Lina Tang

Abstract Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4 + macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3 + T cells with high proportion of TIGIT + cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.

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.

AIMS: Congestive heart failure (CHF) associated with vascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) has emerged as a relevant problem in clinical and scientific communities. We performed an up-to-date, comprehensive meta-analysis to determine the overall incidence and risk of CHF in cancer patients receiving VEGFR-TKIs. METHODS: The databases of PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology up to August 31 2013 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 according to the heterogeneity of included studies. RESULTS: A total of 10 553 patients from 36 clinical trials were included. The overall incidence of all grade and high grade CHF associated with VEGFR-TKIs was 3.2% (95% CI 1.8%, 5.8%) and 1.4% (95% CI 0.9%, 2.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all grade (OR 2.37, 95% CI 1.76, 3.20, P < 0.001) and high grade (OR 3.51, 95% CI 1.74, 7.05, P < 0.001) CHF. In subgroup analyses, the risk of CHF did not significantly vary with tumour types (P = 0.071 for all grade; P = 0.72 for high grade) and VEGFR-TKIs (P = 0.55 for all grade; P = 0.99 for high grade). Meta-regression indicated that CHF might possibly occur early in the treatment of VEGFR-TKIs. No evidence of publication bias was observed. CONCLUSION: The use of VEGFR-TKIs is associated with a significantly increased risk of developing congestive heart failure in cancer patients. Clinicians should be aware of this risk and provide close monitoring in patients receiving these therapies.