Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer
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01.10.2019 |
Iwata T.
Kimura S.
Abufaraj M.
Janisch F.
Parizi M.
Haitel A.
Rink M.
Rouprêt M.
Fajkovic H.
Seebacher V.
Nyirady P.
Karakiewicz P.
Enikeev D.
Rapoport L.
Nasu Y.
Shariat S.
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Urologic Oncology: Seminars and Original Investigations |
10.1016/j.urolonc.2019.05.019 |
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© 2019 Elsevier Inc. Objectives: To assess the role of the urokinase plasminogen activator (uPA) system as a prognostic biomarker in patients with nonmuscle invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB) with or without adjuvant intravesical therapy. Material and methods: We stained TURB tissue from 827 NMIBC patients with uPA, its receptor (uPAR) and its inhibitor (PAI-1). The status of these markers was categorized as normal vs. overexpressed using the cutoffs of 30% for uPA, 50% for uPAR, and 30% for PAI-1. Multivariable Cox regression analyses were performed to evaluate the prognostic value of these markers. Results: uPA was overexpressed in 37.7% of patients, uPAR in 44.7% and PAI-1 in 44.6%. Overexpression of these markers was associated with high tumor grade. Within a median follow-up was 60 months (interquartile range: 22–109), uPA (hazard ratio [HR]: 1.40; P = 0.006), uPAR (HR: 1.70; P < 0.001), PAI-1 (HR: 1.35; P = 0.014), and the combination of all 3 markers (HR: 3.38; P < 0.001) were associated with recurrence-free survival (RFS); uPA (HR: 1.68; P = 0.035) and the combination of all 3 markers (HR: 8.79; P = 0.005) were associated with progression-free survival (PFS). The addition of the uPA system to a base model improved the discrimination by 1.3% for RFS and 2.1% for PFS. In subgroup analyses, uPA (HR: 2.19; P = 0.018) was associated with PFS in T1G3 patients and its addition to a base model improved the discrimination by 2.5%. uPA (HR: 1.44; P = 0.019), uPAR (HR: 1.54; P = 0.006), PAI-1 (HR: 1.46; P = 0.013) and the combination of all 3 markers (HR: 3.48; P < 0.001) were associated with RFS in TaG1-2 patients and their addition to a base model improved the discrimination by 2.1%. Conclusion: uPA, uPAR, and PAI-1 are overexpressed in one-third to half of patients with NMIBC. Their overexpression is an independent prognosticator of RFS and PFS which improved the predictive accuracy of current clinicopathological characteristics. Biomarkers that capture the biological and clinical behavior of individual tumors may help personalize clinical decision-making in patients with NMIBC.
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Predictors of chronic thromboembolic pulmonary hypertension
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01.01.2018 |
Kuznetsov M.
Reshetov I.
Orlov B.
Khotinsky A.
Atayan A.
Shchedrinа M.
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Kardiologiya |
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© 2018 Limited Liability Company KlinMed Consulting. All Rights Reserved. Purpose: to elucidate predictors of development of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary artery thromboembolism (PTE). Material and methods. We included in this study 210 patients hospitalized with diagnosis of submassive and massive PTE from 2013 to 2017. In 1 to 3 years after initial hospitalization these patients were invited for control examination. According to results of this examination patients were divided into two groups: with (group 1, n=45) and without (group 2, n=165) signs of CTEPH. Severity of pulmonary artery vascular bed involvement was assessed by multislice computed tomography (MSCT) angiography and lung scintigraphy. For detection of thrombosis in the inferior vena cava system we used ultrasound angioscanning. Examination also included echocardiography. Results. In the process of mathematical analysis, the following risk factors for the development of CTEPH embolism were determined: duration of thrombotic history (group 1 - 13.70±2.05 days, group 2- 16.16±1.13 days, p=0.015), localization of venous thrombosis in the lower extremities (the most favorable - shin veins, popliteal, and common femoral veins, unfavorable - superficial femoral vein). The choice of the drug for thrombolytic and anticoagulant therapy: streptokinase and urokinase were significantly more effective than alteplase, rivaroxaban was superior to the combination of unfractionated or low molecular weight heparins with warfarin. Also, risk factors for the development of CTEPH were the initial degree of pulmonary hypertension and tricuspid insufficiency, as well as the positive dynamics of these indicators at the background of thrombolytic or anticoagulant therapy. Of concomitant diseases, significant risk factors for development of CTEPH were grade 3 hypertensive disease, diabetes mellitus, postinfarction cardiosclerosis. On the other hand, age, gender, degree of severity at the time of admission, presence of infarction pneumonia, surgical prevention of recurrent pulmonary embolism, number of pregnancies and deliveries, history of trauma and malignancies, cardiac arrhythmias produced no significant impact on the development of CTEPH.
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Effects of tranexamic acid, factor XIII, and fibrinogen on clot formation and lysis in the model of hyperfibrinolysis induced by tissue- vs urokinase-type plasminogen activator
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01.01.2018 |
Budnik I.
Morozova O.
Tsymbal A.
Shenkman B.
Einav Y.
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Gematologiya i Transfusiologiya |
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© 2018 Izdatel'stvo Meditsina. All rights reserved. Aim of the study. To compare the effects of tranexamic acid (TXA), factor XIII concentrate (FXIII) and fibrinogen concentrate on clot formation and fibrinolytic resistance in the in vitro model of hyperfibrinolysis induced by tissue-(tPA) vs urokinase-type (uPA) plasminogen activators. Materials and methods. Citrated whole blood from 28 adult healthy volunteers was supplemented with 10 μg/ mL TXA, 2 lU/mL FXIII, or 3 mg/mL fibrinogen concentrate. Hyperfibrinolysis was induced by spiking the blood with PA or uPA at their half-maximal effective concentrations (90 and 33 lU/mL, respectively). Clotting was induced by recalcification and addition of tissue factor and monitored using rotation thromboelastometry. Results. The use of TXA increased maximal clot firmness in the presence of tPA and markedly inhibited clot lysis in the presence of any of the plasminogen activators. Supplementation of blood with FXIII significantly increased clot firmness and improved fibrinolytic resistance in the presence of either PA or uPA. Supplementation with fibrinogen concentrate elicited a strikingly different effect on clot formation and lysis depending on the type of plasminogen activator. In the presence of tPA, fibrinogen concentrate significantly increased clot firmness and attenuated clot lysis. In contrast, in the presence of uPA, the use of fibrinogen markedly reduced clot firmness and promoted clot lysis. Similar effects of fibrinogen concentrate were observed in platelet-rich and microparticles-free plasma. Conclusion. In hyperfibrinolysis, effect of the hemostatic drugs significantly depends on the type of plasminogen activator used. Therefore, mechanisms of hyperfibrinolysis should be taken into consideration while administering hemostatic drugs.
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