Prognostički značaj serumskog adiponektina u B-ćelijskim limfoproliferativnim bolestima

Abstract

UVOD: Predmet ovog istraživanja su B limfoproliferativne bolesti i to difuzni krupnoćelijski B limfom ( predstavnik agresivne forme nehočkinskih limfoma), folikularni limfom (predstavnik indolentne forme nehočkinskih limfoma) i multipli mijelom predstavnik agresivne lifoproliferativne bolesti. Istraživanju se šristupilo sa idejom iznalaženja novih biohemijskih markera koji bi mogli imati prognozni i/ili terapijski značaj. CILJ: Ustanoviti promene vrednosti inzulinske rezistencije i serumskog adiponektina u vreme postavljanja dijagnoze i nakon sprovedene indukcione hemioterapije kod bolesnika sa B-lelijskim nehočkinskim limfomima i multiplim mijelomom. Utvrditi da li su inicijalno izmerene vrednosti inzulinske rezistencije i serumskog adiponektina kod bolesnika sa B-ćelijskim nehočkinskim limfomom i multiplim mijelomom u korelaciji sa kliničkim stadijumom bolesti i skorom testiranog prognoznog modela. Utvrditi da li postoji povezanost terapijskog odgovora kod bolesnika sa B-ćelijskim nehočkinskim limfomom i multiplim mijelomom sa vrednostima inzulinske rezistencije i serumskog adiponektina nakon sprovedene indukcione hemioterapije.Utvrditi da li su indeks telesne mase i antropometrijski parametri (telesna visina, telesna masa, obim struka, obim kukova, procenat masne mase u ukupnoj telesnoj masi) kod bolesnika sa B-ćelijskim nehočkinskim limfomom i multiplim mijelomom u korelaciji sa skorom testiranog prognoznog modela i postignutim terapijskim odgovorom. MATERIJALI I METODE: Istraživanje je sprovedeno kao prospektivna studija u koju je bilo uključeno 85 ispitanika sa novodijagnostikovanom formom B limfoproliferativne bolesti: 25 sa difuznim krupnoćelijskim B limfomom (predstavnikom agresivne forme B-ćelijskog nehočkinskog limfoma), 25 sa folikularnim limfomom ( predstavnikom indolentne forme B nehočkinskog limfoma) i 35 sa multiplim mijelomom (predstavnik agresivne B-ćelijske limfoproliferativne bolesti). Tokom obrade prikupljenih podataka rađene su korelacije serumskog adiponektina, inzulinske rezistencije kao i antropometrijskih parametara( telesna masa, telesna visina, obim struka, obim kukova, kao i vrednosti indeksa telesne mase i udela masne mase u ukupnoj telesnoj masi) pre i posle primenjene hemioterapije uz dodatne korelacije istih varijabli sa skorovima testiranih prognoznih modela za svaku grupu ispitanika, kliničkim stadijumom bolesti i sa ostvarenim terapijskim odgovorom. Po uključenju u istraživanje, kod ispitanika u svim grupama je rađena analiza pridruženih bolesti koje su skorovane primenom Čarlsonovog indeksa komorbiditeta (Charlson comorbidity score, CCI). Osim prognoznih modela karakterističkih za svaku grupu ispitanika pojedinačno, u analize su uključeni i prognozni nutritivni indeks i neutrofilno-limfocitni indeks. Zbog evidentnog imunomodulatornog uticaja D vitamina i njegovog učešća u patogenetskim procesima maligniteta, rađene su i analize kretanja D vitamina uz korelacije sa varijablama zadatim u hipotezama istraživanja. U odnosu na statističku obradu podataka, opis uzorka i same distribucije korišćenih varijabli vršeni su putem frkvencijske statistike i analize deskriptivnih pokazatelja. Testiranje razlika varijabli pre i posle primenjene terapije je rađeno primenom t-testa (za normalno distribuirane varijable) ili Vilkoksonovog testa (za varijable koje odstupaju od normalne raspodele). Za analize korelacije normalno distribuiranih varijabli je korišćen Pirsonov koeficijent korelacije, a Spirmanov test je korišćen za korelacije varijabli koje odstupaju od normalne raspodele. Doprinosi prediktorskih varijabli ispitivanim kriterijumima su analizirani putem seta višestrukih, odnosno multiplih regresionih analiza. Grafički prikazi i same statističke analize su sprovedene u SPSS programu, verzija 22. REZULTATI: U grupi ispitanika sa difuznim B-krupnoćelijskim limfomom nije detektovano statistički značajno smanjenje vrednosti inzulinske rezistencije kao i povećanje nivoa serumskog adiponektina nakon sprovedene indukcione hemioterapije u odnosu na vrednosti izmerene u vreme postavljanja dijagnoze. U grupi ispitanika sa folikularnim limfomom je serumski adiponektin značajno višeg nivoa nakon sprovedene indukcione hemioterapije (Z = -2.63, p <0.001) u odnosu na vrednosti izmerene u vreme postavljanja dijagnoze. Kod ispitanika sa multiplim mijelomom ne postoji statistički značajno smanjenje vrednosti pokazatelja inzulinske rezistencije, dok je serumski nivo adiponektina značajno višeg nivoa nakon sprovedene indukcione terapije (Z = - 2.93, p <0.001). Kada se govori o relacijama postignutog terapijskog odgovora i vrednosti inzulinske rezistencije, značajna negativna relacija se uočava kod grupe ispitanika sa multiplim mijelomom. Naime, što su veće vrednosti HOMA-IRIn kod ove grupe ispitanika, postiže se i lošiji terapijski odgovor (ρ = -0.34, p = 0.04). Nije detektovana značajna relacija serumskog adiponektina sa postignutim terapijskim odgovorom ni kod jedne grupe ispitanika. Nije detektovana statistički značajna korelacija inicijalnih vrednosti inzulinske rezistencije i serumskog adiponektina sa kliničkim stadijumom i skorovima testiranog prognoznog modela ni kod jedne grupe ispitanika. Kada su antropometrijska merenja u pitanju, značajne negativne korelacije srednjeg intenziteta su primetne samo u grupi ispitanika sa folikularnim limfomom, gde postignut terapijski odgovor ostvaruje značajne relacije sa visinom (ρ = -0.39, p = 0.05), telesnom masom (ρ = -0.47, p = 0.02), obimom struka (ρ = -0.44, p =0.03) i obimom kukova (ρ = -0.46, p = 0.02). Ukoliko su ovi parametri više izraženi kod ispitanika pre terapije, veća je verovatnoća da će odgovor na terapiju biti lošiji. U istoj grupi ispitanika, značajne pozitivne korelacije ostvaruje telesna masa ispitanika posle terapije sa skorovima prognoznih modela FLIPI-2, PRIMA- PI. Naime, veća telesna masa ispitanika korelira sa većim vrednostima FLIPI- 2 (r = 0.42, p = 0.04) i PRIMA- PI (r = 0.42, p =0.04) skora, dakle sa lošijom prognozom. Takođe niži ispitanici grupe folikularnog limfoma, imaju veću šansu za kompletnu remisiju, sobzirom na negativnu korelaciju visine i postignutog terapijskog odgovora (ρ = -0.39, p = 0.05).ZAKLJUČAK: Iako je prediktivni značaj analiziranih varijabli (HOMA-IRIn, HOMA-IRIpp, adiponektin, promena adiponektina, prognozni nutritivni indeks, D vitamin) u svima grupama ispitanika bio očekivan, to ipak nismo uspeli da dokažemo. Ostaje na budućim prospektivno-retrospektivnim istraživanjima i meta-analizama na velikom broju obolelih od B-ćelijskih limfoproliferativnih bolesti da sprovedu konačnu validaciju prediktivnog značaja adipocitokina i inzulinske rezistencije na tok, ishod lečenja i dužinu preživljavanja.

INTRODUCTION: The subject of this research are B lymphoproliferative disorders, specifically the diffuse large-cell B lymphoma (representative of aggressive forms of non-Hodgkin's lymphoma), follicular lymphoma (representative of indolent form of non-Hodgkin’s lymphoma) and multiple myeloma as a representative of aggressive lymphoproliferative disorders. This research is approached with an intention of discovering new biochemical markers which could have a prognostic and/or therapeutic significance. GOAL: To establish changes in insulin resistance levels and serum adiponectin values at the time of diagnosis and after the applied induction chemotherapy in patients with B-leil non-Hodgkin’s lymphoma and multiple myeloma in correlation with the clinical stage of illness and the prognosis model test score. To determine if a connection exists between the therapeutic response of patients with B-cell non Hodgkin’s lymphoma and multiple myeloma and the values of insulin resistance and serum adiponectin after an induction chemotherapy is conducted. To determine if the body mass index and anthropometric parameters (height, body mass, waist circumference, hip circumference, body fat mass percentage of the total body mass) in patients with B-cell non Hodgkin’s lymphoma and multiple myeloma are in correlation with the prognosis model test score and the achieved therapeutic response. MATERIALS AND METHODS: Research was conducted as a prospective study which included 85 participants with a newly diagnosed form B lymphoproliferative illness: 25 with diffuse large cell B lymphoma (representative of aggressive form of B non Hodgkin’s lymphoma), 25 with follicular lymphoma (representative of indolent form B non Hodgkin’slymphoma) and 35 with multiple myeloma (representative of aggressive B lymphoproliferative illness). During the processing of gathered data a correlation was calculated between serum adiponectin, insulin resistance and anthropometric parameters (height, body mass, waist circumference, hip circumference, body fat mass percentage of the total body mass) before and after the applied chemotherapy with additional correlation being calculated between the same parameters and the prognosis model test score for each group of participants, clinical stage of illness and the achieved therapeutic response. After the inclusion in the study, participant comorbidities were analyzed which were scored by applying the Charlson comorbidity score (CCI). Besides the prognostic models characteristic for each individual participant group, the analysis included the prognostic nutritional index and the neutrophil lymphocyte index. Due to evident immunomodulatory influence of vitamin D and its participation in pathogenic processes of the malignancy, analysis of vitamin D level changes was done in correlation with variables given in the research hypothesis. Given the statistical data analysis, sample description and the used variable distribution itself, tests were conducted using frequency statistics and analysis of descriptive indicators. Testing of differences of variables before and after the applied therapy was done by the application of t-test (for normally distributed variables) or the Wilcoxon test (for variables that deviate from normal distribution). For analysis of correlation of normally distributed variables the Pearson coefficient of correlation was used, while the Spearman test was used for correlation of variables that deviate from normal distribution. The contribution of predictor variables to investigative criteria were analyzed with the use of a set of multiple, regression analysis. Graphic representation and the statistical analysis were conducted in the SPSS application, version 22. RESULTS:In the group of participants with diffuse large cell B lymphoma, no statistically significant reduction of insulin resistance was detected nor an increase of serum adiponectin after the applied induction chemotherapy in relation to the values measured at the time of determining the diagnosis. In the group of participants with follicular lymphoma the serum adiponectin was of a significantly increased level after the induction chemotherapy was applied (Z = - 2.63, p < 0.001) in relation to values measured at the time of determining the diagnosis. In participants with multiple myeloma there was no statistically significant decrease of insulin resistance values, while the level of serum adiponectin was significantly increased after the applied induction chemotherapy (Z = -2.93, p < 0.001). When speaking of the relation of achieved therapeutic response and the level of insulin resistance, a significant negative relation was observed in the group of applicants with multiple myeloma. Namely, the greater the values of HOMA-IRInwere in this group, the worse therapeutic response was achieved (ρ = -0.34, p = 0.04). There was no significant relation detected between serum adiponectin with the achieved therapeutic answer in any participant group. No statistically significant correlation was detected between initial values of insulin resistance and serum adiponectin on one side and the clinical stage and prognosis model test scores on the other in any of the participant groups. Looking at the anthropometric measurements, significant negative correlations of medium intensity were noted only in the participant group with follicular lymphoma, in which the achieved therapeutic response were in notable relation with height (ρ = -0.39, p = 0.05), body mass (ρ = - 0.47, p = 0.02), waist circumference (ρ = -0.44, p = 0.03) and hip circumference (ρ = -0.46, p = 0.02). If these parameters were more pronounced in participants before therapy, the possibility of worse therapeutic response was greater. In the same participant group, significant positive correlations with body mass were achieved after therapy with prognostic model scores FLIPI-2, PRIMA-PI. Namely, greater body mass of participants correlates with higher values of FLIPI-2 (r = 0.42, p = 0.04) and PRIMA-PI (r = 0.42, p = 0.04) score, therefore with a worse prognosis. Also, lower participants of the follicular lymphoma group had a greater chance of complete remission, considering the negative correlation of height and therapeutic response (ρ = -0.39, p = 0.05).CONCLUSION:Although the predictive significance of analyzed variables (HOMA-IRIn, HOMA-IRIpp, adiponectin, change in adiponectin, prognostic nutritional index, vitamin D) was expected in all participant groups,the proof was still not achieved. It is left for future prospective and retrospective researchers and meta analysis applied to a larger sample of patients suffering from B lymphoproliferative disorders to conduct a final validation of predictive significance of adipocytokines and insulin resistance to the course, treatment outcome and survival rate.