Izvanstanična cirkulirajuća DNA kao prognostički biljeg u bolesnika s limfomom [Cell-free circulating DNA (cfDNA) as a marker in patients with lymphoma]

Dujmović, Dino (2014) Izvanstanična cirkulirajuća DNA kao prognostički biljeg u bolesnika s limfomom [Cell-free circulating DNA (cfDNA) as a marker in patients with lymphoma]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Extracellular circulating DNA (cfDNA) can be found in small quantities in plasma of healthy persons; higher concentrations are found in various disorders including malignant and autoimmune diseases, myocardial infarction, trauma, inflammation and complications of pregnancy. In patients with tumors, cfDNA is of tumor origin. Although it has been studied extensively in solid cancers, there is a dearth of information on cfDNA in hematologic neoplasia. The goal of this study was to determine the concentration of cfDNA in patients with lymphoma, its relation to demographic, biologic and clinical patient and tumor characteristics and to investigate its potential role as a marker of disease activity, prognosis or response to treatment. The study was performed in 129 patients with lymphoma treated according to standard guidelines. Median age was 56 years, range 17-87; 66% were male. Twenty-nine had Hodgkin's lymphoma (HL), 93 B-NHL, 66 aggressive and 27 indolent. Forty-seven patients had B-large cell lymphoma (B-LCL). Seven had T-NHL. cfDNA concentration was determined using quantitative real-time PCR before any and at the end of treatment. cfDNA concentration is somewhat higher than in the general population (median 20.57 ng/ml vs. 12.1 ng/ml), but only 1/3 of patients had cfDNA concentrations above the highest normal values. We found no clear correlation between lymphoma type aggressivity and cfDNA concentration. In patients with NHL, cfDNA concentration correlated with unfavorable prognostic characteristics: age, LDH, beta 2 microglobulin concentration, disease stage and IPI. Correlation with beta 2 microglobulin was the strongest. In univariate analysis, patients with cfDNA concentrations above the median had worse treatment outcomes than those below the median. In multivariate analysis, cfDNA concentration was not an independent prognostic factor. In patients with HL, cfDNA concentration correlated with LDH, but neither with other tested parameters nor with treatment outcomes. At the end of treatment cfDNA concentrations were lower than at the beginning in the vast majority of patients but neither the absolute nor relative decline correlated with treatment outcomes. Measuring cfDNA oncentrations in lymphoma patients does not seem to be neither of diagnostic nor of prognostic value.

Abstract in Croatian

Slobodna izvanstanična cirkulirajuća DNA (cfDNA) može se naći u malim količinama u plazmi zdravih pojedinaca, a povišene vrijednosti opisane su u različitim kliničkim stanjima kao što su maligne i autoimune bolesti, infarkt miokarda, trauma, upale te komplikacije trudnoće. cfDNA kod bolesnika s tumorom je tumorskog porijekla. Iako je dosta istraživana u solidnih tumora, postoji puno manje podataka o cfDNA u hematoloških malignih bolesti. Cilj ovog ispitivanje je bio odrediti razinu cfDNA u bolesnika s limfomima, njenu korelaciju s demografskim, biološkim i kliničkim značajkama bolesnika i tumora te istražiti može li se koristiti kao biljeg aktivnosti bolesti, prognostički biljeg ili kao biljeg odgovora na terapiju. Ispitivanje je provedeno na skupini od 129 bolesnika s limfomima liječenih na uobičajen način. Prosječna dob ispitanika bila je 56 godina, raspon 17-87, 66% su bili muškarci. Hodgkinov limfom (HL) je imalo 29, B-NHL 93, agresivni 66, a indolentni 27. Bolesnika s B-velikostaničnim limfomom (B-LCL) je bilo 47. Sedam bolesnika je imalo T-NHL. Koncentracija cfDNA određivana je kvantitativnom lančanom reakcijom polimeraze u stvarnom vremenu prije i po završetku liječenja. Koncentracija cfDNA je nešto viša nego u općoj populaciji (medijan 20.57 ng/ml naprema 12.1 ng/ml), no svega 1/3 bolesnika ima koncentraciju cfDNA iznad gornje granice normale. Nema jasne korelacije između agresivnosti tipova limfoma i koncentracije cfDNA. U bolesnika s NHL koncentracija cfDNA korelira s nepovoljnim prognostičkim čimbenicima: dobi, LDH, koncentracijom beta 2 mikroglobulina, stadijem bolesti i IPI. Najjača je korelacija s koncentracijom beta 2 mikroglobulina. Bolesnici s koncentracijama cfDNA iznad medijana imaju u univarijatnoj analizi lošije ishode liječenja od onih ispod medijana. U multivarijatnoj analizi se koncentracija cfDNA nije pokazala neovisnim prognostičkim čimbenikom. U bolesnika s HL, koncentracija cfDNA korelira s LDH, ali ne korelira s drugim čimbenicima niti s ishodom liječenja. Koncentracija cfDNA na kraju liječenja je niža od one na početku u skoro svih bolesnika, no ni apsolutni niti relativni pad koncentracije ne koreliraju s ishodom liječenja. Određivanje koncentracije cfDNA u bolesnika s limfomima nije ni od dijagnostičkog niti od prognostičkog značenja.

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