Prognostic impact of blood and urinary angiogenic factor levels at diagnosis and during treatment in patients with osteosarcoma: a prospective study.

BACKGROUND: Angiogenesis is essential for the progression and metastatic spread of solid tumours. Expression of vascular endothelial growth factor (VEGF) has been linked to poor survival among osteosarcoma patients but the clinical relevance of monitoring blood and urine angiogenic factors is uncertain. The aim of this study was to determine the prognostic significance of blood VEGF and blood and urinary basic fibroblast growth factor (bFGF) levels in osteosarcoma patients, both at diagnosis and during treatment. METHODS: Patients with localised or metastatic osteosarcoma enrolled in OS2005 and OS2006 studies between 2005 and 2011 were prospectively included in this study. VEGF and bFGF levels in serum and plasma and bFGF levels in urine were measured by ELISA at diagnosis, before surgery, and at the end of treatment. Endpoints considered for the prognostic analysis were histological response, progression-free and overall survival. Kruskal-Wallis tests were used to compare the distribution of baseline biomarker values across the different subgroups, and paired sample Wilcoxon rank tests were used to analyze changes over time. Association between biomarker levels and outcomes were assessed in multivariable models (logistic regression for histologic response, and Cox models for survival). RESULTS: Samples were available at diagnosis for 269 patients (54% males; age ≤ 18 years: 73%; localised disease in 68%, doubtful lung lesions in 17%, and metastases in 15%). High serum VEGF and bFGF levels were observed in respectively 61% and 51% of patients. Serum and plasma VEGF values were not strongly correlated with one another (r = 0.53). High serum and plasma VEGF levels were significantly more frequent in patients with large tumours (≥10 cm; p = 0.003 and p = 0.02, respectively). VEGF levels fell significantly during pre-operative chemotherapy (p < 0.0001). No significant correlation was found between this variation and either the histological response, progression-free survival or overall survival (p = 0.26, p = 0.67, and p = 0.87, respectively). No significant association was found between blood or urinary bFGF levels and clinical characteristics, histological response, or survival. CONCLUSIONS: Levels of VEGF and bFGF angiogenic factors are high in most osteosarcoma patients, but have no significant impact on response to chemotherapy or outcome in this large prospective series. OS 2006 TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT00470223; date of registration: May 3th 2007.

Evaluation of serum and urinary angiogenic factors in patients with endometriosis.

PROBLEM: The aim of this study was to evaluate serum and urinary levels of vascular endothelial growth factors, tumor necrosis factor-alpha (TNF-alpha), and soluble fms-like tyrosine kinase (sFlt-1) in patients with endometriosis. METHOD OF STUDY: During surgery for pelvic pain, pelvic mass or infertility, serum and urine were collected. Of 70 patients, 46 had histology-proven endometriosis and 24 patients without endometriosis participated as controls. RESULTS: Serum TNF-alpha levels and urinary sFlt-1 levels corrected for creatinine excretion were significantly increased in the endometriosis group (P=0.001 and P=0.011 respectively). Serum sFlt-1 levels and urinary sFlt-1 levels corrected for creatinine were significantly higher in patients with minimal-to-mild disease (P=0.014 and P=0.015 respectively), where serum TNF-alpha levels were increased in moderate-to-severe endometriosis (P<0.001). CONCLUSION: The pathogenesis of minimal-to-mild endometriosis and moderate-to-severe endometriosis seems to be different. Increased sFlt-1 levels in serum and urine of minimal-to-mild disease indicate that sFlt-1 may have an important role in inhibiting angiogenic process of the disease.

Presence of heparin binding growth factor in mouse bladder tumors and urine from mice with bladder cancer.

Heparin affinity chromatography has been used to partially purify angiogenic factors from normal and neoplastic tissue. The same technique was used to partially purify angiogenic-like factors from two mouse bladder tumors and urine from mice with bladder cancer. Both MBT-2 and MB49 tumors contained heparin-binding 3T3 cell growth factor activity that was eluted by 1.2 to 1.4 M salt. The growth factor isolated from MBT-2 tumor was mitogenic for capillary endothelial cells. Analysis of the 1.2 M heparin eluate by high-pressure liquid chromatography showed that it consisted of two 3T3 cell growth factors with molecular weights of 16,000 and 26,000. The growth factor activity isolated from MB49 tumors had an affinity for Bio-rex 70 which was similar to other cationic heparin binding growth factors. Analysis of urine pooled from tumor-bearing mice by heparin-Sepharose chromatography demonstrated 3T3 cell growth factor activity in fractions eluted with 1 to 1.4 and 2.5 M dsalt, whereas no significant growth factor activity was detected in pooled urine from control mice. The growth factor activity found in mouse bladder tumors differed from epidermal growth factor, transforming growth factor-alpha, and platelet-derived growth factor in terms of affinity for heparin-Sepharose and molecular weight. The observation that urine from tumor-bearing mice contains increased concentrations of this growth factor compared to normal urine suggests that a similar relationship may exist for human urine.

Tumour angiogenesis factor in urological cancers.

The presence of a tumour angiogenesis factor (TAF) was investigated by bioassay and radioimmunoassay (RIA) in tissue and urine from patients with a variety of urological cancers. TAF was present in the majority of tumours studied by both methods and absent from controls. Our results suggest that RIA of urine for TAF may be applicable as a screening test for bladder cancer.