Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors.

Antiangiogenic drugs are currently tested in haematological malignancies. As these drugs target different angiogenic regulators, and as cancers are inherently heterogeneous, a detailed characterization of angiogenesis in individual cancers is needed. Hence, we measured bone marrow microvessel density (MVD), plasma concentrations of eight angiogenesis-related parameters and the expression in blood mononuclear cells of 40 angiogenesis-related mRNAs in 93 patients with haematological neoplasias (acute myeloid leukaemia; chronic lymphatic leukaemia; multiple myeloma (MM); or non-Hodgkin's lymphoma (NHL)) before start and after completion of cancer therapy. Compared with healthy individuals, the patients had significantly increased bone marrow MVD, especially patients with advanced stage disease. A novel finding was that patients with NHL also had increased bone marrow MVD. The plasma levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6 and IL-8 were significantly increased. VEGF levels were highest in those who did not achieve complete remission after cancer therapy. The mRNA expression of IL-8 was upregulated 15-fold. Our data show that patients with haematological malignancies have increased bone marrow MVD; hence, supporting the notion that bone marrow angiogenesis plays a role in the pathogenesis and progression of these cancers. VEGF, IL-6 and IL-8 seem to contribute to the malignant phenotype.

Differential impact of conventional-dose and low-dose postmenopausal hormone therapy, tibolone and raloxifene on C-reactive protein and other inflammatory markers.

BACKGROUND: Postmenopausal hormone therapy (HT) is associated with an increased risk for arterial and venous thrombosis. OBJECTIVES: To compare the impact of HT, tibolone, and raloxifene on C-reactive protein (CRP) and other inflammatory markers, and to investigate possible underlying mechanisms for changes in CRP and D-dimer. METHODS: Two hundred and two healthy women were randomly assigned to treatment for 12 weeks with either low-dose HT containing 1 mg of 17beta-estradiol and 0.5 mg of norethisterone acetate (NETA) (n = 50), conventional-dose HT containing 2 mg of 17beta-estradiol and 1 mg of NETA (n = 50), 2.5 mg of tibolone (n = 51), or 60 mg of raloxifene (n = 51). RESULTS: CRP increased in the conventional-dose HT and low-dose HT groups. These changes were significantly more pronounced in the conventional-dose HT group (RMANOVA, P = 0.02). Also, tibolone was associated with an increase in CRP, in contrast to raloxifene, which reduced CRP. Reductions in levels of Lp(a), intercellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin, monocyte chemotactic protein 1 (MCP-1) and interleukin-6 (IL-6) were observed in all treatment groups. The changes were most pronounced for the conventional-dose HT group, and least pronounced for the raloxifene group, whereas the changes in those allocated to tibolone and low-dose HT were intermediary. Increased levels of tumor necrosis factor (TNF)-alpha and von Willebrand factor (VWF) were seen in the raloxifene group. We observed positive associations between changes in IL-6, VWF, MCP-1, and CRP. CONCLUSIONS: The regimens had markedly different impacts on markers of inflammation. The average increase in CRP was not accompanied by increases in the average levels of IL-6, TNF-alpha or other markers, but women with large reductions in IL-6 had reduced increases in CRP.