Tymoshenko A. Improving the efficiency of early diagnosis of metastases in the bones of the skeleton in prostate cancer

The aim of thesis was identify tumor-associated and circulating biomarkers for the assessment of the risk of PCa progression and early diagnosis of skeletal bone metastases (BM). To perform the work were used special tools and equipment: general clinical, laboratory (molecular biological, polymerase chain reaction method (to analyze microRNA indicators for reverse transcription, a ready-made TaqMan™ MicroRNA Reverse Transcription Kit (Applied Biosystems, USA) was used), radiation (computed tomography, magnetic resonance imaging, osteoscintigraphy), pathomorphological (histological (PrimoStar light microscope (Carl Zeiss, Germany)) and immunohistochemical examination of the primary tumor), methods of assessing the quality of life of patients (SF-36 scale), methods of statistical processing of results using GraphPad Prism v.8.0 (GraphPad Software Inc., USA). In the course of the work, it was identified the clinicopathological and molecular biological signs of PCa associated with the risk of progression and development of metastases to skeletal bones were identified. It was found that a high level of OPN and ON expression (> 200 H-Score points) in the tissue of the prostate in the presence of metabolic syndrome (MS) is associated with a 28% (p<0.05) decrease in the progression-free survival of patients diagnosed with BM. The relationship between the expression of microRNAs involved in the regulation of OPN and ON and the degree of PCa malignancy was established. The existence of direct correlations between the level of circulating microRNA-29b and the categories T and N (r=0.65 and r=0.59, respectively) according to TNM classification, as well as Grade Group (r=0.58) was revealed. An inverse correlation was found between the expression of microRNA-181a in the patients' serum and Grade Group (r=-0.55). For the first time it was proved that the presence of MS is associated with a high level of microRNA-29b expression against the background of a decrease in the expression of microRNA-181a. It has been determined that patients with PCa diagnosed with MS, with a microRNA-29b and -181 expression profile > 1.5 units and <3 units, develop bone metastases 32% more often than patients with microRNA-29b and -181 <1.5 units and >3.5 units, respectively. Scientific novelty: for the first time, based on the study of clinical and laboratory parameters and clinical and pathological features of the tumor process, it was proved that metabolic disorders are a key determinant of PCa progression, which determines the risk of distant metastasis to bone tissue. It has been found that the development of bone metastases of PCa in the presence of MS is associated with high levels of total PSA, alkaline phosphatase and calcium in the serum of patients. Effectiveness of implementation: theoretical and practical results of the dissertation research were put into practice in the leading institutions of Ukraine: SNE "National Cancer Institute" of the Ministry of Health of Ukraine, MNE "City Clinical Hospital No. 10" of Odesa City Council, Lviv National Medical University named after Danylo Halytskyi, ME "Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov" of the Dnipropetrovsk Regional Council, MNE "Ternopil Regional Clinical Oncological Dispansary" of the Ternopil Regional Council.