Correlation of Ki-67 expression in cutaneous primary melanoma with prognosis in a prospective study: Different correlation according to thickness

Moretti, Silvia; Spallanzani, Adelina; Chiarugi, Alessandra; Fabiani, Massimo; Pinzi, Cinzia

doi:10.1067/mjd.2001.110067

Cited by 51 publications

(32 citation statements)

References 13 publications

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“…9 In other studies, the Ki67 index on single IHC stains is typically estimated by counting Ki67-positive and Ki67-negative nuclei in presumed tumor cells. 13,15,17 Because Ki67/MART1 double stains visualize the actual tumor cells, we were unable to make such an index estimation on our double stains. Thus, we chose to use the number of proliferating cells per square millimeter in the ROI as a substitute (No./ROI index).…”

Section: Commentmentioning

confidence: 99%

“…4,10 Generally, the Ki67 index is increased in melanomas compared with nevi, and Ki67 labeling is scattered throughout the dermal compartment in melanomas, but is expressed only in the dermal-epidermal junction or superficial dermal compartment in nevi. 11 In melanomas, primarily thick lesions, several studies 12,13 demonstrate a correlation between the Ki67 index and clinical outcome, though other studies 14,15 have contradictory conclusions. A principal challenge with Ki67 index interpretation in melanocytic lesions is the prominent lymphatic infiltrate often present in both melanomas and some nevi; hence, care should be taken to distinguish Ki67 labeling in melanocytic cells from Ki67 labeling in other proliferating cells, primarily lymphocytes but also histiocytes, stromal cells, and epithelial cells.…”

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confidence: 99%

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Automated Quantification of MART1-Verified Ki67 Indices by Digital Image Analysis in Melanocytic Lesions

Nielsen

Riber-Hansen²,

Raundahl³

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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Context.—The proliferation marker Ki67 is an important diagnostic and prognostic aid in surgical pathology. However, manual quantification in a counting frame to accurately establish the proliferation rate (Ki67 index) is cumbersome and time-consuming. Instead, digital image analysis of Ki67/MART1 double stains may provide fast and novel index computations for entire tumor sections. Objectives.—To design and compare image analysis protocols that compute Ki67 indices of Ki67/MART1 double stains, to compare automated indices with previously published manual indices, and to compare the total number of proliferating cells (mimicking a Ki67 single stain) with the number of MART1-verified proliferating cells. Design.—Whole slide images were captured from 48 melanomas and 77 nevi stained with an immunohistochemical cocktail against Ki67 and MART1. Ki67 indices were determined by digital image analysis and different equations based on number or area. Results.—The differences between mean indices of melanomas and nevi were significant (P < .001) in all index computations. Number-based image analysis of lesions with more than 250 melanocytic cells misclassified 1 of 42 melanomas and 4 of 53 nevi, numbers comparable with manual counting. Automated indices were significantly higher than manual indices, as were indices of mimicked Ki67 single stains compared with MART1-verified Ki67 indices (P < .001). Conclusions.—Ki67 indices established by digital image analysis of Ki67/MART1 double stains demonstrated excellent abilities to discriminate melanomas from nevi with diagnostic performances equal to manually performed indices. Testing different definitions of the automated MART1-verified Ki67 index, no single definition stood out; thus, a variety of definitions may be used.

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Section: Commentmentioning

confidence: 99%

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confidence: 99%

Automated Quantification of MART1-Verified Ki67 Indices by Digital Image Analysis in Melanocytic Lesions

Nielsen

Riber-Hansen²,

Raundahl³

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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“…Ki-67 is a nuclear antigen that is present in all phases of cell cycle, except G 0 and early G 1 . Moretti et al (40) found that Ki-67 proliferative index is an indicator of poor prognosis and a possible predictor of metastasis in primary melanomas. Plaat et al (41) reported that the posttreatment proliferative index in soft tissue sarcomas from patients undergoing hyperthermic isolated limb perfusion with melphalan correlated with overall survival following treatment.…”

Section: Vessels (20)mentioning

confidence: 99%

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Ko¹,

Ueno²,

Yoshimoto³

et al. 2006

Clinical Cancer Research

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Purpose: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion. Experimental Design: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5jC), or hyperthermic (43jC) conditions. Results: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion. Conclusion: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide. Isolated limb perfusion and isolated limb infusion haveemerged as effective forms of treatment for regionally advanced melanoma confined to an extremity. These procedures address all in-transit lesions confined to an extremity in a single procedure by supplying a regional concentration of chemotherapeutic agents at least 10 times higher than that reached after systemic administration, without the systemic side effects.Hyperthermia is widely used in conjunction with isolated limb perfusion and infusion to improve the response to the regional chemotherapy. This is usually done by heating the perfusate (or infusate) to 39jC to 41jC and by applying external warming blankets to prevent heat loss. Hyperthermic isolated limb perfusion was introduced based on in vitro evidence of a synergistic, cytotoxic interaction between heat and melphalan, the alkylating agent that is the current drug of choice for regional therapy of melanoma (1). Melphalan has been extensively studied for its efficacy in hyperthermic isolated limb perfusion, with response rates in the 80% range with 40% to 80% being complete responders (2, 3).However, a recent,...

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“…O nível de expressão de Ki67 correlaciona-se com a progressão do melanoma e seu potencial metastático, 158 diminuindo a taxa de sobrevida global. Desta forma, este marcador está intimamente ligado à proliferação celular (Straume et al, 2000;Moretti et al, 2001; Limonen et al, 2005;Ladstein et al, 2010).A diminuição da proteína Ki67 em todos os protocolos de tratamento indica diminuição da proliferação das células de melanoma B16F10.Somente o quimioterápico DTIC induziu aumento deste marcador em melanócitos normais, corroborando com os dados das proporções das fases do ciclo celular.A apoptose é uma série complexa de alterações morfológicas que incluem a condensação nuclear e ruptura da membrana com empacotamento do conteúdo intracelular, que é cuidadosamente embalado em pequenos fragmentos da membrana, denominados corpos apoptóticos.Estes são posteriormente fagocitados por células adjacentes sem provocar uma resposta inflamatória ou lesão tecidual (Ameisen, 2002;Fink, Cookson, 2005). O intervalo de tempo entre a exposição do agente que desencadeia adenosina trifosfato (ATP), e pró-caspase 9 para formar uma estrutura conhecida como apoptossomo.…”

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Avaliação da atividade antitumoral do composto DM-1 e da terapia de captura de nêutrons por boro em associação ao quimioterápico dacarbazina no tratamento de melanoma

Faião-Flores¹

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DEDICATÓRIADedico esta etapa vitoriosa da minha vida à Deus, por me tornar apta à obter novos conhecimentos, por me dar força para continuar seguindo meu caminho pelo lado bom da fé e da coragem, por ser fonte infinita de sabedoria em que eu pude me amparar nos momentos mais difíceis. AGRADECIMENTOSÀ Deus por me auxiliar nesta conquista e por permitir a realização desta tese.Aos meus pais e meu irmão por todos os anos de dedicação, preocupação, investimento e apoio que foram providenciais na minha formação acadêmica e principalmente moral. Agradeço especialmente minha mãe pelo amor incondicional e por toda forma de apoio imaginável para que eu nunca desistisse dos meus objetivos e sonhos.Ao meu noivo Fernando por ter paciência e compreensão quando eu precisei estudar para as provas, escrever inúmeros relatórios e por sempre me incentivar, dando forças ao dizer que eu era forte o bastante para passar por tudo e conseguir trilhar um bom caminho. Agradeço por ser tão especial e inesquecível em minha vida.Ao meu orientador Prof. Dr. Durvanei Augusto Maria por todo o aprendizado e experiência ao longo desses 7 anos em que realizei minha iniciação científica e meu doutorado no Instituto Butantan e por me auxiliar no desenvolvimento de muitas características profissionais que levarei pelo resto da minha vida.Agradeço imensamente pela oportunidade de aprendizado.Ao Prof. Dr. José Agustín Quincoces Suarez por ter me dado oportunidade de estágio desde o 1° ano de faculdade, por incentivar minhas idéias mirabolantes e por ter acreditado em mim desde o inicio.Ao Prof. Dr. João Arruda Dias de Toledo Neto por me apresentar a BNCT e pelos inúmeros auxílios na correção de artigos, idéias de novos experimentos e por apesar de ser um co-orientador não oficial, sempre participar ativamente na minha construção acadêmica e profissional.Ao Prof. Dr. Ricardo Pérez Tomas da Universidade de Barcelona por me ter me dado a oportunidade fantástica de aprender e vivenciar o âmbito de seu laboratório. Agradeço por me apoiar, incentivar, cobrar e investir no meu crescimento acadêmico.Ao pesquisador Paulo Rogério Pinto Coelho por me auxiliar nos experimentos com BNCT, por disponibilizar a estrutura das irradiações e por me ajudar a liberar as amostras (inúmeras vezes) do IPEN. Não me esquecerei de agradecer ao pessoal da proteção radiológica que se assustavam a me ver com um isopor nas mãos e pensavam: "Meu Deus, esta menina possui câncer dentro do isopor!", sem saber que toda vez que eu entrava no IPEN pensava: "Meu Deus, estas pessoas trabalham com radiação todos os dias!". Ao Dr. Jorge Sarkis do Ipen, pela contribuição no processamento, aquisição e análise dos dados da biodistribuição de boro. À Profa. Dra. Silvya Stuchi Maria-Engler da Faculdade de Ciências Farmacêuticas por ceder os melanócitos para os diversos ensaios, além da revisão e contribuição nos artigos científicos provenientes dos dados da tese. À Dra. Vanessa Soto-Cerrato da Universidade de Barcelona pelos inúmeros ensinamentos, explicações, auxílio nos experimentos, pela grand...

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Correlation of Ki-67 expression in cutaneous primary melanoma with prognosis in a prospective study: Different correlation according to thickness

Cited by 51 publications

References 13 publications

Automated Quantification of MART1-Verified Ki67 Indices by Digital Image Analysis in Melanocytic Lesions

Automated Quantification of MART1-Verified Ki67 Indices by Digital Image Analysis in Melanocytic Lesions

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Avaliação da atividade antitumoral do composto DM-1 e da terapia de captura de nêutrons por boro em associação ao quimioterápico dacarbazina no tratamento de melanoma

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