Immune checkpoint inhibitors for the management of advanced non-small-cell lung carcinoma: a meta-analysis.

This study is a meta-analysis assessing the safety and efficacy of programmed cell death-1/cell death-ligand 1 (PD-1/PD-L1) inhibitors in order to improve their efficacy in advanced non-small-cell lung cancer. We retrieved studies of anti-PD-1/PD-L1 therapies for non-small-cell lung cancer from electronic databases; 17 clinical trials were analyzed. The pooled hazard ratios for overall and progression-free survival (PFS), and the odds ratios (ORs) for the objective response rate (ORR) and adverse effects were calculated using Review Manager 5.3. The pooled hazard ratios for overall and PFS were 0.69 and 0.74, respectively, and the pooled OR for the ORR was 1.78, implying a significant improvement in overall survival (OS), PFS, and ORR with administration of PD-1/PD-L1 inhibitors. In subgroup analysis, the ORs of the ORR were 2.48 in PD-L1 positive versus negative tumors, and 0.99 for a high dose of PD-1/PD-L1 inhibitors versus a low dose. The ORs for the occurrence of any treatment-related adverse effects and grades 3-5 treatment-related adverse effects were 0.33 and 0.30, respectively, suggesting a good safety profile. PD-1/PD-L1 immunotherapy has superior outcomes in terms of the ORR, OS, and PFS with tolerable adverse effects when compared with chemotherapy.

Resveratrol Treatment Inhibits Proliferation of and Induces Apoptosis in Human Colon Cancer Cells.

BACKGROUND: Resveratrol, a natural isolate from plant sources, has a long and important history in traditional Chinese medicine. In the present study we investigated the effect of resveratrol on human colon cancer cell lines. MATERIAL/METHODS: We used the Cell Counting kit-8 (CCK-8) for determination of colon cancer cell viability. Apoptosis induction was analyzed using the DeadEnd™ Colorimetric TUNEL System (Promega, Madison, WI, USA). The siRNA Transfection Reagent kit (Santa Cruz Biotechnology, Inc.) was used for the administration of COX-2 silencer RNA (siRNA) into the colon cancer cells. Primer Express® software for Real-Time PCR ver. 3.0 (Applied Biosystems, Foster City, CA, USA) was used to prepare the primers for RT-PCR. RESULTS: The results revealed that exposure of colon cancer cells to resveratrol inhibited cell viability. Resveratrol exhibited a significant inhibitory effect on cell viability at 30 µM concentration after 48 h of exposure. We observed that 30-µM doses of resveratrol for 72 h led to 18, 29, and 34% reduction in the viability of HCA-17, SW480, and HT29 cells, respectively. It also significantly induced apoptosis in both of the tested carcinoma cell lines. The population of apoptotic cells in HCA-17 and SW480 cell lines after 48 h of resveratrol treatment was 59.8±4 and 67.2±4%, respectively, compared to 2.3±1% in the control cells. The colon cancer cells exposed to resveratrol showed significantly lower cyclooxygenase-2 and prostaglandin receptor expression. Treatment of colon cancer cells with the inhibitor of cyclooxygenase-2, indomethacin, and administration of silencer RNA for cyclooxygenase-2 also produced similar results. CONCLUSIONS: These findings suggest that resveratrol treatment can be a promising strategy for the treatment of colon cancer.

Over-expression of Orai1 mediates cell proliferation and associates with poor prognosis in human non-small cell lung carcinoma.

Orai1 and STIM1 mediate calcium release-activated calcium current (CRAC) which is the best characterized store-operated calcium current involving in a wide range of cell progresses, such as cell proliferation, metastasis, apoptosis. Orai1 has been studied as a carcinogenic biomarker in some cancers such as esophageal cancer. However, its function and clinical significance in non-small cell lung cancer (NSCLC) have not been well studied. The present study was aimed at discussing the relationship between Orai1 and lung cancer malignant behavior with its clinical significance. We used quantitative real-time-PCR and Western blot to detect the expression of Orai1 in NSCLC cell lines and fresh cancer tissues. Immunohistochemistry were performed to test the location and expression of Orai1 in paraffin sections. We found that Orai1 was markedly overexpressed in both NSCLC cell lines and fresh cancer tissues. Immunohistochemistry data also revealed that overexpression of Orai1 was present in 42.4% of NSCLC tissues, compared with the corresponding adjacent nontumorous tissues. Furthermore, NSCLC patients with high Orai1 expression survived shorter than those with low Orai1 expression. In addition, when knockdown Orai1 by RNAi technic, we found the PI3k/AKT/ERK pathway was inhibited which may indicated that Orai1 could influence cell proliferation. Taken together, our study demonstrated that Orai1 was remarkably overexpressed in NSCLC and could be served as a potential prognostic marker for patients with this deadly disease.

Analyzing the differentially expressed genes and pathway cross-talk in aggressive breast cancer.

AIM: The aim of this study was to explore the genes and pathways involved in the aggressive breast cancer cells. METHODS: The gene expression profiles of GSE40057, including four aggressive breast cell lines and six less aggressive cell lines, were downloaded from the Gene Expression Omnibus (GEO) database. The gene differential expression analysis was carried out with limma software with the method of Bayes for multiple tests. The gene ontology (GO) term enrichment and pathway cross-talk analysis were performed with the online tool of DAVID and Cytoscape software. RESULTS: A total of 401 differentially expressed genes (DEG), such as pentraxin 3 (PTX3), snail family zinc finger 2 (SNAI2), interleukin-8/6 (IL-8/6), osteonectin (SPARC), matrix metallopeptidase-1 (MMP-1) and Ras-related protein Rab-25 (Rab 25), were identified between aggressive and less aggressive cell lines. They were mainly enriched in the GO terms of response to wounding, negative regulation of cell proliferation and calcium binding. Pathways in cancer dysfunctionally interacted with glyoxylate and dicarboxylate metabolism (P < 0.0001), basal transcription factors (P < 0.0001), tyrosine metabolism (P < 0.0001), calcium signaling pathway (P = 0.0021), FcγR-mediated phagocytosis (P = 0.0022), metabolism of xenobiotics by cytochrome P450 (P = 0.0097) and phagosome (P = 0.0102). CONCLUSION: The screened aggressive cancer-associated DEG (PTX3, SNAI2, IL-8/6, SPARC, MMP-1 and Rab25) and significant pathways (calcium signaling pathway, tyrosine metabolism, alanine, aspartate and glutamate metabolism) give us new insights into the mechanism of aggressive breast cancer cells, and these DEG may become promising target genes in the treatment of metastatic breast cancer.

Phase II trial of low-dose gemcitabine in prolonged infusion and cisplatin for advanced non-small cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of the combination of gemcitabine at a low dose of 250 mg/m(2) in 6h prolonged infusion with cisplatin in chemonaive patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-eight chemonaive patients with stage IIIB or IV NSCLC were included, 39 males and 19 females, with a median age 61 years (range 28-73). Thirty-four (58.6%) patients had adenocarcinoma, 18 (31.0%) squamous cell, and 6 (10.4%) others. Seventeen (29.3%) had stage IIIB and 41 (70.7%) stage IV. Treatment consisted of 250 mg/m(2) gemcitabine in a 6h infusion on days 1 and 8, and cisplatin at 75 mg/m(2) on day 2 of a 3-week cycle. A total of 219 chemotherapy cycles were administered, with a median of 4 cycles per patient (range 1-6). RESULTS: Of the 58 patients enrolled, all were evaluated for toxicity and 56 assessed for response. The overall response rate was 39.3% (95% confidence interval, 26.5-52.1%) with complete and partial responses of 3.6 and 35.7%, respectively. The median time to disease progression was 5.5 months (95% CI, 4.3-6.7 months), and median overall survival time was 10.5 months (95% CI, 8.5-12.5 months). One-year survival rate was 41.4%. Hematologic toxicity was fairly mild, and grades 3-4 hematologic toxicities consisted of neutropenia in 18.9% of patients, thrombocytopenia in 10.3%, and anemia in 6.9%. No patients required platelet transfusions, no bleeding episodes were recorded, and three patients received packed red blood cells (RBC) transfusions. The main nonhematologic toxicities included grade 3 nausea/vomiting in 27.6% of patients, grade 1-2 alopecia in 63.8%, and grade 1-2 skin rash in 17.3 %. CONCLUSIONS: Low-dose gemcitabine in 6h prolonged infusion plus cisplatin is effective in NSCLC treatment. Toxicity, especially myelosuppression, is remarkably mild.

A phase II trial of modified FOLFOX as first-line chemotherapy in advanced colorectal cancer.

The objective was to evaluate the efficacy and toxicity of leucovorin plus 5-fluorouracil combined with oxaliplatin (modified FOLFOX regimen) every 2 weeks on previously untreated advanced colorectal cancer patients in the Chinese population. Fifty-one inpatients were enrolled to receive 85 mg/m oxaliplatin intravenously over a 2- h period on day 1, together with 400 mg/m2 leucovorin over 2- h, followed by a 46-h infusion of 5-fluorouracil at 2600 mg/m2 every 2 weeks. Treatment was given until progression or unmanageable toxicity ensued. In all, 51 patients received three or more oxaliplatin doses and a median of nine treatment cycles (range 3-16 cycles). Of the 51 eligible patients, two complete responses and 22 partial responses were observed for an overall response rate of 47.0% (95% confidence interval 35-64%). Median progression-free survival was 7.7 months (95% confidence interval 6.8-8.6) and median overall survival was 15.0 months (95% confidence interval 13.1-16.9). Toxicities were mild: five patients (9.8%) reported grade 3-4 neutropenia, 33 patients (64.8%) experienced grade 1-3 neurotoxicity and only six patients (11.8%) experienced grade 3 neurotoxicity. The leucovorin plus 5-fluorouracil combined with oxaliplatin (modified FOLFOX) regimen is active and well tolerated in patients with previously untreated advanced colorectal cancer in the Chinese population.

[Phase II trial of prolonged infusion of low-dose gemcitabine in advanced non-small cell lung cancer treatment].

BACKGROUND & OBJECTIVE: Gemcitabine combined with cisplatin has been taken as the front-line regimen for patients with advanced non-small-cell lung cancer (NSCLC). The routine use of gemcitabine is intravenous injection of a dose of 1,000 mg/m(2) within 30 minutes on days 1 and 8, and the treatment is repeated every 3 weeks. This study was to evaluate the efficacy and safety of 6-hour continuous infusion of low dose of gemcitabine plus cisplatin for patients with advanced NSCLC. METHODS: Forty-eight patients with measurable stage III B/IV NSCLC and without chemotherapy were enrolled. All of them received 6-hour continuous infusion of gemcitabine 250 mg/m(2) on day 1 and 8 plus cisplatin 75 mg/m(2) on day 2-4 for more than 2 cycles. The cycle was repeated every 3 weeks. RESULTS: All 48 patients were evaluated for toxicity and 46 for response. The overall response rate was 32.5% (completed and partial response rates were 2.2% and 30.3%, respectively). The median time to progression was 5.1 months, median survival time was 10.2 months; and 1-year survival rate was 36.6%. The main hematologic toxicity consisted of 60.4% neutropenia, 39.5% thrombocytopenia. Grade III-IV neutropenia and thrombocytopenia were 20.8% and 12.5%, respectively. CONCLUSION: Six-hour prolonged infusion of low dose gemcitabine combined with cisplatin is a relatively safe and effective regimen for patients with advanced NSCLC.