{"id":1006,"date":"2017-04-07T21:39:51","date_gmt":"2017-04-07T19:39:51","guid":{"rendered":"http:\/\/www.newslab.sk\/2017\/04\/07\/maligny-melanom-nove-aspekty-vyskumu\/"},"modified":"2017-10-04T14:18:01","modified_gmt":"2017-10-04T12:18:01","slug":"malign-melanoma-new-aspects-of-research","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/malign-melanoma-new-aspects-of-research\/","title":{"rendered":"Malign melanoma – new aspects of research"},"content":{"rendered":"
*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf\u00a0\r\nattachment at the end of the paper.\r\n<\/span><\/strong><\/pre>\n
 <\/p>\n
Aj ke\u010f mal\u00edgny \u00a0melan\u00f3m nepatr\u00ed v Slovenskej republike medzi \u00a0mal\u00edgne n\u00e1dory \u00a0s najvy\u0161\u0161ou incidenciou, je z\u00e1va\u017en\u00fd svojou \u00a0relat\u00edvne \u00a0vysokou mortalitou, najm\u00e4 \u00a0v pr\u00edpade, ak je zachyten\u00fd v neskor\u0161\u00edch \u0161t\u00e1di\u00e1ch choroby. Alarmuj\u00faca je st\u00e1le st\u00fapaj\u00faca incidencia tohto \u00a0n\u00e1doru v celej \u00a0Eur\u00f3pe. \u00a0V Slovenskej republike sa jeho v\u00fdskyt za posledn\u00fdch 30 rokov viac ako strojn\u00e1sobil, v roku 1978 bola incidencia 3,9 na 100 000 obyvate\u013eov, v roku 2007 \u00a0dosiahla 12,19 \u00a0na 100 \u00a0000 \u00a0obyvate\u013eov (graf 1)<\/em><\/strong>(1). Kritick\u00fd je aj \u0161tvorn\u00e1sobn\u00fd vzostup mortality za rovnak\u00fd \u010dasov\u00fd interval, z 0,8 na 100 000 obyvate\u013eov v roku 1978 \u00a0na hodnotu 3,65 na 100 000 obyvate\u013eov v roku 2010. V\u00fdskyt melan\u00f3mu sa v posledn\u00fdch desa\u0165ro\u010diach zvy\u0161uje najm\u00e4 v popul\u00e1cii \u013eud\u00ed star\u0161\u00edch ako 45 rokov, incidencia u star\u0161\u00edch ako 70 rokov je viac ako 40 na 100 000 obyvate\u013eov (graf 2)<\/em><\/strong>(1).<\/p>\n
K\u013e\u00fa\u010dov\u00fdm rizikov\u00fdm faktorom jeho vzniku je expoz\u00edcia UV \u017eiareniu. \u00a0N\u00e1dor je preventabiln\u00fd, vyh\u00fdbanie priamemu slne\u010dn\u00e9mu \u00a0\u017eiareniu \u00a0\u010di pou\u017e\u00edvanie protekt\u00edvnych pr\u00edpravkov\u00a0 zni\u017euje riziko jeho vzniku u predisponovan\u00fdch \u013eud\u00ed.<\/p>\n
Sekund\u00e1rna prevencia, odborn\u00e9 dermatologick\u00e9 vy\u0161etrenie \u00a0s pou\u017eit\u00edm dermatoskopu umo\u017en\u00ed zachytenie skor\u00fdch neinvaz\u00edvnych alebo n\u00edzkoinvaz\u00edvnych l\u00e9zi\u00ed. Pr\u00e1ve \u00a0skor\u00e1 detekcia \u00a0v\u00fdrazn\u00fdm sp\u00f4sobom zvy\u0161uje pre\u017e\u00edvanie pacientov. V\u00e4\u010d\u0161ina \u00a0melan\u00f3mov \u00a0je \u00a0v\u010faka dostupnosti vy\u0161etrovac\u00edch met\u00f3d a v\u010faka dlhodob\u00e9mu vzdel\u00e1vaniu popul\u00e1cie o rizik\u00e1ch zachyten\u00e1 v skorom, teda \u00a0lie\u010dite\u013enom \u0161t\u00e1diu. P\u00e4\u0165ro\u010dn\u00e9 pre\u017e\u00edvanie je priemerne 91 %, v pr\u00edpade lokalizovan\u00e9ho n\u00e1doru a\u017e \u00a098 %. Pre\u017e\u00edvanie v\u0161ak v\u00fdrazne \u00a0kles\u00e1, ak je choroba zachyten\u00e1 v neskor\u0161om \u0161t\u00e1diu(2). Metast\u00e1zuj\u00faci melan\u00f3m \u00a0predstavuje jeden \u00a0z najagres\u00edvnej\u0161\u00edch a najr\u00fdchlej\u0161ie progreduj\u00facich n\u00e1dorov historicky len s ve\u013emi obmedzen\u00fdmi mo\u017enos\u0165ami efekt\u00edvnej lie\u010dby. V pr\u00edpadoch metast\u00e1zuj\u00faceho melan\u00f3mu je 10-ro\u010dn\u00e9 pre\u017e\u00edvanie men\u0161ie ako 10 %(3). Probl\u00e9mom je aj skuto\u010dnos\u0165, \u017ee napriek v\u010dasn\u00e9mu zachyteniu a terapii v skorom \u0161t\u00e1diu nie s\u00fa v\u00fdnimkou neskor\u00e9 metast\u00e1zy.<\/p>\n
Problematika mal\u00edgneho melan\u00f3mu bola \u00a0a v s\u00fa\u010dasnosti je predmetom intenz\u00edvneho v\u00fdskumu. \u00a0Ten umo\u017enil \u00a0objasni\u0165 viacer\u00e9 molekul\u00e1rne mechanizmy zodpovedn\u00e9 za\u00a0 transform\u00e1ciu \u00a0a rast \u00a0melan\u00f3mov\u00fdch buniek. Pozorovan\u00e9 boli mut\u00e1cie viacer\u00fdch \u00a0g\u00e9nov, k\u013e\u00fa\u010dov\u00fdch v inici\u00e1cii n\u00e1dorovej transform\u00e1cie. Zasiahnut\u00e9 dr\u00e1hy s\u00fa zauj\u00edmav\u00e9 aj z h\u013eadiska h\u013eadania nov\u00fdch cie\u013eov pre protin\u00e1dorov\u00fa terapiu.<\/p>\n
Historicky \u00a0najzn\u00e1mej\u0161\u00ed mechanizmus inici\u00e1cie \u00a0tumorigen\u00e9zy mal\u00edgneho melan\u00f3mu s\u00favis\u00ed s kon\u0161titut\u00edvnou aktiv\u00e1ciou prote\u00ednkin\u00e1zovej dr\u00e1hy aktivovanej mitog\u00e9nom (MAPK), komplexnej sign\u00e1lnej dr\u00e1hy zahr\u0148uj\u00facej prote\u00edny RAS\/RAF a \u010fal\u0161ie prote\u00ednkin\u00e1zy vr\u00e1tane MEK a ERK. T\u00e1to dr\u00e1ha sa ukazuje ako kritick\u00e1 aj pre rastov\u00fa f\u00e1zu melan\u00f3mu(4). Odhaduje sa, \u017ee takmer polovica mal\u00edgnych malan\u00f3mov je asociovan\u00e1 s aktiva\u010dnou mut\u00e1ciou v MAPK dr\u00e1he(2,5). Onkog\u00e9nna aktiv\u00e1cia pri melan\u00f3me m\u00f4\u017ee \u00a0vznikn\u00fa\u0165 v d\u00f4sledku mut\u00e1cie v ktoromko\u013evek komponente alebo \u00a0prom\u00f3tore tejto dr\u00e1hy(6).<\/p>\n
Charakteristick\u00fdm \u00a0inicia\u010dn\u00fdm \u00a0onkog\u00e9nom \u00a0zahrnut\u00fdm v MAPK dr\u00e1he je mutovan\u00fd g\u00e9n BRAF <\/em>s bodov\u00fdmi mut\u00e1ciami. Viac ako \u00a050 percent melan\u00f3mov nesie mut\u00e1ciu v g\u00e9ne BRAF <\/em>a z toho 80 percent predstavuje mut\u00e1cia BRAF <\/em>V600E (resp. V599E) (7,8). Okrem onkog\u00e9nnych mut\u00e1ci\u00ed v BRAF <\/em>s\u00fa dobre \u00a0op\u00edsan\u00e9 inicia\u010dn\u00e9 onkog\u00e9nne bodov\u00e9 mut\u00e1cie v g\u00e9ne NRAS <\/em>(15 \u2013 20 %). Mut\u00e1cie \u00a0v BRAF <\/em>g\u00e9ne \u00a0sa sp\u00e1jaj\u00fa typicky so \u00a0vznikom melan\u00f3mu \u0161\u00edriaceho sa povrchovo, \u00a0v NRAS <\/em>g\u00e9ne s nodul\u00e1rnym melan\u00f3mom(9). Blok\u00e1tory\u00a0 BRAF vemurafe<\/em>nib a dabrafenib \u00a0<\/em>s\u00fa \u0161tandardom v lie\u010dbe \u00a0metast\u00e1zuj\u00faceho mal\u00edgneho melan\u00f3mu ko\u017ee(10). Ukazuje sa, \u017ee s\u00fa\u010dasn\u00e9 pod\u00e1vanie inhib\u00edtora\u00a0 MEK trametinib <\/em>zlep\u0161uje pre\u017e\u00edvanie s dobrou toleranciou lie\u010dby(11).<\/p>\n
Aj ke\u010f mut\u00e1cia v g\u00e9ne \u00a0BRAF <\/em>sa pova\u017euje za k\u013e\u00fa\u010dov\u00fa v inici\u00e1cii tumorigen\u00e9zy, \u00a0vyskytuje \u00a0sa vo vysokom percente aj v bunk\u00e1ch ben\u00edgnych n\u00e9vov, ktor\u00e9 e\u0161te nemaj\u00fa vlastnosti mal\u00edgneho procesu.<\/p>\n
Op\u00edsan\u00e9 boli aj mut\u00e1cie v CDKN2A<\/em>, PTEN<\/em>, APAF1<\/em>, TP53<\/em>, GNAQ<\/em>, GNA11<\/em>(6,7,12) \u00a0aj aktiva\u010dn\u00e9 f\u00fazie \u00a0g\u00e9nu \u00a0BRAF <\/em>s receptorov\u00fdmi\u00a0 tyroz\u00ednkin\u00e1zami \u00a0ALK<\/em>, \u00a0ROS1, \u00a0RET, \u00a0MET<\/em>, \u00a0NTRK1 <\/em>a ROS1<\/em>(13-15). Samotn\u00e9 GNAQ\/GNA11 prote\u00edny \u00a0s\u00edce, ako \u00a0sa zd\u00e1, nie s\u00fa vhodn\u00e9 na cielen\u00fa terapiu, no ich aktiv\u00e1cia je \u010diasto\u010dne regulovan\u00e1 prostredn\u00edctvom prote\u00ednu YAP(16), ktor\u00fd m\u00f4\u017ee ma\u0165 terapeutick\u00fd potenci\u00e1l. V mal\u00edgnom melan\u00f3me ko\u017ee zatia\u013e tento \u00a0pr\u00edstup pou\u017eit\u00fd nebol.<\/p>\n
Opisuj\u00fa sa aj muta\u010dn\u00e9 zmeny v dr\u00e1he p16INK4A-CDK4-RB (s muta\u010dn\u00fdm postihnut\u00edm najm\u00e4 INK4A <\/em>alebo\u00a0 CDK4<\/em>) a dr\u00e1hy ARF-p53(17). V men\u0161ej frekvencii \u00a0boli pozorovan\u00e9 aj mut\u00e1cie v dr\u00e1he AKT\/mTOR, ktor\u00e1 reprezentuje pravdepodobne alternat\u00edvny mechanizmus aktiv\u00e1cie v mal\u00edgnom melan\u00f3me(18).<\/p>\n
Ve\u013emi zauj\u00edmav\u00fa oblas\u0165 \u00a0v\u00fdskumu predstavuj\u00fa aj muta\u010dn\u00e9 zmeny \u00a0vo Wnt sign\u00e1lnej dr\u00e1he s \u03b2-katen\u00ednom ako k\u013e\u00fa\u010dov\u00fdm komponentom. Zmeny aktiv\u00e1cie tejto dr\u00e1hy ved\u00fa k zmen\u00e1m fenotypu melan\u00f3mov\u00fdch buniek, ovplyv\u0148uj\u00fa n\u00e1dorov\u00e9 mikroprostredie, bunkov\u00fd rast, invazivitu n\u00e1dorov\u00fdch buniek aj vznik rezistencie \u00a0na \u00a0terapiu(19). Z h\u013eadiska nov\u00fdch terapeutick\u00fdch pr\u00edstupov sa ukazuje \u00a0ako \u00a0z\u00e1sadn\u00fd aj vz\u0165ah Wnt sign\u00e1lnej dr\u00e1hy k ovplyvneniu \u00a0protin\u00e1dorovej imunity v mikroprostred\u00ed buniek \u00a0mal\u00edgneho melan\u00f3mu a k vzniku rezistencie na imunoterapiu(20). V\u00fdskum nazna\u010duje mo\u017en\u00e9 vyu\u017eitie viacer\u00fdch molek\u00fal \u00a0tejto dr\u00e1hy \u00a0ako \u00a0potenci\u00e1lnych cie\u013eov pre cielen\u00fa \u00a0terapiu.<\/p>\n
Z h\u013eadiska mo\u017en\u00e9ho terapeutick\u00e9ho ovplyvnenia \u00a0s\u00fa\u00a0 zauj\u00edmav\u00e9 aj antiapoptotick\u00e9 prote\u00edny surviv\u00edn a liv\u00edn. Surviv\u00edn je v mal\u00edgnom melan\u00f3me exprimovan\u00fd vo zv\u00fd\u0161enej miere \u00a0vo v\u00e4\u010d\u0161ine pr\u00edpadov(21). Uva\u017euje sa, \u017ee pr\u00e1ve \u00a0upregul\u00e1cia surviv\u00ednu m\u00f4\u017ee \u00a0by\u0165 jedn\u00fdm\u00a0 zo stimulov \u00a0n\u00e1dorovej transform\u00e1cie v n\u00e9vov\u00fdch bunk\u00e1ch. Takeuchi a spol.(22) \u00a0preuk\u00e1zali, \u017ee n\u00edzka expresia surviv\u00ednu v rekurentnom metastatickom mal\u00edgnom melan\u00f3me ko\u017ee\u00a0 je sp\u00e1jan\u00e1 so signifikantne lep\u0161\u00edm \u00a0pre\u017e\u00edvan\u00edm pacientov. Zv\u00fd\u0161en\u00fa \u00a0citlivos\u0165 buniek mal\u00edgneho melan\u00f3mu na chemoterapiu pri s\u00fa\u010dasnej inhib\u00edcii surviv\u00ednu in vitro <\/em>preuk\u00e1zal aj Pennati a spol.(23). V\u00fdsledky publikovan\u00fdch \u0161t\u00fadi\u00ed nazna\u010duj\u00fa, \u017ee m\u00f4\u017ee \u00a0\u00eds\u0165 o n\u00e1dejn\u00fa molekulu \u00a0aj z h\u013eadiska mo\u017en\u00e9ho klinick\u00e9ho ovplyvnenia.<\/p>\n
Liv\u00edn je ned\u00e1vno op\u00edsan\u00fd prote\u00edn \u00a0s komplexn\u00fdm preva\u017ene antiapoptotick\u00fdm, za ur\u010dit\u00fdch okolnost\u00ed proapoptotick\u00fdm \u00fa\u010dinkom. Vy\u0161\u0161ia expresia preuk\u00e1zan\u00e1 v mal\u00edgnom melan\u00f3me ko\u017ee \u00a0koreluje \u00a0s progresiou a so zlou progn\u00f3zou pacientov (24). Pr\u00e1ve vysok\u00e1 expresia liv\u00ednu s\u00favis\u00ed s rezistenciou na chemoterapiu, nazna\u010duj\u00fac bud\u00faci \u00a0cie\u013e v\u00fdskumu \u00a0cielenej protin\u00e1dorovej terapie(25,26).<\/p>\n
S aktivitou apoptotick\u00fdch dr\u00e1h \u00fazko s\u00favis\u00ed regul\u00e1cia PARP prote\u00ednu, \u00a0ktor\u00fd je, naopak, zodpovedn\u00fd za DNA repar\u00e1ciu. Inhib\u00edcia PARP interferuje s k\u013e\u00fa\u010dov\u00fdmi procesmi metast\u00e1zovania a inhibuje invazivitu a metast\u00e1zovanie buniek mal\u00edgneho melan\u00f3mu ko\u017ee do vzdialen\u00fdch org\u00e1nov(27), predstavuje k\u013e\u00fa\u010dov\u00fd marker \u00a0agres\u00edvneho ko\u017en\u00e9ho MM(28). Jeho cielen\u00fd blok\u00e1tor temozolomid <\/em>je v s\u00fa\u010dasnosti v \u0161t\u00e1diu klinick\u00e9ho testovania (II. f\u00e1za).<\/p>\n
Progresia melan\u00f3mu je spojen\u00e1 so s\u00e9riou onkog\u00e9nnych udalost\u00ed, ktor\u00e1 \u00a0je charakterizovan\u00e1 ako geneticky vysokoheterog\u00e9nna. \u00a0Identifikovan\u00e9 boli viacer\u00e9 kandid\u00e1tne \u201edriver\u201c mut\u00e1cie, k naj\u0161tudovanej\u0161\u00edm patria alternat\u00edvne transkripty g\u00e9nu \u00a0ALK<\/em>, identifikovate\u013en\u00e9 na \u00farovni prepisovanej RNA(29). \u010castou \u201edriver\u201c udalos\u0165ou pri r\u00f4znych variantoch melan\u00f3mov je aj bialelick\u00e1 strata\u00a0 hist\u00f3novej deubikvitin\u00e1zy BAP1 ako de novo <\/em>udalos\u0165 u \u013eud\u00ed s germin\u00e1lnou poruchou jednej \u00a0k\u00f3pie g\u00e9nu(30). Viacer\u00e9 subchromozom\u00e1lne aber\u00e1cie, zmeny v po te \u00a0k\u00f3pi\u00ed \u00a0repetit\u00edvnych \u00a0elementov \u00a0ako \u00a0pr\u00ed\u010dina mikrosatelitnej instability boli op\u00edsane pri metast\u00e1zuj\u00facich melan\u00f3moch(31,32).<\/p>\n
\u0160tudovan\u00e9 boli a potenci\u00e1lny klinick\u00fd v\u00fdznam \u00a0m\u00f4\u017eu \u00a0ma\u0165 aj epigenetick\u00e9 zmeny. \u00a0Boli identifikovan\u00e9 viacer\u00e9 \u00a0kandid\u00e1tne g\u00e9ny, ktor\u00e9 \u00a0s\u00fa ovplyvnen\u00e9 aberantnou DNA metyl\u00e1ciou, resp. modifik\u00e1ciou hist\u00f3nov, a kde sa ukazuje, \u017ee tieto zmeny koreluj\u00fa s bunkov\u00fdmi charakteristikami n\u00e1doru a maj\u00fa vplyv na klinickopatologick\u00fd obraz \u00a0choroby. Ako g\u00e9ny s najvy\u0161\u0161ou frekvenciou hypermetyl\u00e1cie s\u00fa \u0161tudovan\u00e9 najm\u00e4\u00a0 RIL <\/em>a ECAD<\/em>, RASSF1A<\/em>, NKX2-3<\/em>, H<\/em>AND1 <\/em>a OLIG2<\/em>. Ich potvrdenie v \u010fal\u0161\u00edch \u0161t\u00fadi\u00e1ch m\u00f4\u017ee \u00a0prinies\u0165 nov\u00e9 mo\u017enosti v terapii. \u00a0Epigenetic- k\u00e1 terapia mal\u00edgneho melan\u00f3mu je s\u00edce nov\u00e1 oblas\u0165, ale perspekt\u00edvne s ve\u013ek\u00fdm potenci\u00e1lom a mo\u017en\u00fdm dosahom na pacientov(33).<\/p>\n
\u0160t\u00fadium transform\u00e1cie n\u00e9vov\u00fdch \u00a0buniek sa v poslednom \u010dase zameriava najm\u00e4 \u00a0na problematiku regul\u00e1cie aktiv\u00e1cie a inhib\u00edcie \u00a0protin\u00e1dorovej imunitnej \u00a0reakcie. Protin\u00e1dorov\u00e1 imunoterapia je zalo\u017een\u00e1 na p\u00f4soben\u00ed vlastn\u00e9ho imunitn\u00e9ho \u00a0syst\u00e9mu pacienta. Vyu\u017e\u00edva fyziologick\u00e9 \u00a0princ\u00edpy, prirodzen\u00fa schopnos\u0165 organizmu ni\u010di\u0165 po\u0161koden\u00e9 bunky vr\u00e1tane n\u00e1dorovo transformovan\u00fdch buniek. S\u00fa\u010dasn\u00e1 lie\u010dba sa orientuje najm\u00e4 \u00a0na inhib\u00edciu kontroln\u00fdch bodov imunitnej odpovede. Ich fyziologickou \u00falohou \u00a0je zabr\u00e1ni\u0165 hyperaktiv\u00e1cii imunitn\u00e9ho \u00a0syst\u00e9mu, a t\u00fdm vzniku imunopatologick\u00fdch stavov. Bunky mal\u00edgneho melan\u00f3mu s\u00fa schopn\u00e9 vyu\u017ei\u0165 ich a unikn\u00fa\u0165 tak \u00a0protin\u00e1dorovej imunitnej odpovedi. Ve\u013ek\u00fdm prevratom v terapii metast\u00e1zuj\u00faceho mal\u00edgneho melan\u00f3mu sa stali ich inhib\u00edtory. V roku 2011 \u00a0bola v lie\u010dbe \u00a0mal\u00edgneho melan\u00f3mu schv\u00e1len\u00e1 molekula ipilimumab, <\/em>protil\u00e1tka proti CTLA-4 receptoru, ktor\u00e1 \u00a0sa stala s\u00fa\u010das\u0165ou be\u017enej \u00a0klinickej praxe(34). Ve\u013emi perspekt\u00edvne sa v \u0161t\u00fadi\u00e1ch ukazuj\u00fa \u00a0aj blok\u00e1tory receptorov PD-1 nivolumab \u00a0<\/em>a pembrolizumab<\/em>(35). <\/em>Perspekt\u00edvna\u00a0m\u00f4\u017ee \u00a0by\u0165 aj protin\u00e1dorov\u00e1 vakcin\u00e1cia, aj adopt\u00edvny transfer imunokompetentn\u00fdch buniek(36).<\/p>\n
 <\/p>\n
Z\u00e1ver<\/strong><\/p>\n
Chirurgick\u00e9 \u00a0odstr\u00e1nenie mal\u00edgneho melan\u00f3mu je z\u00e1kladom \u00a0terapie vo v\u0161etk\u00fdch \u0161t\u00e1di\u00e1ch, nasledovan\u00e1 v pr\u00edpade I. a II. \u0161t\u00e1dia lymfadenekt\u00f3miou, v III., vo IV. \u0161t\u00e1diu a v pr\u00edpadoch rekurentn\u00e9ho melan\u00f3mu imuno- a chemoterapiou. Pr\u00e1ve zavedenie cielenej \u00a0terapie, inhib\u00edtorov imunitnej regul\u00e1cie ako anti-PD-1 (nivolumab, \u00a0pembrolizumab<\/em>), anti-CTLA-4 (ipi<\/em>– <\/em>limumab<\/em>) \u00a0a cielen\u00e1 terapia inhib\u00edtormi BRAF prote\u00ednu (vemu<\/em>r<\/em>afenib a dabrafenib<\/em>), pr\u00edpadne MEK inhib\u00edtorov \u00a0(trametinib, cobimetinib<\/em>) predstavuj\u00fa z\u00e1sadn\u00fd obrat v lie\u010dbe neresekovate\u013en\u00fdch a metast\u00e1zuj\u00facich mal\u00edgnych melan\u00f3mov a s\u00fa testovan\u00e9 v klinick\u00fdch sk\u00fa\u0161kach.<\/p>\n
Probl\u00e9mom je v\u0161ak v\u00fdrazn\u00e1 \u00a0heterogenita melan\u00f3mov\u00fdch buniek, umo\u017e\u0148uj\u00faca n\u00e1doru meni\u0165 n\u00e1dorov\u00e9 mikroprostredie a unika\u0165 terapeutick\u00fdm strat\u00e9gi\u00e1m. Pou\u017eit\u00e1 cielen\u00e1 lie\u010dba sa \u010dasto sp\u00e1ja s mnoh\u00fdmi neobvykl\u00fdmi ne\u017eiaducimi \u00fa\u010dinkami, zni\u017euj\u00facimi \u00a0jej vyu\u017eite\u013enos\u0165 v praxi(37).<\/p>\n
A\u017e doteraz bola \u00a0terapia mal\u00edgneho melan\u00f3mu v neskor\u0161om \u0161t\u00e1diu neefekt\u00edvna. Zav\u00e1dzanie nov\u00fdch\u00a0 poznatkov do praxe spolu \u00a0so \u0161t\u00fadiom spr\u00e1vania n\u00e1dorov\u00fdch buniek a h\u013eadan\u00edm \u00a0\u010fal\u0161\u00edch \u00a0alternat\u00edvnych terapeutick\u00fdch cie\u013eov a ich kombin\u00e1ci\u00ed zvy\u0161uj\u00fa \u00a0aj v pokro\u010dilej\u0161om \u0161t\u00e1diu n\u00e1dej \u00a0na lie\u010dbu choroby, ktor\u00e1 je intenz\u00edvne \u0161tudovanou a aktu\u00e1lnou problematikou.<\/p>\n
 <\/p>\n
P<\/em><\/strong>o\u010fako<\/em><\/strong>v<\/em><\/strong>anie<\/em><\/strong><\/p>\n
T<\/em>ento \u010dl\u00e1nok vznikol v\u010faka podpore \u00a0v r\u00e1mci OP V\u00fdskum a v\u00fd<\/em>v<\/em>oj pre projekt \u201eDobudovanie multidisciplin\u00e1rneho centra pre biomedic\u00ednsky v\u00fdskum \u2013 BIOMEDIRES\u201c, ITMS 26210120041, spolufinancovan\u00fd zo zdrojov Eur\u00f3pskeho fondu region\u00e1lneho rozvoja.<\/em><\/p>\n
 <\/p>\n
Literat\u00fara<\/strong>
\n1. Steliarova-Foucher E, O\u2019Callaghan M, Ferlay J, et al. The European Cancer Observatory: A new data resource. Eur J Cancer 2015; 51(9): p. 1131-43.
\n2. Niezgoda A, Niezgoda P, Czajkowski R, Novel Approaches to Treatment
\nof Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy. Biomed Res Int 2015; 2015: p. 851387.
\n3. Balch, C.M., Buzaid, A.C., Soong, S.J., et al., Final version of the American
\nJoint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19(16): p. 3635-48.
\n4. Junkins-Hopkins JM. Malignant melanoma: molecular cytogenetics
\nand their implications in clinical medicine. J Am Acad Dermatol 2010;
\n63(2): p. 329-32.
\n5. Shah DJ, Dronca, RS. Latest advances in chemotherapeutic, targeted,
\nand immune approaches in the treatment of metastatic melanoma. Mayo
\nClin Proc 2014; 89(4): p. 504-19.
\n6. Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early
\nduring melanoma pathogenesis and are preserved throughout tumor
\nprogression. Clin Cancer Res 2003; 9(17): p. 6483-8.
\n7. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human
\ncancer. Nature 2002; 417(6892): p. 949-54.
\n8. Kumar R, Angelini S, Czene K, et al. BRAF mutations in metastatic
\nmelanoma: a possible association with clinical outcome. Clin Cancer Res
\n2003; 9(9): p. 3362-8.
\n9. Lee JH, Choi JW, Kim YS, Frequencies of BRAF and NRAS mutations
\nare different in histological types and sites of origin of cutaneous melanoma:
\na meta-analysis. Br J Dermatol 2011; 164(4): p. 776-84.
\n10. Atkinson, V., Medical management of malignant melanoma. Aust Prescr
\n2015; 38(3): p. 74-8.
\n11. Lugowska I, Kosela-Paterczyk H, Kozak K, et al. Trametinib: a MEK
\ninhibitor for management of metastatic melanoma. Onco Targets Ther
\n2015; 8: p. 2251-9.
\n12. Romano E, Schwartz GK, Chapman PB, et al. Treatment implications
\nof the emerging molecular classification system for melanoma. Lancet
\nOncol 2011; 12(9): p. 913-22.
\n13. Yeh I, Botton T, Talevich E, et al. Activating MET kinase rearrangements
\nin melanoma and Spitz tumours. Nat Commun 2015; 6: p. 7174.
\n14. Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in Spitz
\ntumours and spitzoid melanomas. Nat Commun 2014; 5: p. 3116.
\n15. Botton T, Yeh I, Nelson T, et al. Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy. Pigment Cell
\nMelanoma Res 2013; 26(6): p. 845-51.
\n16. Yu FX, Zhang K, Guan KL. YAP as oncotarget in uveal melanoma. Oncoscience 2014; 1(7): p. 480-1.
\n17. Dahl C, Guldberg P. The genome and epigenome of malignant melanoma. APMIS 2007; 115(10): p. 1161-76.
\n18. Omholt K, Krockel D, Ringborg U, et al. Mutations of PIK3CA are rare
\nin cutaneous melanoma. Melanoma Res 2006; 16(2): p. 197-200.
\n19. Kaur A, Webster MR, Weeraratna AT. In the Wnt-er of life: Wnt signalling in melanoma and ageing. Br J Cancer 2016; 115(11): p. 1273-9.
\n20. Webster MR, Kugel CH 3rd, Weeraratna AT. The Wnts of change: How
\nWnts regulate phenotype switching in melanoma. Biochim Biophys Acta
\n2015; 1856(2): p. 244-51.
\n21. Grossman D, McNiff JM, Li F, et al. Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 1999;
\n113(6): p. 1076-81. Preh\u013eadov\u00e9 pr\u00e1ce 1\/2017 47
\n22. Takeuchi H, Morton DL, Elashoff D, et al., Survivin expression by metastatic melanoma predicts poor disease outcome in patients receiving adjuvant polyvalent vaccine. Int J Cancer 2005; 117(6): p. 1032-8.
\n23. Pennati M., Binda, M., Colella, G., et al., Radiosensitization of human
\nmelanoma cells by ribozyme-mediated inhibition of survivin expression.
\nJ Invest Dermatol, 2003. 120(4): p. 648-54.
\n24. Lazar I, Perlman R, Lotem M, et al. The clinical effect of the inhibitor of
\napopotosis protein livin in melanoma. Oncology 2012; 82(4): p. 197-204.
\n25. Chang H, Schimmer AD. Livin\/melanoma inhibitor of apoptosis protein
\nas a potential therapeutic target for the treatment of malignancy. Mol
\nCancer Ther 2007; 6(1): p. 24-30.
\n26. Zhou J, Yuen NK, Zhan Q, et al. Immunity to the melanoma inhibitor
\nof apoptosis protein (ML-IAP; livin) in patients with malignant melanoma.
\nCancer Immunol Immunother 2012; 61(5): p. 655-65.
\n27. Rodriguez MI, Peralta-Leal A, O\u2019Valle F, et al. PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant
\ntransformation. PLoS Genet 2013; 9(6): p. e1003531.
\n28. Staibano S, Pepe S, Lo Muzio L, et al. Poly(adenosine diphosphate-ribose) polymerase 1 expression in malignant melanomas from photoexposed areas of the head and neck region. Hum Pathol 2005; 36(7): p. 724-31.
\n29. Busam KJ, Vilain RE, Lum T, et al. Primary and Metastatic Cutaneous
\nMelanomas Express ALK Through Alternative Transcriptional Initiation.
\nAm J Surg Pathol 2016; 40(6): p. 786-95.
\n30. Wiesner T, Obenauf AC, Murali R, et al. Germline mutations in BAP1
\npredispose to melanocytic tumors. Nat Genet 2011; 43(10): p. 1018-21.
\n31. Yeh I, Mully TW, Wiesner T, et al. Ambiguous melanocytic tumors with
\nloss of 3p21. Am J Surg Pathol, 2014. 38(8): p. 1088-95.
\n32. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;. 353(20): p. 2135-47.
\n33. Besaratinia A, Tommasi S. Epigenetics of human melanoma: promises
\nand challenges. J Mol Cell Biol 2014; 6(5): p. 356-67.
\n34. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged Survival
\nin Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med
\n2016; 375(19): p. 1845-55.
\n35. Shu CA, Rizvi NA. Into the Clinic With Nivolumab and Pembrolizumab.
\nOncologist 2016; 21(5): p. 527-8.
\n36. Singh BP, Salama AK. Updates in Therapy for Advanced Melanoma.
\nCancers (Basel) 2016; 8(1).
\n37. Steenbruggen TG, van den Heuvel MM, Blank CU, et al. No hair loss,
\nbut colitis or pneumonitis: unique side effects of immune checkpoint inhibitors for cancer. Ned Tijdschr Geneeskd 2016; 160(0): p. A9873.<\/p>\n","protected":false},"excerpt":{"rendered":"
*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf\u00a0 attachment at the end of the paper.   Aj ke\u010f mal\u00edgny \u00a0melan\u00f3m nepatr\u00ed v Slovenskej republike medzi \u00a0mal\u00edgne n\u00e1dory \u00a0s najvy\u0161\u0161ou incidenciou, je z\u00e1va\u017en\u00fd svojou \u00a0relat\u00edvne \u00a0vysokou mortalitou, najm\u00e4 \u00a0v pr\u00edpade, ak je zachyten\u00fd v neskor\u0161\u00edch \u0161t\u00e1di\u00e1ch<\/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":[290],"tags":[757,755,756,322],"class_list":["post-1006","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-current-perspective","tag-malignant-melanoma","tag-research","tag-review-en","typ_clanku-review-article"],"acf":{"abstrakt":"
In Slovakia, malignant melanoma belongs among the tumours with incessantly rising incidence and mortality. Malignant melanoma has been recently subject to intensive research under multiple projects aimed at identification of new diagnostic and prognostic markers, but primarily, potential therapeutic objectives. Patient prognosis has improved in the recent years. This is mainly related to introduction of new therapeutic procedures in treatment of malignant melanoma. Targeted treatment and particularly inhibitors of immune response represent an important turning point in the treatment of metastatic malignant melanoma. Application of research findings in practice represents a new hope for the future among patients with malignant melanoma.<\/p>\n
 <\/p>\n
Key words:<\/strong> malignant melanoma, research, review, current perspective<\/p>\n
 <\/p>\n","casopis":[{"ID":735,"post_author":"7","post_date":"2017-04-06 13:21:01","post_date_gmt":"2017-04-06 11:21:01","post_content":"
    \r\n \t
  • Pseudoglandular nevus \u2013 a rare morphology of melanocytic nevus (case report)<\/li>\r\n \t
  • Differential molecular diagnosis of multiple myeloma and Waldenstr\u00f6m macroglobulinemia<\/li>\r\n \t
  • Molecular analysis of prognostically significant markers of chronic lymphocytic leukemia<\/li>\r\n \t
  • Prevalence of Streptococcus pneumoniae<\/em> phyla in inflammatory diseases of upper airways in preschool age children and their resistance to antibiotics<\/li>\r\n \t
  • Malign melanoma - new aspects of research<\/li>\r\n \t
  • <\/li>\r\n<\/ul>","post_title":"Newslab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-2017-1","to_ping":"","pinged":"","post_modified":"2017-08-16 21:11:52","post_modified_gmt":"2017-08-16 19:11:52","post_content_filtered":"","post_parent":0,"guid":"http:\/\/www.newslab.sk\/?post_type=casopis&p=735\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"44","upload_clanok":{"ID":947,"id":947,"title":"Mal\u00edgny melan\u00f3m \u2013 nov\u00e9 aspekty v\u00fdskumu","filename":"Mal\u00edgny-melan\u00f3m-\u2013-nov\u00e9-aspekty-v\u00fdskumu.pdf","filesize":747365,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2017\/04\/Mal\u00edgny-melan\u00f3m-\u2013-nov\u00e9-aspekty-v\u00fdskumu.pdf","link":"https:\/\/www.newslab.sk\/en\/malign-melanoma-new-aspects-of-research\/maligny-melanom-nove-aspekty-vyskumu\/","alt":"","author":"7","description":"","caption":"","name":"maligny-melanom-nove-aspekty-vyskumu","status":"inherit","uploaded_to":1006,"date":"2017-04-07 19:22:41","modified":"2017-04-07 19:22:41","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\/1006","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=1006"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1006\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1006"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1006"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1006"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}