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BUBREG (Općenito (Epidemiologija (9/10000 incidencija, 3% svih, SAD 57000,…

- - - - pušenje
      - kadmij
        
        upotreba
        
        industrija
        
        baterija (Ni-Cd), boja, legura, raznih električnih instrumenata, auto industriji, te kao najvažnije, materijal za kontrolu fisije u nukleranim reaktorima.
        
        patogeneza
        
        nakuplja se u bubrezima
      - fenacetin
        
        patogeneza
        
        akumulacija, oštećenje
        
        upotreba
        
        ne koristi
        
        metabolizira se u paracetamol
        
        povučen u 80 zbog oštećenja bubrega
    - - VHL
        
        patogeneza
        
        mutiran
        
        povećana akumulacija HIF zbog smanjene degradacije prolil hidroksilazom
        
        on je transkpicijski faktor
        
        povećana ekspresija gena za
        
        3 more items...
      - Heredutarni papilarni tip 1
        
        MET mutacija
        
        RAS, PIK3
        
        WNT, Notc, STAT
      - Birt-Hog-Dub
        
        Foliculin gen - inhibiramTOR
      - Hereditarna lejomimatozatip 2
        
        fumarat hidrataza mutacija
        
        manje PHD degradira HIF
      - Sukcinat dehidrogenaza obitljeska
        
        kao fumarat
      - Tuberozna skleroza
        
        TSC1, TS-inhibiraju mTOR-aktivator HIF
    - - kronična upala
  - - - clear cell-75%
      - papilarni tip 1, 2
      - kromofobni-15%
      - onkocitom
      - kolekting duct
    - - OS 6.5 mj vs 19 mj drugi
  - - - https://www.google.ba/search?q=renal+cancer+tnm&source=lnms&tbm=isch&sa=X&ved=0ahUKEwikpIL45e7YAhVjAsAKHTRhArUQ_AUICigB&biw=1536&bih=734#imgrc=Rg-5DfDe7gvg1M:
  - - - Dg<1y, KS80%, LDH, Ca, Hgb (0, 1-2, >3)
    - - 6(KS, ATN, Ca, Dg<1y), 5yOS 71vs38vs0%
  - - - dali je dosegnut plato
    - - OS 12 mj do 30 mj
- - - - u tijeku f3
        
        dat će odgovor koja je kombinacija naj u 1 L
        
        CLEAR, L/E ili L/Pem vs S
        
        KN426, Pembro+Axi vs S
        
        Javelin 101, Ave+Axi vs S
        
        IMmotion 151-Ate+B vs S
        
        generalno
        
        RR do 70%
  - - - od 1983-1993- 6% RR, 4100 pts studije
      - 51 studija-1350 pts, RR 5.5%, 33 citostatika
      - nije jedan cito RR >10%
      - mix 5FU+gem-RR10do15%
      - KT+citokini bez benefita-3 studije
      - studija-18 pts, sarko komponenata- doxo+gem-RR28p
      - rezistencija
        
        P glikoprotein visok
        
        inhibitori-studije
        
        putevi
  - - - smanjen protok u tumor
      - prije umjesto debulking kirurgije
      - bez benefita
- - - - rizik
        
        dobar, srednji
        
        po važnosti
        
        Sunitinib
        
        Motzer, 780 pts, S 4/2 vs INFa (9MU 3xtj), PFS+11vs5 mj; HR0.42, , ORR+31vs6%
        
        MOA
        
        https://www.google.ba/search?q=sunitinib+moa&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi7rM2Wz-HaAhVCEJoKHYgkBjcQ_AUICigB&biw=1229&bih=587#imgrc=j5MLMbz5hOu9sM:
        
        pazopanib
        
        Sternberg,
        
        435 pts, 2:1, P vs placebo; , PFS+9vs4 mj, ORR 30vs3%, AE: proljev52%, HTA40%, promjena boje dlaka, mučnina 26%, anorexia 22%, povraćenje 21%, umor 19%, slaost 14%, abdominalna bol 11%, glavobolja 9%, G3 AST30%, ALT 20%; OS nss-krosover; JETRENA TOKSIČNOST %razlog prekida terapije
        
        COMPARZ,
        
        https://www.google.ba/search?q=sunitinib+pazopanib+difference&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi7op_ozuHaAhXsIpoKHeuSBmMQ_AUICigB&biw=1229&bih=587#imgrc=9kVi3yazzZV-vM:
        
        1100 pts, P vs S, isti učinak, različit sigurnosni profil; PFS 8.4 vs 9.5; ORR31vs25%, fatik 55vs63 SS, HFS 29vs50%, gubitak okusa 26vs36, Tr-penija 10vs34% ali trans više 31vs18%, OS 28 vs 29 mj
        
        PISCES, manja studija, poduprla COMPARZ, , 16 pts, Pazo10tj-2tj off-pa 10 tj suni i vice versa, 1 cilj preferencija- 70% P zbog bolje QOL vs 22% S te 8 % bez preferencije
        
        SREDNJ**, CM214
        
        https://www.nejm.org/doi/full/10.1056/NEJMoa1712126?page=2
        
        Beva
        
        Avoren
        
        B10mg/kg/2tj+INFa vs pla+INF, 649 pts, PFS 10vs5.4 mj
        
        Axitinib
        
        1L, vs Sora, PFS SS 10vs6mj
        
        do tad u 2L %Sorafenib
        
        **LOŠI, SREDNJI - Cabozanitinib
        
        CABOSUN
        
        rezultati
        
        https://www.google.ba/search?q=cabosun&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiDj-Ol0eHaAhVhJpoKHbgBDlwQ_AUICygC&biw=1229&bih=587#imgrc=3Kf78Pfi5cY0cM:
        
        https://www.google.ba/search?q=cabosun&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiDj-Ol0eHaAhVhJpoKHbgBDlwQ_AUICygC&biw=1229&bih=587#imgrc=9mBj9w-9jxsUMM:
        
        MOA
        
        VAM(AXL, MET)
        
        dizajn
        
        https://www.google.ba/search?q=cabosun&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiDj-Ol0eHaAhVhJpoKHbgBDlwQ_AUICygC&biw=1229&bih=587#imgrc=IZ2GnTJPVF7AEM:
        
        visokodozni, IL2
        
        IL veći RR, DoR, Manji s INF, mal broj dug DoR
        
        RR 5do27%
        
        studije
        
        1 more item...
        
        kod kontraindikcije za gore, ECOG 0
        
        do 2005 INF, IL
        
        citokini
        
        INF, IL
        
        kad je kontindicirano TKI
        
        aktivno praćenja
        
        tm manji od 4 cm
        
        fit op
        
        studija
        
        indoletne meta, sist toksično i nijekurativno
        
        Rini, 2016 Lancet
        
        3 more items...
        
        loš
        
        ARCC
        
        Tem, 625pts, TvsINFavsmix, poor rg, +OSHE0.73, +PFS vs INF i mix, mOS 10vs7.3vs8.4 mj
        
        LOŠ**, CM214
        
        vs S; 1100pts; ORR+41.5vs26.5%-interm/poor risk, CR 9vs2%; DoR nr vs 18 mj; PFS poboljšan 11.4 vs 8.5 mj; ; PDL>1% ORRR 60vs25%, PFS23vs6mj; dobra riisk-RR 30vs50% za Suni SS; PFS 15 vs 25mj; AE gr3, 54vs63%
      - Općenito
        
        najveći problem stečena rezi
        
        Suni, Pazo, INF+Ava, Tems-loši, IL
        
        med OS 25 mj
        
        RR do 30%
        
        većina ima neki RR
        
        nije drmatian water kao kod melanoma
        
        med PFS-9mj
      - RECORD 3
        
        mTOR nnferioran Sutentu
        
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452072/
    - - po važnosti
        
        cabozatinib
        
        METEOR, (antiVEGFR, antic-MET) vs everolimus, 658 pts; +PFS-HR.51- 7vs4mj; OS 21v.5 vs16.5mj; RR17vs3%; AE:HTA 15%, diareja 13%, fatik 11%, PPE 8%, anemija 3%
        
        Aksitinib
        
        AXIS, AxvsSor, 2:1, 723 pts, PFS6.7 vs 4.7 SS, HR0.66 AE stop th vs8%
        
        Nivo
        
        f2, prije do 3L, ORR 20%, mOS25 mj
        
        CM 025, f3, 821 pts, N vs E, OS+ 25 vs19.6mj HR0.73%, ORR+15vs5%; AE-19vs37%-naj 2%umor vs 8% anemija
        
        Lenvatinib+Everolimus
        
        HOPE 205, Motzer;; f2, Len+Eve vs eve vs len; 100pts, PFS+14.5vs5.5 mj HR0.40; AE gr3, 4 70% vs50% vs80%; % 20% diraje vs anemija12% vs proteinuraija19%; 2 smrti mix(CVI), 1len(IM)
        
        , Ever
        
        RECORD 1
        
        dizajn :
        
        https://www.google.ba/search?q=record+1+rcc&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi4zdOP1eHaAhWFNpoKHbDpDgwQ_AUICigB&biw=1229&bih=548#imgrc=6znZnK6hLgKzBM:
        
        rezultati
        
        https://www.google.ba/search?q=record+1+rcc&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi4zdOP1eHaAhWFNpoKHbDpDgwQ_AUICigB&biw=1229&bih=548#imgrc=uo31knMAOlMHTM:
        
        Nivo+Ipi
        
        CM 016
        
        https://www.ncbi.nlm.nih.gov/pubmed/28678668
        
        Sorafenib
        
        TARGET
        
        dizajn
        
        https://www.google.ba/search?q=target+study+rcc&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiayOH31eHaAhXmK5oKHdYuB48Q_AUICigB&biw=1229&bih=548#imgrc=sB_BRDE7XTMcUM:
        
        rezultati
        
        https://www.google.ba/search?q=target+study+rcc&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiayOH31eHaAhXmK5oKHdYuB48Q_AUICigB&biw=1229&bih=548#imgrc=88N8tEUPVHKfCM:
      - Axi, Eve, Sora
        
        med PFS-4-5 mj
      - 2L TKI, IT
        
        meta otežana-jed dominira tm supresor gen
        
        mTOR dominatna meta
        
        molekularni subset benefit
        
        Gerlinger 2012 NEJM-intratumorska heterogenost, 1 tumor više biopsija, različite mutacije-655 I NISU PRISUTNE U SVAKOJBIOPSIJI
    - - Eve, Sora
        
        med PFS 4-5 mj
  - - - vrste
        
        1L
        
        Clinical trial (preferred)
        
        • Sunitinib (preferred)
        
        studije
        
        ESPEN
        
        ASPEN
        
        • Axitinib
        
        • Bevacizumab
        
        • Bevacizumab + erlotinib for selected patients with advanced papillary RCC including HLRCC (veći rizik uteru, papilarni i koža tumori
        
        f2, RR60%, PFS 24mj-heredi lejo
        
        • Bevacizumab + everolimus for selected patients with hlrcc
        
        f2 PFS 10, OS 18, RR30%
        
        • Cabozantinib
        
        • Erlotinib
        
        ORR11%, OS 27 mj-kod papilaraca
        
        • Everolimus
        
        studije
        
        REACT
        
        RAPTOR
        
        • Lenvatinib + everolimus
        
        • Nivolumab
        
        • Pazopanib
        
        • Sorafenib
        
        • Temsirolimus (category 1 for poor-prognosis risk group;h
        
        subset ARCC
        
        category 2A for other risk groups)
        
        and
        
        Best supportive care:l
- - - - studije
        
        STRAC, 615, clear, T3, N1; S vs placebo, visok rizik za relaps, ; 4/2 50mg,, pFS+6.8vs5.6y HR0.76, AE 60vs20%, prema prethodnim studijama PFS surogat koji se nemora translatira u OS, DAT: vrlo motiviranim koji su voljni prihvatit AE
        
        ASSURE, sličan dizajn STRAC-u, negPFS, OSSora ili Suni vs pl,
        
        PROTECT, Pazvs place, neg PFS, **kritika: reducirana doza 600 mg
        
        EVERST, eve adjuvatno
  - - - ima 1.5 do 3.5%
        
        studije
        
        1 meta-OP, 5y OS 35%
        
        O Dea
        
        5y OS 23%, kasnije meta poslije OP
        
        der Pel
        
        bolji os kod meta pluća vs druga sijela
    - - studije
        
        DeKErnon - CR op bez sist th-OS isti 79 pts
        
        poz
        
        Flanngan-120 pts, OP+ IF-OS 11vs 8 mj
        
        Mickisch- vrijeme do progresije 5vs 3 mj, bolji OS
        
        Ali, samo meta pluća, 5y, 870pts, CSS70 kom res vs 20% inkom res
      - presjek studija
        
        https://www.onclive.com/web-exclusives/cytoreductive-nephrectomy-retains-role-in-modern-rcc-era?p=2
        
        studije
        
        SURTIME
        
        CARMENA
        
        f3, 450 pts, poor, inter; suni vs cito+suni, =OS 18vs14 mj
        
        komentari-Motzer nije iznenađen jer 43% poor (kirurgija ne igra rolu), više T3, T4 u grupi s kirurgijom; 20% nije primilo lijek OP vs 5% Suni grupa; 10% nije operirano vs 20% operirano u Suigrupa
        
        primjenit kod: poor, mal primarni tumor velik meta
    - - smanjivanje simptoma
        
        boli
        
        krvarenja
        
        hipekalcijenije
        
        eritrocitoze
    - - standard
        
        2 prospektivne studije
        
        Flaning, Miškić
    - - kirurški
        
        nefrektomija
        
        radikalna
        
        tm manji od 7 cm
        
        parcijalna
        
        solitarni
        
        bill tm
        
        VHL
        
        slab ostatni bubreg
        
        T1a
        
        prva-Eratus Walkot - 1861