Kliničko značenje urokinaznog aktivatora plazminogena i njegovog inhibitora PAI-1 u bolesnika s diferenciranim karcinomom štitnjače

Horvatić Herceg, Gordana (2010) Kliničko značenje urokinaznog aktivatora plazminogena i njegovog inhibitora PAI-1 u bolesnika s diferenciranim karcinomom štitnjače. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Higher levels of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) are linked to the poor prognosis in a variety of malignances. Aim of the present study was to investigate the expression and clinical relevance of uPA and PAI-1 in differentiated thyroid cancer. Patients and methods: Analysis prospectively included 128 patients with thyroid tumors, among them 105 patients with differentiated thyroid carcinoma, 2 patients with anaplastic carcinoma and 21 patient with thyroid adenoma, who underwent surgery between 2002. and 2008. uPA and PAI-1 in paired cytosol samples of thyroid tumor and normal tissue were determined using enzyme-linked immunosorbent assay and correlated to the known prognostic features. Results: Both uPA and PAI-1 concentrations were significantly higher in differentiated thyroid tumors (uPA = 0.509±0.767 and PAI-1 = 6.337±6.415 ng/mg protein) than in normal tissue (uPA = 0.237±0.051, P<0.001 and PAI-1 =2.368 ±0.418 ng/mg protein, P<0,001) with positive correlation of the two proteins in the tumors (Pearson r=0.817, Spearman ρ=0.475, P<0.001). Both proteins’ concentrations were significantly different among various histological grades (uPA P =0.031 and PAI-1 P<0.001), showing higher values in higher tumor grades. uPA and PAI-1 were significantly higher if extrathyroidal invasion (uPA P=0.015, PAI-1 P <0.001) or distant metastases (PAI-1 P<0.001) had been present, and in tumors whose size exceeded 1 cm in diameter (uPA P=0.002 and PAI-1 P=0.001). Only uPA, but not PAI-1 was significantly higher in multicentric vs. solitary tumors (P=0.015). The differences of uPA and PAI-1 did not reach the significant level when patients with differentiated tumors below and above 40 years of age had been compared and in lymph node positive tumors compared to lymph node negative tumors. Survival analysis revealed the significant impact of both uPA and PAI-1 on the Progression-Free Survival (PFS) (82.22 vs. 49.478 months for patients with low and high uPA, respectively, P < 0.001; 8.068 vs. 44.964 months for patients with low and high PAI-1, respectively, P<0.001). Univariate analysis showed that sex (P= 0.025), tumor size (P<0.001), gradus (P<0.001), extrathyroid invasion (P<0.001), local lymph nodes involvement (P<0.001), distant metastases (P<0.001), uPA (P<0.001) and PAI-1 (P<0.001) were significant predictors of PFS, whereas age (P=0.56), histopathological variant (P= 0.206), and multifocality (P= 0.365) were not. Multivariate analysis confirmed that distant metastases (P = 0.037), tumor tissue uPA (P= 0.009), and PAI-1 (P= 0,06) were strong independent predictors of PFS in patients with differentiated thyroid carcinoma. Conclusion: The correlation of high uPA and PAI-1 with the known prognostic factors of poorer outcome and with lower PFS rate in patients with differentiated thyroid cancers proved that these proteins could be an additional prognostic parameter.

Abstract in Croatian

Visoke vrijednosti urokinaznog aktivatora plazminogena (uPA) i njegovog inhibitora PAI-1 povezane su s lošom prognozom različitih malignih tumora. Cilj rada bio je istražiti ekspresiju i klinički značaj uPA i PAI-1 u diferenciranom karcinomu štitnjače. Bolesnici i metode: U rad je bilo prospektivno uključeno 128 bolesnika s tumorom štitnjače, od toga 105 bolesnika s diferenciranim karcinomom štitnjače, 2 bolesnika s anaplastičnim karcinomom, te 21 bolesnik s adenomom štitnjače. uPA i PAI-1 su određeni u citosolu tumora, kao i u citosolu pripadajućeg zdravog tkiva, koristeći ELISU, te uspoređeni s poznatim prognostičkim čimbenicima. Rezultati: koncentracije uPA i PAI-1 su značajno više u citosolu diferenciranih karcinoma štitnjače (uPA = 0,509±0,767 i PAI-1 = 6,337±6,415 ng/mg proteina), nego u pripadajućem normalnom tkivu štitnjače (uPA = 0,237±0,051 ng/mg, P<0,001 i PAI-1 =2,368 ±0,418 ng/mg P<0,001). Nađena je značajna pozitivna korelacija promatranih proteina u malignom tumorskom tkivu (Pearson r=0,817, Spearman ρ=0,475, P<0,001). Oba proteina su značajno različita u različitim histološkim gradusima (P=0,031, odnosno P<0,001), pokazujući više vrijednosti u višim gradusima. Usporedbom citosola tumora > 1cm i tumora ≤ 1 cm nađene su značajno veće koncentracije uPA (P=0,002) i PAI-1 (P=0,001) u tumorima > 1 cm. Nađena je značajno veća koncentracija uPA u multicentričnim tumorima (P=0,015), te povišena vrijednost PAI-1 u bolesnika s udaljenim metastazama, u odnosu na one bez metastaza (P<0,001). uPA i PAI-1 su značajno viši u diferenciranim karcinomima štitnjače ako je prisutna ekstratireoidna invazija (P za uPA=0,015, P za PAI-1 <0,001). Nije nađena statistički značajna razlika uPA i PAI-1 u uzorcima bolesnika starijih i mlađih od 40 godina, kao niti skupine bolesnika s pozitivnim u usporedbi s onima s negativnim limfnim čvorovima. Kaplan-Meierove krivulje preživljenja pokazuju značajan utjecaj uPA i PAI-1 na preživljenje bez progresije (PFS) 82,22 vs. 49,478 mjeseci u bolesnika s niskim, odnosno visokim uPA, P<0,001; te 87,068 vs. 44,964 mjeseci u bolesnika s niskim, odnosno visokim PAI-1; P<0,001. Univarijatnom analizom nađeno je da slijedeće varijable imaju utjecaj na preživljenje bez progresije diferenciranih tumora: spol (P=0,025), veličina tumora (P<0,001), gradus (P<0,001), ekstratireoidna invazija (P<0,001), pozitivni limfni čvorovi (P<0,001), udaljene metastaze (P<0,001), uPA u tumorskom tkivu (P<0,001) i PAI-1 u tumorskom tkivu (P<0,001), dok dob (P=0,56), histološki tip diferenciranih tumora (P=0,206) i multicentričnost tumora (P=0,365) nemaju značajan utjecaj na PFS. Multivarijatnom analiza potvrdila je da su udaljene metastaze (HR 11,654, 95% CI 1,162-116,898, P=0,037), uPA u tumorskom tkivu (HR 1,987, 95% CI 1,188-3,326, P=0,009) i PAI-1 u tumorskom tkivu diferenciranih tumora (HR 1,131, CI 1,037-1,234, P=0,006) neovisne varijable koje imaju utjecaj na PFS. Zaključak: Povezanost povišenih vrijednosti uPA i PAI-1 u bolesnika s karcinomom štitnjače i standardnih prognostičkih čimbenika lošeg ishoda bolesti, te povezanost uPA i PAI-1 s kraćim preživljenjem bez progresije, ukazuju na prognostički značaj uPA i PAI-1.

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