Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1.

Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/ß-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/ß-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS. KEY MESSAGES: CCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/ß-catenin pathway. CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients. CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma.

Safety and efficacy of multilevel vertebroplasty for painful osteolytic spinal metastases: a single-centre experience.

OBJECTIVE: To retrospectively assess the safety and efficacy of percutaneous vertebroplasty (PVP) for painful osteolytic spinal metastases when treating more than three vertebrae per session. METHODS: A total of 153 patients with painful osteolytic spinal metastases underwent PVP. Group A patients (n = 93) underwent PVP at up to three vertebral levels per session. Group B patients (n = 60) underwent PVP at more than three levels in one session. Pain, quality of life (QoL), and mobility were assessed before and after PVP. Minor and major complications were systematically assessed. RESULTS: Both groups experienced significant pain relief and QoL improvement after the intervention (p < 0.001). Mobility improvement was observed in both groups, despite worse mobility status before PVP in group B compared with group A. There was no significant difference between the two groups throughout the follow-up period in overall pain relief and improvement in QoL and mobility. There was also no significant difference between groups in minor and major complications. CONCLUSIONS: Multilevel vertebroplasty is safe and effective for the treatment of multiple osteolytic spinal metastases. Multilevel PVP relieves pain and improves QoL and mobility. KEY POINTS: • Percutaneous vertebroplasty is safe and effective for painful osteolytic spinal metastases. • Multilevel vertebroplasty does not cause more complications than single-level vertebroplasty. • Multiple spinal metastases patients may regain functional independence after multilevel vertebroplasty.

Vastatin, an Endogenous Antiangiogenesis Polypeptide That Is Lost in Hepatocellular Carcinoma, Effectively Inhibits Tumor Metastasis.

Hepatocellular carcinoma (HCC) is a hypervascular cancer without effective treatment. Here we report that polypeptide of NC1 domain of type VIII collagen (Vastatin) is an endogenous polypeptide expressed in normal liver tissue but lost in the liver of most HCC patients (73.1%). Its expression level is negatively associated with tumor size (P = 0.035) and metastasis (P = 0.016) in HCC patients. To evaluate its potential use as a therapeutic, we constructed a recombinant adeno-associated virus carrying Vastatin (rAAV-Vastatin) to treat HCC in an orthotopic Buffalo rat model. rAAV-Vastatin treatment significantly prolonged the median survival, inhibited tumor growth, and completely prevented metastasis in HCC-bearing rats by decreasing microvessel density and increasing tumor necrosis. No detectable toxicity in nontumor-bearing mice was observed. To investigate its molecular mechanisms, we performed DNA microarray, western blotting assays, and bioinformatic analysis to determine its effect on global gene expression patterns and signal transduction pathways. Our results indicated that rAAV-Vastatin significantly reduced the expressions of Pck1, JAG2, and c-Fos, thus inhibiting the cellular metabolism, Notch and AP-1 signaling pathways, respectively. Hence, we demonstrated for the first time that Vastatin is a novel, safe, and effective antiangiogenic therapeutic and a potential biomarker for HCC.

Continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for recurrent or refractory osteosarcoma patients in China: a retrospective study.

OBJECTIVE: The aim of this retrospective study was to evaluate the feasibility and efficacy of response to continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for patients with recurrent or refractory osteosarcoma. MATERIALS AND METHODS: Eighteen recurrent or refractory osteosarcoma patients who were treated with continuous-infusion ifosfamide and doxorubicin combination between May 1999 and April 2011 were included in the analysis. Ifosfamide at 12 g/m2 was administered by intravenous continuous infusion over 3 days, and doxorubicin 60 mg/m2 was administered as an intravenous bolus injection on day 1. The combination therapy was repeated every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. RESULTS: The patients (ages 7-53 years) received a total of 42 cycles of chemotherapy (median: 2 courses; range: 2-5 courses). The overall response rate was 0% and the disease control rate was 22.3%, with four patients having stable disease. The median time to progression and overall survival time were 2 months (range: 2-5 months) and 9 months (range: 3-29 months), respectively. Major severe toxicities were leucopenia 7 (38.9%), nausea and vomiting 3 (16.7%) and alopecia 9 (50%). There were no treatment-related deaths. CONCLUSIONS: In our experience, continuous-infusion ifosfamide and doxorubicin combination therapy at this dosage and schedule was found to be well tolerated and moderate effective, which could be considered as salvage therapy for patients with recurrent or refractory osteosarcoma. Further assessment is necessary to confirm the safety and efficacy of this treatment.

Risk of interstitial lung disease associated with EGFR-TKIs in advanced non-small-cell lung cancer: a meta-analysis of 24 phase III clinical trials.

PURPOSE: To assess the risk of interstitial lung disease (ILD) with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib, erlotinib, and afatinib. METHOD: PubMed databases were searched for relevant articles. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR), and 95% confidence intervals (CIs) by using either random-effects or fixed-effect models. RESULTS: The incidence of all-grade and high-grade (≧ grade 3) ILD associated with EGFR-TKIs was 1.6% (95% CI, 1.0-2.4%) and 0.9% (95% CI, 0.6%-1.4%), with a mortality of 13.0% (95% CI, 7.6-21.6%). Patients treated with EGFR-TKIs had a significantly increased risk of developing all-grade (OR, 1.74; 95% CI, 1.25-2.43; P = 0.001) and high-grade (OR, 4.38; 95% CI, 2.18-8.79; P<0.001) ILD. No significant difference in the risk of ILD was found in sub-group analysis according to EGFR-TKIs, percentage of EGFR mutation, study location, EGFR-TKIs-based regimens, and controlled therapy. CONCLUSIONS: Treatment with EGFR-TKIs is associated with a significantly increased risk of developing ILD.

KLF8 knockdown suppresses proliferation and invasion in human osteosarcoma cells.

Krüppel-like factor 8 (KLF8) is a transcription factor that is important in the regulation of the cell cycle and has a critical role in oncogenic transformation and epithelial to mesenchymal transition (EMT). EMT is a key process in tumor metastasis. Although overexpression of KLF8 has been observed in a variety of human tumor types, the role of KLF8 in human osteosarcoma is yet to be elucidated. The present study aimed to investigate the biological impact of KLF8 on Saos-2 osteosarcoma cells. KLF8 gene expression was knocked down in vitro using a lentivirus-mediated small interfering (si)RNA method. Cell proliferation and cell cycle distribution were evaluated using 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide and colony formation assays, and flow cytometry, respectively. Cell invasion was analyzed using a Transwell® invasion assay. Knockdown of KLF8 was found to significantly inhibit proliferation and invasion in osteosarcoma cells. These data suggest that KLF8 may exhibit an important role in osteosarcoma tumorigenesis and that KLF8 may be a potential therapeutic target for the treatment of osteosarcoma.

Risk of anti-EGFR monoclonal antibody-related skin rash: an up-to-date meta-analysis of 25 randomized controlled trials.

PURPOSE: To assess the risk of severe skin rash in cancer patients treated with anti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs). METHODS: Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) meeting up to 31 June 2013 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating MoAbs in cancer patients with adequate data on skin rash and/or acne-like skin rash. RESULTS: A total of 14 270 patients from 25 RCTs were included. The overall incidences of all-grade and high-grade rash were, respectively, as follows: skin rash - 55·4 and 10·5%, and acne-like skin rash - 71·9 and 13·3%. Patients who received MoAbs significantly increased the risk of developing all-grade and high-grade skin rash and acne-like skin rash. Meta-regression indicated that the odds ratio (OR) of high-grade skin rash tended to be higher in the study in which the MoAbs treatment was longer. Additionally, similar results were observed in prespecified subgroup analysis. CONCLUSIONS: In patients with advanced solid tumors, EGFR-MoAbs are associated with an increased risk of developing skin rash and acne-like skin rash, and the risk tends to be associated with EGFR-MoAbs treatment duration. Adequate monitoring and early intervention are recommended to prevent decreased quality of life (QoL) and inconsistent dosing.

Risk of gastrointestinal perforation in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis.

BACKGROUND: The use of vascular-endothelial growth factor (VEGF) antibody bevacizumab is associated with an increased risk of gastrointestinal (GI) perforation, but the incidence and risk of GI perforation associated with vascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) has not been well described. We conduct a systematic review and meta-analysis of published trials to evaluate the overall incidence and risk of GI perforation associated with VEGFR-TKIs. METHODS: Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to March 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating VEGFR-TKIs in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS: A total of 5352 patients with a variety of solid tumors from 20 clinical trials were included in our analysis. The incidence of GI perforation was 1.3% (95%CI: 0.8-2.0%) among patients receiving VEGFR-TKIs, with a mortality of 28.6% (15.0-47.6%). Patients treated with VEGFR-TKIs did not significantly increase the risk of GI perforation compared with patients treated with control medication, with an OR of 2.99 (95%CI: 0.85-10.53, p=0.089). Sub-group analysis showed that the incidence of GI perforation did not significantly vary with tumor types, VEGFR-TKIs and treatments regimens. No evidence of publication bias was observed. CONCLUSIONS: The use of VEGFR-TKIs dose not significantly increase the risk of GI perforation in comparison with the controls. Further studies are recommended to investigate this association and the risk differences among different tumor types, VEGFR-TKIs or treatment regimens.

Risk of venous and arterial thromboembolic events in cancer patients treated with gemcitabine: a systematic review and meta-analysis.

AIMS: Gemcitabine has been associated with an increased risk of arterial and venous thromboembolic events (ATEs and VTEs), although the overall risk remains unclear. As indications for its use in oncology are expanding, a comprehensive characterization of these complications becomes imperative. METHODS: Pubmed was searched for articles published from 1 January 1990 to 31 December 2012. Eligible studies included prospective randomized controlled phase II and III trials evaluating gemcitabine based vs. non-gemcitabine based chemotherapy in patients with solid tumours. Data on VTEs and ATEs were extracted. Overall incidence rates, odds ratio (OR), and 95% confidence intervals (CIs) were calculated employing fixed or random effects models depending on the heterogeneity of included trials. RESULTS: A total of 4845 patients from 19 trials were included. Among patients treated with gemcitabine based chemotherapy, the overall incidence of VTEs (13 studies comprising 3823 patients) and ATEs (eight studies consisting of 2431 patients) was 2.1% (95% CI 1.2%, 3.8%) and 2.2% (95% CI 1.4%, 3.2%). The associated ORs of VTEs and ATEs were 1.56 (95% CI 0.86, 2.83, P = 0.15) and 1.82 (95% CI 0.89, 3.75, P = 0.10) compared with non-gemcitabine based therapy. A tendency to increase the risk of ATE and VTEs was also detected in any prespecified subgroup. CONCLUSION: The use of gemcitabine does not significantly increase the risk of VTEs and ATEs in patients with solid tumours when compared with non-gemcitabine based chemotherapy.

The prognostic value of survivin expression in patients with colorectal carcinoma: a meta-analysis.

OBJECTIVE: The prognostic role of survivin in colorectal carcinoma remains controversial. This meta-analysis aimed to explore the association between survivin expression and survival outcomes in patients with colorectal carcinoma. METHODS: A comprehensive literature search for relevant studies published up to April 2013 was performed using PubMed, MEDLINE and ISI Web of Science. Only articles in which survivin was detected by immunohistochemical staining were included. This meta-analysis was done using STATA and Review Manager. RESULTS: A total of 1784 patients from 14 studies were included in the analysis. Our results showed that survivin overexpression in patients with colorectal carcinoma was significantly associated with poor overall survival (hazard ratio, 1.505; 95% confidence interval, 1.197-1.893; P = 0.000) and disease-free survival (hazard ratio, 2.323; 95% confidence interval, 1.687-3.199; P = 0.000). The results indicated that a significant relationship between survivin expression and overall survival was also exhibited in studies with an Asian country (hazard ratio, 1.684; 95% confidence interval, 1.477-1.921), patient number >100 (hazard ratio, 1.604; 95% confidence interval, 1.371-1.877), the cut-off level <50% (hazard ratio, 1.449; 95% confidence interval, 1.045-2.010), the percentage of survivin overexpression >50% (hazard ratio, 1.528; 95% confidence interval, 1.056-2.211) and the hazard ratio estimated (hazard ratio, 1.643; 95% confidence interval, 1.262-2.139). Moreover, upregulation of survivin was associated with stages (III/IV vs. I/II: odds ratio, 1.08; 95% confidence interval, 0.80-1.46), the depth of invasion (T3/T4 vs. T1/T2: odds ratio, 1.79; 95% confidence interval 0.67-4.74), lymph node metastasis (positive vs. negative: odds ratio, 1.49; 95% confidence interval, 0.99-2.26), distant metastasis (positive vs. negative: odds ratio, 2.37; 95% confidence interval, 0.99-5.72) and grade of differentiation (well/moderate vs. poor: odds ratio, 1.02; 95% confidence interval, 0.43-2.41), but without significance. CONCLUSION: The present meta-analysis indicated that upregulation of survivin was associated with poor prognosis in patients with colorectal carcinoma.

Prognostic value of tissue vascular endothelial growth factor expression in bladder cancer: a meta-analysis.

OBJECTIVE: The prognostic role of vascular endothelial growth factor (VEGF) in bladder cancer remains controversial. This meta-analysis aimed to explore any association between overexpression and survival outcomes. METHODS: We systematically searched for studies investigating the relationships between VEGF expression and outcome of bladder cancer patients. Study quality was assessed using the Newcastle-Ottawa Scale. After careful review, survival data were extracted from eligible studies. A meta-analysis was performed to generate combined hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: A total of 1,285 patients from 11 studies were included in the analysis. Our results showed that tissue VEGF overexpression in patients with bladder cancer was associated with poor prognosis in terms of OS (HR, 1.843; 95% CI, 1.231-2.759; P = 0.003), DFS (HR, 1.498; 95% CI, 1.255-1.787; P = 0.000) and DSS (HR, 1.562; 95% CI, 0.996-1.00; P = 0.052), though the difference for DSS was not statistically significant. In addition, there was no evidence of publication bias as suggested by Begg's and Egger's tests except for DFS (Begg's test, P = 0.221; Egger's test, P = 0.018). CONCLUSION: The present meta-analysis indicated elevated VEGF expression to be associated with a poor prognosis in patients with bladder cancer.

Overall survival benefits for combining targeted therapy as second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of published data.

BACKGROUND: Combining targeted therapy has been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but it is still unclear whether combining targeted therapy might offer any benefits against standard monotherapy with erlotinib. We thus performed a meta-analysis of randomized controlled trials to compare the efficacy and safety of combining targeted therapy versus erlotinib alone as second-line treatment for advanced NSCLC. METHODS: Several databases were searched, including Pubmed, Embase and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3 or 4 adverse event (AEs). The pooled hazard ratio (HR) or odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: Eight eligible trials involved 2417 patients were ultimately identified. The intention to treatment (ITT) analysis demonstrated that combining targeted therapy significantly improved OS (HR 0.90, 95% CI: 0.82-0.99, p = 0.024), PFS (HR 0.83, 95% CI: 0.72-0.97, p = 0.018), and ORR (OR 1.35, 95% CI 1.01-1.80, P = 0.04). Sub-group analysis based on phases of trials, EGFR-status and KRAS status also showed that there was a tendency to improve PFS and OS in combining targeted therapy, except that PFS for patients with EGFR-mutation or wild type KRAS favored erlotinib monotherapy. Additionally, more incidence of grade 3 or 4 rash, fatigue and hypertension were observed in combining targeted therapy. CONCLUSIONS: With the available evidence, combining targeted therapy seems superior over erlotinib monotherapy as second-line treatment for advanced NSCLC. More studies are still needed to identify patients who will most likely benefit from the appropriate combining targeted therapy.

Overall survival benefits for irinotecan-containing regimens as first-line treatment for advanced gastric cancer: an updated meta-analysis of ten randomized controlled trials.

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan-containing regimen as first-line treatment for those patients are controversial. We performed a systematic review and meta-analysis of randomized controlled trials to determine the survival benefits of irinotecan-containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan-containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78-0.94, p = 0.002] and progression-free survival [HR = 0.82, 95% CI = 0.69-0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77-1.04, p = 0.15), 1-year survival rate [1-year SR: relative risk (RR) 1.10, 95% CI = 0.97-1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91-1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan-containing regimens. This updated meta-analysis provided strong evidence for a survival benefit of irinotecan-containing regimen as first-line treatment for AGC. A clear advantage of irinotecan-containing over nonirinotecan-containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.

Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials.

AIM: To perform a systematic review and meta-analysis of published clinical trials to determine incidence rate and overall risk of hypertension with vandetanib in cancer patients. METHODS: A comprehensive literature search for studies published up to March 2012 was performed. Summary incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: A total of 11 trials with 3154 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension in patients with cancer were 24.2% [95% confidence interval (CI), 18.1-30.2%] and 6.4% (95% CI, 3.3-9.5%), respectively. Subgroup analysis demonstrated that the pooled incidences of all-grade and high-grade hypertension were 21.8% [95% CI, 15-30.5%] and 7.6% (95% CI, 2.8-18.8%), respectively, among non-small-cell lung cancer (NSCLC) patients, and 32.1% (95% CI: 27.3-37.3%) and 8.8% (5.9%-12.9%), respectively, among MTC patients, and 15.4 (95% CI: 3.2-33.7%) and 3.4% (95% CI: 1%-11.1%) respectively, among non-MTC/NSCLC tumors patients. Furthermore, vandetanib was associated with a significant increased risk of all-grade hypertension (RR 5.1, 95% CI: 3.76-6.92, P = 0.000) and high-grade hypertension (RR 8.06, 95% CI: 3.41-19.04, P = 0.000) in comparison with controls. CONCLUSIONS: There is a significant risk of developing hypertension in cancer patients receiving vandetanib. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

Paclitaxel-based versus docetaxel-based regimens in metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Docetaxel and paclitaxel show significant clinical activity in metastatic breast cancer (MBC) and have been approved for MBC by the U.S. Food and Drug Administration, but it is still unclear whether a paclitaxel-based regimen improves outcomes over a docetaxel-based regimen in patients with MBC. We therefore performed a meta-analysis of randomized controlled trials to compare the safety and efficacy of these two regimens in MBC. METHODS: We systematically searched for randomized controlled trials that comparing paclitaxel-based with docetaxel-based regimens in patients with MBC in PubMed (up to January 2012), Embase (1980 to January 2012), and the Cochrane databases (up to January 2012). Abstracts presented at conferences (up to January 2011) were also searched. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed by Stata version 12.0 software (Stata Corporation, College Station, TX, USA). RESULTS: Seven eligible trials involving 1694 patients with MBC were selected. Our results showed that a paclitaxel-based regimen was comparable to a docetaxel-based regimen for MBC patients in terms of OS (HR: 0.87, 95% CI: 0.60-1.27, p = 0.48), PFS (HR: 0.76, 95% CI: 0.58-1.00, p = 0.052), TTP (HR: 1.13, 95% CI: 0.81-1.58, p = 0.46), and ORR (RR: 1.01, 95% CI: 0.88-1.15, p = 0.92), but fewer grade 3 or 4 adverse events including anemia (RR: 0.64, 95% CI: 0.44-0.94, p = 0.023), neutropenia (RR: 0.74, 95% CI: 0.58-0.93, p = 0.011), febrile neutropenia (RR: 0.38, 95% CI: 0.15-0.96, p = 0.041), thrombopenia (RR: 0.62, 95% CI: 0.41-0.96, p = 0.033), mucositis (RR: 0.082, 95% CI: 0.025-0.27, p < 0.001), diarrhea (RR: 0.19, 95% CI: 0.081-0.47, p < 0.001) and fatigue (RR: 0.43, 95% CI: 0.20-0.96, p = 0.039) were observed in the paclitaxel-based regimen. However, limitations of our study needed to be considered when interpreting these results: our study was a meta-analysis of published data, and there was significant heterogeneity among included trials. Potential publication bias might also exist. CONCLUSION: The present systematic review and meta-analysis demonstrates that both taxane-based regimens have comparable efficacy for patients with MBC, and the paclitaxel-based regimen is associated with less toxicity and better tolerability, especially in older patients and when used in weekly regimens.

Risk of venous thromboembolic events associated with VEGFR-TKIs: a systematic review and meta-analysis.

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been widely used in advanced cancers. Concerns have arisen regarding the risk of venous thromboembolism with the use of these drugs. Currently, the contribution of VEGFR-TKIs to venous thromboembolism is still unknown. We performed a meta-analysis to determine the incidence and relative risk (RR) of venous thromboembolism events (VTEs) associated with these agents. Eligible studies included phase II and III prospective trials evaluating US Food and Drug Administration approved VEGFR-TKIs (pazopanib, sunitinib, sorafenib and vandetanib), and data on VTEs were available. Overall incidence rates, RR and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of included trials. A total of 14 studies (4,430 patients) were selected for this meta-analysis. The incidence of VTEs related to VEGFR-TKIs was 3% (95%CI: 1.7-5.1%), and there was no statistically significant increase in the risk of VTEs for VEGFR-TKIs versus controls in overall population (RR0.912, 95%CI: 0.617-1.348, p = 0.643). On subgroup analysis, no significant increase in the risk of VTEs was found among different VEGFR-TKIs or tumor types. No evidence of publication bias was observed. The use of VEGFR-TKIs does not significantly increase the risk of VTEs, the risk of VTEs in patients with cancer is driven predominantly by tumor types, host factors and concomitant usage of anticancer agents. These results would provide important information for clinicians who use VEGFR-TKIs to treat patients with solid cancer.

Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis.

PURPOSES: To gain a better understanding of the overall incidence and risk of hypertension in cancer patients who receive pazopanib and to compare the differences in incidence among sorafenib, sunitinib, and pazopanib. METHODS: Several databases were searched, including PubMed, Embase, and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned single drug pazopanib 800 mg/day with data on hypertension available. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included trials. RESULTS: A total of 1,651 patients with a variety of solid tumors from 13 clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hypertension in cancer patients were 35.9 % (95 % CI 31.5-40.6 %) and 6.5 % (95 % CI 5.2-8.0 %), respectively. The use of pazopanib was associated with an increased risk of developing all-grade (RR 4.97, 95 % CI 3.38-7.30, p < 0.001) and high-grade hypertension (RR 2.87, 95 % CI 1.16-7.12, p = 0.023). Additionally, there was no significant difference in the incidence of all-grade (RR 1.21, 95 % CI 0.96-1.53, p = 0.11) and high-grade hypertension (RR 1.29, 95 % CI 0.80-2.07, p = 0.30) between RCC and non-RCC patients. Interestingly, the risk of all-grade hypertension with pazopanib was substantially higher than sorafenib (RR 1.99; 95 % CI 1.73-2.29, p = 0.00) and sunitinib (RR 2.20; 95 % CI 1.92-2.52, p = 0.00), while the risk of pazopanib-induced high-grade hypertension was similar to sorafenib (RR 0.98; 95 % CI 0.75-1.30, p = 0.90) and sunitinib (RR 0.81; 95 % CI 0.62-1.06, p = 0.12). CONCLUSIONS: The use of pazopanib is associated with a significantly increased risk of developing hypertension. Close monitoring and appropriate managements are recommended during the therapy. Future studies are still needed to investigate the risk reduction and possible use of pazopanib in selected patients.

Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: a systematic review and meta-analysis.

PURPOSE: To compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitor monotherapy (EFGR-TKIs: gefitinib or erlotinib) with standard second-line chemotherapy (single agent docetaxel or pemetrexed) in previously treated advanced non-small-cell lung cancer (NSCLC). METHODS: We systematically searched for randomized clinical trials that compared EGFR-TKI monotherapy with standard second-line chemotherapy in previously treated advanced NSCLC. The end points were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), 1-year survival rate (1-year SR) and grade 3 or 4 toxicities. The pooled hazard ratio (HR) or risk ratio (RR), with their corresponding 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: Eight randomized controlled trials (totally 3218 patients) were eligible. Our meta-analysis results showed that EGFR-TKIs were comparable to standard second-line chemotherapy for advanced NSCLC in terms of overall survival (HR 1.00, 95%CI 0.92-1.10; p=0.943), progression-free survival (HR 0.90, 95%CI 0.75-1.08, P=0.258) and 1-year-survival rate (RR 0.97, 95%CI 0.87-1.08, P=0.619), and the overall response rate was higher in patients who receiving EGFR-TKIs(RR 1.50, 95%CI 1.22-1.83, P=0.000). Sub-group analysis demonstrated that EGFR-TKI monotherapy significantly improved PFS (HR 0.73, 95%CI: 0.55-0.97, p=0.03) and ORR (RR 1.96, 95%CI: 1.46-2.63, p=0.000) in East Asian patients, but it did not translate into increase in OS and 1-year SR. Furthermore, there were fewer incidences of grade 3 or 4 neutropenia, febrile neutropenia and neurotoxicity in EGFR-TKI monotherapy group, excluding grade 3 or 4 rash. CONCLUSION: Both interventions had comparable efficacy as second-line treatments for patients with advanced NSCLC, and EGFR-TKI monotherapy was associated with less toxicity and better tolerability. Moreover, our data also demonstrated that EGFR- TKI monotherapy tended to be more effective in East Asian patients in terms of PFS and ORR compared with standard second-line chemotherapy. These results should help inform decisions about patient management and design of future trials.

Relationships between levels of CXCR4 and VEGF and blood-borne metastasis and survival in patients with osteosarcoma.

The present study was designed to determine whether the expression of chemokine receptor CXCR4 and vascular endothelial growth factor (VEGF) is correlated with the extent of metastasis and the survival of patients with osteosarcoma. Using tissue microarrays, we analyzed the expression of CXCR4 and VEGF in tumor tissues collected from 56 patients with osteosarcoma. A two-year follow-up was performed to evaluate tumor metastatic behavior and the overall survival of the patients. There was a significant correlation between the expression of CXCR4 and the expression of VEGF in tumor tissues of these patients (P = 0.002). Univariate analysis revealed that expression of these proteins was correlated with clinical stage, but not age, gender, or serum alkaline phosphatase levels. The patients with tumors expressing CXCR4 and VEGF had worse overall survival rates compared with the patients with tumors that did not express CXCR4 (P = 0.03) or VEGF (P = 0.04). These data indicate that CXCR4 and VEGF expression is highly correlated with metastatic progression in patients with osteosarcoma and had predictive value for the metastasis and survival of osteosarcoma patients.

Extraskeletal myxoid chondrosarcoma: a case report of complete remission by chemotherapy and review of the literature.

Extraskeletal myxoid chondrosarcoma is a rare soft tissue sarcoma. Surgery is the cornerstone of the management of this tumour. The response rate to chemotherapy has been very poor; with the exception of one reported case which showed promising results, overall results are disappointing because no significant radiologic or clinical responses have been noted with chemotherapy. Here we report the case of a 15-year-old girl who presented with extraskeletal myxoid chondrosarcoma in the sacrococcygeal region which was regarded as unresectable. After four cycles of chemotherapy the mass showed complete remission which has lasted >6 months.