Margini chirurgici. M. in situ 0,5 cm. < 1 mm 1 cm. > 1 mm 1-2 cm. > 2 mm 2-3 cm

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Amedeo Zamboni
8 anni fa
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1 Margini chirurgici M. in situ 0,5 cm < 1 mm 1 cm > 1 mm 1-2 cm > 2 mm 2-3 cm

2 The 2009 AJCC staging system 0 Melanoma in situ IA T1a IB T1b e T2a IIA T2b e T3a IIB T3b e T4 a Tumor thickness 1 mm without ulceration and mitosis < 1 mm2 Tumor thickness 1 mm with ulceration or mitoses 1 mm2 or Tumor thickness mm without ulceration Tumor thickness mm with ulceration or tumor thickness mm without ulceration Tumor thickness mm with ulceration or tumor thickness 4 mm without ulceration IIC T 4b Tumor thickness > 4 mm with ulceration

3 The 2009 AJCC staging system IIIA T1-4a N1a T1-4a N2a IIIB T1-4b N1a T1-4b N2a T1-4a N1b T1-4a N2b T1-4b N2c Any tumor thickness with no ulceration and 1-3 microscopic nodes Any tumor thickness with ulceration and 1-3 microscopic nodes, or any tumor thickness without ulceration and 1-3 macroscopic nodes, or any tumor thickness with or without ulceration and either satellites(s) or in transit metastasis (es) without metastatic node(s) IIIC T1-4b N1b T1-4b N2b T1-4b N2c Any tumor thickness with ulceration and either 1-3 macroscopic nodes or satellites or intransit metastases without metastatic nodes or any tumor thickness with 4 metastatic nodes or satellites/in-transit metastases with metastatic nodes IV Any tumour thickness, any number of nodes and any distant skin, subcutaneous, nodal or visceral metastases. Non va considerata la dimensione delle meta linfonodali; sufficiente anche solo Immunoistochimica (Melan A, HMB 45, MART-1 )

4 Melanoma-specific survival estimates 5-years survival 10-years survival Stage I 93% 85% Stage II 68% 55% Stage III 45% 36% Stage IV 11% 6%

5 Iter diagnostico terapeutico se stadio Ia, si programma l ampliamento della ferita chirurgica nel nostro ambulatorio. se stadio Ib-IIa, si programma l ampliamento della ferita chirurgica e la ricerca del linfonodo sentinella in Chirurgia (vedi relativo protocollo) e stadiazione con esami di laboratorio, ecografia linfonodi, Rx torace Se poi il linfonodo sentinella risulta positivo, si programma linfadenectomia Se l ecografia rivela linfonodi sospetti, si programma stadiazione approfondita ( TAC o PET-TAC) se da questa non risultano metastasi a distanza, segue lo svuotamento della stazione linfonodale interessata, in Chirurgia da stadio IIb, si programma stadiazione approfondita ( TAC o PET-TAC) e se questa e` neg, poi la ricerca del linfonodo sentinella in Chirurgia (vedi relativo protocollo) Se poi il linfonodo sentinella risulta positivo, si programma linfadenectomia

6 Lymphgefäße - Abflussbahnen

7 Linfoscintigrafia Melanoma alla gamba sin Linfonodo sentinella inguine sin

8 Ricerca del linfonodo sentinella Linfonodo Sentinella Albumine umana marcata con Tc 99m Melanoma Colorante Patent Blue

9 Follow-up Controllo clinico Esami Laboratorio Ecografia Linfonodi Ecografia Addominale Rx Torace Tac/Scintigr. Ossea/Pet-Tac Melanoma in situ Stadio Ia 2x/anno per 1anno poi 1x/anno 2x/annox5aa poi x1/anno Stadio Ib-II 3x/anno x3aa, poi 2x/anno x 10 aa - 2x/anno x 3aa poi stop Stadio IIc e III 4x/anno x5aa, poi 2x/anno x 10aa S100x4/anno x 1 anno, poi x2/anno fino al 10.anno, poi x 1/anno 2x/anno x 10 anni - - RM cerebrale x 1/anno+ TAC x1/anno x 3 aa, poi stop Stadio IV Individuale individuale Individuale individuale individuale individuale

10 Protocollo terapia medica x melanoma Dermatologia BZ Breslow > 3 mm Metastasi linfonodali metastasi a distanza metastasi cerebrali o evoluzione della malattia facoltativamente immunoterapia con Interferone alfa 2b immunoterapia con Interferone alfa-2b chemioterapia con dacarbazina + immunoterapia con interferone chemioterapia con Fotoemustine Temozolamide, Eldisine, Interleuchina 2 e altri chemioterapici, eventualmente associati in polichemioterapia

11 Approved Chemotherapeutic drugs for melanoma before 2011 Dacarbazine (DTIC) RR 5-28% Temozolomide RR 13-24% Fotemustine (no USA) RR 15-

13 CTLA4 modula negativamente l attivazione delle cellule T TCR MHC Antigen Dendritic cell CD28 T cell CTLA4 B7

14 Rationale for CTLA4 Blockade Removing the Brake for T-Cell Activation MHC Antigen TCR Dendritic cell CD28 T cell B7 CTLA4

15 OS 10,1 months vs. 10 months and vs.6,4 months PFS similar in all groups Ipilimumb: approved FDA and EMA 2011

16 New Targets New Drugs Nilotinib Masinitib Dasatinib

17 RAS RAF Pathway Growth factors Normal RAS RAF pathway signaling1 Oncogenic BRAF signaling2 RT K RAS GTP Normal activation of RAS by extracellular factors P Activated RAS BRAF ME K P Mutated BRAF ME K Constitutive activation is independent of extracellular factors Not responsive to normal regulatory signals ERK RTK = receptor tyrosine kinase; GTP = guanosine triphosphate; ERK = extracellular signal-related kinase; MEK = MAP (mitogen-activated protein). P Normal cell proliferation and survival P ERK Excessive cell proliferation and survival 1. Garnett MJ, et al. Cancer Cell 2004;6: Wan PTC, et al. Cell 2004;116:

19 PFS 1.6 mos 5.3 mos

20 OVERALL SURVIVAL 84% 64%

21 dermaupdate

22 PFS 6,8 months OS 15,9 months RR 55% Vemurafenib: Approved FDA on aug2011 EMA on feb 2012

23 Chapman P. et al Abs LBA4 ASCO 2011 Vemurafenib inhibits BRAFV600E Kinase RAS RTK 40-60% of melanomas ATP ATP RAF BRAFV600E MEK VEVEMURAFENIB () ERK Cellular Proliferation

25 PFS 5,1 months vs. 2,7 months

29 PFS 4,8 months vs.1,5 months

30 OS at 6 months 81% vs.67%

32 dermaupdate

33 PFS 9,4 months vs. 5,8 months RR 76% vs. 54% 41% vs 9% alive and progression free at 1 year

34 Ipilimumab (Yervoy, Bristol-Myers Squibb) Is reccomended for the treatment of advanced malignant melanoma in people who have received prior chemotherapy Vemurafenib (Zelboraf, Roche) Si reccomended for the treatment of unresectable locally advanced or metastatic BRAF V600 mutation-positiv melanoma dermaupdate

Immune regulatory molecules B7-H3? B7-H4? PD-L1/PD-L2 PD-1 APC B7.1/B7.2 MHCI/II CTLA-4 CD28 TCR T cell activation CD40 CD40L TNF-R family OX40L CD137L GITRL OX40 CD137 GITR TNF-R family T cell 1.

36 Immune regulatory molecules B7-H3? B7-H4? PD-L1/PD-L2 PD-1 APC B7.1/B7.2 MHCI/II CTLA-4 CD28 TCR T cell activation CD40 CD40L TNF-R family OX40L CD137L GITRL OX40 CD137 GITR TNF-R family T cell 1. Peggs KS, et al. Clinical and Experimental Immunology 2009;157: Abbas AK, et al. Cellular and Molecular Immunology. 6th ed. (updated), Nurieva RI, et al. Immunol Rev 2009;229: Peggs KS, et al. Curr Opin Immunol 2006;16:

37 Molecular classification of melanoma BRAF PTEN CCND1, KIT KIT, CCND1 dermoupdate KIT, CDK4 Curtin J et al. NEJM 2005

38 dermaupdate

39 Response Chemotherapy/Targeted Agents and Immuno-therapy Differ in Action and Outcome Chemotherapy and Targeted Therapies IMMUNOTHERAPY Time (months)

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