Klinički i morfometrijski pokazatelji terapijskog odgovora kod hronične mijeloidne leukemije
Committee membersPopović, Stevan
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PURPOSE: Research aim of this dissertation is to examine and determine the rates of cytogenetic and molecular responses in patients with chronic myeloid leukemia as well as identification of clinical and laboratory parameters that influence clinical course of the disease and achievement of complete cytogenetic and major molecular response to therapy. Also, the goal of this dissertation is determination and comparison of the basic morphometric parameters of bone marrow angiogenesis for studied groups of patients in order to prove the difference in the degree of angiogenesis, as well as identification of prognostic morphometric parameters of angiogenesis affecting the achievement of complete cytogenetic and major molecular responses. Thesis also includes development and comparison of regression predictive models in which single morphometric parameters of angiogenesis were added to the basic clinical parameters in order to increase the accuracy of prediction of complete cytogen...etic and major molecular responses to therapy. METHODOLOGY: This research included 40 patients with chronic myeloid leukemia Philadelphia positive in chronic phase and 20 patients with Hodgkin's and non-Hodgkin's lymphoma in which there was no evidence of lymphoma infiltration of the bone marrow, which were treated at the Clinic of Hematology and Clinical Immunology of the Clinical Center Niš. Morphometric analysis of the microvascular structure of the bone marrow has been performed on biopsy specimens of all patients. Immunohistochemical CD34 stained microscopic preparations have been analyzed on Leica DMR microscope with a digital camera using the direct digitization. Quantification of the digital images was performed using software (ImageJ software, National Institutes of Health, USA) on a personal computer. Firstly total number of microvascular structures by optical field has been determined. For every countable microvascular structure that has been identified, the size dependent and shape dependent morphometric parameters have been evaluated: major axis, minor axis, area, perimeter, feret diameter, circularity, aspect ratio, roundness and solidity. 9 RESULTS: In the study group of patients the cumulative rate of complete cytogenetic response was 75%, and of major molecular response 57.14%. Clinically positive prognostic factors for achieving a complete cytogenetic response have been indentified: the presence of less than 3% of peripheral blasts, less than 4% of the peripheral basophils and less than 4% of basophils in the bone marrow, while the presence of less than 4% of the peripheral basophils was positive prognostic factor for reaching major molecular response (p <0.01). Comparison of angiogenesis morphometric parameters among investigated groups of patients has shown that the microvascular density and all the parameters of size and shape were higher in the chronic phase of chronic myeloid leukemia group compared to controls. The prognostic significance of parameters of angiogenesis in relation to the achievement of a complete cytogenetic response have been analysed and the following positive prognostic factors have been indentified: the value of microvascular density less than 9, the length of the minor axis less than 10 μm, the area less than 350 μm2, circularity less than 0.5, the roundness the blood vessel less than 0.35 and the aspect ratio more than 3.5 (p <0.01). In the study group of patients multiple logistic regression models have been developed with the aim of predicting a complete cytogenetic response after 6, 12 and 18 months of treatment, the cumulative rate of the complete cytogenetic and major molecular responses. In contrast to the basic model that is solely based on EUTOS score, models including morphometric parameters of angiogenesis were superior predictors of treatment response. CONCLUSIONS: The study is significant for understanding of the clinical importance of angiogenesis in patients with chronic myeloid leukemia. Results of the dissertation provide an explanation of the prognostic significance of some basic clinical, laboratory and morphometric parameters of bone marrow angiogenesis in predicting the achievement of cytogenetic and molecular responses to therapy in patients with chronic myeloid leukemia. Results obtained in this research indicate that the addition of individual morphometric parameters of blood vessels to standard prognostic scoring system increases the accuracy of prediction of complete cytogenetic and major molecular responses. Early identification of patients who will not achieve complete cytogenetic and major molecular responses may indicate patients with a significantly higher risk of disease progression and shorter survival which implies the necessity of closer monitoring and early therapeutic intervention.