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    ABSTRACT: The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.
    International Journal of Cancer 04/2011; 130(3):735-42. · 6.20 Impact Factor
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    ABSTRACT: Increasing evidence suggests that angiogenesis plays an important role in the pathogenesis of all major hematopoietic malignancies. For example, increased angiogenesis has been correlated with risk of progression in chronic lymphocytic leukemia and lymphomas and with poor prognosis in myeloma and myeloid metaplasia with myelofibrosis. The balance of various positive and negative angiogenic molecules determines the degree of angiogenesis in the bone marrow and elsewhere for hematopoietic cancers, with the vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) pathway identified as the most important of the known angiogenic promoters. As well as stimulating new vessel formation to promote tumor growth by conveying oxygen and metabolites, VEGF may stimulate malignant hematopoietic cell growth by paracrine and/or autocrine pathways. The use of anti-angiogenic agents, especially those which target the VEGF/VEGFR pathway, in hematopoietic malignancies appears to be an attractive therapeutic option. Newer compounds such as thalidomide analogues, farnesyl transferase inhibitors and receptor tyrosine kinase inhibitors can target the VEGF-VEGFR pathway more specifically and more potently with a low side effect profile. In the future, these agents may be most effective in combination with other modalities of treatment or as maintenance therapy in hematopoietic cancers.
    02/2011: pages 83-106;

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Oct 13, 2014