{"id":1698,"date":"2019-05-09T10:21:54","date_gmt":"2019-05-09T08:21:54","guid":{"rendered":"http:\/\/www.newslab.sk\/2019\/05\/09\/imunitna-odpoved-v-malignom-melanome-vysledky-pilotnej-studie\/"},"modified":"2019-05-09T10:26:28","modified_gmt":"2019-05-09T08:26:28","slug":"immune-response-in-malignant-melanoma-results-of-the-pilot-study","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/immune-response-in-malignant-melanoma-results-of-the-pilot-study\/","title":{"rendered":"Immune response in malignant melanoma \u2013 results of the pilot study."},"content":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/p>\n

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\u00davod <\/strong><\/p>\n

Po kardiovaskul\u00e1rnych ochoreniach s\u00fa onkologick\u00e9 ochorenia druhou naj\u010dastej\u0161ou pr\u00ed\u010dinou smrti. Hoci sa mal\u00edgny melan\u00f3m nenach\u00e1dza na popredn\u00fdch prie\u010dkach naj\u010dastej\u0161ie sa vyskytuj\u00facich n\u00e1dorov, neskor\u00e1 diagnostika tohto n\u00e1doru vedie k zlej progn\u00f3ze pacienta. Jeho progn\u00f3za v\u00fdrazne z\u00e1vis\u00ed od \u0161t\u00e1dia, v ktorom je melan\u00f3m diagnostikovan\u00fd, preto je ve\u013emi d\u00f4le\u017eit\u00fd jeho v\u010dasn\u00fd z\u00e1chyt. Na Slovensku v s\u00fa\u010dasnosti neexistuje spo\u013eahliv\u00fd skr\u00edningov\u00fd program podozriv\u00fdch ko\u017en\u00fdch l\u00e9zi\u00ed. Diagnostika je \u010dasto z\u00e1visl\u00e1 od v\u0161\u00edmavosti pacientov, ich rodinn\u00fdch pr\u00edslu\u0161n\u00edkov, pr\u00edpadne v\u0161eobecn\u00fdch lek\u00e1rov.<\/p>\n

Samovy\u0161etrenie, poznanie vlastn\u00fdch n\u00e9vov, je k\u013e\u00fa\u010dov\u00e9. Vznik mal\u00edgneho melan\u00f3mu je sprev\u00e1dzan\u00fd zmenami tvaru, okrajov, farby aj rastov\u00e9ho vzoru ko\u017enej pigmentovej l\u00e9zie. Ka\u017ed\u00e9 tak\u00e9to podozriv\u00e9 lo\u017eisko by mal vy\u0161etri\u0165 dermatovenerol\u00f3g a v pr\u00edpade potreby n\u00e1lez histologizova\u0165 a definit\u00edvnu diagn\u00f3zu by mal potvrdi\u0165 patol\u00f3g. Pri v\u010dasn\u00fdch \u0161t\u00e1di\u00e1ch posta\u010d\u00ed chirurgick\u00e1 exc\u00edzia, v pr\u00edpade zachytenia v neskor\u0161om \u0161t\u00e1diu, najm\u00e4 pri pr\u00edtomnosti vzdialen\u00fdch metast\u00e1z, sa u\u017e k lie\u010dbe prip\u00e1ja aj syst\u00e9mov\u00e1 terapia, pr\u00edpadne biologick\u00e1 terapia. Rizikov\u00fd faktor vzniku tohto typu n\u00e1doru predstavuje hlavne ultrafialov\u00e9 \u017eiarenie. Je dok\u00e1zan\u00e9, \u017ee hlavne intermitentn\u00e9 vystavenie ko\u017ee slnku a sp\u00e1lenie, s\u00fa predispozi\u010dn\u00fdmi faktormi vzniku melan\u00f3mu. K \u010fal\u0161\u00edm etiologick\u00fdm faktorom patr\u00ed typ ko\u017ee, genetick\u00e9 vplyvy, vek a po\u010det n\u00e9vov. Z\u00e1va\u017en\u00e1 je st\u00fapaj\u00faca incidencia tohto tumoru v celej vyspelej Eur\u00f3pe.<\/p>\n

Uv\u00e1dza sa, \u017ee jeho v\u00fdskyt sa v posledn\u00fdch 30 rokoch strojn\u00e1sobil, alarmuj\u00faci je aj \u0161tvorn\u00e1sobn\u00fd vzostup mortality za toto obdobie(1). Mal\u00edgny melan\u00f3m predstavuje n\u00e1dor s v\u00fdraznou heterogenitou n\u00e1dorov\u00fdch buniek, charakteristick\u00fd akumul\u00e1ciou po\u010detn\u00fdch mut\u00e1ci\u00ed. Aj ke\u010f na jednej strane v\u00fdrazn\u00e1 genetick\u00e1 variabilita mal\u00edgneho melan\u00f3mu predur\u010duje jeho agres\u00edvne spr\u00e1vanie vzh\u013eadom na vznik nov\u00fdch vlastnost\u00ed a schopnost\u00ed vr\u00e1tane rezistencie na pod\u00e1van\u00fa terapiu, na druhej strane t\u00e1to v\u00fdrazn\u00e1 genetick\u00e1 variabilita vedie k vzniku neoantig\u00e9nov, prote\u00ednov, ktor\u00e9 nie s\u00fa vlastn\u00e9 samotn\u00e9mu organizmu a ktor\u00e9 m\u00f4\u017eu aktivova\u0165 jeho imunitn\u00fd syst\u00e9m. Protin\u00e1dorov\u00e1 imunita je v s\u00fa\u010dasnosti intenz\u00edvne \u0161tudovan\u00e1 a predstavuje zauj\u00edmav\u00fa oblas\u0165 na identifik\u00e1ciu nov\u00fdch terapeutick\u00fdch cie\u013eov(2). Lieky zasahuj\u00face do aktiv\u00e1cie protin\u00e1dorovej imunity sa v posledn\u00fdch rokoch stali s\u00fa\u010das\u0165ou \u0161tandardnej lie\u010dby pokro\u010dil\u00e9ho mal\u00edgneho melan\u00f3mu(3).<\/p>\n

Experiment\u00e1lne je testovan\u00e1 aj protin\u00e1dorov\u00e1 vakcin\u00e1cia, ktor\u00e1 m\u00f4\u017ee v bud\u00facnosti zmeni\u0165 priebeh choroby a progn\u00f3zu postihnut\u00fdch pacientov( 4). Cie\u013eom predlo\u017eenej pr\u00e1ce bolo pos\u00fadi\u0165 aktiv\u00e1ciu protin\u00e1dorovej imunity v r\u00f4znych typoch melanocytov\u00fdch l\u00e9zi\u00ed ko\u017ee, zah\u0155\u0148aj\u00fac pr\u00edpady be\u017en\u00fdch n\u00e9vov, dysplastick\u00fdch n\u00e9vov a mal\u00edgneho melan\u00f3mu. Zamerali sme sa na pr\u00edtomnos\u0165 cytotoxick\u00fdch T-lymfocytov a NK buniek, ktor\u00e9 s\u00fa pova\u017eovan\u00e9 za k\u013e\u00fa\u010dov\u00e9 efektorov\u00e9 bunky protin\u00e1dorovej imunity.<\/p>\n

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Metodika <\/strong><\/p>\n

Z\u00e1kladn\u00fd s\u00fabor pilotnej \u0161t\u00fadie tvorilo 17 pacientov s melanocytov\u00fdmi l\u00e9ziami ko\u017ee, ktor\u00fdm bolo realizovan\u00e9 bioptick\u00e9 vy\u0161etrenie a stanoven\u00e1 histopatologick\u00e1 diagn\u00f3za. Vy\u0161etrovan\u00fd materi\u00e1l tvorili arch\u00edvne pr\u00edpady vzoriek fixovan\u00fdch formal\u00ednom a zaliatych v paraf\u00edne (FFPE). Z\u00edskan\u00fd materi\u00e1l poch\u00e1dzal z arch\u00edvu \u00dastavu patologickej anat\u00f3mie Lek\u00e1rskej fakulty Univerzity Komensk\u00e9ho a Univerzitnej nemocnice v Bratislave z rokov 2015 \u2013 2017. Pacienti boli rozdelen\u00ed do \u0161tyroch skup\u00edn: A. pacienti s ben\u00edgnymi komplexn\u00fdmi (zmie\u0161an\u00fdmi) n\u00e9vami (5 pacientov) B. pacienti s dysplastick\u00fdmi (Clakov\u00fdmi) n\u00e9vami (4 pacienti) C. pacienti so superfici\u00e1lne sa \u0161\u00edriacim melan\u00f3mom (SSM) (4 pacienti) D. pacienti s pokro\u010dil\u00fdm nodul\u00e1rnym mal\u00edgnym melan\u00f3mom s pr\u00edtomn\u00fdmi vzdialen\u00fdmi metast\u00e1zami (NMM) (4 pacienti) Dostupn\u00e9 vzorky boli \u0161tandardne histopatologicky spracovan\u00e9 a farben\u00e9 hematoxyl\u00ednom a eoz\u00ednom s n\u00e1sledn\u00fdm histopatologick\u00fdm hodnoten\u00edm pod\u013ea aktu\u00e1lne publikovan\u00fdch WHO \u0161tandardov. Vzorky boli n\u00e1sledne imunohistochemicky zafarben\u00e9 na pr\u00edtomnos\u0165 CD8 + cytotoxick\u00fdch T-lymfocytov a CD56 + NK buniek; odparaf\u00ednovan\u00e9 rezy boli kr\u00e1tko inkubovan\u00e9 v destilovanej vode s 0,5 % roztokom peroxidu vod\u00edka. N\u00e1sledne sme vzorky preniesli do PBS (fyziologick\u00e9ho roztoku pufrovan\u00e9ho fosf\u00e1tmi 10 mM, s 0,5 % BSA, 0,005 % Tween, pH 7,2), kde boli inkubovan\u00e9 20 min\u00fat. Vzorky boli revitalizovan\u00e9 vo vodnom k\u00fapeli s pou\u017eit\u00edm Dako PT Link (Agilent, Santa Clara, California) pri pH 8 a n\u00e1sledne inkubovan\u00e9 po\u010das 1 hodiny pri laborat\u00f3rnej teplote s roztokmi prim\u00e1rnych protil\u00e1tok rieden\u00fdch v roztoku Antibody dilutant (Agilent, Santa Clara, California). Pou\u017eit\u00e9 boli nasleduj\u00face prim\u00e1rne protil\u00e1tky: anti- CD8 (Santa Cruz Biotechnology, Dallas, TX) ready to use, rieden\u00e1 1 : 2 a anti-CD56 (Santa Cruz Biotechnology, Dallas, TX) ready to use, rieden\u00e1 1 : 2. Po prepl\u00e1chnut\u00ed 3x 5 min\u00fat vo fyziologickom roztoku PBS boli n\u00e1sledne rezy inkubovan\u00e9 40 min\u00fat s komer\u010dn\u00fdm polym\u00e9rom proti kr\u00e1li\u010d\u00edm a my\u0161ac\u00edm prote\u00ednom konjugovan\u00fdm s chrenovou peroxid\u00e1zou Envision (Agilent, Santa Clara, California) a po opakovanom prepl\u00e1chnut\u00ed 3x 5 min\u00fat vo fyziologickom roztoku PBS bola reakcia vyvolan\u00e1 inkub\u00e1ciou s Vector-VIP (Vector Laboratories, Burlingame, USA) po\u010das 5 min\u00fat.<\/p>\n

Prepar\u00e1ty boli n\u00e1sledne kr\u00e1tko dofarben\u00e9 hematoxyl\u00ednom. Expresia vybran\u00fdch markerov bola hodnoten\u00e1 samostatne okolo n\u00e1dorovej l\u00e9zie (peritumor\u00f3zne) a vn\u00fatri n\u00e1dorovej l\u00e9zie (intratumor\u00f3zne) semikvantitat\u00edvne nasledovne: \u2013 bunky neboli pr\u00edtomn\u00e9 (DPS sk\u00f3re 0) + bol pr\u00edtomn\u00fd slab\u00fd a nepravideln\u00fd infiltr\u00e1t pozit\u00edvnymi bunkami (do 50 na zorn\u00e9 pole 400x) (DPS sk\u00f3re 1) ++ bol pr\u00edtomn\u00fd pravideln\u00fd infiltr\u00e1t pozit\u00edvnymi bunkami (50 \u2013 100 na zorn\u00e9 pole 400x) (DPS sk\u00f3re 2) +++ bol pr\u00edtomn\u00fd v\u00fdrazn\u00fd dif\u00fazny pravideln\u00fd infiltr\u00e1t pozit\u00edvnymi bunkami (viac ako 100 na zorn\u00e9 pole 400x) (DPS sk\u00f3re 3) \u00dadaje sme n\u00e1sledne \u0161tatisticky spracovali. Miera infiltr\u00e1cie tkaniva pr\u00edslu\u0161n\u00fdm typom imunokompetentn\u00fdch buniek je vyjadren\u00e1 ako priemer \u00b1 \u0161tandardn\u00e1 chyba merania. Normalita hodn\u00f4t bola overen\u00e1 pou\u017eit\u00edm D\u2019Agostino Pearson omnibus normality testu. Rozdiely medzi skupinami boli analyzovan\u00e9 pomocou testu neparametrick\u00e9ho Mannovho-Whitneyho testu. Hodnoty p < 0,05 boli posudzovan\u00e9 ako signifikantne v\u00fdznamn\u00e9.<\/p>\n

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V\u00fdsledky <\/strong><\/p>\n

V pr\u00edpadoch ben\u00edgneho komplexn\u00e9ho melanocytov\u00e9ho n\u00e9vu sme pozorovali len slab\u00fa a nepravideln\u00fa infiltr\u00e1ciu CD8+ cytotoxick\u00fdmi T-lymfocytmi v okol\u00ed l\u00e9zie, v \u017eiadnom pr\u00edpade neboli z\u00e1palov\u00e9 bunky pr\u00edtomn\u00e9 vn\u00fatri melanocytov\u00fdch hniezd. V 4 pr\u00edpadoch sme nepozorovali \u017eiadne CD56+ NK bunky peritumor\u00f3zne ani intratumor\u00f3zne, v 1 pr\u00edpade bol pr\u00edtomn\u00fd slab\u00fd pravideln\u00fd infiltr\u00e1t CD56+ NK bunkami peritumor\u00f3zne.<\/p>\n

V porovnan\u00ed s ben\u00edgnym melanocytov\u00fdm n\u00e9vom sme v pr\u00edpadoch dysplastick\u00e9ho n\u00e9vu aj mal\u00edgneho melan\u00f3mu zaznamenali v\u00fdraznej\u0161iu protin\u00e1dorov\u00fa z\u00e1palov\u00fa odpove\u010f charakteristick\u00fa vzostupom infiltr\u00e1cie tkaniva lymfocytmi (obr\u00e1zok 1)<\/em><\/strong>. Pozorovali sme signifikantn\u00fd vzostup intral\u00e9ziovo aj peril\u00e9ziovo pr\u00edtomn\u00fdch CD8 pozit\u00edvnych cytotoxick\u00fdch T-lymfocytov (obr\u00e1zok 2) <\/em><\/strong>v dysplastickom n\u00e9ve (s hodnotou sk\u00f3re 2,25 \u00b1 0,48, resp. 2 \u00b1 0,41) aj v povrchovo sa \u0161\u00edriacom mal\u00edgnom melan\u00f3me (s hodnotou sk\u00f3re 2,5 \u00b1 0,29) v porovnan\u00ed s ben\u00edgnym melanocytov\u00fdm n\u00e9vom (s hodnotou sk\u00f3re 0,4 \u00b1 0,24, resp. 1,75 \u00b1 0,75). V pr\u00edpadoch pokro\u010dil\u00e9ho nodul\u00e1rneho mal\u00edgneho melan\u00f3mu bol tento vzostup v porovnan\u00ed s ben\u00edgnym n\u00e9vom peritumor\u00f3zne na hranici signifikantnosti (s hodnotou sk\u00f3re 2 \u00b1 0,41), vzostup intratumor\u00f3znych lymfocytov signifikantn\u00fd nebol (obr\u00e1zok 3, 4)<\/em><\/strong>.\u00a0 CD56+ NK bunky peritumor\u00f3zne aj intratumor\u00f3zne nevykazovali \u0161tatisticky signifikantn\u00fd rozdiel medzi skupinami, len v pr\u00edpade dysplastick\u00e9ho n\u00e9vu sme pozorovali vzostup (s hodnotou 1,25 \u00b1 0,4787), ktor\u00fd bol v porovnan\u00ed s ben\u00edgnym komplexn\u00fdm n\u00e9vom (s hodnotou 0,4 \u00b1 0,4) na hranici signifikantnosti. V pr\u00edpadoch superfici\u00e1lne sa \u0161\u00edriaceho melan\u00f3mu (s hodnotou 0,67 \u00b1 0,33) a pokro\u010dil\u00e9ho nodul\u00e1rneho melan\u00f3mu (s hodnotou 0,5 \u00b1 0,29) sa infiltr\u00e1cia NK bunkami neodli\u0161ovala od pr\u00edpadov ben\u00edgnych komplexn\u00fdch n\u00e9vov (obr\u00e1zok 5)<\/em><\/strong>.<\/p>\n

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Diskusia <\/strong><\/p>\n

Protin\u00e1dorov\u00e1 imunita je ve\u013emi d\u00f4le\u017eit\u00e1 s\u00fa\u010das\u0165 obranyschopnosti organizmu pri vznikaj\u00facich n\u00e1doroch. M\u00e1 viacero efektorov\u00fdch zlo\u017eiek, k\u013e\u00fa\u010dov\u00fa \u00falohu zohr\u00e1va \u0161pecifick\u00e1 bunkov\u00e1 imunita. V\u00fdsledky na\u0161ej pilotnej \u0161t\u00fadie poukazuj\u00fa na vzostup infiltr\u00e1cie tkaniva CD8+ cytotoxick\u00fdmi T-lymfocytmi vn\u00fatri aj v okol\u00ed melanocytov\u00fdch l\u00e9zi\u00ed, a to u\u017e v pr\u00edpadoch dysplastick\u00e9ho n\u00e9vu. Minim\u00e1lna, pr\u00edpadne \u017eiadna infiltr\u00e1cia nebola pozorovan\u00e1 v okol\u00ed ben\u00edgneho komplexn\u00e9ho n\u00e9vu. Zauj\u00edmav\u00e9\u00a0 zistenie je, \u017ee v pr\u00edpadoch pokro\u010dil\u00e9ho nodul\u00e1rneho melan\u00f3mu pozorujeme ni\u017e\u0161iu \u00farove\u0148 infiltr\u00e1cie CD8+ cytotoxick\u00fdmi T-lymfocytmi. Podobn\u00e9, ale menej v\u00fdrazn\u00e9 v\u00fdsledky sme pozorovali aj v pr\u00edpade CD56+ NK buniek, kde v\u00fdsledky neboli \u0161tatisticky signifikantn\u00e9. Pod\u013ea Park et al.(5) je pr\u00edtomnos\u0165 lymfocytov v mal\u00edgnom melan\u00f3me priazniv\u00fd prognostick\u00fd faktor, ale klinickopatologick\u00fd v\u00fdznam intra- a peritumor\u00f3znych lymfocytov ost\u00e1va nejasn\u00fd. Autori pozorovali, \u017ee vysok\u00e1 infiltr\u00e1cia lymfocytmi, najm\u00e4 peritumor\u00f3zne, bola asociovan\u00e1 s ni\u017e\u0161\u00edm gradom n\u00e1doru pod\u013ea Clarka a men\u0161ou hr\u00fabkou pod\u013ea Breslowa. U t\u00fdchto pacientov bolo tie\u017e pozorovan\u00e9 dlh\u0161ie pre\u017e\u00edvanie. V pr\u00edpade anal\u00fdzy subtypov melan\u00f3mu neboli dok\u00e1zan\u00e9 \u017eiadne signifikantn\u00e9 rozdiely. To je v s\u00falade aj s na\u0161imi pozorovaniami. Naopak, v \u0161t\u00fadii Rahbar et al.(6) sa u pacientov s prim\u00e1rnou formou ko\u017en\u00e9ho melan\u00f3mu uk\u00e1zala pozit\u00edvna korel\u00e1cia medzi hr\u00fabkou a \u0161t\u00e1diom n\u00e1doru a infiltr\u00e1ciou cytotoxick\u00fdmi T-lymfocytmi. Autori v\u0161ak nehodnotili samostatne r\u00f4zne histologick\u00e9 typy mal\u00edgnych melan\u00f3mov so zameran\u00edm na progresiu choroby. Sk\u00famanie pr\u00edtomnosti lymfocytov a progn\u00f3zy pacienta doposia\u013e neprinieslo jednozna\u010dn\u00e9 z\u00e1very o klinickom v\u00fdzname tohto hodnotenia. Predpoklad\u00e1 sa v\u0161ak, \u017ee imunitn\u00fd syst\u00e9m je zodpovedn\u00fd za inhib\u00edciu vzniku vzdialen\u00fdch metast\u00e1z, de\u0161trukciu n\u00e1dorov\u00fdch buniek a m\u00f4\u017ee by\u0165 zodpovedn\u00fd za spont\u00e1nnu regresiu mal\u00edgneho melan\u00f3mu.<\/p>\n

Viacer\u00ed autori op\u00edsali, \u017ee mal\u00edgny melan\u00f3m bez d\u00f4kazu prim\u00e1rneho origa m\u00e1 lep\u0161iu progn\u00f3zu a menej agres\u00edvny priebeh ako porovnate\u013en\u00fd n\u00e1dor, kde je prim\u00e1rne lo\u017eisko dok\u00e1zate\u013en\u00e9. Za tento paradox je pravdepodobne zodpovedn\u00e1 pr\u00e1ve aktiv\u00e1cia imunitn\u00e9ho syst\u00e9mu(7,8). Mal\u00edgny melan\u00f3m je vysokoimunog\u00e9nny tumor, je charakteristick\u00fd vysokou bunkovou variabilitou v d\u00f4sledku akumul\u00e1cie po\u010detn\u00fdch mut\u00e1ci\u00ed ved\u00facich k v\u00fdraznej heterogenite tumoru. Pr\u00e1ve akumul\u00e1cia po\u010detn\u00fdch mut\u00e1ci\u00ed vedie k tvorbe n\u00e1dorov\u00fdch neoantig\u00e9nov aktivuj\u00facich imunitn\u00fd syst\u00e9m. Bunky imunitn\u00e9ho syst\u00e9mu vo ve\u013ekej miere reaguj\u00fa na pr\u00edtomnos\u0165 n\u00e1dorov\u00fdch antig\u00e9nov, o \u010dom sved\u010d\u00ed pr\u00edtomnos\u0165 t\u00fdchto buniek v n\u00e1dore a jeho okol\u00ed. N\u00e1dor m\u00e1 mechanizmy, ktor\u00fdmi m\u00f4\u017ee ovplyvni\u0165 aktiv\u00e1ciu imunitn\u00e9ho syst\u00e9mu(9). To m\u00f4\u017ee vies\u0165 k nekontrolovanej prolifer\u00e1cii buniek. Ukazuje sa, \u017ee imunitn\u00e1 odpove\u010f zohr\u00e1va d\u00f4le\u017eit\u00fa \u00falohu v procese vzniku a progresie mal\u00edgneho melan\u00f3mu. Jednou z mo\u017enost\u00ed terapie melan\u00f3mu je pr\u00e1ve ovplyvnenie imunitnej odpovede. T\u00e1to terapia v s\u00fa\u010dasnosti znamen\u00e1 v\u00fdrazn\u00fd pokrok v terapii metast\u00e1zuj\u00faceho mal\u00edgneho melan\u00f3mu. V\u00fdsledky na\u0161ej pilotnej \u0161t\u00fadie nazna\u010duj\u00fa, \u017ee pri progresii mal\u00edgneho melan\u00f3mu doch\u00e1dza k \u00fatlmu protin\u00e1dorovej imunitne odpovede. Ni\u017e\u0161iu infiltr\u00e1ciu tkaniva cytotoxick\u00fdmi T-lymfocytmi intratumor\u00f3zne sme pozorovali vo v\u0161etk\u00fdch pr\u00edpadoch pokro\u010dil\u00e9ho nodul\u00e1rneho mal\u00edgneho melan\u00f3mu. Pr\u00e1ve pochopenie princ\u00edpov regul\u00e1cie imunitnej odpovede vo vz\u0165ahu k \u0161t\u00e1diu choroby bude ma\u0165 ve\u013ek\u00fd v\u00fdznam pre vyu\u017eitie t\u00fdchto poznatkov v terapii pacientov v bud\u00facnosti.<\/p>\n

 <\/p>\n

Po\u010fakovanie: <\/em><\/strong>Tento \u010dl\u00e1nok vznikol v\u010faka podpore v r\u00e1mci OP V\u00fdskum a v\u00fdvoj pre projekt: Dobudovanie multidisciplin\u00e1rneho centra pre biomedic\u00ednsky v\u00fdskum \u2013 BIOMEDIRES, ITMS 26210120041, spolufinancovan\u00fd zo zdrojov Eur\u00f3pskeho fondu region\u00e1lneho rozvoja.<\/em><\/p>\n

 <\/p>\n

\u00a0<\/em>LITERAT\u00daRA <\/strong><\/p>\n

    \n
  1. Janega P, Szemes T, Minarik G. Mal\u00edgny melan\u00f3m \u2013 nov\u00e9 aspekty v\u00fdskumu Newslab 2017; 8(1): 44-47.<\/li>\n
  2. Zeuthen J, Dzhandzhugazyan K, Hansen MR, et al. The immunogenic properties of human melanomas and melanoma-associated antigens recognized by cytotoxic T lymphocytes. Bratisl Lek Listy 1998; 99(8-9): 426\u2011434.<\/li>\n
  3. Jacquelot N, Roberti MP, Enot DP, et al. Predictors of responses to immune checkpoint blockade in advanced melanoma. Nature Communications 2017; 8(1): 592.<\/li>\n
  4. Ridolfi L, de Rosa F, Fiammenghi L, et al. Complementary vaccination protocol with dendritic cells pulsed with autologous tumour lysate in patients with resected stage III or IV melanoma: protocol for a phase II randomised trial (ACDC Adjuvant Trial). BMJ Open 2018; 8(8): e021701.<\/li>\n
  5. Park CK, Kim SK. Clinicopathological significance of intratumoral and peritumoral lymphocytes and lymphocyte score based on the histologic subtypes of cutaneous melanoma. Oncotarget 2017; 8(9): 14759-14769.<\/li>\n
  6. Rahbar M, Naraghi ZS, Mardanpour M, et al. Tumor-Infiltrating CD8+ Lymphocytes Effect on Clinical Outcome of Muco-Cutaneous Melanoma. Indian J Dermatol 2015; 60(2): 212.<\/li>\n
  7. van der Ploeg AP, Haydu LE, Spillane AJ, et al. Melanoma patients with an unknown primary tumor site have a better outcome than those with a known primary following therapeutic lymph node dissection for macroscopic (clinically palpable) nodal disease. Ann Surg Oncol 2014; 21(9): 3108-3116.<\/li>\n
  8. Weide B, Faller C, Elsasser M, et al. Melanoma patients with unknown primary site or nodal recurrence after initial diagnosis have a favourable survival compared to those with synchronous lymph node metastasis and primary tumour. PLoS One 2013; 8(6): e66953.<\/li>\n
  9. Passarelli A, Mannavola F, Stucci LS, et al. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget 2017; 8(62): 106132-106142.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    *All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.     \u00davod Po kardiovaskul\u00e1rnych ochoreniach s\u00fa onkologick\u00e9 ochorenia druhou naj\u010dastej\u0161ou pr\u00ed\u010dinou smrti. Hoci sa mal\u00edgny melan\u00f3m nenach\u00e1dza na popredn\u00fdch prie\u010dkach naj\u010dastej\u0161ie sa vyskytuj\u00facich n\u00e1dorov, neskor\u00e1 diagnostika tohto n\u00e1doru vedie<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[297],"tags":[1144,1145,755,1146],"class_list":["post-1698","post","type-post","status-publish","format-standard","hentry","category-pathology","tag-antitumor-immune-response","tag-cytotoxic-t-lymphocytes","tag-malignant-melanoma","tag-nk-cells","typ_clanku-original-work"],"acf":{"abstrakt":"

    Malignant melanoma is a tumour with marked heterogeneity of tumour cells, determining its aggressive behaviour. .Accumulation of mutations, however, leads to the formation of neoantigens, proteins that are capable .of eliciting an antitumour immune response in patients. The objective of the presented pilot study was to assess .the activation of antitumor immunity in various types of skin melanocytic lesions, including cases of benign .complex nevi, dysplastic nevi and superficial spreading malignant melanoma as well as advanced nodular .malignant melanoma. We have focused on the presence of cytotoxic T-lymphocytes and NK cells, which are key .effector cells of antitumour immunity. Compared to benign melanocytic nevi, we have seen a more pronounced .anticancer inflammatory response in other melanocytic lesions, characterized by increased tissue infiltration by .lymphocytes with predominance of cytotoxic T- lymphocytes. A significant increase in both peritumoural and intratumoural .cytotoxic T- lymphocytes was observed in dysplastic nevi as well as cases of superficial spreading .malignant melanoma. In cases of advanced nodular malignant melanoma, the increase was at the significance .limits; intratumoral lymphocytes were not increased. Immune response plays a role in the process of malignant .melanoma progression. Understanding the regulation of immune response may be a key point in the therapy of .malignant melanoma in the future. <\/p>\n

    Keywords: malignant melanoma, antitumor immune response, cytotoxic T-lymphocytes, NK cells. <\/p>\n","casopis":[{"ID":1633,"post_author":"7","post_date":"2019-05-09 08:56:48","post_date_gmt":"2019-05-09 06:56:48","post_content":"

      \r\n \t
    • Primary pancreatic liposarcoma \u2013 the case report and iterature review<\/li>\r\n \t
    • DNA sequencing in laboratory diagnostics of bacterial pathogens<\/li>\r\n \t
    • Importance and diagnostic of anti-phospholipid antibodies in women with reproductive disorders<\/li>\r\n \t
    • Development of complex chromosome rearrangements in a patient with ALL<\/li>\r\n \t
    • HCV infection \u2013 more than 20 years of drug development<\/li>\r\n<\/ul>","post_title":"newsLab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-3","to_ping":"","pinged":"","post_modified":"2019-05-09 08:56:48","post_modified_gmt":"2019-05-09 06:56:48","post_content_filtered":"","post_parent":0,"guid":"http:\/\/www.newslab.sk\/?post_type=casopis&p=1633","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"20-24","upload_clanok":{"ID":1696,"id":1696,"title":"Imunitn\u00e1 odpove\u010f v mal\u00edgnom melan\u00f3me \u2013 v\u00fdsledky pilotnej \u0161t\u00fadie","filename":"Imunitn\u00e1-odpove\u010f-v-mal\u00edgnom-melan\u00f3me-\u2013-v\u00fdsledky-pilotnej-\u0161t\u00fadie.pdf","filesize":535991,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2019\/05\/Imunitn\u00e1-odpove\u010f-v-mal\u00edgnom-melan\u00f3me-\u2013-v\u00fdsledky-pilotnej-\u0161t\u00fadie.pdf","link":"https:\/\/www.newslab.sk\/en\/immune-response-in-malignant-melanoma-results-of-the-pilot-study\/imunitna-odpoved-v-malignom-melanome-vysledky-pilotnej-studie-2\/","alt":"","author":"7","description":"","caption":"","name":"imunitna-odpoved-v-malignom-melanome-vysledky-pilotnej-studie-2","status":"inherit","uploaded_to":1698,"date":"2019-05-09 08:20:23","modified":"2019-05-09 08:20:23","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1698","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=1698"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1698\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1698"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1698"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1698"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}