PROGNOSTICKI CINIOCI KOD OBOLELIH OD DIFUZNOG KRUPNOCELIJSKOG B-LIMFOMA
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1 Med Pregl 2009; LXII (3-4): Novi Sad: mart-april. 171 Klinicki centar Vojvodine, Novi Sad Klinika za hematologiju I Dorn zdravlja "Dr Milorad Mika Pavlovic", Indija Laboratorija za histopatologiju, Histolab, Beograd' Strucni clanak Professional article UDK : 1o2298/MPNS U PROGNOSTICKI CINIOCI KOD OBOLELIH OD DIFUZNOG KRUPNOCELIJSKOG B-LIMFOMA PROGNOSTIC FACTORS IN PATIENTS WITH DIFFUSE LARGE B-CELL LYlvfPHOA1A Vera UZUROV-DINIC 1, Aleksandar SAVIC\ Tanja LAZAREVIC 2, Vesna CEMERIKIC-MARTINOVIC\ Danijela AGIC 1 i Stevan POPOVIC 1 Sazetak - Difuzni krupnocelijski B-limfom agresivni je limfom sa heterogenom prognozom. Cilj rada je utvrdivanje prognostickog znacaja klinicko-laboratorijskih i imunohistohemijskih cinilaca. Retrospektivnim ispitivanjem kod SO obolelih od difuznog krupnocelijskog B-limfoma utvrdivani Sl.l sledeci parametri: demografski (pol, godine starosti). klinicki (vrerne do postavljanja dijagnoze, B-simptomi. stadijum bolesti). laboratorijski (sedimentacija. hemoglobin. laktat-dehidrogenaza, albumini). internacionalni prognosticki indeks (standardni i rcvidirani). imunohistohemijski (ekspresija CD20 anti gena. bcl-2 proteina i proliferativni indeks - Ki 67). Lecenje je sprovedeno kod 72% (36) Rituksimab-Ciklofosfamid, Hidroksidaunorubicin. Vinkristin. Predniznlon i Rituksirnab Ciklofosfamid. Hidroksidaunorubicin. Vinkristin. Etopozid, Prednizolon protokolom. a kod 28% (14) bolesnika Ciklofosfamid. Hidroksidaunorubicin. Vinkristin. Prednizolon i Ciklofosfamid. Hidroksidaunorubicin. Vinkristin. Prednizolon-slicnim protokolom. Kompletna remisijaje postignuta kod 74% bolesnika. Verovatnoca petogodisnjeg prezivljavanja je 69%. Statisticki znacajna razlika u prezivljavanju utvrdena je u grupi srednje niskog i srednje visokog rizika standardnog internacionalnog prcgnostickog indeksa, u grupi bolesnika sa elobrom i losorn prognozom revidiranog internacionalnog prognostickog indeksa. i u slucajevima kornpletne remisije i drugih ishoda lecenja. Nasi rezultati pokazuju da internacionalni prognosticki indeks i prisustvo kornpletne remisije irnaju prognosticki znacai kod obolelih oel difuznog krupnocelijskog B-limfoma. Kljucne reci: Difuzni krupnocelijski B-limfom: Prognoza: Analiza prezivljavanja: Indeks tezine bolesti: Retrospektivne studije Uvod vidirani IPI (R-IPI) [7]. Navedeni klinicki prognosticki parametri su prognosticki validni i posebno Difuzni krupnocelijski B-limfom (DKBL) predstavlja primenljivi u klinickim studijarna. Medutirn, difuznu proliferaciju velikih neoplasticnih navedeni prognosticki modeli nisu dokazali klinicki B-limfocita koja je veoma heterogena, kako na znacaj u smislu poboljsanja rezultata lecenja kada klinickorn tako i na genetskom i molekularnom su primenjivani sa ciljern individualizacije terapije. nivou. Ova razlicitost je uslovljena stanjern bolesnika, prosirenoscu bolesti, podtipom difuznog krup molekularnih markera koji bi irnali prognosticki Stalni su pokusaji iznalazenja novih morfoloskih iii nocelijskog Bvlimfoma, genetskim aberacijama, ekspresijorn znacaj. i mutacijorn razlicitih gena. molekularnirn Imunohistohemijski cinioci, ekspresija bcl-2, X podgrupama definisanim profilom genske ekspresije vezanih inhibitora apoptoze, CDS, FOXP I, PKCbeta, ICAM 1, HLA DR, c-flip, povezuje se s losi [1]. To je i najcesci obi ik limforna i cini 30-40% svih limfoma kod odraslih [2]. jom prognozorn, a ekspresija bcl-6. CO 1O. LMO 2 U klasifikaciji limfoma Svetske zdravstvene organizacije sa povoljnim ishodom [I]. (WHO) u okviru DKBL navode se glavne Uvodenje monoklonskog anti-cd20 antitela ri morfoloske varijante: centroblastna, irnunoblastna, tuksimaba u terapiju DKBL dovelo je do znacajnog anaplasticna i 'l-iimfocitima/histiocitima bogata varijanta, i kao retke varijante, plazmoblastni DKBL i poboljsanja rezultata leccnja, a R-CHOP protokol ucinilo novim zlatnirn standardom prve linije terapije DKBL sa ekspresijom ALK proteina pune duzine DKBL [8,9]. [3]. Pored DKBL posebno su izdvojeni entiteti Cilj rada je utvrdivanje znacaja klinickih, laboratorijskih i imunohistohemijskih parametara u pro medijastinalni (timusni) krupnocelijski B-limfom, intravaskulni krupnocelijski B-limfom, i prirnarni gnozi toka i ishoda bolesti. efuzijski limforn [3]. Razlikovanje ovih podtipova je znacajno ne samo zbog prognoze toka i ishoda Materijal i metode nego i zbog od luke 0 terapij i s obzirorn da su na primer plazmoblastni limforn i ALK + DKBL obicno C020 negativni te se ne moze ocekivati da odgoyore na terapiju rituksimaborn. Klinicki prognostick: faktori ukljuceni u internacionalni prognosticki indeks (IPI) koriste se za procenu ishoda kod bolesnika sa DKBL preko IO godina [4]. Postoje pokusaj i modifikacije standardnog IPL kao sto su godinama prilagodeni IPI [5,6] i re- Ispitivanje je sprovedeno retrospektivnorn anali ZOIll dokumentacije bolesnika kod koj ih je dijagnostikovanje i lecenje sprovedeno od januara do februara godine 1I Klinici za bematologiju, Klinickog centra Vojvodine. Praceni Sll sledeci parametri: demografski (pol, godine starosti), klinicki (vreme do postavljanja dijagnoze, Bvsimptomi, stadijurn bolesti). laboratorij- Adresa aurora: Asist. dr Vera Uzurov-Dinic. Klinika za hematologiju Novi Sad. Hajduk Vcljkova 1-7
2 172 Uzurov-Dinic V, i sar. Difuzni krupnocelijski B-limfom Skracenice DKBL R-CHOP R-CHOEP CHOP IPI S-IPI R-IPI LDH LSAB Rezultati - difuzni krupnocelijski B-limfom - Rituksimab-Ciklofosfamid Hidroksidaunorubicin. Vinkristin (Onkovin), Prednizolon protokol - Rituksirnab-Ciklofosfamid, Hidroksidaunorubicin, Vinkristin (Onkovin). Etopozid. Prednizolon protokol - Ciklofosfarnid. Hidroksidaunorubicin. Vinkristin (Onkovin), Prednizolon - internacionalni prognosticki indeks - standardni internacionalni prognosticki indeks - revidirani internacionalni prognosticki indeks - laktat-dehidrogenaza - Labeled streptavidin biotin ski (SE, hemoglobin, laktat-dehidrogenaza (LDH), albumini), Internacionalni prognosticki indeks standardni - S-IPI [4], revidirani - R-IPI [7], i imunohistohemijski (CD 20, bcl-2, Ki-67]. Ekspresija CD20, bcl-2 i Ki-67 proteina je odredivana primenom imunohistohemijske metode LSAB (Labeled streptavidin biotin) i monoklonskog antitela na CD20, bcl-2 i Ki-67 (DAKO) pri cernu je ekspresija utvrdivana brojanjem pozitivnih celija na malom uvelicanju i primenom sledecih kriterijuma za pozitivnost: (+) > 80% pozitivnih eelija;.(+/.-) 50-80% pozitivnih celija, (-/+) 10-50% pozitivnih celija, (-) < 10% pozitivnih celija [10]. Pr.i.menjiva~ jc krjterijum za klini~k.i znacajnu ek~pre~lju bcl-2 I Ki-67 protema u slucaju pozrtrvnosti vece od 50% eel ija [II]. Ukupno vreme prezivljavanja je odredivano.o.d momenta postavljanja dijagnoze do Vreme!la.lspltlvanja iii smrtnog ishoda. Odgovor na lecenje je ocenjivan prema kriterijumima Internacionalne radne f,rupe [12].. Za obradu podataka koriscene su statisticke metode: deskriptivna statistika, Fiserov egzaktni test, Kaplan-Meier test, log-rank test. Za st'.l~isticku analizu koriscen je program Statistica verzija 7.1. Retrospektivno ispitivanje sprov~deno je kod 50 bolesnika lecenih od DKBL u periodu od januara do februara godine. Grupu je cinilo,20 zena i 30 muskaraca, prosecne starosti 54.godme (od 22 do 83 godinc) pri cernu je 18.bolesl~lka starje, a 32 ~ol.;;sni~~ mlade ad 60 g~dl~~a.. Pnm~n?m log-rank testa mje utvrdena statisticki znacajna -Tabela 1. Laboratorijski parametri u ispitivanoj grupi Fabela 1. Laboratorv parameters in the studv group Pararnetri" Uccstalcst pato- Aritmeticka Medijana Minimum Maksimum Standardna Parameters loskih rezultata sredina Median Minimum..vlaxrmum devijacija l-requencv (~lah- Standard /f()rnil1! res/ills d..: 1ruuon Se 27 (54%) LDH HB Albumini ]7(74%) 16 (52%) 10(20%) ) ~4~ *Se > 40mm/l h, LDH> '<, Hb <" 120g/J. albumin <"35g/l 'ESR> 40mm/lh, LDH > N, Hb <" 120g/J. albumin <35g/l razlika u prezivljavanju u odnosu na pol (p = 024) i zivotno doba bolesnika (p=o,16). Prosecno vreme do postavljanja dijagnoze je 2,6 (1-12) meseci, a B-simptomi su prisutni kod 76% bolesnika. Statisticka znacajnost, u odnosu na B-pozitivne i B-negativne simptome nije utvrdena, iako postoji tendencija ka kracem prezivljavanju bolesnika sa B-simptomima (log-rank test p = 0,10). Enzim LDH bio je povisen u 74%, a hemoglobin snizen kod 52% bolesnika. Sedimentacija je bila ubrzana kod 54%, a albumin snizen kod 20% bolesnika (Tabela I). Primenom log-rank testa nije utvrden statisticki znacajan uticaj na prezivljavanje povisene koncetracije LDH u serurnu, smanjene koncentracije hemoglobina i snizene serumske koncetracije albumina. Od ukupnog broja bolesnika, 78% je bilo 1I III i IV stadijumu bolesti pre pocetka lecenja (Tabela 2). Primenom log-rank testa uocena je tendencija ka statisticki znacajnoj razlici 1I prezivljavanju izrnedu bolesnika stadijuma III i IV (p=o,093), ali ne I pri drugim poredenjirna. Tabela 2. Stadijurn bolesti (Ann Arbor) kod bolesnika sa difuznim krupnocelijskirn B-limfomom Table 2. Ann Arbor staging ill patients with diffuse large 13 cell!vmphoma Stadijllll1/Stuge Bml oboklil1/.\'u old/semel! 0,,, I -I :.; II III C) ](; IV UkupnolTotal 5U IOU Zastupljenost bolesti.u limfnim cvo~ovima izi:osila je 70% (35 obolelih). Kod ostalih bolesnika (30%) bolest je zahvatila ekstralimfaticne organ~: Primenom log-rank testa litvrdeno.je. da t1~ postoj I statisticki znacajna razlika 1I prezivljavanju u odnosu na zastupljenost bolesti II limfnim cvorovirna i ekstralirnfaticnim organima (p = 0.13), Od 50 boesnika, njih 19 (38%) nije irnalo e~~st~al~odalj~ll bolest. Statisticki znacajna razlika u prezivljavanju poredenjern bolesnika sa samo nodalnorn lokalizacijn : i t olenika kod ko-ih je prisutna 1 ekstranodalra lokalizacija nije utvrdena (p = 0.20),. v' Testiranje S-IPI skora na ukupnorn broju uasih bolesnika pokazuju da je 38% nasih bolesnika u grupi visokog rizika (Tabela 3). Primenom log-rank testa utvdena je statisticki znacajll~ ra~lika ~l prezivljavanju poredenjern grupe sr~dnje niskog 1 srednje visokog rizika (p<0.04) (Grafikon 1 A). Tabela 3. Distribucija bolcsnika prcma Standardnom Internacionalnom prognostickorn indeksu (S-IPl.~ Table 3. Distribution ofpatients according J(),':tulle/ore! Internationo! prognostic index rs- IPI) erupe rizlkarisk groups hlktcmfac/or l3llieslliclfpulic'iij.1 ('~I)I Nizakll"01I" 0.1 Srednje nizak.\1ediiljii 10\1".2 \'ir~c1nie viso~!.iledilljii high 3 Visok rizik/i-li!{h 4.:'
3 Med Preg12009; LXII (3-4): Novi Sad: mart-april. 173 Tabela 4. Distribucija bolesnika prema Revidiranom internacionalnorn prognostickorn indeksu (R-IPI) Table 4. Distribution ofpatients according to Revised International prognostic index (R-IPI) Grupe rizika,risk groups Faktor/Factor Bolesnici/Patients (%) Vrlo dobar/t'er)' good a 2 Dobar/Good 1,2 36 Los/Poor ,9 :f: 0,8 Q) > ;~ 0,7 a. o ~ 0,6 :::l 0,5 0,4 A. 0 Prezivljavanje - S-IPI S-IPI 3 0,3 L..-_~~_~_~~_~ ~_~---' Prezivljavanje (Kaplan-Meier) rank testa nije utvrdena statisticki znacajna razlika u prezivljavanju u odnosu na pozitivnost bcl-2 za ukupnu grupu bolesnika (p = 0,68). a ni za bolesnike lecene samo R-CHOP i R-CHOEP terapijorn (p=0,83). Poredenjem bolesnika sa znacajnorn bcl-2 pozitivnoscu i bolesnika bez znacajne bcl-2 pozitivnosti nije utvrdena statisticki znacajna razlika u postignutim kornpletnim remisijama primenorn Fiserovog egzaktnog testa (p=0,45). U odnosu na ekspresiju Ki-67 koja je odredena kod 29 bolesnika, 10% je bilo negativno, 28% je bi 10 slabo do srednje pozitivno, a 62% je bilo izrazito pozitivno. Statisticka znacajnost u prezivljavanju u odnosu na ekspresiju Ki-67 nije utvrdena (logrank test p= 0,49). Ciklofosfamid, Hidroksidaunorubicin, Vinkristin (Onkovin). Prednizolon (CHOP) i Ciklofosfamid, Hidroksidaunorubicin, Vinkristin (Onkovin), Prednizolon-slicnirn protokolom (CHOP-like) leceno je 28% nasih ispitanika, a protokolom Rituksimab- 0,8 ~ 0.6 > in ~ 0.4 o CD '0 :::l 0,2 Prezivljavanje (Kaplan-Meier) 1,0..., l ~... '"' ~""I----+<' t ,0 D,S S,4 - R-IPI R-IPI 3 Grafikon 1. A) Prezivljavanje bolesnika po gruparna rizika Standardnog internacionalnog prognostickog indeksa (S-IP!) B) Prczivljavanje bolesnika po grupama rizika Revidiranog Internacionalnog prognostickog indeksa (R-IPI) Graph J. A) Survival according to Standard International prognostic index risk groups (S- IPf) B) Survival according to Revised International prognostic index risk groups (R-IPI) Ispitivanjern R-IPI skora ustanovljeno je da 62~0 nasih bolesnika irna losu prognozu (Tabela 4). PrJmenorn log-rank testa utvrdena je statisticki znacajna razlika u prezivljavanju poredenjern grupe bolesnika sa dobrorn i losorn prognozom (p= 0,03) (Grafikon 1 B). Od ukupnog broja bolesnika kod kojih je imu.nohistohemijski ispitivana ekspresija bcl-2 proterna, 57% je bilo pozitivno. Medutim, prirnenorn log- A 0, ,1 -KR Ostali ishodi Th g :: ~, '".~. ~ 0,6 ;o:j l!! 0,5 a. B Prezivliavanje 0,7 '1> ;11,...,11> ,3 0.0 '-'-_~_~_~_~_~_~_~_~_~_._.J Q 100 Grafikon 2. A) Prezivljavanje U odnosu na ishod terapije 81 Ukupno prczivljavanje bolesuika sa difuznim krupnocclij-kim 8-1irnfomom Graph 2. A) Survival according to treatment response B) Overall survival in patients with diffuse large B-c.ell lymphoma
4 174 Uzurov-Dinic V, i sar. Difuzni krupnocelijski B-Iimfom C iklofosfarnid, Hidroksidaunorubicin, Vinkristin (Onkovin), Prednizolon (R-CHOP) i Rituksirnab Ciklofosfamid, Hidroksidaunorubicin, Vinkristin (Onkovin), Etopozid, Prednizolon (R-CHOEP) 72%. Prema log-rank testu nije utvrdena statisticka znacajna razlika u prezivljavanju poredenjem bolesnika lecenih protokolom CHOP i CHOP-like i bolesnika lecenih R-CHOP i R-CHOEP protokolom (p = 0,98). Kompletna remisija (kompletna nepotvrdena) je postignuta kod 74% bolesnika, parcijalna remisija u 9%, a stabilna bolest iii progresija bolesti u 15%. Kod jedne bolesnice doslo je do smrtnog ishoda u prvom mesecu lecenja, Kod 4 bolesnika nije moguca evaluacija terapijskog odgovora jer su napustili lecenje. Log-rank testom utvrdena je statisticki znacajna razlika (p=0,0052) u prezivljavanju izmedu obolelih kod kojih je postignuta kompletna remisija i obolelih sa drugim ishodom terapije (Grafikon 2 A). Medijana pracenja bolesnika iznosila je 19,5 meseci, od 1 do 84 meseci. Ishod kod nasih bolesnika pokazuje sledece: od 50 bolesnika, zivo je 35 (70%), izgubljen kontakt sa 6 (12%), a 9 (18%) bolesnika je umrlo. Verovatnoca ukupnog petogodisnjeg prezivljavanja kod nasih bolesnika sa DKBL je 69% (Grafikon 2 B). Diskusija Ispitivanjem kod obolelih od DKBL pokusali srno da utvrdima prognosticki znacaj klinickih, laboratorijskih i imunohistohemijskih parametara i njihovu klinicku primenljivost kod nase bolesnicke populacije. Distribucija bolesnika po polu i starosti II ispitivanoj populaciji ne razlikuje se bitnije od podataka iz literature [13-15]. Kod obolelih od DKBL cesca je zastupljenost muskeg pola i starijeg zivotnog doba. U nasoj grupi nije bilo statisticki znacajne razlike u prezivljavanju u odnosu na zivotno doba. Razlog za ovo je verovatno manj i broj ispitanika u nasoj grupi u poredenju sa velikim multicentricnirn studijama koje su utvrdile prognosticki znacaj zivotnog doba [4,5,7,16]. Nasi bolesnici se javljaju kadaje bolest uznapredovala sa B-simptomima prisutnim kod 78% obolelih, dok po podacima iz literature, B-simptome ima manje od 50% bolesnika [4]. Veoma veliki broj obolelih (78%) dijagnostikovan je 1I III i IV stadijumu bolesti prema Ann Arbor klasifikaciji, sto takode ukazuje da je dijagnoza bolesti veoma kasno postavljena. Prema podacima iz literature, III i IV stadijum bolesti nalaze se kod ne vise od 50% bolesnika [16,17]. lako mi ne nalazimo statisticki znacajnu razliku u prezivljavanju u odnosu na stadijum bolesti, ipak postoji tendencija ka razlici u prezivljavanju izmedu bolesnika stadijurna III i IV. U velikim studijama dokazan je prognosticki znacaj stadijuma bolesti [4-6]. Zbog malog broja bolesnika u grupi obolelih stadijuma I i II umanj ila je znacaj statistickog ispitivanja. Cinjenice 0 uznapredovaloj bolesti kod nasih bolesnika namecu zakljucak 0 potrebi rada na unapredenju zdravstvene sluzbe od primarne do tercijarne, kao i na edukacij i stanovnistva. Povisen nivo enzima laktat-dehidrogenaze, snizen nivo hemoglobina i ubrzana sedirnentacija nalaze se kod vise od polovine obolelih, sto je slucaj i kod bolesnika u drugim studijama [17-191madaje broj obolelih sa snizenim nivoom albumina manji u nasoj grupi bolesnika i iznosi oko 20%. U odnosu na ekspresiju imunohistohemijskog markera bcl-2 nije utvrdena statisticki znacajna razlika u prezivljavanju. Dosadasnja ispitivanja prognostickog znacaja ekspresije antiapoptoickog proteina bcl-2 dala su protivrecne rezultate. Neke studije su pokazale nepovoljan prognosticki znacaj prisustva bcl-2 proteina [16-19], dok druge studije ne potvrduju ovaj nalaz [20.21]. Dodatni problem je sto su u navedenim studijama korisceni razliciti kriterijumi za pozitivnost bcl-2 i razlicite metode za njegovo utvrdivanje. Visok proliferativni indeks ispitivanjern ekspresije Ki-67 irnalo je 62% ispitanih bez uticaja na prezivljavanje. Rezultati ispitivanja ekpresije Ki-67 su kontroverzni, a visoka ekspresija Ki-67 bila je znak lose [22], dobre prognoze [23]. iii nije imala uticaj na prezivljavanje [24]. Nas nalaz se moze objasniti i cinjenicorn da agresivni, visoko proliferativni tumori cesto dobro reaguju na terapiju. Pored navedenih imunohistohemijskih parametara ispitivan je prognosticki znacaj drugih imunohistohemijskih, genetskih i rnolekulskih cinilaca [I]. rnedu kojima je II poslednje vrerne veliki znacaj dat ispitivanju profila genske ekspresije. Ovorn metcdom kod bolesnika sa DKBL utvrdene Sll dye osnovne grupe [25]. Prva grupa je porekla genninativnog centra (germinative center GC like), a druga porekla aktivisanih B-limfocita (activated B-cell-ABC-like), kao i treca grupa cije je poreklo nejasno definisano [26,27]. Druga grupa je imala losiju prognozu II odnosu na prvu grupu [25]. Medutim, primena rituksimaba II lecenju izbrisala je ovu razliku [28]. Vrsta primenjene terapije (CHOP i CHOP-like versus R-CHOP i R-CHOEP) nije statisticki znacajno uticala na prezivljavanje 1I nasem ispitivanju. Ova razlika u odnosu na publikovane rezultate velikih studija [7,8], kao i rezultate domacih autora [29] verovatno je posledica manjeg broja ispitanika kod nas. Prognosticki znacaj su i Ll nasoj grupi pokazali standardni i revidirani internacionalni prognosticki indeks. Internacionalni prognosticki indeksi SLl sireko prihvaceni prognosticki sistemi 1I DKBL [4-7]. sto potvrduje i nase ispitivanje. Kompletna rernisija je postignuta kod 74% bolesnika i pokazano je statisticki znacajno duze prezivljavanje ove grupe u odnosu na bolesnike s drugim terapijskirn ishodirna. Ovo je 11 skladu sa podacima iz literature koji ukazuju na veorna losu prognozll bolesnika kod koj ih nije postignuta kornpletna rernisija [30]. Kompletnu remisiju moguce je
5 Med Pregl 2009; LXII (3-4): Novi Sad: mart-april. 175 preciznije odrediti primenom pozitronske errusione tomografije sa [18FJfluoro-2-deoksi-O-glukozom (FOG-PET) nakon sprovedene terapije [31,32J iii u ran oj fazi lecenja [33J. Na osnovu FOG-PET razvijaju se strategije individualizacije lecenja u ranijim fazama nakon sprovedenih dva do cetiri ciklusa terapije. Zakljucak Nasi rezultati su jasno pokazali da Internacionalni prognosticki indeks, standardni i revidirani imaju prognosticki znacaj i da je njihova primena opravdana i kod nase populacije bolesnika. Potvrdena je i cinjenica da bilo koji terapijski ishod osim kompletne remisije ima veoma nepovoljnu prognozu. Neophodno je dalje pracenje ove populacije bolesnika uz ukljucivanje novih bolesnika kako bi se u duzem vremenskom periodu i na vecern broju ispitanika realnije sagledao znacaj ispitivanih parametara. Sem toga, uvodenjern novih dijagnostickih procedura kao sto je pozitronska emisiona tomografija sa [18FJ fluoro-2-deoksi-o-glukozom sken i preciznijim klasifikovanjem difuznog krupnocelijskcg B-limfoma mozda cerno u buducnosti moci da lecenje prilagodimo bolesniku i da postignemo bolje rezultate. Literatura I. Stein H. How to translate molecular prognostic markers into clinical practice. Hematology education: the education program for the annual congress. Copenhagen: European Hematology Association: 2008:2: Salles G. Treating diffuse large B-cel1 lymphoma: optimising the use of anti-cd20 antibodies. Hematology education: the education program for the annual congress. Copenhagen: European Hematology Association: 2008:2: Brunning RD. Bennett JM. Flandrin G. Matutes E. Head D. Vardiman JW. et al. Mature B-cell neoplasms. In: Jaffe ES. Harris NL Stein H. Vardiman JW. editors. World Health Organization classification of tumours: pathology and genetics of tumours of haemutopoietic and lymphoid tissues. Lyon: IARC Press: 200 I. p The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non Hodgkin's lymphoma. N EnglJ Med. 1993:329: Shipp MA. Prognostic factors in aggressive non-hod :;kin's lymphoma: who has 'high-risk' disease') Blood 1994:83: Hamlin PA. Zelcnetz AD. Kewalramani T. Qin J. Satagopan JM. Verbcl D. et al. Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma. Blood 2003: 102: Sehn LH. Berry B. Chhanabhai M. Fitzgerald e. Gill K. Hoskins P. et al. The revised International Prognostic Index (R IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R CHOP Blood 2007: I09: Fcugier P. Van Hoof A. Sebban e. Solal-Celigny P. Bouabdallah R. Ferrne C. ct al. Long-term results of the R CHOP study in the treatment of elderly patients with diffuse l;l..ge Bvce'J lymphoma: a study by the Groupe d'etude des lyrnphornes de l'adulte. J Clin Oncol. 2005:23: Pfeundschuh M. Trumper L Osterborg A. Pettengell R. Trneny M. Imrie K. et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good prognosis diffuse large-b-cell lymphoma: a randomized controlled trial by the MahThera International Trial (M!nT) Group. Lancet Oncol 2006:7: Bain B. Clark D. Lampert I. Wilkins B. Bone marrow pathology. 3 rd ed. Oxford: Blackwell Publishing; Grange F. Petrella T. Beylot-Barry M. Joly P. D'lncan M. Delaunay M. et al. Bel-2 protein expression is the strongest independent prognostic factor of survival in 'primary cutaneous large B-cel! lymphomas. Blood 2004:103: Cheson BD. Horning SJ. Coiftier B, Shipp MA. Fisher RI. Connors.1M. et al. Report of an International workshop to standardize response criteria for non-hodgkins lymphomas. J Clin Onco! 1999:17: Menendez P. Vargas A. Bueno e. Barrena S. Almeida J. De Santiago M. et al Quantitative analysis of Bcl-2 expression ill normal and leucernic human B-cell differentiation Leukemia 2004:18: Winter.TN. Andersen.J. John RC. Krajewski S. Variakojis D. Bauer KD. et al. Bcl-2 expression correlates with lower proliferative activity in the intermediate- and high-grade nonhodgkins lymphomas: an Eastern cooperative oncology group and Southwest oncology group cooperative laboratory study. Blood. 1998:9: Sweeten ham JW. Diffuse large Bvccll lymphoma: risk stratification and management of relapsed disease Hematology 2005 :2005 : Maartensea E. Kramerb MHH. Le Cessicc S. Kluin Nelernansd.Ie. Kluine PM. Snijderf S. et al, Lack of prognostic significance of bel2 and p53 protein ovcrexpression in elderly patients with diffuse large B-cell non-hcdgkins lymphoma: results from a population-based non-hodgkius lymphoma registry. Lcuk Lymphoma 2004:45: Gascoyne RD. Adomat SA, Krajewski S. Krajewska M. Horsman DE. Tolchcr AW. ct al. Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-hodgkins lymphoma. Blood 1997:90: Hill ME. Macl.ennan KA. Cunningham DC. Vaughan Hudson B. Burke M. Clarke P. et al. Prognostic significance of Bcl-2 expression and Bcl-2 major breakpoint region rearrangment in diffuse large cell non-hodgins lymphoma. Blood, 1996: 88: Olivier H. Haioun C. Lepage E. d'agay MF. Briere J. I.avignac C. et al. Prognostic Significance or BcI-2 protein expresion in aggressive non-hodgkins lymphoma. Blood. 1996: 87: Wilson WHo Teruya-Feldstein J. rcsl T. Harris c. Steinberg SM. Jaffe ES. et al. Relationship of p53. Bcl-2. and tumor proliferation to clinical drug resistance in non-i lodgkins I; 111 phornas. Blood 1997:89:601-9.
6 176 Uzurov-Dinic V, i sar. Difuzni krupnocelijski B-Iimfom 21. Piris MA, Pezella F, Martinez-Montero Jc, Orradre JL, Villuendas R, Sanchez-Beato M, et al. P53 and Bcl-2 expression in high-grade B-cell lymphomas: correlation with survival time. Br J Cancer 1994:69: Jerkeman M. Anderson H. Dictor M. Kvaloy S. Akerman M. Cavallin-Stahl E. Assessment of biological prognostic factors provides clinically relevant information in patients with diffuse large B-cell lymphoma: a Nordic lymphoma group study. Ann Hematol 2004: 83(7): Hasselblom S. Ridell B. Sigurdardottir M, Hansson U. Nilsson-Ehle H. Andersson P. Low rather than high Ki-67 protein expression is an adverse prognostic factor in diffuse large B-cell lymphoma. Leuk Lymphoma. 2008:49(8): Llanos M. Alvarez-Arguelles H, Aleman R. Oramas.I. Diaz-Flores L. Batista N. Prognostic significance of Ki-67 nuclear proliferative antigen, Bcl-2 protein. and p53 expression in follicular and diffuse large B-cell lymphoma. Med Oncol 2001;18(1): , 25. Alizadeh A. Elsen M, Davis R. Ma C. Lossos IS, Rosenwald A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000:4051 : Rosenwald A. Wright G. Chan Wc, Connors JM. Campo E. Fisher RI. et a!' The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma. N Engl.I Med 2002:346: Wright G. Tan B, Rosenwald A, Hurt E. Wiestner A. Staudt L. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA. 2003;100: Nyman H. Adde M, Karjalainen-Lindsberg ML. Taskinen M. Berglund M: Amini RM. et al. Prognostic impact of irnmunohistochernically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunechemotherapy. Blood 2007: I 09: Mihaljevic B. Sretenovic S. Jancic-Nedeljkov R. Jankovic S. Andelic B. Jakovic Li, i dr. Rezultati visegodisnjeg pracenja bolesnika sa difuznim B krupnocelijskirn limfornom (DBKL) lecenih CHOP/CHOPLIKE hemioterapijom ± rituxima [abstract]. Bilt Hematol 2007:35(3 ):4~. 30. Haw R. Sawka CA, Franssen E. Berinstcin NL. Significance of a partial or slow response to front-line chemotherapy in the management of intermediate-grade or high-grade non Hodgkin's lymphoma: a literature review..i Clin Oneal 1994: 12: Mikhaeel NG. Timothy AR. O'Doherty MJ. HaiJ! S. Maisey MN. 18-FDG-PET as a prognostic indicator in the treatment of aggressive non-hodgkin's lymphoma-comparison with CT. Leuk Lymphoma 2000;39: Spaepen K. Stroobants S. Dupont P. Van Steenweghen S. Thomas J. Vandenberghe P. et a!' Prognostic value of positron emission tomography (PET) with fluorine-l ~ fluorodeoxyglucose ([18F]FDG) after first-line chemotherapy in non-hodgkin's lymphoma: is [18F]FDG-PET a valid alternative to conventional diagnostic methods').j Clin Oneal 200 I:] 9: Haioun C. lui E. Rahmouni A. Brice P. Rain.rD. BeIhadj K. et a!' [I8F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma an early prognostic tool for predicting patient outcome. Blood 2005: 106: Summary Diffuse large B-cell lymphoma is an aggressive type of lymphoma, potentially curable, with heterogeneousprognosis. The aim ofthis study was to determine prognostic significance ofclinical, laboratory and immunohystochemicalfactors. The retrospective study was done in 50 patients with diffuse large B-cell lymphoma. The following parameters were investigated: demographic (age, sex), clinical (time to diagnosis, B symptoms, clinical stage), laboratory (erythrocyte sedimentation rate, haemoglobin, lactate dehydrogenase, albumine), standard and revised international prognostic index, and immunohystochemical parameters, cluster designation 20. B-cell-2, and Ki67 expression. There were 20 females and 30 males, their average age being 54 (22-83) years. The majority ofpatients had advanced disease: B symptoms in 76%, III and IV stage in 78%, increased lactate dehydrogenase in 74%, high risk standard international prognostic index in 62% ofpatients. B-cellieukemia/(vmphoma 2 expression was found in 57%, and high Ki67 in 62% of patients. Rituximab-Cyclophosphamide. Hydroxydaunornb.cin. I'incristine. Prednisolone and Rituximcb-Cyctophosphamide. Hydroxydaunorubicin, Vincristine. Etoposide. Prednisolone were conducted in 72% (36), and Cyclophosphamide. Hydroxydaunorubicin. Vincristine, Prednisolone and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone-like treatment in 28% (I-i) ofpatients. The complete remission rate was 7.f%, and the partial remission rate was 9% A significant difference in survival was found between low intermediate and high intermediate S-IPI risk groups. good and bad risk. R-IPI. and patients with complete remission and patients With other treatment responses. The other parameters. including Bcl-Z and Ki67 expression, and type a/treatment did not show significant influence on survival. The expectedjive-year survival IWS 69 % J u., Our results have shown that international prognostic Index, and complete remission status have prognostic significance in diffuse large Bvcell lymphomas. Key words: Lymphoma, Large B-Cell, Diffuse; Prognosis; Survival Analysis; Severity ofillness Index: Retrospective studies Rad je primljen 29. IX Prihvacen za stampu 21. X DfBLID :(2009):LXII :3-4:
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