A Network Meta-analysis Comparing the Efficacy and Safety of Anti-PD-1 with Anti-PD-L1 in Non-small Cell Lung Cancer.

Background: This network meta-analysis aimed at comparing anti-programmed death 1 (anti-PD-1) with anti-programmed death ligand 1(anti-PD-L1) immunotherapy in patients with metastatic, previously treated non-small cell lung cancer (NSCLC) who failed first-line treatment. Methods: We searched electronic databases to identify all eligible clinical trials. End-points included overall survival (OS), progression-free survival (PFS) and objective response. Hazard ratios (HRs) or odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were extracted. Network meta-analysis was performed using the frequentist approach for multiple treatment comparisons. Results: In total, 3024 patients were randomly assigned: 1117 received anti-PD-1 therapy (nivolumab + pembrolizumab), 569 received anti-PD-L1 (atezolizumab) and 1338 received docetaxel. Anti-PD-1 (HR, 0.56; 95% CI, 0.48-0.66) and anti-PD-L1 (HR, 0.64; 95% CI, 0.51-0.79) achieved better OS than docetaxel, and anti-PD-1 was superior to docetaxel in terms of PFS (HR, 0.75; 95% CI, 0.62-0.89). Moreover, anti-PD-1 achieved the highest effect on OS and PFS, with a P-score of 91.2% and 95.5%, respectively. With regard to tumor response, anti-PD-1 group had a higher rate of responders than that in anti-PD-L1 (HR, 0.35; 95% CI, 0.19-0.65) and docetaxel (HR, 0.36; 95% CI, 0.25-0.52) groups. Undoubtedly, anti-PD-1 and anti-PD-L1 obtained less toxicity profile than docetaxel, and no significant difference was observed between anti-PD-1 and anti-PD-L1 groups. Conclusions: Anti-PD-1 may be a better choice for patients with metastatic and previously treated NSCLC who failed first-line treatment in terms of the treatment ranking.

MiRNA-27a promotes the proliferation and invasion of human gastric cancer MGC803 cells by targeting SFRP1 via Wnt/ß-catenin signaling pathway.

This study aims to elucidate the effects of microRNA-27a (miR-27a) on the proliferation and invasion of gastric cancer (GC) cells by targeting SFRP1 via Wnt/ß-catenin signaling pathway. GC and normal adjacent tissues were collected from 273 GC patients. Human gastric cancer cell line (MGC803) and normal human gastric mucosal cell line (GES-1) were cultured. The miR-27a mRNA expression was analyzed using Quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry (IHC) test was used to detect miR-27a and SFRP1 protein expressions. After transfection, cells were divided into five groups: the negative control (NC) group, the miR-27a inhibitor group, the miR-27a mimics group, the miR-27a inhibitor + SFRP1 siRNA group and the miR-27a mimics + SFRP1 overexpression group. Western blotting was conducted to test SFRP1 and Wnt/ß-catenin protein expression. Analysis for the target gene of miR-27a was performed using Luciferase assay. Cell proliferation, migration and invasion were determined by CCK8 and Transwell assay. The dual-luciferase reporter assay system was applied to analyze the effects of miR-27a on Wnt/ß-catenin signaling pathway. In GC tissue and cell line, miR-27a protein and mRNA expressions were up-regulated, and SFRP1 protein and mRNA expressions were down-regulated. Luciferase assay indicated that miR-27a might target SFRP1 and regulate its expressions. When miR-27a was down-regulated, SFRP1 was up-regulated, and ß-catenin, Wnt, p-ß-catenin, and p-Wnt were significantly down-regulated. Compared with the NC group, the proliferation, migration and invasion of GC cells were remarkably increased in the miR-27a group, but these were declined in the miR-27a mimics + SFRP1 overexpression group. The proliferation, migration and invasion of GC cells were elevated in the miR-27a inhibitor + SFRP1 siRNA group compared with the miR-27a inhibitor group. These results showed that miR-27a was highly expressed in GC tissues and cells, and it might promote cell proliferation, migration and invasion by targeting SFRP1 via the activation of Wnt/ß-catenin signaling pathway.

Polymorphism in miR-146a associated with clinical characteristics and outcomes in gastric cancer patients treated with adjuvant oxaliplatin and fluoropyrimidines.

PURPOSE: Polymorphism in miR-146a (rs2910164) has been reported to be associated with gastric cancer risk in the Chinese population. We aimed at evaluating the relationship between rs2910164 and the clinical characteristics and outcomes in stage IB-III gastric cancer patients treated with adjuvant chemotherapy after surgery. MATERIALS AND METHODS: Ninety-eight patients with stage IB-III gastric cancer treated with surgical resection followed by adjuvant chemotherapy of oxaliplatin and fluoropyrimidines were included in the analysis. Genomic DNA was extracted from peripheral blood sample of all patients. Polymerase chain reaction-based restriction fragment length polymorphism assay was used to determine the genotypes. RESULTS: The 2-year disease-free survival rate was 63%, and the 3-year overall survival (OS) rate was 73.4%. In dominant model, we found that rs2910164 GC + CC (G: guanine, C: cytosine) genotype carriers were less likely to develop lymph node metastasis (P=0.059). The 3-year OS was significantly different for patients with or without lymph node metastasis (89.3% vs 63.7%, P=0.015) and for patients with stage I-III disease (100.0%, 88.6%, and 56.9%; P=0.018). The 3-year OS for GC + CC carriers was significantly higher than for GG carriers (75.1% vs 66.7%, P=0.041). After the multivariant Cox regression analysis, histological grade (P=0.033, relative risk: 5.116, 95% confidence interval: 1.145-22.865) and lymph node status (P=0.031, relative risk: 6.648, 95% confidence interval: 1.191-37.118) were found to be independent prognostic factors for these patients. CONCLUSION: rs2910164 could be associated with the lymph node metastasis and prognosis of Chinese gastric cancer patients treated with oxaliplatin and fluoropyrimidines after surgical resection.

Antitumor activity of chloroquine in combination with Cisplatin in human gastric cancer xenografts.

PURPOSE: To investigate the antitumor activity and mechanism of chloroquine (CQ) in combination with cisplatin (DDP) in nude mice xenografted with gastric cancer SGC7901 cells. MATERIALS AND METHODS: 35 cases of gastric cancer patients with malignant ascites were enrolled and intraperitoneal cisplatin injection was performed. Ascites were collected before and 5 days after perfusion for assessment of autophagy levels in cancer cells. In addition, 24 tumor-bearing mice were randomly divided into control, DDP, CQ and CQ + DDP groups. RESULTS: In 54.3% (19/35) of patients the treatment was therapeutically effective (OR), 5 days after peritoneal chemotherapy, 13 patients had the decreased ascites Beclin-1 mRNA levels. In 16 patients who had NR, only 2 cases had decreased Beclin-1 (P=0.001). Compared with the control group, the xenograft growth in nude mice in the DDP group was low, and the inhibition rate was 47.6%. In combination with chloroquine, the inhibition rate increased to 84.7% (P<0.01). The LC3-II/I ratio, and Beclin1 and MDR1/P-gp expression were decreased, while caspase 3 protein levels increased (P<0.05). CONCLUSIONS: Antitumor ability of cisplatin was associated with autophagy activity and chloroquine can enhance chemosensitivity to cisplatin in gastric cancer xenografts nude mice.

Autophagy inhibition sensitizes cisplatin cytotoxicity in human gastric cancer cell line SGC7901.

We aimed to investigate the mechanism and effects of autophagy on cisplatin (DDP)-induced apoptosis in human gastric cancer cell line SGC7901. After SGC7901 cells were treated with DDP and/or chloroquine, cell proliferation was measured using MTT assay; cell apoptosis was determined by flow cytometry; autophagy and apotosis-related proteins expression were detected by Western blot; and quantitative analysis of autophagy after monodansylcadaverine (MDC) staining was performed using fluorescence microscopy. We found after treatment with 5 mg/L DDP for 24 h, the rates of cell apoptosis were (21.07±2.12)%. Autophagy, characterized by an increase in the number of autophagic vesicles and the level of LC3-II protein was observed in cells treated with DDP. After inhibition of autophagy by chloroquine, the rates of cell apoptosis were increased to (30.16±3.54)%, and the level of Caspase-3 and P53 protein were increased, and Bcl-2 protein was decreased. Therefore, autophagy protects human gastric cancer cell line SGC7901 against DDP-induced apoptosis, inhibition of autophagy can promote apoptosis, and combination therapy with DDP and chloroquine may be a promising therapeutic strategy for gastric cancer.

[Relationship between P-glycoprotein function in peripheral blood cells and multidrug resistance in breast carcinoma].

OBJECTIVE: To analyze the relationship between P-glycoprotein function in peripheral blood cells and primary multidrug resistance in breast carcinoma. METHODS: P-gp function was investigated by flow cytometry in NK cells of 16 breast cancer patients treated with anthracyclines and taxanes. Among all the patients, 8 were in chemotherapy-sensitive group and 8 in chemotherapy-resistant group. P-gp function was determined by rhodamine 123 (Rh123)-ejection test. Mathematical model was established by a regression of the fluorescence-time curve. The efflux rate constants of the chemotherapy-sensitive and -resistant groups were compared. RESULTS: There was no significant difference of Rh123 accumulation, retention or efflux between the two groups. The mathematical model of F(t) = F(0) · e(-kt) was established. K was the efflux rate constant, which was significantly different between the chemotherapy-sensitive and -resistant groups (P = 0.025). When k > 3.9 was used as diagnostic criterium for primary resistance, the sensitivity, specificity and accuracy were 75.0%, 100% and 87.5%, respectively. CONCLUSION: P-glycoprotein function in peripheral blood cells is associated with primary multidrug resistance in breast carcinoma. The efflux rate constant may be a good predictor for chemotherapy sensitivity.

[Clinical features and prognostic factors of small breast cancer with multiple axillary lymph node metastasis].

OBJECTIVE: To analyse the clinical features and prognostic factors of small breast cancer patient (T < or =2 cm) with multiple axillary lymph node metastasis (N > or =4). METHODS: The data of 118 small breast cancer patients (T < or =2 cm) with multiple axillary lymph node metastasis (N > or =4) surgically treated from 1993 to 2003 were retrospectively analysed by SPSS 13.0 software. RESULTS: The overall 5-year survival rate was 75.0% in this series. It was found by single-variant Kaplan-Merier analysis that the stage, adjuvant chemotherapy and adjuvant endocrine therapy significantly influenced the outcome of the patients. For patients with 4-9 or > or =10 metastatic axillary lymph nodes, the 5-year OS was 89.5% and 59.8%, respectively (P = 0.009). It was 82.1% and 53.3% in the patients with or without adjuvant chemotherapy (P = 0.001), respectively. For patients with or without adjuvant endocrine therapy, the 5-year OS was 89.2% and 61.9% (P = 0.001). Multi-variant Cox regression analysis showed that the stage, adjuvant chemotherapy and adjuvant endocrine therapy were independent prognostic factors. CONCLUSION: Small breast cancer with multiple axillary lymph node metastasis usually has a tendency of metastasis with a poor prognosis, especially in those with > or =10 metastatic axillary lymph nodes. The stage, adjuvant chemotherapy and adjuvant endocrinetherapy were independent prognostic factors. Reasonable multi-modality therapy may be able to improve the outcome of these patients.