Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-ß signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).

Immunohistochemical Evaluation of Angiogenesis and Cell Proliferation in Tongue Squamous Cell Carcinoma.

OBJECTIVES: Squamous cell carcinoma (SCC) is the most common malignant neoplasm of the oral cavity and a public health threat. Tumor progression is believed to be influenced by angiogenesis as well as tumor cell proliferation; however, the correlation of these two factors in tongue SCC still remains unclear. This study aimed to assess the correlation of these two factors in tongue SCC. MATERIALS AND METHODS: Twenty-four paraffin block sections of tongue SCC were stained with monoclonal antibodies against CD105 and Ki-67. In order to assess the expressions of CD105 and Ki-67 to evaluate CD105 microvessel density (MVD), positively stained microvessels were counted in a predominantly vascular area (hot spot) in each specimen at ×400 magnification. The proliferation index was expressed as a percentage of Ki-67 positive cells. Data were analyzed by t-test and Pearson's correlation coefficient (P<0.05). RESULTS: The CD105 MVD was related to histological grading as well as Ki67 labeling index (LI; P= 0.045 and P=0.047, respectively). Both CD105 MVD and KI67 LI were unrelated to sex (P=0.41 and P=0.78, respectively) and age (P=0.20 and P=0.36, respectively) of the patients. No correlation was found between CD105 MVD and Ki67 LI (P=0.86). CONCLUSION: The mean CD105 MVD was significantly lower in poorly differentiated tumors. This finding suggests that CD105 MVD may serve as a valuable prognostic factor in tongue SCC. Absence of correlation between MVD and tumor cell proliferation indicates that these processes may be guided by unrelated mechanisms.