INTRODUCTIONOsteosarcoma treatment has experienced a renaissance in the last 3 decades with the institution of multimodality treatment involving multiagent chemotherapy and surgery. Yet globally, treatment success has stagnated at about 70% survival at 5 years in most single institution series. We performed survival analyses on 2 national databases in 2 countries and compared these with corresponding institution specific survival.

MATERIALS AND METHODSAll patients with the diagnostic code of non-metastatic intramedullary osteosarcoma in the long bones of the upper and lower limbs less than 30 years of age were selected from the Surveillance Epidemiology and End Result (SEER) database to ensure uniformity with respect to disease and treatment. We studied the factors: ethnicity, gender, age, grade, histology, size, site, surgery, compartmentalisation, number of primaries and venue of treatment for their contribution to survival. In addition, the data were stratified into 3 decades (seventies, eighties and nineties) to account for variations due to the evolution of treatment paradigms and imaging modalities.

RESULTSInstitution-specific survival was predictably better than national survival in the 4 databases. One thousand patients were selected from the SEER database. Oriental descent, state-specific treatment, female gender, treatment in the nineties, low-grade disease, intra-compartmental disease, small size, wide resections as opposed to forequarter or hindquarter amputations, and single primaries were good prognostic factors on univariate analysis as well as multivariate analysis (P <0.05). Survival was better in the more affluent states (P <0.05). Males were affected at an older age than females (P = 0.004). Blacks tended to have larger tumours although their overall survival was similar to whites. Orientals were more likely to be treated in the nineties with wide resections for smaller tumours and were located around states associated with good treatment. Orientals in Singapore and the United States had the same survival (P = 0.45). Survival in Orientals in Singapore was not significantly different from other races. The standard of healthcare for osteosarcoma varies greatly across the United States but is uniform in Singapore. Hence the observed differences in the United States were likely due to socioeconomic factors.

CONCLUSIONThis analysis confirms the importance of a number of prognostic variables in osteosarcoma and suggests the possibility of an ethnic and economic bias for good survival.

Adolescent ; Adult ; African Continental Ancestry Group ; Asian Continental Ancestry Group ; Bone Neoplasms ; epidemiology ; ethnology ; mortality ; Child ; Child, Preschool ; Databases, Factual ; European Continental Ancestry Group ; Female ; Humans ; Infant ; Infant, Newborn ; Internationality ; Kaplan-Meier Estimate ; Male ; Osteosarcoma ; epidemiology ; ethnology ; mortality ; Prognosis ; Registries ; Singapore ; epidemiology ; Young Adult

Objective　To analyze the expression of osteoblast-associated genes in chondrosarcomas and to identify phenotypes of tumor cell differentiation.　Methods　Expression of osteocalcin (OC),alkaline phosphatase (AP),osteonectin (ON)　and core binding factor A1 (Cbfa1) was analyzed semi-quantitatively by RT-PCR and blotting and　was correlated with histologic grade and prognosis in 32 chondrosarcoma patients.　Results　There were statistically significant relations between the pathologic grade and the presence of OC, AP or Cbfa1 transcripts. These osteoblast-associated genes were more often expressed in grade Ⅲ chondrosarcomas. Osteocalcin mRNA expression was detected in 9 of 12 (75%) grade Ⅲ chondrosarcomas and 4 of 20 (20%) grade Ⅰ-Ⅱ chondrosarcomas (P=0.008). AP mRNA was found in 21 of 32 chondrosarcomas,including 11 of 12 (92%) grade Ⅲ and 10 of 20 (50%) grade Ⅰ-Ⅱ chondrosarcomas (P=0.018).OC or AP transcript was associated with decreased disease free survival (P=0.016 for OC,and P=0.018 for AP, Log-rank test).Cbfa1 mRNA was only detected in 4 grade Ⅲ chondrosarcomas. ON was detected in all chondrosarcoma samples. No correlation was observed between ON transcript and pathological grade or disease free survival.　Conclusions　OC transcript may be detected in the majority of high grade, but in a few grade Ⅰ-Ⅱ chondrosarcomas, and is associated with poor prognosis in patients with chondrosarcoma. The difference in AP mRNA positivity between grade　Ⅰ-Ⅱ and grade Ⅲ group is significant. AP expression is also related to decreased disease free survival. OC or AP expression in chondrosarcoma might be of independent prognostic value. Cbfa1 appears to have similar features with OC in that it is expressed more frequently in high grade chondrosarcomas.

Objective　To analyze the expression of osteoblast-associated genes in chondrosarcomas and to identify phenotypes of tumor cell differentiation.　Methods　Expression of osteocalcin (OC),alkaline phosphatase (AP),osteonectin (ON)　and core binding factor A1 (Cbfa1) was analyzed semi-quantitatively by RT-PCR and blotting and　was correlated with histologic grade and prognosis in 32 chondrosarcoma patients.　Results　There were statistically significant relations between the pathologic grade and the presence of OC, AP or Cbfa1 transcripts. These osteoblast-associated genes were more often expressed in grade Ⅲ chondrosarcomas. Osteocalcin mRNA expression was detected in 9 of 12 (75%) grade Ⅲ chondrosarcomas and 4 of 20 (20%) grade Ⅰ-Ⅱ chondrosarcomas (P=0.008). AP mRNA was found in 21 of 32 chondrosarcomas,including 11 of 12 (92%) grade Ⅲ and 10 of 20 (50%) grade Ⅰ-Ⅱ chondrosarcomas (P=0.018).OC or AP transcript was associated with decreased disease free survival (P=0.016 for OC,and P=0.018 for AP, Log-rank test).Cbfa1 mRNA was only detected in 4 grade Ⅲ chondrosarcomas. ON was detected in all chondrosarcoma samples. No correlation was observed between ON transcript and pathological grade or disease free survival.　Conclusions　OC transcript may be detected in the majority of high grade, but in a few grade Ⅰ-Ⅱ chondrosarcomas, and is associated with poor prognosis in patients with chondrosarcoma. The difference in AP mRNA positivity between grade　Ⅰ-Ⅱ and grade Ⅲ group is significant. AP expression is also related to decreased disease free survival. OC or AP expression in chondrosarcoma might be of independent prognostic value. Cbfa1 appears to have similar features with OC in that it is expressed more frequently in high grade chondrosarcomas.

PURPOSEWe have previously shown that osteosarcomas have states of increased interstitial fluid pressure (IFP) which correlate with increased proliferation and chemosensitivity. In this study, we hypothesized that constitutively raised IFP in osteosarcomas regulates angiogenesis.

MATERIALS AND METHODSSixteen patients with the clinical diagnosis of osteosarcomas underwent blood fl ow and IFP readings by the wick-in-needle method at the time and location of open biopsy. Vascularity was determined by capillary density in the biopsy specimens. We performed digital image analysis of immunohistochemical staining for CD31, VEGF-A, VEGF-C and TPA on paraffin-embedded tissue blocks of the biopsy samples. Clinical results were validated in a pressurised cell culture system.

RESULTSIFPs in the tumours (mean 33.5 +/- SD 17.2 mmHg) were significantly higher (P = 0.00001) than that in normal tissue (2.9 +/- 5.7 mmHg). Pressure readings were significantly higher in low vascularity tumours compared to high vascularity tumours (P <0.001). In the osteosarcoma cell lines, growth in a pressurised environment was associated with VEGF-A downregulation, VEGF-C upregulation and TPA upregulation. The reverse was seen in the OB cell lines. Growth in the HUVEC cell line was not significantly inhibited in a pressurised environment. Immunohistochemical assessment for VEGF-A (P = 0.01), VEGF-C (P = 0.008) and TPA (P = 0.0001) translation were consistent with the findings on PCR.

CONCLUSIONOur data suggest that some molecules in angiogenesis are regulated by changes in IFP.

Adolescent ; Angiogenic Proteins ; physiology ; Bone Neoplasms ; blood supply ; Cells, Cultured ; Extracellular Fluid ; physiology ; Female ; Humans ; Male ; Neovascularization, Pathologic ; Osteosarcoma ; blood supply ; Pressure