Osteosarcoma

Abstract: Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. The incidence rates and 95% confidence intervals of osteosarcoma for all races and both sexes are 4.0 (3.5-4.6) for the range 0-14 years and 5.0 (4.6-5.6) for the range 0-19 years per year per million persons. Among childhood cancers, osteosarcoma occurs eighth in general incidence and in the following order: leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). The incidence rates of childhood and adolescent osteosarcoma with 95% confidence intervals areas follows: Blacks, 6.8/year/million; Hispanics, 6.5/year/million; and Caucasians, 4.6/year/million. Osteosarcoma has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood. The first peak is in the 10-14-year-old age group, coinciding with the pubertal growth spurt. This suggests a close relationship between the adolescent growth spurt and osteosarcoma. The second osteosarcoma peak is in adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Paget's disease. The incidence of osteosarcoma has always been considered to be higher in males than in females, occurring at a rate of 5.4 per million persons per year in males vs. 4.0 per million in females, with a higher incidence in blacks (6.8 per million persons per year) and Hispanics (6.5 per million), than in whites (4.6 per million). Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates. The most common sites are the femur (42%, with 75% of tumors in the distal femur), the tibia (19%, with 80% of tumors in the proximal tibia), and the humerus (10%, with 90% of tumors in the proximal humerus). Other likely locations are the skull or jaw (8%) and the pelvis (8%). Cancer deaths due to bone and joint malignant neoplasms represent 8.9% of all childhood and adolescent cancer deaths. Death rates for osteosarcoma have been declining by about 1.3% per year. The overall 5-year survival rate for osteosarcoma is 68%, without significant gender difference. The age of the patient is correlated with the survival, with the poorest survival among older patients. Complete surgical excision is important to ensure an optimum outcome. Tumor staging, presence of metastases, local recurrence, chemotherapy regimen, anatomic location, size of the tumor, and percentage of tumor cells destroyed after neoadjuvant chemotherapy have effects on the outcome.

Abstract: 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.

Abstract: Neoplasms have a striking tendency to metastasize or "home" to bone. Hematopoietic cells also home to bone during embryonic development, where evidence points to the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12; expressed by osteoblasts and endothelial cells) and its receptor (CXCR4) as key elements in these processes. We hypothesized that metastatic prostate carcinomas also use the SDF-1/CXCR4 pathway to localize to the bone. To test this, levels of CXCR4 expression were determined for several human prostate cancer cell lines by reverse transcription-PCR and Western blotting. Positive results were obtained for cell lines derived from malignancies that had spread to bone and marrow. Prostate cancer cells were also observed migrating across bone marrow endothelial cell monolayers in response to SDF-1. In in vitro adhesion assays, pretreatment of the prostate cancer cells with SDF-1 significantly increased their adhesion to osteosarcomas and endothelial cell lines in a dose-dependent manner. Invasion of the cancer cell lines through basement membranes was also supported by SDF-1 and inhibited by antibody to CXCR4. Collectively, these results suggest that prostate cancers and perhaps other neoplasms may use the SDF-1/CXCR4 pathway to spread to bone.

Abstract: Purpose: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. Patients and Methods: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. Results: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respe...