was decreased in tumor tissues compared to corresponding adjacent normal lung tissues (0.37 ± 0.12 vs. 1.00 ± 0.53, P < 0.05). Low miR-148b expression was significantly associated with TNM stage (P = 0.014), lymph node metastasis (P = 0.031), and distant metastasis (P = 0.008). Kaplan-Meier survival analysis showed that patients with low expression of miR-148b had significantly worse overall survival rates compared with those who had cancers with high miR-148b expression (log-rank test P = 0.039). Furthermore, multivariate Cox proportional hazards model analysis showed that miR-148b expression was independently associated with overall survival of patients with NSCLC (HR = 2.357, 95% CI: 1.612-9.212, P = 0.011). CONCLUSION: our data indicate that decreased expression of miR-148b in NSCLC tissues has prognostic value.

[Efficacy and safety of rh-endostatin combined with docetaxel in second-line or intolerant toxicity for first-line treatment in patients with advanced non-small cell lung cancer].

OBJECTIVE: To analyze the efficacy and safety of combination of rh-endostatin (Endostar) with docetaxel treatment on patients of non-small cell lung cancer (NSCLC) who presented PD or intolerable toxicity in/after first-line chemotherapy. METHODS: A randomized, double-blind, placebo-controlled and multi-center clinical trial was conducted. Patients with stage IIIB/IV of NSCLC experienced previous chemotherapy of one-regimen were screened for this trial. A total of 68 cases were included in this study. Single docetaxel and that combined with endostar were conducted in two arms. The response, time to progression (TTP) and adverse effects were observed in both arms. RESULTS: The objective response rate (ORR) and clinical benefit rate (CBR) were 0 and 62.5% in the combined arm, along with 0 and 53.3% in the single docetaxel arm, with a non-significant difference between the two groups (all P > 0.05), respectively. The median TTPs in the combined and single docetaxel arms were 2.63 and 2.07 months, respectively (P = 0.079). The median TTPs of the participants with progressive disease (PD) after first-line chemotherapy were 1.33 and 1.67 months in the combined and single docetaxel arms, respectively (P = 0.946). The median TTPs of the participants with intolerant adverse effects in first-line chemotherapy were 4.70 months and 3.17 months in the combined and single docetaxel arms, respectively (P = 0.070). The median TTPs of the patients with SD after 2 therapeutic cycles in the combined and single docetaxel arms were 6.23 months and 3.27 months, respectively (P = 0.040). The differences between two arms were non-significant in adverse, serious adverse and cardiovascular adverse effects (all P > 0.05). CONCLUSIONS: Endostar may prolong TTP in patients with advanced NSCLC benefited from docetaxel treatment without increased toxicities.

[Effects of hydrogen sulfide on pulmonary surfactant in rats with acute lung injury induced by lipopolysccharide].

OBJECTIVE: To observe the changes of pulmonary surfactant (PS) in rats with acute lung injury(ALI) induced by lipopolysaccharide (LPS) and to explore the effects of hydrogen sulfide (H2S) on PS. METHODS: Fourty- eight male rats were randomly divided into six groups (n = 8). They were control group, LPS group, LPS+ NaHS low, middle, high dose groups and LPS+ PPG group. Saline was administrated in Control group. LPS was administrated in LPS group. In LPS + NaHS low, middle, high dose groups or LPS + PPG group, sodium hydrosulfide (NaHS) of different doses or DL-propargylglycine (PPG) were respectively administrated when the rats were administrated of LPS after 3 hours. All the rats were killed at 6 hours after administration of Saline or LPS. The morphological changes of alveolar epithelial type II cells (AEC-II) were respectively observed by transmission electron microscopes. The content of H2S in plasma and activity of cystathionine-gamma-lyase (CSE) in lung tissues were respectively detected. The contents of total protein (TP) and total phospholipids (TPL) in bronchoalveolar lavage fluid (BLAF) were respectively measured. The pulmonary surfactant protein A (SP-A), surfactant protein B (SP-B) and surfactant protein-C (SP-C) mRNA expressions in lung tissues were analysed. RESULTS: (1) Compared with control group, the content of H2S in plasma, activity of CSE, content of TPL, and SP-A, SP-B and SP-C mRNA expressions were respectively decreased in LPS group (P < 0.05 or P < 0.01). But the content of TP was increased in LPS group (P < 0.01); (2) Compared with LPS group, the content of H2S, activity of CSE and SP-A mRNA expression were significantly increased in LPS + NaHS low, middle and high dose groups (P < 0.05). The SP-B mRNA expression and content of TPL were significantly increased in LPS + NaHS Middle and High dose groups (P < 0.05). The content of TP was decreased in LPS + NaHS High dose group (P < 0.05). The SP-C mRNA expression was not altered in LPS+ NaHS low, middle and high dose groups (P > 0.05); (3) Compared with LPS group, the content of H2S, activity of CSE, content of TPL, and SP-A, SP-B and SP-C mRNA expressions were respectively decreased, but content of TP was increased in LPS + PPG group (P < 0.05). CONCUSION: The decrease of PS is the important physiopathologic process of ALI induced by LPS. Exogenously applied H2S could attenuate the process of ALI that possibly because H2S could adjust the compose and secretion of PS.

[The interleukin-6 level in exhaled breath condensate of patients with obstructive sleep apnea-hypopnea syndrome].

OBJECTIVE: To explore whether the airway inflammation marker in exhaled breath condensate is increased in obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: Thirty-one patients with OSAHS (15 smokers and 16 non-smokers) and 10 healthy age-matched and weight-matched controls were included in the study. Exhaled breath condensate (EBC) was collected before and after sleep at the same night from both groups. Interleukin-6 (IL-6) in EBC was measured by a specific enzyme immunoassay. RESULTS: (1) There was no difference in the pre-sleep IL-6 level among OSAHS smoker group, OSAHS non-smoker group and the control subjects (F = 0.515, P > 0.05). Compared with the level of pre-sleep [(2.5 +/- 1.0) ng/L in OSAHS smoker, and (2.3 +/- 0.8) ng/L in OSAHS non-smoker], the post-sleep level of IL-6 was elevated significantly in EBC from OSAHS patients of non-smokers [(3.1 +/- 1.2) ng/L] and smokers [(3.7 +/- 1.9) ng/L, P < 0.05]. Nevertheless, IL-6 level from the control group showed a reverse change. IL-6 was decreased significantly [(2.0 +/- 0.8) ng/L in pre-sleep vs (2.7 +/- 1.0) ng/L in post-sleep] after sleep in this group. There was no difference in post-sleep IL-6 level between OSAHS smokers [(3.7 +/- 1.9) ng/L] and non-smokers [(3.1 +/- 1.2) ng/L, P > 0.05]. A significant higher IL-6 level was observed in both OSAHS smokers [(3.7 +/- 1.9) ng/L] and non-smokers [(3.1 +/- 1.2) ng/L] compared with the controlled group [(2.0 +/- 0.8) ng/L, P < 0.05]. IL-6 level in EBC was correlated positively with AHI (r = 0.441, P < 0.05), ODI(4) (r = 0.533, P < 0.05), and negatively with minimal oxygen saturation (r = -0.529, P < 0.05). CONCLUSIONS: These findings suggest that inflammation was characteristic in the airways of OSAHS patients. Nocturnal hypoxia could be responsible for this change. The levels of IL-6 in EBC are associated with the severity of OSAHS and may prove to be useful in monitoring of airway inflammation in OSAHS.