| Objective:In clinical practice, synchronous multiple primary non-small cell lung cancer (NSCLC) is increasing year by year as a result of the worldwide use of high resolution imaging systems. However, due to the small sample of study patients and the difference in the inclusion criteria or baseline patients’characteristics, it is difficult to draw solid conclusions that can be widely used to evaluate prognoses in patients with synchronous multiple primary NSCLC. The aim of this study is to explore the clinical characteristics of patients with synchronous multiple primary NSCLC and investigate the prognostic values of various clinical parameters for long-term survival with the modified diagnosis criteria and largest cohort of patients.Method:From January 2010 to December 2014, data for 290 synchronous multiple primary NSCLC patients who met the modified Martini-Melamed criteria and underwent radical surgical resection at the Department of Thoracic surgery, Cancer Hospital, Chinese Academy of Medical Sciences were retrospectively reviewed. A total of 285 patients were included in this study. All the tumors were radically resected and had the final pathological diagnosis. The Kaplan-Meier method were used for survival analysis including disease-free survival (DFS) and overall survival (OS), and the clinical parameters associated with survival were analyzed using a log-rank test. Multivariate analysis using the Cox proportional hazards regression models was used for risk factors evaluation.Results:A total of 285 patients were analyzed (5 were excluded from data analysis). Among them,234 (82.1%) had 2 tumors and 51 (17.9%) had 3 or more tumors; 94 (33.0%) patients had bilateral tumors. For all patients, the DFS rates were 90.1%at 1 year,68.5% at 3 years, and 58.7% at 5 years; the OS rates were 92.7% at 1 year,81.6% at 3 years, and 77.6% at 5 years, respectively. Univariate analysis identified parameters conferring shorter OS including male gender, symptomatic disease, negative family history, large maximal tumor size, not all adenocarcinomas, advanced highest T stage, and lymph node involvement. Multivariate analysis showed that male gender (p=0.020), symptomatic disease (p=0.017), and lymph node involvement (p<0.001) were independent adverse prognosticators. For patients with multiple adenocarcinomas, the DFS rates were 85.0% at 1 year,71.7% at 3 years, and 59.6% at 5 years; the OS rates were 95.5% at 1 year,85.2% at 3 years, and 82.4% at 5 years, respectively. The subtypes other than lepidic predominant (p<0.001) and lymph node involvement (p=0.002) were the independent unfavorable prognosticators. For patients with bilateral synchronous multiple primary NSCLC, the DFS rates were 87.4% at 1 year,70.8% at 3 years, and 58.1% at 5 years; the OS rates were 97.6% at 1 year,89.0% at 3 years, and 82.7% at 5 years. Multivariate analysis showed that highest pT stage (p=0.006) and lymph node metastasis (p=0.008) were independent prognosticators of survival. For patients with positive lymph node involvement, the DFS rates were 59.8% at 1 year,61.6% at 3 years, and 17.3% at 5 years; the OS rates were 82.1% at 1 year,63.6% at 3 years, and 56.5% at 5 years, respectively. No postoperative adjuvant chemotherapy (p=0.019) affected the OS unfavorably.Conclusion:The diagnosis for the patients with synchronous multiple primary lesions should be very careful in order to avoid the misdiagnosis as a metastatic diseases. Patients with synchronous multiple primary NSCLCs would be benefit from surgery with relatively high survival rate on the basis of principle of safety and radical resection. Lymph node status is the important predictor for long-term survival, and thus adequate pulmonary tissue resection with systemaic lymphadenectomy is suggested in order to investigate the prognosis. The identified prognosticators will provide valuable clues for the postoperative management of patients with synchronous multiple primary NSCLC.Objective:Cancer has become the leading cause of death at present and endangered human health seriously. As to the problem of poor selectivity, side effects and drug resistance for the traditional anti-cancer drugs, it is still not the ideal treatment method for chemotherapy. Therefore, to find chemotherapy drugs with strong specificity and less side effects is urgent and valuable for the treatment of cancer. Natural plants have become the hot spot of the anti-cancer drugs. In the present study, we detected and preliminary evaluated the anti-tumor activity of four compounds isolated from plant.Methods:Four kinds of ent kaurane diterpenoids exacted from Isodon (PH12, PH15, PH17 and PH27) were studied in the present study. The anti-proliferation effects of these 4 compounds on esophageal squamous cell carcinoma (ESCC) and lung cancer cells were detected using CCK8 assay. Moreover, the proliferation curves and IC50 value of PH17 on ESCC cells (KYSE30 and KYSE450) and lung cancer cells (A549 and H1299) were analyzed.In addition, the effect of PHI 7 on cell cycle and apoptosis were detected using flow cytometry.Results:Firstly, we analyzed the proliferation inhibition rate of 4 compound (PH12, PH15, PH17 and PH27 at concentration of 5μM) on 7 ESCC cell lines and 7 lung cancer cell lines for 72 hours. The results showed that, among these 4 compounds, PH17 has the strongest inhibitory activity. Next, we treated ESCC cells (KYSE30 and KYSE450) and lung cancer cells (A549 and H1299) by 9 different concentration of PH17, and detected cell viability using CCK8 assay after treatment for 12,24,48 and 72 hours, then the proliferation curve were drawed and IC50 value of 72 hours were calculated. The results showed that the different concentration of PH17 exhibited markedly inhibitory activity after treatment for 48 hours. The 72-hour IC50 value of PH17 on 4 cell lines were as follows:KYSE301.40μM, KYSE450 1.35μM, A549 2.20μM, H1299 0.54μM, and the 72-hour IC50 value of PHI 7 for human non-tumor cell line NIH3T3 and HEK293 were 1.13μM and 0.95μM respectively. In addition, we detected the effect of PH17 on cell cycle of ESCC and lung cancer cells. The results showed that high concentration of PH17 (5μM or 8μM) led to significantly decrease of G0/G1 and S phase cells and increase of G2/M phase cells compared with low concentration of PHI 7 (2μM or 4μM), which indicated that PH17 induced the cell cycle G2/M arrest in ESCC and lung cancer cells. At the same time, we detected the effects of PH17 on apoptosis of ESCC and lung cancer cells. The results showed that high concentration of PH17 (5μM or 8μM) led to significantly increase of cell apoptosis compared with low concentration of PHI 7 (2μM or 4μM), and 48-hours treatment led to significantly increase of late apoptosis cells, which indicated that PHI 7 induced cell apoptosis in ESCC and lung cancer cells.Conclusions:The present study demonstrated that ent kaurane diterpenoids PH17 had powerful proliferation inhibition activity on ESCC and lung cancer cells, and this proliferation inhibition activity was achieved by inducing cell cycle G2/M arrest and increased apoptosis. These results provided the basis for further mechanism investigation and in vivo study. |
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