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  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

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    :1. Dummer R, Hauschild A, Guggenheim M, Keilholz

    U, Pentheroudakis G. ESMO Guidelines WorkingGroup. Cutaneous melanoma: ESMO ClinicalPractice Guidelines for diagnosis, treatment andfollow-up. Ann Oncol. 2012; 23 (7):vii86-91.

    2.

    Garbe C, Peris K, Hauschild A, Saiag P, MiddletonM, Spatz A, Grob JJ, Malvehy J, Newton-Bishop J,Stratigos A, Pehamberger H, Eggermont AM.European Dermatology Forum; EuropeanAssociation of Dermato-Oncology; EuropeanOrganization of Research and Treatment of Cancer.Diagnosis and treatment of melanoma. Europeanconsensus-based interdisciplinary guideline Update2012. Eur J Cancer 2012; 48(15):2375-90.

    3.

    Pflugfelder A, Kochs C, Blum A, Capellaro M,Czeschik C, Dettenborn T, Dill Det al. S3-guidelinediagnosis, therapy and follow-up of melanoma

    short version. J Dtsch Dermatol Ges. 2013;11(6):563-602.

    4.

    NCCN Clinical Practice guidelines in oncologyv2.2014. Available at:

    http://www.nccn.org/professionals/physician-gls/pdf/melanoma.pdf5. Clinical Practice Guidelines for the Management of

    Melanoma in Australia and New Zealand 2010.Available at: www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdf

    6.

    Balch CM, Gershenwald JE, Soong SJ, et al: Finalversion of 2009 AJCC melanoma staging andclassification. J Clin Oncol 27:6199-6206, 2009

    7. . . , . http://www.azus.gov.rs/wp-content/uploads/2011/02/Vodic-za-vodice.pdf

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    1.

    Clinical Practice Guidelines for the Management ofMelanoma in Australia and New Zealand 2010.Available at: www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdf

    2. Ferlay J, Soerjomataram I, Ervik M, Dikshit R,Eser S, Mathers C, Rebelo M, Parkin DM, FormanD, Bray, F. GLOBOCAN 2012 v1.0, Cancer

    Incidence and Mortality Worldwide: IARCCancerBase No. 11 [Internet]. Lyon, France:International Agency for Research on Cancer;

    2013. Available from: http://globocan.iarc.fr,accessed on 19/Jan/2014.

    3.

    Milju D, ivkovi-Perii S. Registar za rakRepublike Srbije. Available at:http://www.batut.org.rs/download/publikacije/Registar%20za%20rak%20u%20Centralnoj%20Srbiji%202010.pdf

    4.

    Kandolf-Sekulovic L, Babovic N, Balic M, NikolinB, Nikolic D, Janjic Z, Jokic N, Milosavljevic M,Mijuskovic Z, Rajovic M, Novakovic M, Vrbic S,Pejcic I, Kovacevic P, Mihajlovic D, Roganovic T,

    12

    http://www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdfhttp://www.batut.org.rs/download/publikacije/Registar%20za%20rak%20u%20Centralnoj%20Srbiji%202010.pdfhttp://www.batut.org.rs/download/publikacije/Registar%20za%20rak%20u%20Centralnoj%20Srbiji%202010.pdfhttp://www.batut.org.rs/download/publikacije/Registar%20za%20rak%20u%20Centralnoj%20Srbiji%202010.pdfhttp://www.batut.org.rs/download/publikacije/Registar%20za%20rak%20u%20Centralnoj%20Srbiji%202010.pdfhttp://www.batut.org.rs/download/publikacije/Registar%20za%20rak%20u%20Centralnoj%20Srbiji%202010.pdfhttp://www.batut.org.rs/download/publikacije/Registar%20za%20rak%20u%20Centralnoj%20Srbiji%202010.pdfhttp://www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdf
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    Vicko F, Nikolic J, Marinkovic M. Epidemiology,clinicopathological characteristics, diagnosis andtreatment of melanoma in Serbia the MelanomaFocus study. Vojnosanit Pregl

    5.

    Kandolf-Sekulovi L, ivkovi-Perii S, RadeviT, Rajovi M, Dini M, Zolotarevski L, MijukoviZ, Zeevi RD, Novakovi M. Melanoma in South-

    East Europe: epidemiological data from the centralcancer registry and clinicopathologicalcharacteristics from the hospital-based registry inSerbia. Int J Dermatol. 2012; 51(10):1186-94.

    6.

    Vranje N, Miladinov-Mikov M, Nikolin B, BaltiV. Epidemiology of cutaneous melanoma in theprovince of Vojvodina. Arch Oncol 1998; 6(1):13-8.

    7.

    U.S. Department of Health and Human Services.The Surgeon Generals Call to Action to PreventSkin Cancer. Washington, DC: U.S. Dept of Healthand Human Services, Office of the SurgeonGeneral; 2014.Surgeons General Call to Action toPrevent Skin Cancer. Available at

    http://www.surgeongeneral.gov.8. Garbe C, Peris K, Hauschild A, Saiag P, MiddletonM, Spatz A, Grob JJ, Malvehy J, Newton-Bishop J,Stratigos A, Pehamberger H, Eggermont AM.European Dermatology Forum; EuropeanAssociation of Dermato-Oncology; EuropeanOrganization of Research and Treatment of Cancer.Diagnosis and treatment of melanoma. Europeanconsensus-based interdisciplinary guideline Update2012. Eur J Cancer 2012; 48(15):2375-90.

    9. International Agency for Research on CancerWorking Group on artificial ultraviolet (UV) lightand skin cancer. The association of use of sunbedswith cutaneous malignant melanoma and other skincancers: a systematic review. Int J Cancer 2007;

    120(5): 111622.10.

    Cust AE, Armstrong BK, Goumas C, Jenkins MA,Schmid H, Hopper JL et al. Sunbed use duringadolescence and early adulthood is associated withincreased risk of early-onset melanoma. Int JCancer 2011; 128(10): 2425-35.

    11. Zeljic K, Kandolf-Sekulovi L, upi G. Melnaomarisk is assoicated with vitamin D receptorpolymorphism. Melanoma Res 2013; in press.

    12. Katalinic A, Waldmann A, Weinstock MA, GellerAC, Eisemann N, Greinert R et al. Does skincancer screening save lives? an observational studycomparing trends in melanoma mortality in regionswith and without screening. Cancer 2012; 118(21):

    5395-402.13.

    Feit NE, Dusza SW, Marghoob AA. Melanomasdetected with the aid of total cutaneousphotography. Br J Dermatol 2004; 150(4): 70614.

    14. Carli P, de Giorgi V, Chiarugi A, Nardini P,Weinstock MA, Crocetti E et al. Addition ofdermoscopy to conventional naked-eye

    examination in melanoma screening: a randomizedstudy. J Am Acad Dermatol 2004; 50(5): 6839.

    15.

    Banky JP, Kelly JW, English DR, Yeatman JM,Dowling JP. Incidence of new and changed neviand melanomas detected using baseline images anddermoscopy in patients at high risk for melanoma.Arch Dermatol 2005; 141(8): 9981006.

    16.

    Haenssle HA, Krueger U, Vente C, Thoms KM,Bertsch HP, Zutt M et al. Results from anobservational trial: digital epiluminescencemicroscopy follow-up of atypical nevi increases thesensitivity and the chance of success ofconventional dermoscopy in detecting melanoma. JInvest Dermatol 2006; 126(5): 9805.

    17.

    Vestergaard M, Macaskill P, Holt P, Menzies SW.Dermoscopy compared to naked eye examinationfor the diagnosis of primary melanoma: a meta-analysis of studies performed in a clinical setting.Br J Dermatol 2008; 159(3): 669-76.

    18. Kittler H, Guitera P, Riedl E, Avramidis M, TebanL, Fiebiger M et al. Identification of clinically

    featureless incipient melanoma using sequentialdermoscopy imaging. Arch Dermatol 2006; 142(9):11139.

    19. Argenziano G, Giacomel A, Abramavicus A et al.Improving triage and management of patients withskin cancer: challenges and considerations for thefuture. Expert Rev Anticancer Ther 2012; 12(5),609621.

    20.

    Pflugfelder A, Kochs C, Blum A, Capellaro M,Czeschik C, Dettenborn T, Dill Det al. S3-guidelinediagnosis, therapy and follow-up of melanomashort version. J Dtsch Dermatol Ges. 2013;11(6):563-602.

    21.

    Balch CM, Soong SJ, Gershenwald JE, ThompsonJF, Reintgen DS, Cascinelli N et al. Prognostic

    factors analysis of 17,600 melanoma patients:validation of the American Joint Committee onCancer melanoma staging system. J Clin Oncol2001; 19(16):36223634.

    22.

    MacKelfresh J, Chen SC, Monthrope YM.Pregnancy and changes in melanocytic nevi. ObstetGynecol 2005; 106(4):857860.

    23. Katz VL, Farmer RM, Dotters D. Focus on primarycare: from nevus to neoplasm: myths of melanomain pregnancy. Obstet Gynecol Surv 2002;57(2):112119.

    24.

    Holly EA, Cress RD, Ahn DK. Cutaneousmelanoma in women. III. Reproductive factors andoral contraceptive use. Am J Epidemiol 1995;

    141(10):943950.25. Persson I, Yuen J, Bergkvist L, Schairer C. Cancerincidence and mortality in women receivingestrogen and estrogen-progestin replacementtherapy--long-term follow-up of a Swedish cohort.Int J Cancer 1996; 67(3):327332.

    13

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    :1. Balch CM, Gershenwald JE, Soong SJ, et al: Final

    version of 2009 AJCC melanoma staging andclassification. J Clin Oncol 27:6199-6206, 2009

    2.

    Clinical Practice Guidelines for the Management ofMelanoma in Australia and New Zealand 2010.Available at: www.nhmrc.gov.au/-files-nhmrc/publications/attachments/cp111.pdf

    3.

    Dummer R, Hauschild A, Guggenheim M, KeilholzU, Pentheroudakis G. ESMO Guidelines WorkingGroup. Cutaneous melanoma: ESMO ClinicalPractice Guidelines for diagnosis, treatment andfollow-up. Ann Oncol. 2012; 23 (7):vii86-91.

    4.

    Garbe C, Peris K, Hauschild A, Saiag P, MiddletonM, Spatz A, Grob JJ, Malvehy J, Newton-Bishop J,Stratigos A, Pehamberger H, Eggermont AM.European Dermatology Forum; EuropeanAssociation of Dermato-Oncology; European

    Organization of Research and Treatment of Cancer.Diagnosis and treatment of melanoma. Europeanconsensus-based interdisciplinary guideline Update2012. Eur J Cancer 2012; 48(15):2375-90.

    5. Pflugfelder A, Kochs C, Blum A, Capellaro M,Czeschik C, Dettenborn T, Dill Det al. S3-guidelinediagnosis, therapy and follow-up of melanomashort version. J Dtsch Dermatol Ges. 2013;11(6):563-602.

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    :

    1.

    Dummer R, Hauschild A, Guggenheim M, KeilholzU, Pentheroudakis G. ESMO Guidelines WorkingGroup. Cutaneous melanoma: ESMO ClinicalPractice Guidelines for diagnosis, treatment andfollow-up. Ann Oncol. 2012; 23 (7):vii86-91.

    2. Garbe C, Peris K, Hauschild A, Saiag P, MiddletonM, Spatz A, Grob JJ, Malvehy J, Newton-Bishop J,Stratigos A, Pehamberger H, Eggermont AM.European Dermatology Forum; EuropeanAssociation of Dermato-Oncology; EuropeanOrganization of Research and Treatment of Cancer.Diagnosis and treatment of melanoma. European

    consensus-based interdisciplinary guideline Update2012. Eur J Cancer 2012; 48(15):2375-90.

    3.

    Pflugfelder A, Kochs C, Blum A, Capellaro M,Czeschik C, Dettenborn T, Dill Det al. S3-guidelinediagnosis, therapy and follow-up of melanomashort version. J Dtsch Dermatol Ges. 2013;11(6):563-602.

    4. NCCN Clinical Practice guidelines in oncologyv2.2014. Available at:http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf

    5.

    Clinical Practice Guidelines for the Management ofMelanoma in Australia and New Zealand 2010.Available at:

    www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdf6. Testori A, Soteldo J, Powell B, Sales F,

    Borgognoni L, Rutkowski P, Lejeune F, vanLeeuwen P, Eggermont A (Dzodic R participating

    physician). Surgical management of melanoma: anEORTC Melanoma Group survey.Ecancermedicalscience. 2013;7:294.

    7. Leung AM, Hari DM, Morton DL. Surgery fordistant melanoma metastasis. Cancer J. 2012;18(2):176-84.

    8. Schlagenhauff B, Ellwanger U, Breuninger H,Stroebel W, Rassner G, Garbe C. Prognostic impactof the type of anaesthesia used during the excisionof primary cutaneous melanoma. Melanoma Res20050; 10(2):165-9.

    9.

    Kelemen PR, Essner R, Foshag LJ, Morton DL.Lymphatic mapping and sentinel lymphadenectomyafter wide local excision of primary melanoma. JAm Coll Surg. 1999 Sep;189(3):247-52.

    10.

    Ariyan S, Ali-Salaam P, Cheng DW, Truini C.Reliability of lymphatic mapping after wide localexcision of cutaneous melanoma. Ann Surg Oncol.2007 Aug;14(8):2377-83.

    11. Pflugfelder A, Weide B, Eigentler TK, et al.Incisional biopsy and melanoma prognosis: factsand controversies. Clin Dermatol 2010; 28(3):3168.

    12.

    Parrett BM, Accortt NA, Li R, Dosanjh AS,

    Thummala S, Kullar R, Cleaver JE, Kashani-SabetM, Leong SP. The effect of delay time betweenprimary melanoma biopsy and sentinel lymph node

    25

    http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdf
  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    26/90

    dissection on sentinel node status, recurrence, andsurvival. Melanoma Res. 2012 Oct; 22(5):386-91.

    13.

    Lent WM, Ariyan S. Flap reconstruction followingwide local excision for primary malignantmelanoma of the head and neck region. Ann PlastSurg. 1994 Jul;33(1):23-7.

    14. Buck D 2nd, Rawlani V, Wayne J, Dumanian GA,

    Mustoe TA, Fine NA, Galiano R, Kim JY.Cosmetic outcomes following head and neckmelanoma reconstruction: The patient'sperspective. Can J Plast Surg. 2012Spring;20(1):e10-5.

    15. Janji Z, Nikoli J. Rekonstruktivni zahvati nakonoperacija melanoma koe. In: Ini M, Dodi R,Guduri B. Melanom (monografija). Beograd;UOHS 2007: 112- 122.

    16. Gillgren P, Drzewiecki KT, Niin M, Gullestad HP,Hellborg H, Mnsson-Brahme E, Ingvar C,Ringborg U. 2-cm versus 4-cm surgical excisionmargins for primary cutaneous melanoma thickerthan 2 mm: a randomised, multicentre trial. Lancet.

    2011; 378(9803): 1635-42.17.

    Moehrle M, Dietz K, Garbe C, Breuninger H.Conventional histology vs. three-dimensionalhistology in lentigo maligna melanoma. Br JDermatol. 2006; 154(3): 453-9.

    18. Hilari H, Llorca D, Traves V, Villanueva A, Serra-Guilln C, Requena C, Llombart B, Sanmartn O,Guilln C, Nagore E. Conventional surgerycompared with slow Mohs micrographic surgery inthe treatment of lentigo maligna: a retrospectivestudy of 62 cases. Actas Dermosifiliogr. 2012Sep;103(7):614-23.

    19. Cohen T, Busam KJ, Patel A, Brady MS.Subungual melanoma: management considerations.

    Am J Surg 2008; 195 (2): 2448.20. Balch CM, Gershenwald JE, Soong SJ, et al: Final

    version of 2009 AJCC melanoma staging andclassification. J Clin Oncol 2009; 27: 6199-206.

    21. Wong SL, Balch CM, Hurley P et al. Sentinellymph node biopsy for melanoma: AmericanSociety of Clinical Oncology and Society ofSurgical Oncology joint clinical practice guideline.J Clin Oncol 2012; 30 (23):2912-8.

    22. Chakera AH, Hesse B, Burak Z, Ballinger JR,Britten A, Carac C, et al. European Association ofNuclear Medicine-European Organisation forResearch and. EANM-EORTC general

    recommendations for sentinel node diagnostics inmelanoma. Eur J Nucl Med Mol Imaging 2009;36(10): 1713-42.

    23.

    Balch CM, Morton DL, Gershenwald JE, et al:Sentinel node biopsy and standard of care formelanoma. J Am Acad Dermatol 60:872-875, 2009.

    24.

    Reintgen D, Pendas S, Jakub J, Swor G, GiulianoR, Bauer J, Cassall R, Duhaime L, Alsarrai M,Shivers S. National trials involving lymphaticmapping for melanoma: the Multicenter Selectivelymphadenectomy Trial, the Sunbelt MelanomaTrial, and the Florida Melanoma Trial. SeminOncol. 2004 Jun;31(3):363-73.

    25.

    Rajovic M, Jaukovic Lj, Kandolf-Sekulovic L,Sijan G, Zolotarevski L, Novakovic M. Sentinellymph node status clinicopathological andprognostic associations initial experience fromthe single center. 6th Meeting of InterdisciplinaryMelanoma Skin Cancer Centers. Barcelona, 2012;P65.

    26.

    Rajovic M, Jaukovic L, Kandolf-Sekulovic,Zolotarevski L, Sijan G, Novakovic M. Sentinellymph node tumor burden and its correlation toclinicopathologic characteristics of primarymelanoma and fi nding of non-sentinel lymph nodein complete lymph node dissection. J DeutschDermatol Ges 2013; 11 (Supp 7).

    27.

    Kienstra MA. Padhy TA. Head and NeckMelanoma. Cancer Control. 2005; 12:242247.28. Patuzzo R, Maurichi A, Camerini T, Gallino G,

    Ruggeri R, Baffa G, Mattavelli I, Tinti MC, CrippaF, Moglia D, Tolomio E, Maccauro M, SantinamiM. Accuracy and prognostic value of sentinellymph node biopsy in head and neck melanomas. JSurg Res. 2013 Oct 23.

    29.

    Han D, Zager JS, Han G, Marzban SS, Puleo CA,Sarnaik AA, Reed D, Messina JL, Sondak VK. Theunique clinical characteristics of melanomadiagnosed in children.Ann Surg Oncol. 2012;19(12): 3888-95.

    30.

    Jhaveri MB, Driscoll MS, Grant-Kels JM.Melanoma in pregnancy. Clin Obstet Gynecol.2011; 54(4):537-45.

    31. Nikolin B, veljo O. Metastatic melanoma andpregnancy-case report. Arch Oncol 2005; 13(1):31-4

    32. Andtbacka RH, Donaldson MR, Bowles TL,Bowen GM, Grossmann K, Khong H,Grossman D,Anker C, Florell SR, Bowen A, Duffy KL,Leachman SA, Noyes RD. Sentinel lymph nodebiopsy for melanoma in pregnant women. AnnSurg Oncol. 2013; 20(2): 689-96.

    33.

    Broer N, Buonocore S, Goldberg C, Truini C,Faries MB, Narayan D, Ariyan S. A proposal forthe timing of management of patients withmelanoma presenting during pregnancy. J SurgOncol. 2012 Jul 1; 106(1):36-40.

    26

  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    27/90

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  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    30/90

    :

    1. Lpez F, Rodrigo JP, Cardesa A,

    Triantafyllou A, Devaney KO, MendenhallWM, Haigentz M, Strojan P, Pellitteri PK,Bradford CR, Shaha AR, Hunt JL, de Bree R,Takes RP, Rinaldo A, Ferlito A. Update on

    primary head and neck mucosal melanoma.Head Neck. 2014 Sep

    2. Lourenco SV, Fernandes JD, Hsieh R, et al.Head and neck mucosal melanoma: a review.Am J Dermatopathol 2014 Jan 13. [Epubahead of print]

    3. Satzger I, Schaefer T, Kuettler U, et al.Analysis of c-KIT expression and KIT genemutation in human mucosal melanomas. Br J

    Cancer 2008;99:2065-2069.4. Papaspyrou G, Garbe C, Schadendorf D,

    Werner JA, Hauschild A, Egberts F. Mucosal

    melanomas of the head and neck: new aspectsof the clinical outcome, molecular pathology,and treatment with c-kit inhibitors. MelanomaRes 2011; 21:475-482.

    5. Edge SB, Byrd DR, Compton CC, Fritz AG,Greene FL, Trotti A. AJCC Cancer Staging

    Manual. 7th ed. New York: Springer; 2009.6. Koivunen P, Back L, Pukkila M, et al.Accuracy of the current TNM classification in

    predicting survival in patients with sinonasalmucosal melanoma. Laryngoscope2012;122:1734-1738

    7. NCCN Clinical Practice guidelines inoncology v2.2014. Available at:http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf

    8. Krengli M, Masini L, Kaanders JH, et al.Radiotherapy in the treatment of mucosalmelanoma of the upper aerodigestive tract:

    analysis of 74 cases. A rare cancer networkstudy. Int J Radiat Oncol Biol Phys 2006; 65:751-759.

    30

    http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf
  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    31/90

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    , . . (Clark) , (Breslow) .

    , ,

    . , 50% 5 . 70% ( 1.5 mm in patients with stage IImelanoma: results of the EORTC 18961

    66

  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    67/90

    randomized phase III trial. J Clin Oncol. 2013 Oct20;31(30):3831-7.

    25.

    GSK official report. Available at:http://www.gsk.com/media/press-releases/2013/the-investigational-mage-a3-antigen-specific-cancer-immunotherap.html

    26. Loutfi A, Shakr A, Jerry M, Hanley J, Shibata HR.

    Double blind randomized prospective trial oflevamisole/placebo in Stage I cutaneous malignantmelanoma. Clin Invest Med 1987; 10:325328

    27.

    Eggermont A, Chiarion-Sileni V, Grob, JJ, et al. JClin Oncol 32:5s, 2014 (suppl; abstr LBA9008).

    28. Corrie PG, Marshall A, Dunn JA, et al. Adjuvantbevacizumab in patients with melanoma at high

    risk of recurrence (AVAST-M): preplanned interimresults from a multicentre, open-label, randomisedcontrolled phase 3 study. Lancet Oncol 2014;15(6): 620-30.

    29.

    Moschos SJ, Edington HD, Land SR, Rao UN,Jukic D, Shipe-Spotloe J, Kirkwood JM.Neoadjuvant treatment of regional stage IIIB

    melanoma with high-dose interferon alfa-2binduces objective tumor regression in associationwith modulation of tumor infiltrating host cellularimmune responses. J Clin Oncol 2006; 24(19):3164-71.

    67

  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    68/90

    0, I , II

    III , JCC (, I).

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    , .

    in transit/ ( IIIC) , e (L-PAM), TNF- . (RR) a o, OS(C, III).

    . , .

    , -2,- BCG . ,

    .

    III - (PV-10) -2 ,

    . , (GCP).

    IV

    (DTIC) , RR 7.5-20% ( , CR 1%) 2.5 (A, Ia).

    RR , , , .

    , DTIC (CVD) , ,RR40%, OS (A, Ia). Darthmouth

    , ,BCNU (CDBT) , (A, Ia).

    , IL-2 /IFN- (DTIC, TMZ,, , ,

    , ) RR OS . , (A, Ia).

    68

  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    69/90

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    II

    :1. Dummer R, Hauschild A, Guggenheim M, Keilholz U,Pentheroudakis G. ESMO Guidelines Working Group.Cutaneous melanoma: ESMO Clinical Practice Guidelinesfor diagnosis, treatment and follow-up. Ann Oncol 2012; 23(7):vii86-91.2. NCCN Clinical Practice guidelines in oncology v2.2014.Available at:http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf3. Turza K, Dengel LT, Harris RC, et al. Effectiveness ofimiquimod limited to dermal melanoma metastases, withsimultaneous resistance of subcutaneous metastasis. J Cutan

    Pathol 2010; 37(1):94-98.4. Lens MB, Dawes M: Isolated limb perfusion withmelphalan in the treatment of malignant melanoma of theextremities: a systematic review of randomised controlledtrials. Lancet Oncol 2003; 4(6):359-364.5. Cornett WR, McCall LM, Petersen RP et al. Randomizedmulticenter trial of hyperthermic isolated limb perfusion withmelphalan alone compared with melphalan plus tumornecrosis factor: American College of Surgeons OncologyGroup Trial Z0020. J Clin Oncol 2006; 24:41962016. Beasley GM, Petersen RP, Yoo J et al. Isolated limbinfusion of in-transit malignant melanoma of the extremity: awelltolerated but less effective alternative to hyperthermicisolated limb perfusion. Ann Surg Oncol 2008; 15:2195205.

    7. Babovi N, Jeli S, Kreai S. Hemioterapija i hormonskaterapija u leenju melanoma i aktuelne klinike studije.Melanom, Udruenje onkolokih hirurga Srbije 2007: 139-44,8. Babovi N, Jeli S, Popov I. Terapija metastatskogmelanoma. Pregledi: Serijal Savremena terapija uonkologiji 2002; 128:284-9.9. Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-basedchemotherapy for metastatic melanoma: thirty-yearexperience overview. J Exp Clin Cancer Res 2000; 19(1):21-34.10. Chapman PB, Einhorn LH, Meyers ML, et al. Phase IIImulticenter randomized trial of the Dartmouth regimenversus dacarbazine in patients with metastatic melanoma. JClin Oncol 1999; 17 (9): 2745-2751.11. Mays SR, Nelson BR. Current therapy of cutaneousmelanoma. Cutis 1999; 63 (5).12. Wagner JD, Gordon MS, Chuang TY, et al. Currenttherapy of cutaneous melanoma. Plast Reconstr Surg2000;105 (5): 1774-99.

    13. Middleton MR, Grob JJ, Aaronson N, et al. Randomizedphase III study of temozolomide versus dacarbazine in thetreatment of patients with advanced metastatic malignantmelanoma. J Clin Oncol 2000; 18 (1): 158-66.14. Patel PM, Suciu S, Mortier L, et al. Extended schedule,escalated dose temozolomide versus dacarbazine in stage IVmelanoma: final results of a randomised phase III study(EORTC 18032). Eur J Cancer 2011; 47 (10): 1476-83.15. Legha SS, Ring S, Papadopoulos N, et al. A prospectiveevaluation of a triple-drug regimen containing cisplatin,vinblastine, and dacarbazine (CVD) for metastatic melanoma.Cancer 1989; 64:20249.

    16. and two regimens without dacarbazine in metastaticmelanoma: a single-centre randomized four-arm study.Melanoma Res. 2002 Feb;12(1):91-8.17. Rao RD, Holtan SG, Ingle JN, et al. Combination ofpaclitaxel and carboplatin as second line therapzfor patientsvith metastatic melanoma. Cancer 2006; 106(2):375-82.18.Jeli S, Babovic N, Kovcin V, Milicevic N, Milanovic N,Popov I, Radosavljevic D. Comparison of the efficacy of twodifferent dosage dacarbazine-based regimens19. Hauschild A, Agarwala SS, Trefzer U, et al.: Results of aphase III, randomized, placebo-controlled study of sorafenibin combination with carboplatin and paclitaxel as second-linetreatment in patients with unresectable stage III or stage IVmelanoma. J Clin Oncol 2009; 27(17): 2823-30.

    20. Ives NJ, Stowe RL, Lorigan P, et al.: Chemotherapycompared with biochemotherapy for the treatment ofmetastatic melanoma: A meta-analysis of 18 trials involving2,621 patients. J Clin Oncol 2007; 25:5426-34.21. Hamm C, Verma S, patrella T,et al. Biochemotherapy forthe treatment of metastatic melanoma: A systematic review.Cancer Treat Rev 2008; 34:146-56.22. Pejcic I, Vrbic S, Filipovic S, Scekic M, Petkovic I,Pejcic Lj. Concurrent chemoimmunotherapy: is it still thebest option for the treatment of metastatic melanoma inpatients with good performance status? J BUON 2010; 15(3):470-423.Thompson JF, Agarwala SS, Smithers BM, Ross MI,Scoggins CR, Coventry BJ,Neuhaus SJ, Minor DR, SingerJM, Wachter EA. Phase 2 Study of Intralesional PV-10inRefractory Metastatic Melanoma. Ann Surg Oncol. 2014 Oct28.

    69

    http://www.nccn.org/professionals/physician_gls/http://www.nccn.org/professionals/physician_gls/http://www.nccn.org/professionals/physician_gls/
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    :

    1. Kaufman HL, Kirkwood JM, Hodi FS, et al. TheSociety for Immunotherapy of Cancer consensusstatement on tumour immunotherapy for thetreatment of cutaneous melanoma. Nat Rev ClinOncol. 2013;10: 588-598.

    2. Whiteman DC, Pavan WJ, Bastian BC. Themelanomas: a synthesis of epidemiological,clinical, histopathological, genetic, and biologicalaspects, supporting distinct subtypes, causalpathways, and cells of origin. Pigment CellMelanoma Res 2011; 24(5): 879897.

    3. Schadendorf D, Vaubel J et al. Advances andperspectives in immunotherapy of melanoma. AnnOncol 2012; 23 (suppl 10): x104-x108.

    4. Dummer R, Guggenheim M, Arnold AW et al.Updated Swiss guidelines for the treatment andfollow-up of cutaneous melanoma. Swiss MedWkly 2011; 141: w13320.

    5.

    Dummer R, Hauschild A, Guggenheim M, KeilholzU, Pentheroudakis G. ESMO Guidelines WorkingGroup. Cutaneous melanoma: ESMO ClinicalPractice Guidelines for diagnosis, treatment and

    follow-up. Ann Oncol. 2012; 23 (7):vii 86-91.6.

    Pflugfelder A, Kochs C, Blum A, Capellaro M,Czeschik C, Dettenborn T, Dill Det al. S3-guidelinediagnosis, therapy and follow-up of melanoma -

    short version. J Dtsch Dermatol Ges. 2013;11(6):563-602.

    7. NCCN Clinical Practice guidelines in oncology v4.2014. Available at:http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf

    8.

    Wolchok JD, Weber JS, Hamid O, Lebb C, MaioM, et. al. Ipilimumab efficacy and safety in patientswith advanced melanoma: a retrospective analysisof HLA subtype from four trials. Cancer Immun.2010;10:9

    9. Hodi FS, ODay SJ, McDermott DF, Weber RW, etal. Improved survival with ipilimumab. Ann Oncol2012;23 (suppl 10): x104-x108.

    10. Robert C, Thomas L, Bondarenko I, et al.Ipilimumab plus dacarbazine for previouslyuntreated metastatic melanoma. N Engl J Med2011; 364:2517-2526.

    11.

    Fecher LA, Agarwala SS, Hodi FS, Weber JS.Ipilimumab and its toxicities: a multidisciplinaryapproach. Oncologist. 2013;18:733-743.

    12.

    Downey SG, Klapper JA, Smith FO, et al.

    Prognostic factors related to clinical response inpatients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res2007;13:6681-6688.

    75

    http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf
  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    76/90

    13. Camacho LH, Antonia S, Sosman J, et al. Phase I/II

    trial of tremelimumab in patients with metastaticmelanoma. J Clin Oncol 2009;27:1075-1081.

    14.

    Antoni Ribas. "Tumor immunotherapy directed atPD-1". N Engl J Med 2012; 366 (26): 25179.

    15.

    Topalian SL, Hodi FS, Brahmer JR, et al. Safety,activity, and immune correlates of anti-PD-

    1 antibody in cancer. N Engl J Med.2012;366(26):2443-2454.

    16. Hamid O, Robert C, Daud A, et al. Safety andTumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma.N Engl J Med.2013;369(2):134-144

    17.

    Hamid O, Sosman JA, Lawrence DP, et al. Clinicalactivity, safety, and biomarkers of MPDL3280A,an engineered PD-L1 antibody in patients withlocally advanced or metastatic melanoma (mM). JClin Oncol. 2013;31,(suppl; abstr 9010).

    18. Wolchok JD, Kluger H, Callahan MK, et al.:Nivolumab plus ipilimumab in advancedmelanoma. N Engl J Med 2013;369 (2): 122-33

    19.

    Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patientswith metastatic melanoma: analysis of 270 patientstreated between 1985 and 1993. J Clin Oncol1999;17 (7): 2105-16.

    20.

    Atkins MB, Kunkel L, Sznol M, Rosenberg SA.High-dose recombinant interleukin-2 therapy in

    patients with metastatic melanoma: long-termsurvival update. Cancer J Sci Am 2000;6 Suppl1:S11-14.

    21.

    Smith FO, Downey SG, Klapper JA, et al.Treatment of metastatic melanoma usinginterleukin-2 alone or in conjunction with vaccines.Clin Cancer Res 2008;14(17):5610-5618.

    22.

    Schwartzentruber DJ, et al. A phase III multi-institutional randomized study of immunizationwith the gp100: 209-217(210M) peptide followedby high-dose IL-2 compared with high-dose IL-2alone in patients with metastatic melanoma. J ClinOncol 2009;27. ASCO Meeting Abstracts: 9011.

    23. Ribas A. ASCO 2014. Abstract 9000.24. Hodi S. ASCO 2014. Abstract 9002.25.

    Sznol M. ASCO 2014. Abstract 9003.26. Kirkwood JM, Lee S, Moschos SJ, et al.

    Immunogenicity and antitumor effects ofvaccination with peptide vaccine +/- granulocyte-monocyte colony-stimulating factor and/or IFN-2b in advanced metastatic melanoma: Eastern

    Cooperative Oncology Group phase II trial E1696.Clin Cancer Res. 2009; 15(4):1443-1451.27. Demierre, M.F., Swetter, S., Sondak, V. Vaccine

    therapy of melanoma: An update. Current CancerTherapy Reviews, 2005;1, 115-125.

    76

    http://www.ncbi.nlm.nih.gov/pubmed/22658127http://www.ncbi.nlm.nih.gov/pubmed/22658127http://www.ncbi.nlm.nih.gov/pubmed/23724846http://www.ncbi.nlm.nih.gov/pubmed/23724846http://www.ncbi.nlm.nih.gov/pubmed/23724846http://www.ncbi.nlm.nih.gov/pubmed/23724846http://www.ncbi.nlm.nih.gov/pubmed/22658127
  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

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    :1.Collaborative Ocular Melanoma Study Group : COMSreport no. 15. Arch Ophtalmol 2001; 119:670-6.2.Van Raamsdonk CD, Bezrookove V, Green G et al. N EnglJ Med 2010; 36: 2191-9..

    3.Carvajal CD, Sosman JA, Quervedo JF et al. Effect ofSelumetinib vs Chemotherapy on Progression-Free Survivalin Uveal Melanoma: A Randomized Clinical Trial. JAMA2014; 311 (23): 2397-405.

    :1.

    Gray-Schopfer V, Wellbrock C, and Marais R.Melanoma biology and new targeted therapy.Nature 2007; 445:851-7.

    2.

    Curtin JA. Distinct sets of genetic alterations inmelanoma. N Engl J Med 2005; 353:2135-47.

    3. Jacob J, Basett R. Clinical characteristics andoutcomes associated with BRAF and NRAASmutations in metastatic melanoma. J Clin Oncol2011; 29: abstract 8500.

    4. Jiang X, Zhou J, Yuen N et al. Imatinib targeting ofKIT mutant oncoprotein in melanoma. Clin CancerRes 14:7726-7732,2008.

    5.

    Hauschild A, Agarwala SS, Trefzer U, et al.

    Results of a phase III, randomized, placebo-controlled study of sorafenib in combination withcarboplatin and paclitaxel as second-line treatmentin patients withunresectable stage III or stage IV melanoma. J Clin

    Oncol 2009; 27(17): 2823-30.6. Chapman PB, Hauschild A, Robert C, et al.

    Improved survival with vemurafenib in melanomawith BRAF V600E mutation.N Engl J Med2011; 364: 2507-16.

    7. Chapman PB, Hauschild A, Robert C, et al.Updated overall survival (OS) results BRIM- 3, aphase III randomized,open-label, multicenter trialcomparing BRAF inhibitor vemurafenib (vem) with

    dacarbazine (DTIC) in previosly untreated patientswith BRAF V600E- mutated melanoma. J ClinOncol 2012; 30: abstract 8502.

    8. NCCN Clinical Practice guidelines in oncologyv2.2014. Available at:

    http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf

    9.

    Dummer R, Hauschild A, Guggenheim M, KeilholzU, Pentheroudakis G. ESMO Guidelines WorkingGroup. Cutaneous melanoma: ESMO ClinicalPractice Guidelines for diagnosis, treatment andfollow-up. Ann Oncol. 2012; 23 (7):vii 86-91.

    10. Hauschild A, Grob JJ, Demidov LV et al. BREAK3: A phase III randomized, open-label studycomparing dabrafenib toDTIC in previouslyuntreated subjects with B-RAF mutated metastatic(stage III/IV) melanoma, ASCO Meeting, 2012.

    11.

    Robert C, Flaherty KT, Hersey P et al. METRIC

    phase III study: Efficacy of trametinib, a potent andselective MEK inhibitor, in progession-freesurvival and overall survival, compared withchemotherapy in patients with B-RAFV600E/Kmutant advanced or metastatic melanoma. ASCOMeeting, 2012.

    12. Flaherty KT,Infante JR, Daud A, et al. CombinedBRAF and MEK inhibition in melanoma withBRAF V600 mutations. N Engl J Med, 2012;367:1694-1703,

    13. Pflugfelder A, Kochs C, Blum A, Capellaro M,Czeschik C, Dettenborn T, Dill Det al. S3-guidelinediagnosis, therapy and follow-up of melanoma -short version. J Dtsch Dermatol Ges. 2013;

    11(6):563-602.14.

    Larkin J, Del Vecchio M, Ascierto PA et al.Vemurafenib in patients with BRAF V600 mutatedmetastatic melanoma: An open-label multicentre,safety study, Lancet Oncol, 27 feb 2014.

    15. Long GV et al. ASCO 2014. Abstract 9011

    83

  • 7/23/2019 NACIONALNI VODIC ZA MELANOM

    84/90

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    84

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    :1.

    NCCN Clinical Practice guidelines in oncologyv1.2015. Available at:http://www.nccn.org/professionals/physician-gls/pdf/melanoma.pdf

    2.

    Dummer R, Hauschild A, Guggenheim M, KeilholzU, Pentheroudakis G. ESMO Guidelines WorkingGroup. Cutaneous melanoma: ESMO ClinicalPractice Guidelines for diagnosis, treatment andfollow-up. Ann Oncol. 2012; 23 (7):vii86-91.

    3. Pflugfelder A, Kochs C, Blum A, Capellaro M,Czeschik C, Dettenborn T, Dill Det al. S3-guidelinediagnosis, therapy and follow-up of melanoma -

    short version. J Dtsch Dermatol Ges. 2013;11(6):563-602.

    4.

    Fife Km, Colman MH, Stevens GN, et al.Determinants of outcome in melanoma patients

    with cerebral metastases. J Clin Onol 2004;22:1293-1300.5. Gibney GT, Forsyth PA, Sondak VK. Melanoma in

    the brain: biology and therapeutic options.Melanoma Research 2012; 22:17783.

    6. Ramakrishna N, Margolin KA. Multidisciplinaryapproach to brain metastasis from melanoma; localtherapies for central nervous system metastases.Am Soc Clin Oncol Educ Book 2013; 33: 399-403.

    85

    http://www.nccn.org/professionals/physician-gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician-gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician-gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician-gls/pdf/melanoma.pdfhttp://www.nccn.org/professionals/physician-gls/pdf/melanoma.pdf
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    :

    1. Dummer R, Hauschild A, GuggenheimM, Keilholz U, Pentheroudakis G. ESMOGuidelines Working Group. Cutaneous

    melanoma: ESMO Clinical PracticeGuidelines for diagnosis, treatment andfollow-up. Ann Oncol 2012; 23 (7):vii86-91.

    2. Garbe C, Peris K, Hauschild A, Saiag P,Middleton M, Spatz A, Grob JJ, MalvehyJ, Newton-Bishop J, Stratigos A,Pehamberger H, Eggermont AM.European Dermatology Forum; EuropeanAssociation of Dermato-Oncology;European Organization of Research andTreatment of Cancer. Diagnosis and

    treatment of melanoma. Europeanconsensus-based interdisciplinaryguideline Update 2012. Eur J Cancer2012; 48(15): 2375-90.

    3.

    Pflugfelder A, Kochs C, Blum A,Capellaro M, Czeschik C, Dettenborn T,Dill Det al. S3-guideline diagnosis,therapy and follow-up of melanoma shortversion. J Dtsch Dermatol Ges 2013;11(6): 563-602.

    4.

    NCCN Clinical Practice guidelines inoncology v2.2014. Available at:http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf

    5.

    Clinical Practice Guidelines for theManagement of Melanoma in Australiaand New Zealand 2010. Available at:www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdf

    6. , , , . .

    http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdf