Authors evaluated some markers of angiogenetic activity in patients with chronic myeloproliferative diseases (CMDs). In this study by using a cytofluorimetric analysis we evaluated circulating endothelial progenitor cells (EPCs) in patients with chronic myeloproliferative disease. Moreover, in the same group of subjects, we evaluated serum levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR2). In our patients, we have found an increase in the number of endothelial progenitor cells in primary myelofibrosis (PMF) and polycythaemia vera (PV) patients, while an increase of circulating endothelial cells (CECs) was found in all patients with CMD. Moreover, we found higher serum levels of VEGF with respect to control subjects in every group of patients with CMD, and a not significant reduction of VEGFR2 levels in essential thrombocythaemia (ET) patients. A correlation was also found in PV patients between VEGF levels and erythrocyte number and in PMF subjects with the count of white cells. Our data suggest that some markers of angiogenesis are activated in CMD patients and angiogenesis may have a role in the pathophysiology of chronic myeloproliferative disorders.
Osteonecrosis of the jaw is an unremitting adverse outcome associated with bisphosphonate therapy in patients with multiple myeloma or bone metastases from solid tumors. Twelve patients who presented with exposed bone associated with bisphosphonates were reviewed to determine the type, dosage and duration of their bisphosphonate therapy, presenting findings, comorbidities and the event that incited the bone exposure. The discontinuation of bisphosphonate therapy has not helped reverse the presence of osteonecrosis, and the surgical manipulation of the involved site appears to worsen the underlying bone pathology. Hyperbaric oxygen, which has proven efficacious in other forms of osteonecrosis by establishing an oxygen gradient, is of no definitive benefit to patients with bisphosphonate-induced exposed bone. Antibiotic therapy is useful in controlling pain and swelling but ineffective in preventing the progression of the exposed bone. To date, prevention is the only currently possible therapeutic approach to the management of this complication.
Osteonecrosis of the jaws (ONJ) associated with the use of bisphosphonates is a newly described entity. To elucidate the mechanism leading to ONJ and to test the hypothesis that in patients with ONJ the bisphosphonates may interfere with endothelial cell proliferation, using flow cytometric analysis we evaluated the number of circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in eight patients with bisphosphonate treatment and osteonecrosis, eight multiple myeloma (MM) patients with bisphosphonates treatment without ONJ and five normal subjects. MM patients showed an increase of CD34+ cells with respect the control subjects and ONJ subjects. EPCs and CECs were higher in MM patients compared to controls and ONJ patients. ONJ patients showed a decrease of EPCs compared to control subjects while CECs were similar to the controls group. Our results seem to show the possibility that bisphosphonates could have a antiangiogenic effect and a suppressive effect on CECs of patients with ONJ.
The system involving angiopoietin-2 (Ang-2) and its receptor, Tie-2, appears to play an important role not only in tumor angiogenesis, but also in the biology of haematological and non-haematological malignancies. In the present study we evaluated the serum levels of soluble Ang-2 (sAng-2) and soluble Tie-2 (sTie-2) in patients with haematological malignancies. Measurements were carried out in 15 patients with chronic myeloid leukaemia (CML), 25 with essential thrombocythemia (ET), 24 with multiple myeloma (MM) and six with monoclonal gammopathy of undetermined significance (MGUS). In addition, we correlated the levels of angiopoietins with known prognostic factors. sAng-2 and sTie-2 were quantified with enzyme-linked immunosorbent assay (ELISA). In patients with CML and MM the levels of sAng-2 were significantly higher (1686.53 +/- 936.41 pg/mL and 1917.82 +/- 1427 pg/mL, respectively) than in controls (n = 15; 996.096 +/- 414.65 pg/mL) (P < 0.01). In patients with MM sAng-2 levels were significantly increased with increasing stage of disease, from stage I to stage III (P < 0.03) and presented a trend of correlation with Beta2-microglobulin levels (r = 0.317) and grade of bone involvement. Furthermore, the levels of sAng-2 determined after 6 months of chemotherapy in CML patients were significantly lower than at diagnosis in the patients who achieved haematological remission. Circulating sTie-2 levels were increased in patients with ET (17.5 +/- 9.2 vs 9 +/- 3.5 ng/mL; P < 0.01) and in those with CML (16.29 +/- 8.7 ng/mL; P < 0.04). In conclusion, abnormal levels of sAng-2 and sTie-2 are present in some haematological malignancies. These markers may play a role in the pathophysiology of these conditions and their progression.
Angiogenesis is critical for the clinical progression of haematopoietic malignancies and depends on angiogenic factors. Angiogenin is a powerful factor produced by neoplastic cells and host microenvironment. High levels of soluble angiogenin (sAng) correlate with a poor prognosis in patients affected by acute myeloid leukaemia and myelodysplastic syndromes, but no data are available on sAng in chronic myeloproliferative disorders (CMD). Therefore, in this study we investigated the clinical significance of the angiogenin in sera of patients with chronic myeloid leukaemia (CML) (n = 14) or essential thrombocythaemia (ET) (n = 20), and correlated them with those of soluble transforming growth factor-beta(1) (sTGF beta(1)). Enzyme-linked immunosorbent assay detected (P < 0.05) higher levels of sAng in CMD compared with healthy subjects (1026.74 +/- 464.60 pg/mL and 196.00 +/- 39.90 pg/mL, respectively). The highest levels of sAng were detected in CML patients (1349.23 +/- 549.55 pg/mL). Interestingly, CML patients who achieved haematological remission after interferon therapy showed circulating levels of angiogenin significantly (P < 0.05) decreased when compared with those at diagnosis. In ET patients, levels of angiogenin (889.34 +/- 267.66 pg/mL) and sTGF beta(1) (76.69 +/-6.08 pg/mL) were higher (P < 0.05) compared with healthy controls (57.93 +/- 19.39 pg/mL). No correlation was found between levels of sAng and levels of sTGF beta(1) or platelet count among ET patients. Our results show for the first time that elevated blood levels of angiogenin feature chronic myeloid malignancies, suggesting a role of angiogenin in the pathogenesis of these diseases.
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