The impact of primary tumor location on efficacy of cetuximab in metastatic colorectal cancer patients with different Kras status: a systematic review and meta-analysis.

OBJECTIVE: To assess the prognostic role of primary tumor location along with Kras status in metastatic colorectal cancer (mCRCs) treated with cetuximab. MATERIALS AND METHODS: Databases of EMBASE, Pubmed, the Cochrane library, China National Knowledge Infrastructure and other databases from inception to July 2016 were searched. Randomized controlled trial (RCT) and/or retrospective studies of influence of primary tumor location on efficacy of cetuximab in patients with mCRC were identified. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR) and disease control rate (DCR). RESULTS: Ten studies including 2977 cases were finally included. The results of meta-analysis were in favor of cetuximab to patients with left-sided colorectal cancer in terms of OS (HR = 0.52, 95% CI: 0.40-0.66; p < 0.01), PFS (HR = 0.64, 95% CI: 0.58-0.70; p < 0.01), and ORR (OR = 2.17, 95% CI: 1.57-2.99; p < 0.01). Patients with right-sided CRC gained less benefit from cetuximab in terms of OS (HR = 1.89, 95% CI: 1.43-2.50; p < 0.01), compared with left-sided CRC. Regarding Kras status, left-sided mCRC with wild type Kras had better PFS (HR = 0.61, 95% CI: 0.51-0.74; p < 0.01) and OS (HR = 0.49, 95% CI: 0.35-0.69; p < 0.01) than right-sided cases when treated with cetuximab. We also found that cetuximab was both significantly effective in different treatment lines and regions when comparing by primary tumor locations (p < 0.01). CONCLUSIONS: mCRC Patients with left-sided, wild type Kras have a better prognosis than those with right-sided diseases when treated with cetuximab. The clinical application of cetuximab should be determined by the primary tumor location and molecular gene mutation status.

Autophagic cell death induced by reactive oxygen species is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells.

AIM: To investigate whether autophagic cell death is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells, and to explore the underlying mechanism. METHODS: Human hepatocellular carcinoma cells were treated with hyperthermia and ionizing radiation. MTT and clonogenic assays were performed to determine cell survival. Cell autophagy was detected using acridine orange staining and flow cytometric analysis, and the expression of autophagy-associated proteins, LC3 and p62, was determined by Western blot analysis. Intracellular reactive oxygen species (ROS) were quantified using the fluorescent probe DCFH-DA. RESULTS: Treatment with hyperthermia and ionizing radiation significantly decreased cell viability and surviving fraction as compared with hyperthermia or ionizing radiation alone. Cell autophagy was significantly increased after ionizing radiation combined with hyperthermia treatment, as evidenced by increased formation of acidic vesicular organelles, increased expression of LC3II and decreased expression of p62. Intracellular ROS were also increased after combined treatment with hyperthermia and ionizing radiation. Pretreatment with N-acetylcysteine, an ROS scavenger, markedly inhibited the cytotoxicity and cell autophagy induced by hyperthermia and ionizing radiation. CONCLUSION: Autophagic cell death is involved in hyperthermic sensitization of cancer cells to ionizing radiation, and its induction may be due to the increased intracellular ROS.

Therapeutic role of glutamine in management of radiation enteritis: a meta-analysis of 13 randomized controlled trials.

OBJECTIVE: To systematically evaluate the clinical efficacy of glutamine in treating radiation enteritis in cancer patients treated with radiotherapy. METHODS: Electronic databases including Pubmed, Embase, the Cochrane library, and CNKI were systematically searched, until April 2016. Randomized controlled trials (RCT) of glutamine in the treatment of radiation enteritis in cancer patients were searched, and RevMan 5.3 software was used for Meta-analysis. RESULTS: A total of 13 RCTs were included, involving 979 patients. The results of meta-analysis showed that the total efficacy of glutamine was higher for patients with radiation enteritis compared with that in control group, however, there was no statistically significant difference(OR = 3.07, 95%CI: 0.79-11.96; P > 0.05). The combined ORs for all 5 grades(from grade 0 to grade 4) of radiation enteritis in patients receiving glutamine were 2.06, 1.35, 0.55, 0.62 and 0.59, respectively(P > 0.05 for all). Glutamine also failed to significantly improve the symptoms of radiation enteritis in terms of tenesmus, abdominal cramping and blood in bowel movement(P > 0.05). CONCLUSIONS: Implementation of glutamine fails to improve the severity and symptoms in patients with radiation enteritis.

Thalidomide combined with transcatheter artierial chemoembolzation for primary hepatocellular carcinoma: a systematic review and meta-analysis.

OBJECTIVE: Transcatheter arterial chemoembolization (TACE) and thalidomide have been used for treating primary hepatocellular carcinoma(HCC). This study aims to evaluate the clinical efficacy and safety of thalidomide and TACE in primary HCC. METHODS: Randomized controlled trials(RCTs) about efficacy and safety of thalidomide combined with TACE for primary HCC were identified from the Cochrane Library, Pubmed, Embase, CNKI, and Wan Fang until August, 2016. The retrieved trials were reviewed and the data were extracted by two reviewers, independently. Combined analyses of survival rates, overall response rate(ORR), disease control rate(DCR), changes of KPS, parameters of cellular immunity and vascular endothelial growth factor(VEGF), and adverse events were performed using RevMan 5.3 software. RESULTS: A total of 23 RCTs involving 1836 patients were included. The results showed that thalidomide plus TACE was significantly superior in increasing 6-month survival rate(OR=1.79, 95% CI:1.02-3.15, P=0.04), 1-year survival rate(OR=1.76, 95% CI:1.38-2.24, P<0.0001), 1.5-year survival rate(OR=4.72, 95% CI:2.64-8.43, P<0.001), 2-year survival rate(OR=1.78, 95% CI:1.37-2.30, P<0.001), ORR(OR=1.89, 95% CI:1.48-2.42, P<0.0001), DCR(OR=2.62, 95% CI:1.90-3.63, P<0.001), improvement in cellular immunity(MD=0.63, 95% CI:0.45-0.80, P<0.0001), and reduction of VEGF(MD=-119.71, 95% CI:-135.75-103.68, P<0.0001), when compared with TACE group. The incidences of gastrointestinal reactions, myelosuppression, and liver dysfunction were similar between combination group and TACE group(P>0.05). However, compared to TACE, the combination of thalidomide and TACE had a higher incidence of drug rash(OR=6.35, 95% CI:2.75-14.68, P<0.0001). CONCLUSION: Our findings suggest that thalidomide combined with TACE shows better clinical efficacy and tolerable adverse events in patients with primary HCC when compared with TACE alone.

Adipocytes secreted leptin is a pro-tumor factor for survival of multiple myeloma under chemotherapy.

Accumulating evidences have shown that adipokines secreted from adipocytes contributes to tumor development, especially leptin. However, underlying mechanisms remain unclear. This study aims to explore the effect of leptin on development and chemoresistance in multiple myeloma cells and the potential mechanism. Analysis of levels of adipokines including leptin and adiponectin in 28 multiple myeloma patients identified significantly higher leptin compared with 28 normal controls(P < 0.05), and leptin level was positively correlated with clinical stage, IgG, ER, and ß2MG. Next, by using co-culture system of myeloma and adipocytes, and pharmacologic enhancement of leptin, we found that increased growth of myeloma cells and reduced toxicity of bortezomib were best observed at 50 ng/ml of leptin, along with increased expression of cyclinD1, Bcl-2 and decreased caspase-3 expression. We also found that phosphorylated AKT and STAT3 but not the proteins expression reached peak after 1h and 6h treatment of leptin, respectively. By using AG490, an agent blocking the phosphorylation of AKT and ERK, the proliferation of myeloma cells was inhibited, as well as the phosphorylation of AKT and STAT3, even adding leptin. Taken together, our study demonstrated that up-regulated leptin could stimulate proliferation of myeloma and reduce the anti-tumor effect of chemotherapy possibly via activating AKT and STAT3 pathways, and leptin might be one of the potential therapeutic targets for treating myeloma.

Endostar enhances the antitumor effects of radiation by affecting energy metabolism and alleviating the tumor microenvironment in a Lewis lung carcinoma mouse model.

Lung cancer is a leading cause of morbidity and mortality. Previous studies have identified that an improvement in treatment efficacy was achieved using Endostar; however, the role of Endostar in lung cancer remains poorly understood. The present study investigated whether the enhanced antitumor effects of Endostar in combination with radiation involved changes in the metabolism and microenvironment in non-small cell lung cancer. A Lewis lung carcinoma mouse model was used, including the control, Endostar (ES), radiotherapy (RT) and Endostar plus radiotherapy (ES + RT) groups. The tumor inhibition rates and growth were described based on changes in tumor volume. In addition, ultraviolet enzymatic analysis was performed to determine the lactate level and reverse transcription-polymerase chain reaction was used to measure the mRNA expression of lactate dehydrogenase (LDH). A Meph-3 pH meter was used to detect the ranges of tumor interstitial tissue pH, and immunohistochemical analysis was adopted to examine hypoxia within the tumor microenvironment. The tumor inhibition rate of the ES + RT group was significantly higher compared with the other three groups (P<0.05). Following treatment, the lactate levels decreased in all three treatment groups compared with the control, particularly in the ES + RT group (P<0.05). Reduced LDH expression and hypoxic fraction in the tumor microenvironment were also observed in the ES + RT group (P<0.05). Furthermore, changes from acidic to alkaline pH in the tumor microenvironment were detected in the ES + RT group. The present study suggested that Endostar is involved in the regulation of metabolism and tumor microenvironment hypoxia, which may be responsible for the enhanced antitumor effect of Endostar in combination with radiotherapy.

Endostar combined with chemotherapy versus chemotherapy alone for advanced NSCLCs: a meta-analysis.

BACKGROUND: Use of recombinant human endostatin combined with conventional cytotoxic therapy to treat tumors has been growing because of evidence of increased efficacy. However, whether antiangiogenic therapy combined with chemotherapy really benefits patients with advanced non-small cell lung cancers (NSCLCs) remains unclear. OBJECTIVES: This study was conducted to evaluate the clinical efficacy and safety of rh-endostatin (Endostar) combined with chemotherapy in the treatment of NSCLC patients. METHODS: We selected data from the Cochrane Library, EMBASE, Medline, SCI,CBM, CNKI, to obtain all clinical controlled trials, including the addition of endostar to chemotherapy in advanced NSCLC patients. Fifteen trials with 1335 patients were included according to the inclusion criteria. All were randomized controlled trials, and two trials were adequate in reporting randomization. Seventeen trials did not mention the blinding methods. RESULTS: Meta-analysis indicated that the NPE arm (Vinorelbine+cisplatin+Endostar) had a different response rate compared with NP(Vinorelbine+cisplatin) arm (OR2.16, 95%CI 1.57 to 2.99). The incidences of severe leukopenia (OR0.94, 95%CI 0.66 to 1.32) and severe thrombocytopenia (OR 1.00, 95%CI 0.64 to 1.57) and nausea and vomiting (OR 0.85, 95%CI 0.61 to 1.20) were similar in the two arms. The NPE plus radiotherapy (RT) arm had a similar response rate compared with NP plus RT arm (OR 2.39, 95%CI 0.99 to 5.79), as were the incidences of leukopenia (OR0.83, 95%CI 0.35 to 1.94), thrombocytopenia (OR 0.78, 95%CI 0.19 to 3.16) and radiation esophagitis (OR 1.00, 95%CI 0.40 to 2.49). CONCLUSIONS: Our results suggested that in the treatment of advanced NSCLC, endostar in combination with platinum-based chemotherapy could improve the response rate without obviously increasing side effects.

Endostar combined with chemotherapy versus chemotherapy alone for advanced NSCLCs: a meta-analysis.

To evaluate the clinical efficacy and safety of rh-endostatin (Endostar) combined with chemotherapy in the treatment of patients with non-small cell lung cancer (NSCLC), we selected data from the Cochrane Library, EMBASE, Medline, SCI, CBM, CNKI, etc to obtain all clinical controlled trials, including the addition of endostar to chemotherapy in advanced NSCLC patients. The quality of included trials was evaluated by two reviewers independently. The software RevMan 5.0 was provided by Cochrane Collaboration and used for meta-analyses. Fifteen trials with 1335 patients were included according to the including criterion. All trials were randomized controlled trials, and two trials were adequate in reporting randomization. Thirteen trials didn't mention the blinding methods. Meta-analysis indicated that the NPE arm (Vinorelbine+ cisplatin+Endostar) had a different response rate compared with NP(Vinorelbine+ cisplatin) arm (OR2.16, 95%CI 1.57 to 2.99). The incidences of severe Leukopenia (OR0.94, 95%CI 0.66 to 1.32) and severe thrombocytopenia (OR 1.00, 95%CI 0.64 to 1.57) and Nausea and vomiting (OR 0.85, 95%CI 0.61 to 1.20) were similar in the NPE arm compared with those in the NP arm. The NPE plus radiotherapy(RT) arm had a similar response rate compared with NP plus RT arm (OR 2.39, 95%CI 0.99 to 5.79). The incidences of Leukopenia (OR0.83, 95%CI 0.35 to 1.94) and thrombocytopenia (OR 0.78, 95%CI 0.19 to 3.16) and radiation esophagitis (OR 1.00, 95%CI 0.40 to 2.49)were similar in the NPE plus RT arm compared with those in the NP plus RT arm. Our results suggest that in the treatment of advanced NSCLCs, Endostar in combination with platinum-based chemotherapy can improve the response rate without obviously increasing side effects.