For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.

Translational biology of osteosarcoma

Osteosarcoma typically occurs during the adolescent growth spurt and is the most common primary cancer of bone. Here, Sharon A. Savage and colleagues discuss how advances in germline and somatic genetics, tumour biology and animal models have enhanced our understanding of osteosarcoma aetiology and could lead to new therapeutic approaches to treat the disease. Clinical outcomes and treatment modalities for osteosarcoma, the most common primary cancer of bone, have changed very little over the past 30 years. The peak incidence of osteosarcoma occurs during the adolescent growth spurt, which suggests that bone growth and pubertal hormones are important in the aetiology of the disease. Tall stature, high birth weight and certain inherited cancer predisposition syndromes are well-described risk factors for osteosarcoma. Common genetic variants are also associated with osteosarcoma. The somatic genome of osteosarcoma is highly aneuploid, exhibits extensive intratumoural heterogeneity and has a higher mutation rate than most other paediatric cancers. Complex pathways related to bone growth and development and tumorigenesis are also important in osteosarcoma biology. In this Review, we discuss the contributions of germline and somatic genetics, tumour biology and animal models in improving our understanding of osteosarcoma aetiology, and their potential to identify novel therapeutic targets and thus improve the lives of patients with osteosarcoma.

Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy.

http://jbjs.org/content/jbjsam/72/4/637.3.full.pdf

Bone Tumors. Clinical, Radiologic, and Pathologic Correlations.

Cancer prevention and therapy through the modulation of the tumor microenvironment.

Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.

The Osteosarcoma Microenvironment: A Complex But Targetable Ecosystem.

Vascular endothelial growth factor (VEGF) is considered as a prime mediator of angiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF overexpression with the clinical outcome in patients with osteosarcoma but yielded conflicting results. Electronic databases updated to April 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF overexpression and survival of patients with osteosarcoma. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of eight studies that evaluated the correlation between VEGF overexpression and survival in patients with osteosarcoma. Combined hazard ratios suggested that VEGF overexpression had an unfavorable impact on overall survival (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.21-2.28) in patients with osteosarcoma for overall populations, 2.37 (1.35-3.39) in Asian studies but not in non-Asian studies (HR = 1.51, 95% CI: 0.89-2.14). No significant heterogeneity was observed among all studies. VEGF overexpression indicates a poor prognosis for patients with osteosarcoma. However, the prognostic value of VEGF on survival in osteosarcoma patients still needs further large-scale prospective trials to be clarified.

Prognostic significance of VEGF expression in osteosarcoma: a meta-analysis.

Calcium phosphate cement (CPC) has been widely used in orthopedic and dental applications. A critical limitation of CPC is low strength and high susceptibility to severe fracture. Surgeons can use it only to reconstruct non-stress bearing bone, raising the need for a tougher new generation of CPC. Fibers have been used as a reinforcement of CPC to improve the strength of a pure CPC scaffold. The RGD peptides (Arg-Gly-Asp) have been used to improve the biocompatibility of the scaffold, via physical adsorption. The purpose of this study was to develop a novel CPC scaffold reinforced by RGD peptide-bearing chitosan fibers (RGD-fiber-CPC). Our data showed that the RGD-fiber-CPC scaffold had an increased flexural strength, and stimulated new bone formation in an animal model. The RGD-fiber-CPC is a novel bone graft substitute in orthopedic surgery. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 68–75, 2014.

Xiao Wei Yu

Papers

Prognostic significance of VEGF expression in osteosarcoma: a meta-analysis.

Reinforcement of a new calcium phosphate cement with RGD-chitosan-fiber